Parnell T et al., 2026·Journal of Restorative Reproductive Medicine
To evaluate adherence to published American Society for Reproductive Medicine (ASRM) and American Urological Association (AUA) infertility evaluation and treatment recommendations among commercially insured infertility patients who subsequently underwent in vitro fertilization (IVF), and to assess whether observed care gaps support the need for a restorative reproductive medical framework.
A retrospective claims-based analysis was performed using MarketScan® Commercial Claims and Encounter Data between January 1, 2021, and December 31, 2024. Approximately five million commercially insured members were evaluated. Patients with infertility-related diagnoses who subsequently underwent IVF were identified. Claims were analyzed for evidence of selected diagnostic testing, medical treatment, or surgical interventions recommended by ASRM or AUA/ASRM guidance for specific infertility-related diagnoses before IVF initiation. Cumulative adherence rates were assessed up to nine months following initial infertility diagnosis and compared with the timing of initiating IVF.
IVF initiation started early and consistently preceded completion of most recommended evaluations and treatments. By 3 months, the proportion of patients with IVF initiation ranged from 28% to 39% across different infertility-related diagnoses, while adherence to most recommended interventions remained low. Overall, by 9 months, IVF utilization had reached 70–85%, while many recommended evaluations and treatments remained below 40% adherence, with several interventions remaining below 15%. Observed care gaps (percentage of patients receiving IVF prior to other evaluation or treatment recommendations) ranged from approximately 13% to 78% for most recommended evaluations and treatments, with several measures demonstrating gaps over 50% of patients.
These findings suggest substantial divergence between published infertility-care recommendations and observed practice patterns. From the perspective of restorative reproductive medicine (RRM), the gaps are clinically important because many recommended steps are directed toward identifying, correcting, restoring, or preserving reproductive function and anatomy before offering or initiating IVF treatment. Limitations to these data include lack of individualized patient medical data, preferences, or circumstances, and not capturing any treatment that was not reimbursed by commercial insurance (i.e., any cash payment for services). In addition, the recommendations assessed have variable levels of underlying evidence, and likely vary in the level of their acceptance among practicing clinicians.
Many commercially insured infertility patients progressed to IVF without documented evidence of diagnostic evaluation or therapeutic interventions recommended in ASRM and AUA/ASRM guidance. These findings raise important questions regarding the implementation of adequate evaluation before IVF and the extent to which patients receive meaningful opportunities for diagnosis-directed treatment of potentially reversible causes of infertility. The findings further suggest an important role for RRM as a quality-of-care framework focused on comprehensive evaluation, correction of underlying dysfunction, preservation of reproductive anatomy and physiology, and optimization of patient-centered fertility care, prior to considering IVF.
This narrative review examines the evidence for medical optimization of inflammatory conditions, vitamin deficiencies, endocrine disorders, immune dysregulation, oligo-ovulation, and luteal phase factors to improve fertility outcomes in women attempting to conceive through natural or timed intercourse. Overall, there is a paucity of data with respect to these categories among patients pursuing timed intercourse, precluding our ability to draw strong recommendations. However, there is strong evidence supporting treatment of endocrine disorders, specifically overt thyroid dysfunction and hyperprolactinemia, as well as oligo-ovulation. Conversely, treatment of subclinical hypothyroidism is not recommended. The current data are insufficient to support empiric use of antiinflammatory medications, corticosteroids, thyroid hormones, or vitamins or supplements to improve chances of pregnancy in a general infertility population.
To identify preconception clinical and multi-omics factors associated with conception and early pregnancy loss in women with unexplained recurrent pregnancy loss (URPL). In this prospective cohort study, 149 women with URPL selected from 420 outpatients based on guideline-recommended criteria were enrolled between November 2024 and May 2025 and followed-up for 12 months. Preconception fasting plasma was analyzed for clinical biomarkers, untargeted metabolomics, and data-independent acquisition proteomics. Outcomes included conception, ongoing pregnancy beyond 12 weeks and early pregnancy loss before 12 weeks. Multivariable logistic regression was used to evaluate the associations of clinical and multi-omics factors with reproductive outcomes, adjusting for maternal age, body mass index, number of prior losses, and use of assisted reproductive technology. Of 149 women, 99 conceived (66.4%) during the follow-up. By 12 weeks of gestation, 67 (67.7%) had ongoing pregnancies and 32 (32.3%) experienced early pregnancy loss. Higher testosterone was associated with lower probability of conception (adjusted odds ratio [aOR] 0.50, 95% confidence interval [CI] 0.28-0.89, p = 0.019). Women who conceived showed higher levels of progesterone-related metabolites, including 17-hydroxyprogesterone (fold change, FC = 3.89), pregnanediol 3-O-glucuronide (FC = 2.37), and pregnanetriol 3α-O-β-D-glucuronide (FC = 2.39). Among women who conceived, higher prolactin was associated with higher odds of early pregnancy loss (aOR 1.09, 95% CI 1.01-1.18, p = 0.036), and anti-phosphatidylserine/prothrombin showed a borderline association (aOR 1.07, 95% CI 1.00-1.14, p = 0.052). Early pregnancy loss was characterized by lower bile acid-related metabolites and higher caffeine and methylxanthine metabolites. Proteomic analysis showed enrichment of bile acid biosynthetic process. After adjustment, higher 7α,12α-dihydroxy-3-oxocholest-4-en-27-oic acid was associated with lower odds of early pregnancy loss (aOR 0.64, 95% CI 0.44-0.95, p = 0.025). Higher testosterone was associated with lower odds of conception. Among women who conceived, early pregnancy loss was associated with higher prolactin, borderline higher anti-PS/PT, lower bile acid-related metabolites, and higher caffeine-related metabolites, with 7α,12α-dihydroxy-3-oxocholest-4-en-27-oic acid identified as an exploratory metabolomic candidate. These findings suggest that potential androgen-related biology, prolactin, non-criteria antiphospholipid antibodies, and bile acid metabolism may be associated with reproductive outcomes in URPL, warranting validation in independent cohorts.
Bulletti FM et al., 2025·Clin Med�Insights�Reprod�Health·
Open Access
Infertility affects around 17.5% of reproductive-aged individuals worldwide, posing significant personal and public health challenges. Although Medically Assisted Reproduction and Assisted Reproductive Technology (ART; e.g., in vitro fertilization) have advanced outcomes, many couples fail to conceive due to unaddressed pelvic, uterine, or systemic factors. We aim to (1) define the current usage of Restorative Reproduction Medicine (RRM) in clinical practice, (2) compare RRM outcomes with conventional ART, and (3) propose an integrated model of RRM plus ART for optimal fertility care.
A systematic review following PRISMA guidelines was conducted (INPLASY registration no. INPLASY2024110069). Data sources and We searched PubMed, Scopus, and Web of Science (January 1995–October 2024), combining terms such as “restorative reproductive medicine,” “intrauterine adhesions,” “myomas,” “polyps,” “hydrosalpinx,” “endometritis,” “BMI,” “thyroid dysfunction,” “microbiome,” and “assisted reproductive technology.” Inclusion criteria: studies on uterine/systemic factors affecting infertility, focusing on surgical/pharmacological RRM interventions and ART limitations. Exclusion criteria: male-only infertility, case reports, narrative reviews, non-English publications. Quality assessment employed the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool. We also briefly noted potential publication bias due to language and study-type restrictions. From >25,000 initial titles, 3 sequential screenings yielded 145 key articles addressing uterine (septum, myomas, polyps, adhesions) and systemic (body mass index (BMI) extremes, thyroid dysfunction, microbiome imbalance) factors. Surgical corrections (e.g., hysteroscopic removal of polyps/myomas, salpingectomy for hydrosalpinx) significantly improved natural conception and ART success (⩾20%–40% increase in clinical pregnancy). Chronic endometritis treatment, endometrial microbiome modulation, and BMI/thyroid optimization further improved pregnancy rates by 15%–20%. Comparisons of RRM versus ART alone indicated that RRM often lowers overall cost and may reduce miscarriage, while ART offers immediate embryo transfer. Combining RRM to correct pathologies prior to ART can boost implantation and live birth rates (⩾40%–70% improvement in some studies). Restorative Reproductive Medicine comprehensively addresses pelvic and systemic abnormalities, thereby enhancing fertility outcomes and complementing ART. A proposed integrated model—RRM diagnostics/interventions followed by ART if needed—maximizes success, reduces time/cost, and emphasizes holistic reproductive health. Further multicenter trials are warranted to standardize protocols and fully realize RRM’s potential in modern fertility care.
Sun Y et al., 2024·Ther Adv Reprod Health·
Open Access
Chronic endometritis (CE), frequently asymptomatic, is associated with female infertility. Fallopian tube obstruction (FTO) is also one of the factors contributing to female infertility. More than 90% of cases of proximal FTO can be successfully treated after fallopian tubal recanalization (FTR) and the spontaneous pregnancy rate of treated women after FTR is only about 30%. Potential factors affecting the success rate of FTR remain unclear. We speculate that CE may be one of the reasons affecting the recanalization of the fallopian tubes. To identify the correlation between CE and FTO, as well as the influence of CE on pregnancy outcomes following FTR.
Retrospective observational study. We retrospectively analyzed 498 women of childbearing age who underwent laparoscopy and hysteroscopy surgery for infertility. Endometrial samples were collected during surgery for CD138 immunohistochemistry staining for the diagnosis of CE. Based on the results of the tubal patency test, they were divided into two groups: the fallopian tubal patency group and the proximal FTO group. The prevalence of CE was compared between these two groups. All women with FTO underwent FTR during the operation until successful treatment was achieved. Pregnancy outcomes were assessed after a 12-month follow-up period following the procedures. Logistic regression was used to analyze factors that might affect pregnancy after FTR. The prevalence of CE in women with tubal obstruction was 30.5%, which was significantly higher than that in the fallopian tubal patency group (10.75%), p < 0.001. After FTR, the prevalence of CE in non-pregnant women was 40.18%, which was higher than that in pregnant women (40.18% vs 13.11%), and the difference was significant (p < 0.001). Multiple regression analysis showed that CE was a significant risk factor for FTO (OR: 2.54, 95% CI: 1.368-4.717, p < 0.05). In addition, CE was identified as a risk factor for infertility after FTR (OR: 4.730, 95% CI: 2.012-11.122). The presence of CE seems to decrease the likelihood of achieving spontaneous pregnancy following FTR. This observation underscores the clinical importance of early detection and treatment of CE, emphasizing the necessity for immediate intervention to prevent potential fertility complications.
Recurrent Pregnancy Loss · Immune and Thrombophilia Factors
Could the risk of subsequent pregnancy loss be predicted based on the risk factors of recurrent pregnancy loss (RPL) patients? A nomogram, constructed from independent risk factors identified through multivariate logistic regression, serves as a reliable tool for predicting the likelihood of subsequent pregnancy loss in RPL patients. Approximately 1-3% of fertile couples experience RPL, with over half lacking a clear etiological factor. Assessing the subsequent pregnancy loss rate in RPL patients and identifying high-risk groups for early intervention is essential for pregnancy counseling. Previous prediction models have mainly focused on unexplained RPL, incorporating baseline characteristics such as age and the number of previous pregnancy losses, with limited inclusion of laboratory and ultrasound indicators. STUDY DESIGN, SIZE, The retrospective study involved 3387 RPL patients who initially sought treatment at the Reproductive Immunology Clinic of Renji Hospital, Shanghai Jiao Tong University School of Medicine, between 1 January 2020 and 31 December 2022. Of these, 1153 RPL patients met the inclusion criteria and were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, RPL was defined as two or more pregnancy losses (including biochemical pregnancy loss) with the same partner before 28 weeks of gestation. Data encompassing basic demographics, laboratory indicators (autoantibodies, peripheral immunity coagulation, and endocrine factors), uterine and endometrial ultrasound results, and subsequent pregnancy outcomes were collected from enrolled patients through initial questionnaires, post-pregnancy visits fortnightly, medical data retrieval, and telephone follow-up for lost patients. R software was utilized for data cleaning, dividing the data into a training cohort (n = 808) and a validation cohort (n = 345) in a 7:3 ratio according to pregnancy success and pregnancy loss. Independent predictors were identified through multivariate logistic regression. A nomogram was developed, evaluated by 10-fold cross-validation, and compared with the model incorporating solely age and the number of previous pregnancy losses. The constructed nomogram was evaluated using the AUC, calibration curve, decision curve analysis (DCA), and clinical impact curve analysis (CICA). Patients were then categorized into lowand high-risk subgroups. MAIN We included age, number of previous pregnancy losses, lupus anticoagulant, anticardiolipin IgM, anti-phosphatidylserine/prothrombin complex IgM, anti-double-stranded DNA antibody, arachidonic acid-induced platelet aggregation, thrombin time and the sum of bilateral uterine artery systolic/diastolic ratios in the nomogram. The AUCs of the nomogram were 0.808 (95% CI: 0.770-0.846) in the training cohort and 0.731 (95% CI: 0.660-0.802) in the validation cohort, respectively. The 10-fold cross-validated AUC ranged from 0.714 to 0.925, with a mean AUC of 0.795 (95% CI: 0.750-0.839). The AUC of the nomogram was superior compared to the model incorporating solely age and the number of previous pregnancy losses. Calibration curves, DCAs, and CICAs showed good concordance and clinical applicability. Significant differences in pregnancy loss rates were observed between the lowand high-risk groups (P < 0.001). LIMITATIONS, This study was retrospective and focused on patients from a single reproductive immunology clinic, lacking external validation data. The potential impact of embryonic chromosomal abnormalities on pregnancy loss could not be excluded, and the administration of medication to all cases impacted the investigation of risk factors for pregnancy loss and the model's predictive efficacy. This study signifies a pioneering effort in developing and validating a risk prediction nomogram for subsequent pregnancy loss in RPL patients to effectively stratify their risk. We have integrated the nomogram into an online web tool for clinical applications. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (82071725). All authors have no competing interests to declare. N/A.
Endometriosis, a systemic ailment, profoundly affects various aspects of life, often eluding detection for over a decade. This leads to enduring issues such as chronic pain, infertility, emotional strain, and potential organ dysfunction. The prolonged absence of diagnosis can contribute to unexplained obstetric challenges and fertility issues, necessitating costly and emotionally taxing treatments. While biopsy remains the gold standard for diagnosis, emerging noninvasive screening methods are gaining prominence. These tests can indicate endometriosis in cases of unexplained infertility, offering valuable insights to patients and physicians managing both obstetric and non-obstetric conditions. In a retrospective cross-sectional study involving 215 patients aged 25 to 45 with unexplained infertility, diagnostic laparoscopy was performed after unsuccessful reproductive technology attempts. Pathology results revealed tissue abnormalities in 98.6% of patients, with 90.7% showing endometriosis, confirmed by the presence of endometrial-like glands and stroma. The study underscores the potential role of endometriosis in unexplained infertility cases. Although the study acknowledges selection bias, a higher than previously reported prevalence suggests evaluating endometriosis in patients who have not responded to previous reproductive interventions may be justified. Early detection holds significance due to associations with ovarian cancer, prolonged fertility drug use, pregnancy complications, and elevated post-delivery stroke risk.
Ghobrial S et al., 2023·Journal of clinical medicine
Postoperative intraabdominal adhesions can occur after more than 90% of gynecologic surgeries. They not only cause chronic pelvic pain and small bowel obstruction, but are also one of the main reasons for infertility. Adhesions are not only a burden for the affected patients, but are also a burden for the healthcare system, since the treatment of adhesion-associated complications costs a considerable amount of money. The gold standard for the diagnosis of adhesions is by laparoscopy, although other methods, such as transvaginal hydro-laparoscopy, are being discussed as better alternatives. Ideally, adhesions are avoided inherently, by operating carefully and by using microsurgical principles. If this is not possible, gel barriers have been shown to be successful in reducing postoperative adhesions.
Infertility is a world-wide problem, defined as failure to achieve pregnancy after 12 months of regular unprotected sexual intercourse. There are multiple causes for infertility involving both male and female factors. Fallopian tube occlusion is a common reason for female infertility. The initial attempts to treat proximal obstruction involved the use of a whalebone bougie positioned in the uterine cornua to dilate the proximal tube by Smith as early as 1849. Fluoroscopic fallopian tube recanalization for the treatment of infertility was first described in 1985. Since that time, there have been over 100 papers describing various methods for recanalization of occluded fallopian tubes. Fallopian tube recanalization is a minimally invasive procedure which is performed on an outpatient basis. It should be a first line therapy for patients with proximal occlusion of fallopian tubes.
Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org et al., 2021·Fertility and sterility
Diagnostic evaluation for infertility in women should be conducted in a systematic, expeditious, and cost-effective manner to identify all the relevant factors with an initial emphasis on the least invasive methods for detecting the most common causes of infertility. The purpose of this committee opinion is to provide a critical review of the current methods and procedures for the evaluation of in fertile women, and it replaces the document of the same name, last published in 2015 (Fertil Steril 2015;103:e44-50). This guidance is intended for any provider evaluating women for infertility.
Garolla A et al., 2020·Front Endocrinol (Lausanne)·
Open Access
This expert opinion summarizes current knowledge on risk factors for infertility and identifies a practical clinical and diagnostic approach for the male and female partners of an infertile couple aimed to improve the investigation and management of fertility problems. Infertility represents an important and growing health problem affecting up to 16% of couples worldwide. In most cases, male, female, or combined factor can be identified, and different causes or risk factors have been related to this condition. However, there are no standardized guidelines on the clinical-diagnostic approach of infertile couples and the recommendations concerning infertility are sometimes lacking, incomplete, or problematic to apply. The aim of this work is to provide an appropriate clinical and diagnostic pathway for infertile couples designed by a multidisciplinary-team of experts. The rationale is based on the history and physical examination and then oriented on the basis of initial investigations. This approach could be applied in order to reduce variation in practice and to improve the investigation and management of fertility problems. Prominent Italian experts of the main specialties committed in the ART procedures, including gynecologists, andrologists, embryologists, biologists, geneticists, oncologists, and microbiologists, called "InfertilItaly group", used available evidence to develop this expert position. Starting from the individuation of the principal risk factors that may influence the fertility of females and males and both genders, the work group identified most appropriate procedures using a gradual approach to both partners aimed to obtain a precise diagnosis and the most effective therapeutic option, reducing invasive and occasionally redundant procedures. This expert position provides current knowledge on risk factors and suggests a diagnostic workflow of infertile couples. By using this step-by-step approach, health care workers involved in ART, may individuate a practical clinical management of infertile couples shared by experts.
To examine potential risk factors associated with the success rate following fallopian tube recanalization (FTR) in infertile women with obstruction of the proximal fallopian tube. We retrospectively studied patients who underwent FTR for tubal obstructive infertility between January 2016 and December 2018 at the Third Affiliated Hospital of Guangzhou Medical University. FTR was performed using a catheter and guidewire system to clear tubal obstruction. Predictive factors potentially associated with the success rate were assessed by logistic regression. A total of 762 patients were included. Multivariable analysis showed that age (odds ratio [OR] = 2.38, 95% confidence interval [CI]: 1.24-4.58), infertility type (OR = 2.82, 95% CI: 1.36-6.21), history of ectopic pregnancy (OR = 7.87, 95% CI: 4.05-15.81), history of abdominal surgery (OR = 4.30, 95% CI: 2.22-8.60), history of artificial abortion curettage (OR = 4.08, 95% CI: 2.12-8.03), and duration of infertility (OR = 2.03, 95% CI: 1.06-3.85) were independently associated with postoperative tubal patency. Our findings suggest that risk factors, such as age ≥35 years, secondary infertility, duration of infertility ≥5 years, and histories of ectopic pregnancy, abdominal surgery, and artificial abortion curettage, affect the success rate of FTR. These factors may also predict surgical success in treating tubal obstructive infertility.
Wang JW et al., 2020·Therapeutic Advances in Reproductive Health
Previous studies show good technical success rates for fallopian tube recanalization. Scarce literature exists regarding advance techniques currently used by interventional radiologists during fallopian tube recanalization procedures. This study investigates the level of intervention and tubal patency and its association with technical success and associated pregnancy outcomes. We retrospectively evaluated fallopian tube recanalization procedures performed at a single center in a 24-year period. A total of 160 couples undergoing a basic infertility evaluation were included. Hysterosalpingography with high pressure contrast injection followed by selective contrast, guidewire catheterization at the tubal ostium, and/or microcatheter/microwire recanalization were performed. Comparisons of the tubal fertilization rate by relevant characteristics were tested for statistical significance with t tests for continuous data or with Pearson chi-square tests for categorical data. Technical success rate was 94% (319 of 341 tubes). High pressure contrast injection alone (184 of 341, 54%), selective catheterization (40%), and microcatheter/microwire (6%) interventions yielded technical success rates of 98%, 90%, and 73%, respectively. The overall rate of conception was 35% (17 of 48). Current techniques of fallopian tube recanalization offer a desirable and safe option with high technical success for patients seeking treatment for infertility due to proximal fallopian tube obstruction.
Endometrial BCL6 protein levels are significantly elevated in women with unexplained recurrent pregnancy loss and unexplained infertility compared with fertile controls, with 79% of subfertile women displaying elevated BCL6. Among those with abnormal BCL6 who underwent laparoscopy, most were found to have endometriosis, suggesting a continuum of progesterone resistance and inflammatory/endometriosis-related endometrial dysfunction.
Sawant S et al., 2019·Clinical medicine insights. Reproductive health
Polycystic ovary syndrome is the most common endocrinological disorder in women of reproductive age. It is commonly associated with anovulatory subfertility, for which there are a range of treatment options available to help them conceive. These options are given in a step-wise manner with an appropriate selection of patients to maximise success rates with minimal complications. This review discusses the importance and involvement of multidisciplinary care when offering treatment to women with subfertility. Multidisciplinary care gives an excellent opportunity to identify, assess risk, and potentially prevent future morbidities and complications while treating women for fertility issues. We have also summarised the various options available for fertility treatment: pharmacological treatments, nonpharmacological intervention, and assisted reproductive technology.
Vander Borght M et al., 2018·Clinical Biochemistry
Infertility is a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse. It is estimated to affect between 8 and 12% of reproductive-aged couples worldwide. Males are found to be solely responsible for 20-30% of infertility cases but contribute to 50% of cases overall. Secondary infertility is the most common form of female infertility around the globe, often due to reproductive tract infections. The three major factors influencing the spontaneous probability of conception are the time of unwanted non-conception, the age of the female partner and the disease-related infertility. The chance of becoming spontaneously pregnant declines with the duration before conception. The fertility decline in female already starts around 25-30 years of age and the median age at last birth is 40-41 years in most studied populations experiencing natural fertility. The disease-related infertility may affect both genders or be specific to one gender. The factors affecting both genders' fertility are hypogonadotrophic hypogonadism, hyperprolactinemia, disorders of ciliary function, cystic fibrosis, infections, systemic diseases and lifestyle related factors/diseases. Premature ovarian insufficiency, polycystic ovary syndrome, endometriosis, uterine fibroids and endometrial polyps may play a role in female infertility. Male infertility may be due to testicular and post-testicular deficiencies. Semen decline that has been observed over the years, endocrine disrupting chemicals and consanguinity are other factors that may be involved.
What is the chance of clinical pregnancy when fallopian tube catheterization is used for proximal tubal obstruction? The pooled clinical pregnancy rate of tubal catheterization after proximal tubal obstruction is 27% (95% CI 25-30%). Restoring fallopian tube patency by performing tubal catheterization has fallen out of favour since the increased availability of IVF. Our study is the first systematic review and meta-analysis to investigate reproductive outcomes following tubal catheterization for proximal tubal obstruction. STUDY DESIGN, SIZE, We undertook a systematic review and meta-analysis of 27 observational studies consisting of 1720 patients undergoing tubal catheterization for proximal tubal obstruction, who attempted to conceive naturally after the procedure. PARTICIPANTS/MATERIALS, SETTING, Systematic literature searches were performed in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. A total of 2195 titles and abstracts were reviewed. Only studies that reported outcomes when tubal catheterization was performed with no other tubal surgery were included. Twenty-seven cohort studies matched the inclusion criteria for the meta-analysis. MAIN The meta-analysis showed a pooled clinical pregnancy rate of 27% (95% CI 25-30%) after the use of tubal catheterization for unilateral or bilateral proximal tubal obstruction (27 studies, 1556 patients). In women with bilateral obstruction (14 studies, 617 patients), the clinical pregnancy rate was 27% (95% CI 23-32%). Our meta-analysis demonstrated that the pooled cumulative clinical pregnancy rates were 22.3% (95% CI 17.8-27.8%) at 6 months, 25.8% (95% CI 21.1-31.5%) at 9 months, 26.4% (95% CI 23.0-30.2%) at 12 months, 26.0% (95% CI 22.8-29.7%) at 18 months, 27.0% (95% CI 24.0-30.5%) at 24 months, 27.9% (95% CI 24.9-31.3%) at 36 months and 28.5% (95% CI 25.5-31.8%) at 48 months. The pooled live birth rate (14 studies, 551 patients) was 22% (95% CI 18-26%). The pooled ectopic pregnancy rate (27 studies, 1556 patients) was 4% (95% CI 3-5%). The included studies scored satisfactorily on the Newcastle-Ottawa quality assessment scale. LIMITATIONS, The pooled clinical pregnancy rate after tubal catheterization was found to be almost comparable to that after IVF. However, included studies were small, non-comparative series with significant clinical heterogeneity in population characteristics, follow-up and surgical equipment, technique and experience. These findings suggest fallopian tube catheterization as an alternative strategy to IVF in patients presenting with proximal tubal obstruction. Further research should focus on comparing different surgical techniques of fallopian tube catheterization with IVF and provide cumulative reproductive outcomes over long-term follow-up. STUDY FUNDING/COMPETING INTEREST(S): No funding was required and the authors have no competing interests to declare. N/A.
Female infertility is a complex issue encompassing a wide variety of diagnoses, many of which are caused or affected by adhesions. The study intended to examine the rates of successful treatment of infertile women using a protocol of manual physical therapy to address underlying adhesive disease leading to infertility. Methods • The research team designed a retrospective chart review.
The study took place in a private physical therapy clinic. Participants were 1392 female patients who were treated at the clinic between the years of 2002 and 2011. They had varying diagnoses of infertility, including occluded fallopian tubes, hormonal dysfunction, and endometriosis, and some women were undergoing in vitro fertilization (IVF). Intervention • All patients underwent whole-body, patient-centered treatments that used a protocol of manual physical therapy, which focused on restoring mobility and motility to structures affecting reproductive function. Improvements demonstrated in the condition(s) causing infertility were measured by improvements in tubal patency and/or improved hormone levels or by pregnancy. Results • The results included a 60.85% rate of clearing occluded fallopian tubes, with a 56.64% rate of pregnancy in those patients. Patients with endometriosis experienced a 42.81% pregnancy rate. The success rate was 49.18% for lowering elevated levels of follicle stimulating hormone (FSH), with a 39.34% pregnancy rate in that group, and 53.57% of the women with polycystic ovarian syndrome (PCOS) achieved pregnancy. The reported pregnancy rate for patients who underwent IVF after the therapy was 56.16%. The results also suggested that the treatment was effective for patients with premature ovarian failure (POF). The manual physical therapy represented an effective, conservative treatment for women diagnosed as infertile due to mechanical causes, independent of the specific etiology.
Knowledge regarding the role of the cervix in fertility has expanded considerably over the past 20 years and in this article, we propose that it is now time for its function to be reappraised. First, we review the anatomy of the cervix and the vaginal ecosystem that it inhabits. Then, we examine the physiology and the role of the cervical mucus. The ongoing mystery of the exact mechanism of the sperm-cervical mucus interaction is reviewed and the key players that may unlock this mystery in the future are discussed. The soluble and cellular biomarkers of the lower female genital tract which are slowly being defined by contemporary research are reviewed. Attempts to standardize these markers, in this milieu, are hindered by the changes that may be attributed to endogenous or exogenous factors such as: age, hormonal changes during the menstrual cycle, ectropion, infection, smoking and exposure to semen during sexual intercourse. We review what is known about the immunology of the cervix. With the widespread use of large loop excision of the transformation zone (LLETZ) for treatment of cervical intraepithelial neoplasia, the anatomy of the cervix is changing for many women. While LLETZ surgery has had very positive effects in the fight against cervical cancer, we debate the impact it could have on a woman's fertility.
This report presents nationally representative estimates and trends for infertility and impaired fecundity-two measures of fertility problems-among women aged 15-44 in the United States. Data are also presented on a measure of infertility among men aged 15-44. Data for this report come primarily from the 2006-2010 National Survey of Family Growth (NSFG), which consisted of 22,682 interviews with men and women aged 15-44, conducted from June 2006 through June 2010. The response rate for women in the 2006-2010 NSFG was 78%, and for men was 75%. Selected trends are shown based on prior NSFG years. The percentage of married women aged 15-44 who were infertile fell from 8.5% in 1982 (2.4 million women) to 6.0% (1.5 million) in 2006-2010. Impaired fecundity among married women aged 15-44 increased from 11% in 1982 to 15% in 2002, but decreased to 12% in 2006-2010. Among all women, 11% had impaired fecundity in 2006-2010. Both infertility and impaired fecundity remain closely associated with age for nulliparous women. Among married, nulliparous women aged 35-44, the percentage infertile declined from 44% in 1982 to 27% in 2006-2010, reflecting greater delays in childbearing over this period. Among married women in 2006-2010, non-Hispanic black women were more likely to be infertile than non-Hispanic white women. Some form of infertility (either subfertility or nonsurgical sterility) was reported by 9.4% of men aged 15-44 and 12% of men aged 25-44 in 2006-2010, similar to levels seen in 2002.
Infertility remains a common and often unresolved condition afflicting certain couples. Numerous animal studies have demonstrated that alterations in the light-dark cycle can affect reproduction as mediated by the pineal gland and its hormone, melatonin. To examine whether a similar disruption could affect human fertility, a pilot study was conducted with infertile women enrolled in a Natural Family Planning program.
Gelbaya TA et al., 2014·Obstetrical & gynecological survey
The diagnosis of unexplained infertility can be made only after excluding common causes of infertility using standard fertility investigations,which include semen analysis, assessment of ovulation, and tubal patency test. These tests have been selected as they have definitive correlation with pregnancy. It is estimated that a standard fertility evaluation will fail to identify an abnormality in approximately 15% to 30% of infertile couples. The reported incidence of such unexplained infertility varies according to the age and selection criteria in the study population. We conducted a review of the literature via MEDLINE. Articles were limited to English-language, human studies published between 1950 and 2013. Since first coined more than 50 years ago, the term unexplained infertility has been a subject of debate. Although additional investigations are reported to explain or define other causes of infertility, these have high false-positive results and therefore cannot be recommended for routine clinical practice. Couples with unexplained infertility might be reassured that even after 12 months of unsuccessful attempts, 50% will conceive in the following 12 months and another 12% in the year after.
Thurmond AS, 2013·Seminars in Interventional Radiology·
Open Access
Fallopian tube catheterization is used for treatment of infertility caused by proximal tubal occlusion, and has replaced surgical treatment for this condition. More recently, fallopian tube catheterization has been used for tubal sterilization. Interventional radiologists tested numerous methods for tubal occlusion using the rabbit as an animal model. As a result, a tubal device has recently been Food and Drug Administration approved for permanent sterilization using hysteroscopic guidance; it can also be placed fluoroscopically by fallopian tube catheterization as an "off-label" procedure. This is a 5-year continuation and update on a procedure that has been done by interventional radiologists for 25 years; history of the development of fallopian tube catheterization in women has been published in detail in this journal. Highlighted in this article will be description of the basic components needed for fallopian tube catheterization.
The current approach to infertility of assisted reproductive technology (ART) completely misses and then bypasses the evaluation and treatment of cervical factor infertility. In contrast, the Creighton Model Fertility Care System (CrMS), a method of fertility awareness that has the unique ability to quantify cervical mucus observations, and natural procreative technology (NaProTECHNOLOGY or NPT) directly evaluate and treat cervical factor infertility. The ART treatment of choice for cervical factor infertility--intrauterine insemination (IUI)--is also morally disparate from the NPT treatment protocol: while the latter genuinely assists the infertile couple's act of sexual union to achieve its natural end of pregnancy, IUI replaces the natural act, depriving human conception of the one context worthy of the dignity of human life and procreation, a reciprocal self-gifting act of love between husband and wife. A renewed interest and focus on the direct evaluation and treatment of cervical factor infertility is needed.
Livshits A et al., 2009·Women's health (London, England)
Diabetes mellitus Type 1 and Type 2 should be considered in the differential diagnosis of menstrual abnormalities and infertility. The reproductive period of diabetic women may be reduced due to delayed menarche and premature menopause. During the reproductive years, diabetes has been associated with menstrual abnormalities, such as oligomenorrhea and secondary amenorrhea. It was found that better glycemic control and prevention of diabetic complications improves these irregularities and increases fertility rates close to those that are seen in the general population. Women with persistent menstrual abnormalities despite adequate treatment need to be approached by broader evaluation, which will include the examination of the hypothalamic-pituitary-ovarian axis and the hormonal status, presence of autoimmune thyroid disease and antiovarian autoantibodies, and hyperandrogenism.
We evaluated outcomes in couples treated for infertility with natural procreative technology (NaProTechnology [corrected] NPT), a systematic medical approach for optimizing physiologic conditions for conception in vivo, from an Irish general practice. All couples receiving treatment from 2 NPT-trained family physicians between February 1998 and January 2002 were studied. The main outcome was live birth, and secondary outcomes included conceptions and multiple births. Crude proportions and adjusted life-table proportions were calculated per 100 couples. A total of 1239 couples had an initial consult for NPT, of which 1072 had been trying for at least a year to conceive and initiated treatment. The average female age was 35.8 years, the mean duration of attempting to conceive was 5.6 years, 24% had a prior birth, and 33% had previously attempted treatment with assisted reproductive technology (ART). All couples were taught to identify the fertile days of the menstrual cycle with the Creighton Model FertilityCare System, and most received additional medical treatment, including clomiphene (75%). In life-table analysis, the cumulative proportion of first live births for those completing up to 24 months of NPT treatment was 52.8 per 100 couples. The crude proportion was 25.5. Younger couples and couples without previous ART attempts had higher rates of live birth. Among live births, there were 4.6% twin births. NPT provided by trained general practitioners had live birth rates comparable to cohort studies of more invasive treatments, including ART. Further studies are warranted to compare NPT directly to other treatments.
Over the past decade, significant advances have occurred in the diagnosis and treatment of reproductive disorders. In this review, we discuss the routine testing performed to diagnose unexplained infertility. We also discuss additional testing, such as assessment of ovarian reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the available therapeutic options and discuss the efficacy and the cost-effectiveness of the existing treatment modalities. The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile, and cost considerations.
Das S et al., 2007·Reproductive BioMedicine Online
Tubal disease is the cause of subfertility in approximately 30% of women, and 10-25% of these are due to proximal tubal obstruction. False-positive diagnosis of proximal tubal obstruction can be as high as 50%. A decrease in expertise in tubal microsurgery has resulted largely from the use of IVF as the treatment option for most causes of infertility and more specifically for tubal factor infertility. Selective salpingography and tubal cannulation have a unique role in the management of tubal infertility and should be offered to selected candidates prior to IVF. Tubal cannulation can be used effectively to restore patency in a proportion of cases of proximal tubal obstruction thus avoiding the need for expensive assisted reproductive techniques. This review examines the evidence supporting the effectiveness of tubal cannulation and aims to enhance awareness of the procedure as an option for the management of female subfertility secondary to isolated proximal tubal obstruction.
Effective tubal transport of ova, sperm and embryos is a prerequisite for successful spontaneous pregnancy. Although there is much yet to be discovered about the mechanisms involved, it is evident that tubal transit is a far more complicated process than initially thought. Propulsion of gametes and embryos is achieved by complex interaction between muscle contractions, ciliary activity and the flow of tubal secretions. Evidence is accumulating of the important and possibly pre-eminent role of ciliary motion in this process; and this review describes current knowledge about ciliary activity and its physiological regulation. There is also a description of the effects on ciliary function of cigarette smoking and various pathological states, including endometriosis and microbial infection, with consideration given as to how altered ciliary activity may impact upon fertility.
Hilgers TW et al., 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Patients who have undergone multiple failed IVF cycles and are counseled to abandon fertility treatment represent a significant NaProTECHNOLOGY cohort in whom undiagnosed correctable pathology — including subtle endometriosis, luteal insufficiency, or immunological factors — is subsequently identified and treated. Published data demonstrate clinically meaningful pregnancy rates in this population following NaProTECHNOLOGY evaluation and treatment, demonstrating that ART failure does not predict failure of restorative approaches.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
A photographic atlas documents the intraoperative appearance of endometriosis, adhesions, polycystic ovarian morphology, tubal pathology, and uterine anomalies as encountered during near-contact laparoscopy. Standardized visual reference supports consistent surgical classification, intraoperative decision-making, and communication of findings across the NaProTECHNOLOGY surgical team.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Conventional infertility care has shifted toward assisted reproductive technologies that bypass underlying pathology rather than diagnose and treat root causes, leaving a large proportion of couples with unresolved, correctable conditions. NaProTECHNOLOGY addresses this systemic deficiency by emphasizing standardized evaluation, cycle-based hormonal profiling, and targeted medical and surgical treatment before any bypass technology is considered.
The likelihood of spontaneous conception in subsequent cycles is important for a balanced management of infertility. Previous studies on time to pregnancy are mostly retrospective and biased because of exclusion of truly infertile couples. The study aim was to present a non-parametric estimation of cumulative probabilities of conception (CPC) in natural family planning (NFP) users illustrating an ideal of human fertility potential. A total of 346 women was observed who used NFP methods to conceive from their first cycle onwards. The couples practising NFP make optimal use of their fertility potential by timed intercourse. The CPC were estimated for the total group and for couples who finally conceived by calculating Kaplan-Meier survival rates. A total of 310 pregnancies occurred among the 346 women; the remaining 36 women (10.4%) did not conceive. Estimated CPC for the total group (n = 340 women) at one, three, six and 12 cycle(s) were 38, 68, 81 and 92% respectively. For those who finally conceived (truly fertile couples, n = 304 women), the respective pregnancy rates were 42, 75, 88 and 98% respectively. Although the numbers of couples in both groups were similar, the impact of age on time to conception, as judged by the Wilcoxon test, was less in the truly fertile than in the total group. Most couples conceive within six cycles with timed intercourse. Thereafter, every second couple is probably either subfertile or infertile. CPC decline with age because heterogeneity in fecundity increases. In the subgroup of truly fertile couples, an age-dependent decline in CPC is statistically less obvious because of high homogeneity, even with advancing age.
To analyze retrospectively the frequency, long-term prognosis and pregnancy rate in infertile women diagnosed with endometrial hyperplasia or carcinoma by endometrial biopsy. From 1989 to 2000, endometrial biopsies were performed on 2,573 patients to investigate the cause of infertility. The main outcome measures were frequency, long-term prognosis and pregnancy rate for patients with each type of endometrial abnormality. Twenty-four patients (0.93%) were diagnosed with an endometrial abnormality. Of them, 10 were diagnosed with simple hyperplasia, 7 with complex hyperplasia, 3 with complex hyperplasia with atypia and 4 with endometrial carcinoma. All 4 patients (0.16%) with endometrial carcinoma were infertile as a result of complications arising from polycystic ovary syndrome. Two of them underwent hysterectomies. High-dose medroxyprogesterone acetate therapy combined with assisted reproductive technology resulted in pregnancy in 1 of the 2 patients with endometrial carcinoma. Of infertile women, 0.93% have endometrial abnormalities, and those with polycystic ovary syndrome have a high risk of endometrial carcinoma. Assisted reproductive technology combined with high-dose medroxyprogesterone acetate may be effective means of overcoming infertility, allowing women with endometrial carcinoma to readily achieve pregnancy.
To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). Single center, case-controlled, prospective study. University-associated reproductive endocrinology clinical practice. PATIENT(S): Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI). INTERVENTION(S): Both groups consented to obtaining fasting insulin and glucose levels. MAIN OUTCOME MEASURE(S): Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5. RESULT(S): Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92). CONCLUSION(S): Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.
Corson SL et al., 2000·J Am Assoc Gynecol Laparosc·
To determine the prevalence of reproductive pathology in a group of infertile women thought to be at low risk for altered pelvic anatomy. Retrospective chart review and follow-up (Canadian Task Force classification II-2). Academic-affiliated, private reproductive endocrinology practice. One hundred infertile women. Diagnostic and/or therapeutic laparoscopy. MAIN Of 100 patients with a negative reproductive work-up up to the point of laparoscopy, 68 had pathology of reproductive intrinsic tubal disease 24, peritubal adhesive disease 34, and endometriosis 43, some in combination. Laparoscopy was especially helpful in establishing treatment protocols for older women, who were referred for assisted reproductive techniques earlier than otherwise might have been the case. Women conceived after hormone therapy and after operative intervention. Although the hysterosalpingogram was read as normal in all women, tubal disease was diagnosed laparoscopically, independent of endometriosis, in 27 patients, with 2 having complete obstruction. Endometriosis stage I-II was found in 22 patients, stage III in 13, and stage IV in 6. Even in women thought to be at low risk for significant pelvic pathology affecting reproduction, the yield was high. Although some pregnancies were achieved after operative intervention, frequently laparoscopy was helpful in making a decision to go to assisted reproductive technology, particularly when infertility had been of long duration and in older women. Frequently the degree of pathology was such that a full operating suite was necessary to provide adequate instrumentation and anesthesia for operative intervention, which would not have been the case with office laparoscopy.
Hull MG et al., 1999·Endocrinol Metab Clin North Am·
This article has provided outcome-based evidence using easily understood graphic representation of cumulative pregnancy rates whenever possible for the methods used to investigate and treat female infertility. A scheme of basic routine investigations in specialist practice is developed and clear guidance provided on the choice of treatment for each couple.
Stephen EH et al., 1998·Fertil Steril·
Open Access
To project the number of infertile women aged 15-44 every 5 years from 2000 to 2025. Data are used from Cycle 5 of the National Survey of Family Growth conducted by the National Center for Health Statistics. Population projections prepared by the U.S. Bureau of the Census are used as the base population for 2000-2025. Prospective demographic projections are used to estimate the number of infertile women. The National Survey of Family Growth (Cycle 5) interviewed 10,847 women aged 15-44 in 1995. MAIN OUTCOME MEASURE(S): Number of infertile women. RESULT(S): The number of women experiencing infertility will range from 5.4-7.7 million in 2025, with the most likely number to be just under 6.5 million. CONCLUSION(S): This is a substantial revision (upward) in the number of infertile women, largely a result of the increase in the observed percentage of infertile women in 1995. This is the base population of concern to providers; of particular interest is the percentage of infertile women who seek medical treatment.
Houston JG et al., 1998·Cardiovasc Intervent Radiol·
To evaluate the technical success and outcome of fallopian tube recanalization (FTR) in salpingitis isthmica nodosa (SIN). SIN is a well-recognized pathological condition affecting the proximal fallopian tube and is associated with infertility and ectopic pregnancy. We reviewed the presentations, films, and case records of all patients attending for FTR for infertility from 1990 to 1994. Technical success and total, intrauterine, and ectopic pregnancy rates at follow-up were determined. SIN was observed in 22 of 349 (6%) patients. FTR was attempted in 34 tubes in these 22 patients. Technical success was achieved in 23 of 34 (68%) tubes affected by SIN. In 5 of the 11 failed recanalizations, failure was due to distal obstruction. At least one tube was patent on selective postprocedural salpingography in 17 of 22 (77%) patients. There were no recorded perforations or complications. At follow-up (mean 14 months), total, intrauterine, and ectopic pregnancy rates were 23%, 18%, and 4.5%, respectively. FTR in SIN is technically successful and, compared with previously reported results in unselected infertility patients, is associated with only a slightly less favorable intrauterine pregnancy rate and a comparable ectopic pregnancy rate. The findings of SIN at FTR should not discourage attempted fluoroscopic transcervical recanalization.
The 1995 National Survey of Family Growth (NSFG) provides new nationally representative data to test the accuracy of the commonly held assumption that impaired fecundity has been rising in the United States over the past decade. Using data from the 1982, 1988 and 1995 rounds of the NSFG, trends in both the proportions and numbers of women with impaired fecundity and of those who received infertility services were examined. Multiple logistic regressions were carried out to estimate the effects of demographic characteristics on the likelihood of currently having impaired fecundity and of ever having received medical help for infertility. The proportion of U.S. women aged 15-44 who reported some form of fecundity impairment rose from 8% in 1982 and 1988 to 10% in 1995, an increase in absolute numbers from 4.6 million to 6.2 million women. Although the proportion of fecundity-impaired women who had ever sought medical help did not change between 1988 and 1995 (44%), the absolute numbers of such women grew by nearly 30%, from 2.1 million to 2.7 million. Women who had ever sought help for fertility problems were older and had a higher income than those who had not, and were more likely to be married. The dramatic increase in the numbers of U.S. women with impaired fecundity occurred because the large baby-boom cohort, many of whom delayed childbearing, had reached their later and less fecund reproductive years. This increase in both rates and numbers occurred across almost all age, parity, marital status, education, income, and race and ethnicity subgroups.
To determine how board-certified reproductive endocrinologists vary in their approach to the clinical tests performed on the infertile couple. A cross-sectional study to assess differences in the approach to evaluating the infertile couple. A population-based national survey. PARTICIPANT(S): United States board-certified reproductive endocrinologists. MAIN OUTCOME MEASURE(S): The frequency of clinical tests and evaluation procedures by physician age, sex, size and setting of practice, institutional affiliation, and geographic location. RESULT(S): The overall response rate was 84%. Although the majority of practitioners routinely order a semen analysis (99.9%), an assessment of ovulation (98%), a hysterosalpingogram, (HSG; 96%), laparoscopy (89%), and a postcoital test (PCT, 79%), there was less agreement regarding hormonal testing (range, 22% [LH] to 66% [PRL]), use of pelvic ultrasounds (55%), hysteroscopy (53%), cervical cultures (range, 24% to 54%), and antisperm antibody testing (24%). Compared with male colleagues, female physicians order two to three times more cervical cultures and endometrial biopsies. Serum hormonal testing was two to three times more commonly ordered by younger (< 40 years) compared with older physicians, and physicians in private practice twice as frequently ordered hormonal testing, cervical cultures, PCTs, and antisperm antibody studies compared with their academic-affiliated colleagues. Western U.S. physicians order hormonal tests and cervical cultures 50% less often than their midwest and eastern counterparts. CONCLUSION(S): Trained specialists rely heavily on five "traditional" infertility tests: semen analysis, an assessment of ovulation, HSG, laparoscopy, and PCT. With regard to additional modes of testing, there is marked variability by physician sex, age, type of practice, and geographic location.
We describe the epidemiologic characteristics of conception, including subclinical early pregnancy loss, in a population of healthy women volunteers who had heterogeneous fertility experiences, and we describe the conception experience of women within this group who had evidence of impaired fertility. This was a prospective observational study of a cohort of women employed in two semiconductor manufacturing facilities. A total of 148 volunteers completed interviews and daily diaries and collected daily urine specimens for an average of 7 months. Conception, including subclinical losses and clinical pregnancies, was determined with a highly sensitive and specific assay for urinary human chorionic gonadotropin, and ovulation was determined with assays of urinary ovarian steroid hormones. There were 679 menstrual cycles at risk for pregnancy contributed by 124 (84%) of the 148 women. Women with evidence of subfertility before or during the study period had a rate of early pregnancy loss of 70% compared with 21% in women without fertility problems (relative risk 2.6, 95% confidence interval 1.8 to 3.8). The risk of pregnancy loss associated with subfertility increased with age and remained the same in women treated with clomiphene citrate. These results suggest that subfertile women have increased subclinical pregnancy losses regardless of fertility treatment and that the association between reduced fertility and advancing age may be related, in part, to early subclinical pregnancy loss.
To investigate the role of transcervical tubal catheterization in diagnosis and treatment of proximal tubal obstruction associated with salpingitis isthmica nodosa. Retrospective case study. University hospital and outpatient radiology practice. Fifty-two women with proximal tubal obstruction associated with salpingitis isthmica nodosa. Selective salpingography and catheter recanalization using fluoroscopic guidance. The number of tubes visualized to the fimbria as a percentage of the tubes with proximal tubal obstruction on the initial hysterosalpingogram was determined as a measure of diagnostic efficacy. To evaluate the treatment potential of catheter recanalization, the patients were grouped according to tubal status at the conclusion of the procedure and subsequent pregnancies were evaluated. Forty-seven of 65 tubes (72%) with proximal tubal obstruction were recanalized successfully. Among the 19 women who were able to conceive only via a recanalized salpingitis isthmica nodosa tube, there were 6 live births (32%) and two tubal pregnancies (10%). Selective salpingography allows complete tubal diagnosis in almost three fourths of patients with proximal tubal obstruction and salpingitis isthmica nodosa. The radiographic diagnosis of salpingitis isthmica nodosa may be pressure dependent. Intrauterine pregnancies occur via recanalized salpingitis isthmica nodosa tubes, therefore catheter recanalization may be attempted before tubal microsurgery or IVF in patients with proximal tubal obstruction and associated salpingitis isthmica nodosa.
To determine the relationship between some reproductive variables and infertility caused by tubal obstruction. A retrospective, case-control study. A tertiary care university hospital that is a referral center for infertility patients. Subjects were interviewed between March 1990 and December 1991. Cases were 215 consecutively recruited infertile women with either evidence of tubal obstruction found at laparoscopy or hydrosalpinx diagnosed by hysterosalpingography. Women with a history of surgical sterilization were excluded. Controls, selected in the same hospital, were women in the puerperium who had no history of infertility. Two controls were matched by age at the time of tubal obstruction diagnosis to each case. History of pelvic surgery and use of alcohol were significantly associated with the risk of infertility caused by tubal obstruction. The use of barrier, oral, and medroxyprogesterone acetate (MPA) contraceptives was associated with a protective effect. When only women with secondary infertility were analyzed, history of pelvic surgery and number of lifetime sexual partners were significant risk factors, and the previous use of oral contraceptives was the only protective factor. History of pelvic surgery was the most important risk factor for tubal infertility. All precautions must be taken to avoid infection and adhesion formation when pelvic surgery is performed. In addition, women can be protected from tubal infertility by using barrier, oral, or MPA contraceptive methods.
To examine and discuss the pathology, diagnosis, incidence, and patient profile of salpingitis isthmica nodosa and to question its natural history, propose management strategies, and identify areas of promising research. Over 50 studies were reviewed, evaluated, and compared to offer the clinician a foundation on which to generate treatment plans. Salpingitis isthmica nodosa is diagnosed by the pathological presence of isthmic diverticula and may be suggested by characteristic changes on hysterosalpingogram. Its incidence in healthy, fertile women ranges from 0.6% to 11%, but it is significantly more common in the setting of ectopic pregnancy and infertility. There are no studies, retrospective or prospective, that clearly dictate appropriate therapy. Given its progressive nature and probable deleterious effects on fertility, we propose that microtubal surgery be the definitive treatment for qualified women who have salpingitis isthmica nodosa.
Recurrent Pregnancy Loss · Immune and Thrombophilia Factors
Women experiencing recurrent spontaneous abortion have a higher frequency of infertility than that expected in the general population. To further define the relationships between infertility and spontaneous abortion, the obstetrical histories of 43 women with unexplained secondary infertility were evaluated for the frequency of spontaneous abortion. Of the 88 pregnancies studied, 39 (44%) resulted in spontaneous abortion. Women with unexplained secondary infertility experienced a three-fold increase (P less than 0.0001) in the frequency of spontaneous abortions and half the number of live births (P less than 0.0001) compared with the general population. We conclude that the association between infertility and spontaneous abortion includes a higher frequency of spontaneous abortion among infertile couples as well as a higher prevalence of infertility among recurrent spontaneous aborters compared with the general population.
Excised tubal segments from 94 infertile women with tubal obstruction, with a mean infertility duration of 5.3 years, and 40 women with ectopic tubal pregnancy were studied histopathologically to evaluate the association with salpingitis isthmica nodosa (SIN). The mean age of the 94 infertile women with tubal obstruction was 24.5 years. Hysterosalpingographies and laparoscopy were performed on all of them. Only the women with ectopic pregnancies we performed salpingectomy on were included in the present study. The incidence of SIN in women with tubal obstruction was 7.4%, in women with ectopic tubal pregnancy 10%, and in the control group the incidence was 0.2%. In 60% of the cases, SIN was present in both of the tubes. Based on this study, we conclude that SIN is significantly associated with infertility and ectopic tubal pregnancy.
Audebert A, 1990·J Gynecol Obstet Biol Reprod (Paris)·
Luteinization of a follicle without its rupture and without the oocyte being expelled which is also called the LUF-syndrome by English speaking authors is one of a number of functional abnormalities that can occur to the follicle in the ovary and is diagnosed by ultrasound methods. It is one that has been known for quite a long time. Many publications have appeared since 1978 to describe this syndrome, which all the same is still very controversial. One has learnt how to diagnose it fairly well. One knows more about its physiopathogenesis and how often it occurs. This seems to be more often when there is pelvic endometriosis or so-called unexplained infertility. What is more difficult however is to find out how important it is as a cause of lowered fertility, and it is also difficult to decide whether: it just happens occasionally or is a true syndrome? It is still not possible today to give a definite answer to this question because of reasons of methodology. Finally, as far as treatment goes, even if the facts about its pathogeneiity have been found out and should be able to help decide on a logical treatment there have been no controlled studies to find out whether the treatment works.
From 1979 to 1985, 18 patients who were found to have proximal tubal obstruction by hysterosalpingography and laparoscopic chromopertubation underwent resection of the obstructed tubal segment and reimplantation or microanastomosis. Resected tubal segments were studied histologically, and in 11 of the 18 cases no tubal occlusion could be demonstrated. A variety of histologic abnormalities were noted, however, including six cases in which the tubal lumen contained an amorphous material of unknown etiology, often appearing to form a cast of the tube. Such "plugs," which the authors believe to be previously unreported, have no clearly established clinical significance at present. However, if they cause tubal occlusion, this would explain several previously published findings, and would also have implications for therapy.
Women with a history of recurrent spontaneous abortions (repeaters) are compared with women who have had live births and no spontaneous abortions (multiparae) and women who have had live births and only one spontaneous abortion (sporadics) to identify characteristics of the women and their abortuses that might predict subsequent fetal loss. A number of risk factors for recurrent spontaneous abortion have been identified: the loss of a chromosomally normal conception, loss after the first trimester of pregnancy, a delay in conceiving prior to the study pregnancy, a diagnosis of cervical incompetence, and a history of very low birthweight deliveries. The odds ratios associated with being a repeater vary from 1.4 to 5.6 depending on the number of characteristics present.
Excised tubal segments from 42 women with uterotubal junction obstruction were studied histologically to evaluate the pathologic spectrum of disease and correlate this with clinical data. The most frequent lesion encountered was obliterative fibrosis (38.1%), confirmed by connective tissue stains, which was not associated with cornual nodularity. Other pathologic entities included salpingitis isthmica nodosa (23.8%), intramucosal endometriosis (14.3%), and chronic tubal inflammation (21.4%). Intramucosal endometriosis was distinguishable from salpingitis isthmica nodosa by virtue of its unique stroma confirmed by connective tissue staining. Women with previous pregnancies were included in all the groups. In all instances, the obstruction was present in the transmural portion of the tube and extended a variable distance into the isthmic segment. These observations on uterotubal junction obstruction demonstrate that: 1) There are multiple distinct histologic patterns, 2) Intraabdominal findings do not predict the histology of the uterotubal junction pathology, 3) Any histologic pattern can be associated with a previous intrauterine or ectopic pregnancy, and 4) The obstruction begins within the transmural portion of the oviduct, extends a variable distance into the isthmic segment, but does not obstruct the ampullary segment. These data suggest that the initiating process originates within the uterus and that fibrosis may represent a nonspecific response to chronic injury of the transmural and isthmic segments of the oviduct.
Eighteen women with cervical ectropion and 12 women with ectropion and vaginal discharge were treated by cryosurgery. Evaluation of the cervical mucus characteristics by cervical score and in vitro penetration test was performed before treatment and 2 months later. In the group with ectropion only (group A) the total cervical score was 5.7 +/- 0.4 and 11.9 +/- 0.06 (P less than 0.001) (mean +/- standard error) before treatment and 2 months later, respectively. In the group with ectropion and vaginal discharge (group B) the total cervical score before and after cryosurgery was 3.8 +/- 0.4 and 11.8 +/- 0.1 (P less than 0.001), respectively. In vitro penetration tests in group A before and after treatment were 0.72 +/- 0.1 and 2.9 +/- 0.08 (P less than 0.001), respectively. In group B, in vitro penetration tests before and after cryosurgery were 0.25 +/- 0.1 and 2.8 +/- 0.1 (P less than 0.001), respectively. It appears that cryosurgery improves the cervical mucus characteristics. It is recommended that infertile patients with hostile cervical mucus and ectropion will be treated by cryosurgery.
It is generally accepted that laparoscopy should be performed if a woman's basic infertility evaluation reveals no abnormalities. Although it has been shown that a significant number of these patients have unsuspected pelvic pathology that can be detected by laparoscopy, there is concern about the real benefit of this procedure, ie, does the laparoscopic examination truly lead to more pregnancies than otherwise expected? Presented is a review of a series of 50 female patients whose basic infertility evaluation had failed to reveal any abnormalities. Laparoscopy revealed significant pelvic pathology in 28 cases; of the 16 who had appropriate therapy, eight became pregnant.
The cervical canal mucus is important to human fertility since conception can only occur if sperm pass through the contents of the cervical canal to reach the ovum. The biophysical properties of the cervical mucus and their relation to sperm migration are, therefore, curcial. A variety of laboratory experimentation methods have been used in studies of cervical mucus: 1) sperm migration measurements; 2) reheological studies; 3) cell countings; 4) crystallization studies; 5) Nmr: 6) EPR; and 7) photoelectron spectroscopy. Cervical mucus is the end result of complicated biosynthetic processes occurring in the epithelial cells of the cervical mucosa; this biosynthesis is regulated by many factors. Type E, characteristic for estrogenic stimuli on mucus biosynthesis, and type G, for gestagenic stimulation, are the 2 main types of cervical secretions. The 2 types always occur together, in differing proportions. For example, at normal ovulation there is a 97:3 ratio of type E to type G; at normal corpus luteum, the ratio is 10:90. The string variety of type E seems to aid in conveying sperm from the vagina while the loaf variety is inactive. The very low viscosity of the string variety intermicellar fluid permits very rapid sperm swimming. Not much is known regarding cervical mucus pathology or therapy.
A discussion of infertility would be incomplete without a comment on the changing concepts of the definition. For statistical purposes it may be necessary to retain the criterion of a three year barren marriage. However, for the most satisfactory therapeutic results it appears that investigations for infertility must be instituted before these three, possibly most valuable, years have been wasted. The validity of shortening the period is substantiated by work of Diddle1 and Guttmacher,2 who independently obtained a figure of six months as the average time for a normal couple to achieve pregnancy. Relative infertility may be considered to exist any time after a six month interval. As late marriages and prolonged use of contraceptives are an integral part of our present society (especially in the private practice group) the foregoing fact is extremely important. Patients who marry after the age of 28 are contending, after a three
Reimão Miller KA et al., 2026·Reproductive biomedicine online
This review explores whether the clomiphene citrate stair-step protocol (SSP) for ovulation induction in patients with polycystic ovary syndrome (PCOS) outperforms the traditional protocol. The following databases were searched: PubMed, Cochrane Library, ClinicalTrials.gov, EMBASE and Google Scholar from inception to 15 June 2025, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and with PROSPERO registration (CRD420251050294). Of 847 screened records, five randomized controlled trials were included (n = 520: n = 255; traditional protocol: n = 265). Analyses were conducted in Review Manager 5.4 using random-effects models. Risk ratios, mean differences and 95% confidence intervals were calculated. Heterogeneity was assessed with I², risk of bias with RoB2, certainty with GRADE and robustness with leave-one-out sensitivity analysis. The SSP increased ovulation rates compared with the traditional protocol (RR 1.28, 95% CI 1.10 to 1.49; five randomized controlled trials [RCTs], n = 520, I² = 0%). Clinical pregnancy also favoured SSP (RR 1.46, 95% CI 1.04 to 2.05; four RCTs, n = 460; I² = 0%), although this result was largely driven by one study. The SSP shortened treatment duration (mean difference -32.59 days, 95% CI -38.66 to -26.52 days; three RCTs, n = 320, I² = 83%). Endometrial thickness was similar (mean difference 0.32 mm, 95% CI -0.95 to 1.59 mm; four RCTs, n = 460, I² = 91%). SSP improves ovulation rate and shortens treatment without affecting endometrial thickness and may increase clinical pregnancy rates.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
Practice Committee of the American Society for Reproductive Medicine, 2026·Fertility and Sterility
Current strategies for the assessment and treatment of recurrent pregnancy loss are discussed. This replaces the previous document, titled, "Evaluation and treatment of recurrent pregnancy loss: a committee opinion," last published in 2012.
Pelvic inflammatory disease (PID) remains a major cause of tubal factor infertility. Although in vitro fertilization (IVF) has largely replaced reconstructive surgery, selected patients with mild tubal damage may still achieve natural conception after surgical repair. This case highlights a spontaneous conception following bilateral fimbrioplasty in a patient with mild post-PID distal tubal occlusion. A 33-year-old, gravida 4 para 2, woman presented with three years of secondary infertility. Hysterosalpingogram (HSG) showed mild bilateral hydrosalpinx and distal tubal occlusion, with normal ovarian reserve and hormonal evaluation. The patient underwent robotic fimbrioplasty on July 23, 2025. Operative findings included Fitz-Hugh-Curtis changes, bilateral filmy adhesions, and grade-I distal occlusion. Bilateral adhesiolysis and fimbrioplasty were performed with restoration of tubal patency on chromotubation. The postoperative course was uncomplicated. Ten weeks after surgery, the patient conceived spontaneously with a normal intrauterine pregnancy. Tubal reconstructive surgery remains a valuable fertility-preserving option for selected patients who decline or lack access to IVF. Success depends on careful patient selection, minimal tubal damage, and meticulous microsurgical technique. Tubal reconstruction can offer selected women an affordable, fertility-preserving option, especially in low-resource settings where IVF is inaccessible.
In infertile couples whose male partner has alterations in semen parameters frequently, a comprehensive andrological approach is lacking and approximately 30-50% are classified as idiopathic infertility. These couples are often directly addressed to assisted reproduction techniques (ARTs). However, several clinical conditions may benefit from medical treatment. By acting on etiology and/or risk factors, this aims at improving seminal parameters and restoring natural fertility. To verify the impact of a comprehensive andrological assessment on the management of infertility (in particular, in couples with isolated male factor infertility) using as the primary outcome the natural pregnancy rate. A multicenter retrospective study was conducted between 2015 and 2022 in 1014 couples with primary infertility seeking natural conception (including 266 couples with previous ART failure). Each couple underwent a multidisciplinary evaluation. This involved: a gynecologist and an andrologist both with expertise in infertility, a psychologist when requested, and a fertility awareness practitioner according to a unique diagnostic and therapeutic multidisciplinary protocol. An isolated male factor was found in 23% of couples. In 45%, it was associated with female factors also. The comprehensive diagnostic approach reduced the proportion of idiopathic infertility to 8% of the couples. Targeted treatment, based on diagnostic categories, was associated with spontaneous pregnancy in 40.9% of the couples. In the 233 cases without female factors, normal semen parameters were observed only in 13% of patients. Male genital tract inflammation was observed in 48.8% of the patients, genital tract infection in 43.1%, and hypospermatogenesis in 16.7%. Patients with infections were treated with antibiotics and probiotics. If further inflammation was documented, this was followed by low-dose corticosteroids and antioxidants. Follicle stimulating hormone (FSH) treatment was used in patients with hypospermatogenesis, and varicocele repair surgery was performed in four patients. Our data underline the efficacy of a comprehensive approach to the diagnostic process of male factor infertility, both in reducing the percentage of idiopathic infertility and in restoring natural fertility based on a targeted treatment.
Several studies have associated seminal microbiota abnormalities with male infertility but have yielded differing results owing to their limited sizes or depths of analyses. The semen microbiota during recurrent pregnancy loss (RPL) has not been investigated. Comprehensively assessing the seminal microbiota in men with reproductive disorders could elucidate its potential role in clinical management. We used semen analysis, terminal-deoxynucleotidyl-transferase-mediated-deoxyuridine-triphosphate-nick-end-labelling, Comet DNA fragmentation, luminol reactive oxidative species (ROS) chemiluminescence, and metataxonomic profiling of semen microbiota by 16S rRNA amplicon sequencing in this prospective, cross-sectional study to investigate composition and bacterial load of seminal bacterial genera and species, semen parameters, ROS, and sperm DNA fragmentation in men with reproductive disorders and proven fathers. 223 men were enrolled, including healthy men with proven paternity (n=63), the male partners in a couple encountering RPL (n=46), men with male factor infertility (n=58), and the male partners of couples with unexplained infertility (n=56). Rates of high sperm DNA fragmentation, elevated ROS, and oligospermia were more prevalent in the study group compared with control. In all groups, semen microbiota clustered into three major genera-dominant groups (1, Streptococcus; 2, Prevotella; 3, Lactobacillus and Gardnerella); no species clusters were identified. Group 2 had the highest microbial richness (p<0.001), alpha-diversity (p<0.001), and bacterial load (p<0.0001). Overall bacterial composition or load has not been found to associate with semen analysis, ROS, or DNA fragmentation. Whilst global perturbation of the seminal microbiota is not associated with male reproductive disorders, men with unidentified seminal Flavobacterium are more likely to have abnormal seminal analysis. Future studies may elucidate if Flavobacterium reduction has therapeutic potential.
Garmendia JV et al., 2025·International journal of molecular sciences·
Open Access
Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation. It affects 3-5% of women who are attempting to conceive. RPL can stem from a variety of causes and is frequently associated with psychological distress and a diminished quality of life. By contrast, recurrent implantation failure (RIF) refers to the inability to achieve a successful pregnancy after three or more high-quality embryo transfers or at least two instances of egg donation. RIF shares several causative factors with RPL. The immunological underpinnings of these conditions involve alterations in uterine NK cells, reductions in M2 macrophages and myeloid-derived suppressor cells, an increased Th1/Th2 ratio, a decreased Treg/Th17 ratio, the presence of shared ≥3 HLA alleles between partners, and autoimmune disorders. Various therapeutic approaches have been employed to address these immunological concerns, achieving varying degrees of success, although some therapies remain contentious within the medical community. This review intends to explore the immunological factors implicated in RPL and RIF and to analyze the immunological treatments employed for these conditions, which may include steroids, intravenous immunoglobulins, calcineurin inhibitors, anti-TNF antibodies, intralipid infusions, granulocyte colony-stimulating factor, and lymphocyte immunotherapy.
Yan X et al., 2025·Frontiers in endocrinology·
Open Access
Chronic endometritis (CE) is a subtle but persistent inflammatory disorder of the endometrium that is often underdiagnosed due to its asymptomatic or non-specific presentation. The etiology of CE primarily involves microbial infections and immune dysregulation, often accompanied by microbial dysbiosis. Diagnosis relies on histopathological examination, especially the identification of stromal plasma cells, alongside hysteroscopic findings and microbiological testing, though standardization remains lacking. Mechanistically, CE-induced infertility stems from altered immune cell profiles, impaired endometrial receptivity, aberrant decidualization, dysbiosis of the endometrial microbiota, and abnormal uterine peristalsis. Aberrant gene expression and hormone receptor dysregulation further disrupt the implantation window. This review summarizes current understanding of the diagnostic criteria, pathogenic mechanisms, and therapeutic strategies for CE, emphasizing its crucial role in infertility and the need for standardized clinical management.
[BACKGROUND] Thin endometrium (TE) is a common cause of female infertility in clinical practice. Platelet-rich Plasma (PRP) therapy becomes a novel treatment for thin endometrium; however, its clinical application remains controversial. This meta-analysis aims to evaluate the therapeutic effects of intrauterine autologous PRP infusion in women with thin endometrium through relevant randomized controlled trials (RCTs). [METHODS] We systematically searched studies published in English from inception until June 2024 in databases such as PubMed, The Cochrane Library, Embase, Web of Science, and MEDLINE. Search terms included "Platelet-Rich Plasma," "thin endometrium," "endometrial thickness," "infertility," "pregnancy," "reproduction," and "adverse reactions". RCTs identified through the search were subjected to systematic review and meta-analysis, and data were analyzed using fixed-effects or random-effects models based on heterogeneity. [RESULTS] Eight RCTs involving 678 patients with thin endometrium were included. Patients receiving PRP infusion demonstrated significantly superior outcomes compared to the control group in endometrial thickness (MD: 1.23, 95%CI: 0.87 to 1.59, P = 0.000), clinical pregnancy rate (RR: 2.04, 95%CI: 1.52 to 2.76, P = 0.000), live birth rate (RR: 2.46; 95%CI: 1.57 to 3.85, P = 0.000), cycle cancellation rate (RR: 0.46, 95%CI: 0.23 to 0.93, P = 0.000), and embryo implantation rate (RR: 2.71; 95%CI: 1.91 to 3.84, P = 0.000). There were no statistically significance in spontaneous abortion rate (RR: 0.85, 95%CI: 0.40 to 1.78, P = 0.659), chemical pregnancy rate (RR: 1.84, 95%CI: 0.72 to 4.72, P = 0.204) and endometrial vascular improvement rate (RR: 1.10; 95%CI: 0.89 to 1.38, P = 0.367) between the two groups. The limitations of this study includes that, we only included single lauguage for literature research, the sample size and heterogeneity which could cause criteria bias. [CONCLUSION] Intrauterine PRP infusion may be an effective and safe treatment for women with thin endometrium. Further high-quality, large-sample, randomized controlled trials are needed to validate the reliability of our results. [TRIAL REGISTRATION] The review protocol is registered on PROSPERO with registration number CRD42023490421, and no modifications were made to the information provided at registration.
Hosseini R et al., 2024·Turkish journal of obstetrics and gynecology
To evaluate the clinical outcomes of laparoscopic and hysteroscopic surgical approaches for treating symptomatic isthmocele and identify their associated factors. Forty-six patients with symptomatic isthmocele diagnosed using transvaginal saline infusion sonohysterography were enrolled in this prospective cohort study. Patients underwent either laparoscopic or hysteroscopic isthmoplasty based on their residual myometrial thicknesses and fertility desires and were subsequently followed by clinical and ultrasonographic examinations. Twenty-two patients underwent laparoscopy and 24 underwent hysteroscopic surgery. At baseline, there was no significant difference in the mean age and years since the last cesarean section between the two groups. However, the hysteroscopy group had a higher mean parity and previous cesarean sections (p=0.00, 0.03). The most common symptoms were abnormal uterine bleeding, infertility, and dysmenorrhea. The mean baseline residual myometrial thickness was significantly higher in the laparoscopy group (p=0.00), and only laparoscopic surgery led to a significant increase in residual myometrial thickness in patients (p=0.00). Both procedures significantly reduced abnormal uterine bleeding (p=0.00), but only laparoscopy reduced infertility (p=0.00) and hysteroscopy reduced dysmenorrhea (p=0.03). Hysteroscopy showed better symptom resolution in younger patients (p=0.01), whereas age did not affect laparoscopy outcomes. Both approaches showed similar effectiveness in resolving abnormal uterine bleeding, with laparoscopy excelling in infertility resolution and hysteroscopy excelling in dysmenorrhea resolution. AMAÇ: Bu çalışmanın amacı semptomatik istmosel tedavisinde laparoskopik ve histeroskopik cerrahi yaklaşımların klinik sonuçlarını değerlendirmek ve ilişkili faktörleri belirlemektir. GEREÇ VE YÖNTEMLER: Bu prospektif kohort çalışmasına transvajinal salin infüzyon sonohisterografi kullanılarak semptomatik istmosel tanısı konan 46 hasta dahil edildi. Hastalara rezidüel miyometrial kalınlık ve doğurganlık isteklerine göre laparoskopik veya histeroskopik istmoplasti uygulandı ve ardından hastalar klinik ve ultrasonografik muayenelerle takip edildi. Yirmi iki hastaya laparoskopi, yirmi dört hastaya ise histeroskopik cerrahi uygulandı. Başlangıçta, iki grup arasında ortalama yaş ve son sezaryenden bu yana geçen yıllar açısından anlamlı bir fark yoktu. Ancak histeroskopi grubunda ortalama parite ve önceki sezaryenlerin sayısı daha yüksekti (p=0,00, 0,03). En sık görülen semptomlar anormal uterin kanama, kısırlık ve dismenore idi. Başlangıçtaki ortalama rezidüel miyometrial kalınlık laparoskopi grubunda anlamlı derecede yüksekti (p=0,00) ve yalnızca laparoskopik cerrahi hastalarda anlamlı rezidüel miyometrial kalınlık artışına yol açtı (p=0,00). Her iki prosedür de anormal uterin kanamayı önemli ölçüde azalttı (p=0,00), ancak yalnızca laparoskopi kısırlığı azalttı (p=0,00) ve histeroskopi dismenoreyi azalttı (p=0,03). Histeroskopi genç hastalarda semptomlarda daha fazla düzelme sağladı (p=0,01), yaş ise laparoskopi sonuçlarını etkilemedi. SONUÇ: Her iki yaklaşım da anormal uterin kanamanın çözümünde benzer etkinlik göstermiştir; laparoskopi kısırlığın çözümünde ve histeroskopi dismenorenin çözümünde üstündür.
Raperport C et al., 2024·BJOG : an international journal of obstetrics and gynaecology
There is no consensus on tests required to either diagnose unexplained infertility or use for research inclusion criteria. This leads to heterogeneity and bias affecting meta-analysis and best practice advice. This systematic review analyses the variability of inclusion criteria applied to couples with unexplained infertility. We propose standardised criteria for use both in future research studies and clinical diagnosis. CINAHL and MEDLINE online databases were searched up to November 2022 for all published studies recruiting couples with unexplained infertility, available in full text in the English language. Data were collected in an Excel spreadsheet. Results were analysed per category and methodology or reference range. Of 375 relevant studies, only 258 defined their inclusion criteria. The most commonly applied inclusion criteria were semen analysis, tubal patency and assessment of ovulation in 220 (85%), 232 (90%), 205 (79.5%) respectively. Only 87/220 (39.5%) studies reporting semen analysis used the World Health Organization (WHO) limits. Tubal patency was accepted if bilateral in 145/232 (62.5%) and if unilateral in 24/232 (10.3%). Ovulation was assessed using mid-luteal serum progesterone in 115/205 (56.1%) and by a history of regular cycles in 87/205 (42.4%). Other criteria, including uterine cavity assessment and hormone profile, were applied in less than 50% of included studies. This review highlights the heterogeneity among studied populations with unexplained infertility. Development and application of internationally accepted criteria will improve the quality of research and future clinical care.
Isthmocele is a gynecological condition characterized by a disruption in the uterine scar, often associated with prior cesarean sections. This anatomical anomaly can be attributed to inadequate or insufficient healing of the uterine wall following a cesarean incision. It appears that isthmocele may impact a woman's quality of life as well as her reproductive capacity. The incidence of isthmocele can range from 20% to 70% in women who have undergone a cesarean section. This review aims to sum up the current knowledge about the effect of isthmocele on fertility and the possible therapeutic strategies to achieve pregnancy. However, currently, there is not sufficiently robust evidence to indicate the need for surgical correction in all asymptomatic patients seeking fertility. In cases where surgical correction of isthmocele is deemed necessary, it is advisable to evaluate residual myometrial thickness (RMT). For patients with RMT >2.5-3 mm, hysteroscopy appears to be the technique of choice. In cases where the residual tissue is lower, recourse to laparotomic, laparoscopic, or vaginal approaches is warranted.
Boyle PC et al., 2024·Front Med (Lausanne)·
Open Access
Hypoandrogenemia is not usually considered as a potential cause of recurrent miscarriage. We present the case of a 30-year-old female with 6 previous pregnancies resulting in one live birth and 5 pregnancy losses, including fetal demise at 24 weeks gestation. She had standard investigations after her 4th loss, at a specialized miscarriage clinic. Lupus anticoagulant, anticardiolipin antibodies, thyroid function, parental karyotypes were all normal. Fetal products confirmed triploidy for her 4th miscarriage at 16 weeks gestation. She was reassured and advised to conceive again but had fetal demise after 24 weeks gestation. This was her 5th pregnancy loss with no explanation. She attended our Restorative Reproductive Medicine (RRM) clinic in January 2022. In addition to poor follicle function, we found hypoandrogenemia for the first time. Treatment included follicle stimulation with clomiphene and DHEA 25 mg twice daily pre-conception with DHEA 20 mg once daily maintained throughout pregnancy. She delivered a healthy baby boy by cesarean section at 36 weeks gestation in November 2023. Hypoandrogenemia should be considered as a contributory factor for women with recurrent miscarriage or late pregnancy loss. Restoration of androgens to normal levels with oral DHEA is safe and can improve pregnancy outcome.
Chronic Endometritis · Treatment of Chronic Endometritis
Boychuk AV et al., 2024·Wiadomosci lekarskie (Warsaw, Poland : 1960)
[OBJECTIVE] of our study was to improve the pregravid preparation of women with chronic endometritis to develop individual approaches to overcoming infertility, taking into account the state of endometrium. [PATIENTS AND METHODS] The study included 90 women (main group, n=90), 28 to 38 years with an anatomically normal uterus and chronic endometritis (CE). Patients were divided into 2 groups: group I - 45 women with CE who received conventional treatment; group II - 45 women with CE who received pregravid preparation by subendometrial injections of Platelet-Rich Plasma (PRP). [RESULTS] At the first stage of study, the ART statistical reports from 2015 to 2022 were analyzed at the Medical Center of Reproductive Health ≪Damia≫, (Ivano-Frankivsk). Analysis of the vaginal flora parameters before treatment at the first stage revealed the presence of conditionally pathogenic flora in culture from the cervical canal (Candida albicans - 2.4%, Escherihia coli - 4.8%, Staphylococcus epidermidis - 6.2% Enterococcus faecalis - 6.9%), and was evidence of a possible recurrence of inflammation during gestation. In the age category, the groups of patients were homogeneous, with no significant differences by the level of AMH and the level of CD 138. Biochemical pregnancy be present in 20 patients (44.4%) of group I and 28 (62.2%) of group II. Fertility within a year after the end of therapy was restored with the proposed method of therapy in most women (51.1%), in the comparison group this number was 11.1% lower. Pregnancy rate between the groups (I and II) did not differ significantly. The number of live births in group II - 19 births (42.2%) - was 2 times higher than I group (9 (20.0%), P<0.05). The most common complication for women in the comparison groups was early pregnancy loss. Among 18 (40.0%) clinical pregnancies of group I, 8 women (17.8%) had early miscarriage, 1 ectopic pregnancy (2.2%), while in group II clinical pregnancy be present in 23 women (51.1%). The number of terminated pregnancies was two times lower than in the first group (8.9% vs. 17.8%, P<0.05). [CONCLUSION] Chronic endometritis is one of the main causes of pregnancy loss after in vitro fertilization. Patients of the second group were treated with the proposed method of subendometrial injections with Platelet-Rich Plasma (PRP), prepared from autologous blood, is an effective method of preparing the endometrium for embryo transfer and can increase the number of live births in patients with chronic endometritis.
Zheng H et al., 2024·Photochem & Photobiology·
Intrauterine adhesion (IUA), a major cause of uterine infertility, is pathologically characterized by endometrial fibrosis. Current treatments for IUA have poor efficacy with high recurrence rate, and restoring uterine functions is difficult. We aimed to determine the therapeutic efficacy of photobiomodulation (PBM) therapy on IUA and elucidate its underlying mechanisms. A rat IUA model was established via mechanical injury, and PBM was applied intrauterinely. The uterine structure and function were evaluated using ultrasonography, histology, and fertility tests. PBM therapy induced a thicker, more intact, and less fibrotic endometrium. PBM also partly recovered endometrial receptivity and fertility in IUA rats. A cellular fibrosis model was then established with human endometrial stromal cells (ESCs) cultured in the presence of TGF‐β1. PBM alleviated TGF‐β1‐induced fibrosis and triggered cAMP/PKA/CREB signaling in ESCs. Pretreatment with the inhibitors targeting this pathway weakened PBM's protective efficacy in the IUA rats and ESCs. Therefore, we conclude that PBM improved endometrial fibrosis and fertility via activating cAMP/PKA/CREB signaling in IUA uterus. This study sheds more lights on the efficacy of PBM as a potential treatment for IUA.
Guidelines by Clinical Area · Obstetric Guidelines
Presentation covering three topics: (1) Review of RCOG Green-top Guideline No. 17 on Recurrent Miscarriage (Regan et al., BJOG 2023), (2) Key concepts of Restorative Reproductive Medicine with NeoFertility for recurrent miscarriage, and (3) An RRM case report demonstrating the NeoFertility multifactorial approach to recurrent pregnancy loss.
The use of platelet-rich plasma (PRP) has become popular as an adjunct to fertility treatment for women with infertility, particularly those with low ovarian reserve and premature ovarian insufficiency. Recent data in a polycystic ovary syndrome (PCOS) animal model demonstrated that intraovarian PRP administration improved folliculogenesis, ovarian antioxidant potential, and serum hormonal imbalance, suggesting that PRP could be considered a novel technique to alleviate PCOS-induced pathogenesis. With injection of PRP into the ovaries, it has been hypothesized that the infusion of cytokines and growth factors may exhibit a local effect that changes the expression of genes important in folliculogenesis and steroidogenesis, decreases inflammation, and partially restores normal ovarian function. This report is the first to present a case of a long-term amenorrheic woman with PCOS who has been trying to conceive, who resumed spontaneous ovulatory cycles, and had improvement in several aspects of her hormonal imbalance following intraovarian PRP administration. The purpose of this case report is to increase awareness regarding the possible benefits of intraovarian PRP injections for women with PCOS. There is a clear need for larger prospective studies to properly elucidate the effect of intraovarian PRP administration on both the reproductive and metabolic dysfunctions observed in women with PCOS.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
Beneficial and detrimental effect of surgical adenomyomectomy is still controversial in infertile women with severely diffuse adenomyosis. The primary objective of this study was to assess whether a novel method of fertility-preserving adenomyomectomy could improve pregnancy rates. The secondary objective was to evaluate whether it could improve dysmenorrhea and menorrhagia symptoms in infertile patients with severe adenomyosis. A prospective clinical trial was conducted between December 2007 and September 2016. Fifty women with infertility due to adenomyosis were enrolled in this study after clinical assessments by infertility experts. A novel method of fertility-preserving adenomyomectomy was performed on 45 of 50 patients. The procedure included T- or transverse H-incision of the uterine serosa followed by preparation of the serosal flap, excision of the adenomyotic tissue using argon laser under ultrasonographic monitoring, and a novel technique of suturing between the residual myometrium and serosal flap. All patients obtained dysmenorrhea relief 6 months postoperatively (NRS 7.28 vs 1.56, P<.001). The amount of menstrual blood decreased significantly (140.44 vs 66.33 mL, P<.05). Of the 33 patients who attempted pregnancy postoperatively, 18 (54.5%) conceived either by natural means, in vitro fertilization and embryo transfer (IVF-ET), or thawing embryo transfer. Miscarriage occurred in 8 patients, while 10 (30.3%) had viable pregnancies. This novel method of adenomyomectomy resulted in improved pregnancy rates, as well as relief of dysmenorrhea and menorrhagia. This operation is effective in preserving fertility potential in infertile women with diffuse adenomyosis.
Bortoletto P et al., 2023·Fertil Steril·
Open Access
For years, reproductive surgery was the mainstay of reproductive care. With the evolution and ultimate success of in vitro fertilization (IVF), reproductive surgery became an adjuvant therapy, indicated mainly for severe symptoms or to enhance success rates with assisted reproductive technologies. As success rates for IVF have plateaued, and emerging data rekindles the enormous benefits of surgically correcting reproductive pathologies, there is renewed interest among reproductive surgeons in reviving research and surgical expertise in this area. In addition, new instrumentation and surgical techniques to preserve fertility have gained traction and will solidify the need to have skilled reproductive endocrinology and infertility surgeons in our practice.
Kicińska AM et al., 2023·Healthcare (Basel)·
Open Access
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Absent, impaired, or rare ovulation induces progesterone deficiency in the luteal phase, which is a critical problem in PCOS. A usual pattern of progesterone administration from a fixed and arbitrary pre-determined day of a menstrual cycle may preserve infertility but can easily be avoided. We present the case of a 29-year-old infertile woman who had been ineffectively treated for over two years. We introduced a line of therapy that was suited to her individual menstrual cycle by implementing biomarker recording. Supplementation based on a standardized observation of the basal body temperature (BBT) and cervical mucus stopped the vicious circle of absent ovulation and hyperandrogenism, restoring regular bleeding, ovulation cycles, and fertility. The implementation of a reliable fertility awareness method (FAM), accompanied by a standardized teaching methodology and periodic review of the observations recorded by the patient, validated through an ultrasound examination and plasma gonadotropins, estrogens, and progesterone concentrations, is key to achieving therapeutic success. The presented case is an example of a clinical vignette for many patients who have successfully managed to improve their fertility and pregnancy outcomes by applying the principles of a personalized treatment approach together with gestagens by recording their fertility biomarkers.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
Cimadomo D et al., 2023·Human Reproduction Open·
Open Access
Abstract How should recurrent implantation failure (RIF) in patients undergoing ART be defined and managed? This is the first ESHRE good practice recommendations paper providing a definition for RIF together with recommendations on how to investigate causes and contributing factors, and how to improve the chances of a pregnancy. RIF is a challenge in the ART clinic, with a multitude of investigations and interventions offered and applied in clinical practice, often without biological rationale or with unequivocal evidence of benefit. STUDY DESIGN, SIZE, This document was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, if available, and the results of a previously published survey on clinical practice in RIF and the expertise of the working group. A literature search was performed in PubMed and Cochrane focussing on ‘recurrent reproductive failure’, ‘recurrent implantation failure’, and ‘repeated implantation failure’. PARTICIPANTS/MATERIALS, SETTING, The ESHRE Working Group on Recurrent Implantation Failure included eight members representing the ESHRE Special Interest Groups for Implantation and Early Pregnancy, Reproductive Endocrinology, and Embryology, with an independent chair and an expert in statistics. The recommendations for clinical practice were formulated based on the expert opinion of the working group, while taking into consideration the published data and results of the survey on uptake in clinical practice. The draft document was then open to ESHRE members for online peer review and was revised in light of the comments received. MAIN The working group recommends considering RIF as a secondary phenomenon of ART, as it can only be observed in patients undergoing IVF, and that the following description of RIF be adopted: ‘RIF describes the scenario in which the transfer of embryos considered to be viable has failed to result in a positive pregnancy test sufficiently often in a specific patient to warrant consideration of further investigations and/or interventions'. It was agreed that the recommended threshold for the cumulative predicted chance of implantation to identify RIF for the purposes of initiating further investigation is 60%. When a couple have not had a successful implantation by a certain number of embryo transfers and the cumulative predicted chance of implantation associated with that number is greater than 60%, then they should be counselled on further investigation and/or treatment options. This term defines clinical RIF for which further actions should be considered. Nineteen recommendations were formulated on investigations when RIF is suspected, and 13 on interventions. Recommendations were colour-coded based on whether the investigations/interventions were recommended (green), to be considered (orange), or not recommended, i.e. not to be offered routinely (red). LIMITATIONS, While awaiting the results of further studies and trials, the ESHRE Working Group on Recurrent Implantation Failure recommends identifying RIF based on the chance of successful implantation for the individual patient or couple and to restrict investigations and treatments to those supported by a clear rationale and data indicating their likely benefit. This article provides not only good practice advice but also highlights the investigations and interventions that need further research. This research, when well-conducted, will be key to making progress in the clinical management of RIF. STUDY FUNDING/COMPETING INTEREST(S)
The meetings and technical support for this project were funded by ESHRE. N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); Honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update, and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for re
Is sequential letrozole/human menopausal gonadotrophin (HMG) superior to letrozole alone in ovulation induction and pregnancy promotion among infertile women with polycystic ovary syndrome (PCOS)?
This open-label randomized controlled trial comparing sequential letrozole/HMG and letrozole alone included 174 participants enrolled from August 2019 to January 2020 at the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. Infertile women aged between 18 and 40 years who met Rotterdam criteria for PCOS and without other known causes of infertility were selected for this study. Patients were randomly assigned at a 1:1 ratio to receive 2.5 mg letrozole on cycle days 3-7 (n = 87) or 2.5 mg letrozole on cycle days 3-7 with a sequential injection of 75 IU HMG on cycle days 8-10 for one treatment cycle (n = 87). The pregnancy outcome was recorded after one treatment cycle.
Women receiving sequential treatment achieved a significantly higher ovulation rate than those in the letrozole group (90.8% versus 70.1%, P = 0.001) and the live birth rate of the sequential group was significantly higher than that of the letrozole protocol (23.0% versus 10.3%, P = 0.025); there was no statistical variation with respect to adverse events. The data suggest that the sequential letrozole/HMG protocol may be superior to the letrozole alone protocol in terms of ovulation induction and pregnancy promotion among infertile women with PCOS.
Keltz M et al., 2022·JSLS : Journal of the Society of Laparoendoscopic Surgeons
To evaluate the cannulation success rate, cumulative pregnancy, and time to intrauterine pregnancy rate following fluoroscopically-guided hysteroscopic tubal cannulation (FHTC) for infertile subjects with proximal tubal obstruction. This retrospective study evaluated subjects with unilateral or bilateral proximal tubal obstruction on hysterosalpingography, who failed concomitant selective salpingography and subsequently underwent FHTC at the time of a hysteroscopy performed for findings seen on sonohysterography. FHTC employed a Novy Catheter (CooperSurgical, Inc, Trumbull, CT.) with or without the 3 French inner catheter and guidewire, to cannulate the occluded fallopian tube(s), followed by the injection of HypaqueTM (Amersham Health, Inc, Princeton, NJ.) contrast under C-arm imaging. Technical success rates, complications, post-procedure pregnancies, and average time from surgery to pregnancy were evaluated. Thirty-two women between January 1, 2017 and December 31, 2019 met the entry criteria and underwent FHTC. Of those women with bilateral obstruction, 6/6 (100%) of subjects achieved at least unilateral patency, while patency was achieved in 23/26 (88.5%) subjects with unilateral obstruction. Twenty-nine of 32 (90.6%) subjects had at least one tube successfully cannulated with 34/38 (89.5%) of proximally obstructed tubes opened. Asymptomatic tubal perforation occurred in 1/38 tubes (2.6%). Ten subjects (34.5%) achieved intrauterine pregnancies without in vitro fertilization in an average of 64.9 days from the procedure. There were no multiple pregnancies and one ectopic pregnancy. FHTC is a safe, effective, incision free procedure that results in 90% of tubes successfully cannulated, and an observed short time to intrauterine pregnancy.
Tamblyn JA et al., 2022·Fertility and sterility·
Open Access
To investigate whether a significant association between vitamin D status and the risk of miscarriage or recurrent miscarriage (RM) exists. Systematic review and meta-analysis. Not applicable. PATIENT(S): Women with miscarriage and RM. INTERVENTION(S): We searched the Ovid MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials from database inception to May 2021. Randomized and observational studies investigating the association between maternal vitamin D status and miscarriage and/or vitamin D treatment and miscarriage were included. MAIN OUTCOME MEASURE(S): The primary outcome was miscarriage or RM, with vitamin D status used as the predictor of risk. Whether vitamin D treatment reduces the risk of miscarriage and RM was also assessed. RESULT(S): Of 902 studies identified, 10 (n = 7,663 women) were included: 4 randomized controlled trials (n = 666 women) and 6 observational studies (n = 6,997 women). Women diagnosed with vitamin D deficiency (<50 nmol/L) had an increased risk of miscarriage compared with women who were vitamin D replete (>75 nmol/L) (odds ratio, 1.94; 95% confidence interval, 1.25-3.02; 4 studies; n = 3,674; I2 = 18%). Combined analysis, including women who were vitamin D insufficient (50-75 nmol/L) and deficient (<50 nmol/L) compared with women who were replete (>75 nmol/L), found an association with miscarriage (odds ratio, 1.60; 95% confidence interval, 1.11-2.30; 6 studies; n = 6,338; I2 = 35%). Although 4 randomized controlled trials assessed the effect of vitamin D treatment on miscarriage, study heterogeneity, data quality, and reporting bias precluded direct comparison and meta-analysis. The overall study quality was "low" or "very low" using the Grading of Recommendations, Assessment, Development and Evaluations approach. CONCLUSION(S): Vitamin D deficiency and insufficiency are associated with miscarriage. Whether preconception treatment of vitamin D deficiency protects against pregnancy loss in women at risk of miscarriage remains unknown. CRD42021259899.
To analyze outcomes and postoperative complications in patients undergoing robot-assisted isthmocele repair. This retrospective cohort study included 33 patients who had robot-assisted laparoscopic surgical management of an isthmocele between September 2013 and August 2020 in two French university hospitals. All charts were reviewed to identify patient characteristics, preoperative and postoperative anatomical findings, complications, and postoperative fertility and symptoms. Patients who had undergone this procedure were asked to complete a telephone questionnaire about their treatment satisfaction and symptoms. The isthmocele was discovered most often as a result of subfertility (57.6%), but also ectopic pregnancy (18.2%), pelvic pain (15.2%), and postmenstrual bleeding (9.1%). Robot-assisted repair of the isthmocele significantly improved myometrial thickness (from 1.55 mm before surgery to 4.26 mm after surgery [mean difference 2.71; 95% confidence interval, 1.91-3.51], P = 0.0005). Among 20 patients who still desired a child after surgery, 15 became pregnant and 14 had full-term live births. Among the nine patients who had surgery for disabling symptoms, five had no persistent symptoms, three reported global improvement, and one had the same gynecologic discomfort. Seventeen patients agreed to complete the questionnaires (51.5%), and all stated that they would choose to have this surgery again. Robot-assisted repair of an isthmocele is a viable minimally invasive procedure.
Outcomes and Effectiveness · Outcomes by Diagnosis
Restorative reproductive medicine represents a comprehensive approach to subfertility (infertility and miscarriage) with investigations, diagnoses, and treatments combined with fertility charting to restore optimal reproductive function. Restorative reproductive medicine assumes that multiple factors need to be identified and treated (cycle optimization) for up to 12 cycles to achieve a successful pregnancy. Conception can occur during normal intercourse without intrauterine insemination or in vitro fertilization. A 35-year-old Croatian female presented for fertility treatment in May 2019 with a previous diagnosis of polycystic ovaries, infertility of 16 years duration, and 8 unsuccessful embryo transfers with in vitro fertilization and intracytoplasmic sperm injection. She was gravida 3 para 0, with 2 miscarriages after spontaneous conception at 5-6 weeks gestation in 2002 and 2004, followed by a miscarriage after in vitro fertilization at 12 weeks gestation in 2011. We initially found poor follicle function and suboptimal progesterone levels. Restorative reproductive medicine treatment resulted in conception after two cycles of treatment. This pregnancy ended in miscarriage at 7 weeks 4 days. Additional investigations found a balanced Robertsonian translocation (13, 14) and a uterine septum. We achieved repeat fertilization with restorative reproductive medicine after three cycles of treatment following resection of the uterine septum and ovulation induction with letrozole and human chorionic gonadotrophin. She had a full-term healthy pregnancy and live birth in 2021. We propose that a full evaluation of underlying factors, and up to 12 cycles of cycle optimization, should be offered to subfertile patients before considering in vitro fertilization treatment.
Obrzut B et al., 2022·Journal of clinical medicine·
Open Access
Tubal diseases account for 25-40% of female factor infertility. Mainly, they involve the distal part of the fallopian tube, and hydrosalpinx is the most severe manifestation. Usually, the management decision is made between reconstructive surgery and ART, depending on the severity of the tubal damage, patient age, ovarian reserve, and seminogram, as well as financial, religious, ethical, and psychological factors. Estimated live-birth rates after corrective surgery range from 9% to 69%. The success rate of IVF is about 30% live-birth rate per cycle initiated in women across all ages with tubal factor infertility. Surgery offers a long-term cure and patients may attempt conception many times but are burdened with perioperative adverse events. IVF bypasses potential complications of operative treatment; however, this has its own unique risks. The effectiveness of reconstructive surgery versus ART has not been adequately evaluated. The success of fertility management depends on a thorough interpretation of existing data and careful patient selection. The presented review provides updates on the most recent progress in this area.
Recent studies on fertility awareness among the reproductive population have reported the lack of accurate knowledge about fertility and assisted reproductive technologies. However, there has been little information regarding women trying to get pregnant at home. The aim of this study was to explore the prevalence of subclinical infertility among women trying to get pregnant at home, and to evaluate awareness regarding infertility and reasons for not visiting infertility clinics among women who use pregnancy-assist mobile applications to help them conceive. A total of 2084 Japanese women responded to this online survey. We selected 1541 women according to the study criteria. Based on the results of 61 questions, we evaluated knowledge regarding fertility, prevalence of subclinical infertility, and reasons for not visiting the clinic among the participants. Despite the desire to conceive, the participants had an apparent tendency to overestimate the age limit for childbearing. A total of 338 (21.9%) women answered that in general women aged > 45 years could get pregnant. Approximately 40% of the women had possible subclinical infertility and were unaware of the fact. Additionally, about 70% of the women considered themselves to have infertility problems. Women who were aware of the possibility of infertility hesitated to visit the clinic due to unfamiliarity with a gynecologist or clinic, and apprehensions about the gynecologic examination. In our study, some women required treatment for infertility. Nonetheless, they hesitated to visit an infertility clinic. Sexual health education, together with proper accessibility to gynecology clinics, are necessary to reduce involuntary childlessness.
Reproductive Immunology · Autoimmune Conditions and Fertility
Tańska K et al., 2022·Frontiers in endocrinology·
Open Access
Thyroid autoimmunity (TAI) is commonly defined as the presence of thyroperoxidase antibodies (TPOAbs) and/or thyroglobulin antibodies (TgAbs), which predisposes an individual to hypothyroidism. TAI affects nearly 10% of women of reproductive age and evokes great interest from clinicians because of its potentially negative impact on female fertility and pregnancy course. In this mini-review, we review the current literature concerning the influence of TPOAb or TPOAb/TgAb positivity without thyroid dysfunction on reproduction. TAI may negatively affect female fertility; several studies have found an increased prevalence of TAI in infertile women, especially in those with unexplained infertility and polycystic ovary syndrome. According to some observations, TAI might also be connected with premature ovarian insufficiency and endometriosis. The relationship between TAI and an increased risk of pregnancy loss is well documented. The pathophysiological background of these observations remains unclear, and researchers hypothesize on the direct infiltration of reproductive organs by thyroid antibodies, co-existence of TAI with other autoimmune diseases (either organ specific or systemic), immunological dysfunction leading to inhibition of immune tolerance, and relative thyroid hormone deficiency. Interestingly, in the current literature, better outcomes of assisted reproductive technology in women with TAI have been reported compared with those reported in earlier publications. One plausible explanation is the more widespread use of the intracytoplasmic sperm injection method. The results of randomized clinical trials have shown that levothyroxine supplementation is ineffective in preventing adverse pregnancy outcomes in women with TAI, and future research should probably be directed toward immunotherapy.
Kuroda K et al., 2021·Reprod Med Biol·
Open Access
Does the OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy, developed for treating repeated implantation failure (RIF), contribute to improving pregnancy outcomes in patients with a history of recurrent pregnancy loss (RPL)? Between 2018 and 2019, women with RPL after two or more clinical pregnancy losses underwent RPL testing. We treated chronic endometritis with antibiotics, high Th1/Th2 cell ratios with vitamin D and/or tacrolimus, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin. Of 168 consecutive women aged ≤43 years, 115 underwent RPL testing. We compared 100 pregnancies (90 women) and 46 pregnancies (41 women) with and without the OPTIMUM treatment strategy, respectively. RPL testing identified intrauterine abnormalities in 66 (57.4%), elevated Th1/Th2 cell ratios in 50 (43.5%), thyroid dysfunction in 33 (28.7%), and thrombophilia in 33 (28.7%). The live birth rate in the OPTIMUM group was significantly higher than that in the control group among women aged <40 years (78.1% and 42.3%, respectively; p = 0.002), but no significant difference was observed in women aged ≥40 years (55.6% and 30.0%, respectively; p = 0.09). The OPTIMUM treatment strategy improved pregnancy outcomes in patients with not only RIF but also RPL.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
Practice Committee of the American Society for Reproductive Medicine, 2021·Fertility and Sterility
This document reviews surgical options for reparative tubal surgery and the factors that must be considered when deciding between surgical repair and in vitro fertilization. This document replaces the document of the same name, last published in 2012 (Fertil Steril 2015;103:e37-43). This document reviews surgical options for reparative tubal surgery and the factors that must be considered when deciding between surgical repair and in vitro fertilization.
To evaluate the efficacy of surgical management for isthmoceles in patients presenting with secondary infertility. Data Sources: A systematic search was performed in MEDLINE, EMBASE, and Cochrane Library databases from inception to May 2020. The search was limited to studies published in English. METHODS OF Study Selection: After the removal of duplicates, 3380 articles were screened for inclusion independently by 2 authors. These 2 authors assessed for studies which focused on women of reproductive age with a diagnosed isthmocele and secondary infertility who underwent any surgical intervention for defect repair with at least 1 of the goals being fertility restoration. TABULATION, INTEGRATION, A total of 13 studies, comprising of 1 randomized controlled trial, 6 prospective case series, and 6 retrospective case series describing 234 patients who underwent surgical management for an isthmocele and secondary infertility were included. The methodologic quality of the included studies was assessed independently by both reviewers. Next, the data extraction was performed independently and then compared to ensure no discrepancies. A total of 188 patients were treated by hysteroscopy, 36 by laparoscopy, 7 by laparotomy, and 3 through a vaginal approach. In total, 153 of the 234 patients (65.4%) achieved pregnancy across all studies within their respective study periods. Pregnancy rates in the randomized controlled trial were 21 of 28 (75%) for those treated by hysteroscopy compared with 9 of 28 (32%) for those untreated. Among the studies reporting pregnancy outcomes, 101 of 116 (87.1%) pregnancies resulted in a live birth. The incidence of adverse events was 2%, including the risk of reoperation. The results of this systematic review suggest that the surgical treatment of an isthmocele, particularly through hysteroscopy, in patients with residual myometrial thickness of at least 2.5 mm, may be effective in treating isthmocele-associated secondary infertility with a relatively low complication rate. Further high-quality studies are needed because of the small sample sizes and observational nature of most available data.
Platelet-rich plasma (PRP) has become a novel treatment in various aspects of medicine including orthopedics, cardiothoracic surgery, plastic surgery, dermatology, dentistry, and diabetic wound healing. PRP is now starting to become an area of interest in reproductive medicine more specifically focusing on infertility. Poor ovarian reserve, menopause, premature ovarian failure, and thin endometrium have been the main areas of research. The aim of this article is to review the existing literature on the effects of autologous PRP in reproductive medicine providing a summation of the current studies and assessing the need for additional research. A literature search is performed using PubMed, MEDLINE, and CINAHL Plus to identify studies focusing on the use of PRP therapy in reproductive medicine. Articles were divided into 3 categories: PRP in thin lining, PRP in poor ovarian reserve, and PRP in recurrent implantation failure. In women with thin endometrium, the literature shows an increase in endometrial thickness and increase in chemical and clinical pregnancy rates following autologous PRP therapy. In women with poor ovarian reserve, autologous intraovarian PRP therapy increased anti-Mullerian hormone (AMH) levels and decreased follicle-stimulating hormone (FSH), with a trend toward increasing clinical and live birth rates. This trend was also noted in women with recurrent implantation failure. Limited literature shows promise in increasing endometrial thickness, increasing AMH, and decreasing FSH levels, as well as increasing chemical and clinical pregnancy rates. The lack of standardization of PRP preparation along with the lack of large randomized controlled trials needs to be addressed in future studies. Until definitive large RCTs are available, PRP use should be considered experimental.
Sills ES et al., 2020·International journal of reproductive biomedicine
The use of autologous platelet-rich plasma as an ovarian treatment has not been standardized and remains controversial. A 41½-year old woman with diminished ovarian reserve (serum anti- Müllerian hormone = 0.163 mg/mL) and a history of 10 unsuccessful in vitro fertilization cycles presented for reproductive endocrinology consult. She and her partner declined donor oocyte in vitro fertilization. They were both in good general health and laboratory tests were unremarkable, except for mild thrombocytosis (platelets = 386K; normal range 150-379K) discovered in the female. The patient underwent intraovarian injection of fresh platelet-derived growth factor concentrate administered as an enriched cell-free substrate. Serum anti- Müllerian hormone increased by 115% within 6 wks of treatment. Spontaneous ovulation occurred the month after injection and subsequently the serum human chorionic gonadotropin was noted at 804 mIU/mL. Following an uneventful obstetrical course, a male infant was delivered at term without complication. This is the first description of intraovarian injection of enriched platelet-derived growth factors followed by unassisted pregnancy and live birth. As a refinement of conventional ovarian platelet-rich plasma therapy, this procedure may be particularly valuable for refractory cases where prognosis for pregnancy appears especially bleak. A putative role for thrombocytosis is also viewed in parallel with mechanisms of action as advanced earlier. With continued experience in ovarian application of autologous platelet growth factors, additional research will evaluate laboratory protocol/sample preparation, injection technique, and patient selection.
Bordewijk EM et al., 2020·The Cochrane database of systematic reviews
Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line treatment in women with PCOS. Ovulation induction with letrozole should be the first-line treatment according to new guidelines, but the use of letrozole is off-label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC-resistant can be treated with gonadotrophins or other medical ovulation-induction agents. These medications are not always successful, can be time-consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions. To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC-resistance. We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies. We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second-look laparoscopy versus expectant management, or different techniques of LOD. Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes. This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I2 = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I2 = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I2 = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I2 = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I2 = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I2 = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I2 = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I2 = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose. AUTHORS' Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.
Chronic Endometritis · Endometritis and Reproductive Outcomes
Chronic endometritis (CE) is a poorly investigated pathology which has been related to adverse reproductive outcomes, such as implantation failure and recurrent miscarriage. In this paper, we aim to provide an overview of diagnosis, etiology, pathophysiology and treatment of CE, its impact on endometrial microenvironment and its association with infertility. We present a narrative review of the current literatures, synthesizing the findings retrieved from searches of computerized databases. CE is more prevalent in infertile patients. Effective antibiotic treatment of CE seems to improve the pregnancy and live birth rate in patients with unexplained recurrent pregnancy loss (RPL), and increase ongoing pregnancy rate in patients with recurrent implantation failure. In order to increase the diagnostic accuracy, immunohistochemistry is recommended besides the conventional histology. In addition, hysteroscopy could be considered as gold standard tool for diagnosis, considering its high correlation with histological findings. CE, as the chronic inflammation of endometrium, is usually asymptomatic and probably underestimated. Interaction of bacteria with endometrial microenvironment promotes changes in leukocyte population, cytokine production and growth factors which support its negative impact on endometrial receptivity. Nevertheless, standardization of the criteria for histopathological diagnosis and immunohistochemistry technique needs to be defined.
Costello MF et al., 2019·Aust N Z J Obstet Gynaecol·
Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where firstor second-line ovulation induction therapies have failed. This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.
Hysteroscopic Surgery · Hysteroscopic Septum Resection
Wang X et al., 2019·Medicine (Baltimore)·
Open Access
Different sizes of uterine septum between infertile women and patients with abortions may have a clinical relevance in reproductive performance after surgery. This study aimed to assess if the fecundity of women after surgical correction of the uterine septum is associated with septum size.A retrospective, single-center, cohort study was conducted in Peking Union Medical College Hospital using patients aged between 21 and 37 years. Hysteroscopic metroplasty was performed on 121 patients with a uterine septum. The septum size was assessed by ultrasonography and hysteroscopy. The subjects were divided into 3 groups: Group A consisted of 35 women with complete uterine septum (mean ± standard deviation (SD) age 28.29 ± 3.53; group B consisted of 48 women with uterine septum >2.5 cm (mean ± SD age 28.85 ± 3.63); and group C consisted of 48 women with uterine septum ≤2.5 cm (mean ± SD age 28.79 ± 3.74). Age and body mass index (BMI) were not significantly different among the 3 groups.No serious hysteroscopic complications occurred. However, uterine septa were observed in 4 cases after surgery and 6 cases of intrauterine adhesions were observed after long-term follow-up. The abortion rate decreased, and term delivery rate increased significantly in the 3 groups after hysteroscopic metroplasty. The infertility rate was significantly lower in group C after surgery. However, no significant difference was observed in the infertility rate between groups A and B. The recurrent abortion rate was significantly lower in group A than in groups B and C before surgery. After surgery, the infertility rate was significantly higher in group A than in group B (28.57% and 10.53%, respectively; P = .048). After at least 12-months of follow-up, the pregnancy rate in group A was significantly lower than that in group C (71.43% and 89.47%, respectively; P = .048).Uterine septum resection improves obstetrical outcomes. After surgery, the infertility rate was significantly higher in patients with complete uterine septum than in those with a large partial uterine septum, and the pregnancy rate in patients with complete uterine septum was lower than that in the patients with a small partial uterine septum.
To investigate the rate of sperm DNA fragmentation in male partners of women with recurrent pregnancy loss and fertile control women.
Systematic review and meta-analysis.
Not applicable. PATIENT(S): A total of 579 male partners of women with recurrent pregnancy loss and 434 male partners fertile control women. INTERVENTION(S): Prospective studies were identified through a Pubmed search. Recurrent pregnancy loss was defined as two or more previous pregnancy losses. Fertile control women had a history of a live birth or ongoing pregnancy. MAIN OUTCOME MEASURE(S): The primary outcome was the rate of sperm DNA fragmentation. The summary measures were reported as mean difference with 95% confidence interval (CI). RESULT(S): Fifteen prospective studies were included in a qualitative review. Pooled data from 13 studies with sufficient data for meta-analysis suggest that male partners of women with a history of recurrent pregnancy loss have a significantly higher rate of sperm DNA fragmentation compared to the partners of fertile control women: mean difference 11.91, 95% CI 4.97-18.86. CONCLUSION(S): These findings support an association between sperm DNA fragmentation and recurrent pregnancy loss. However, given the significant heterogeneity between studies and lack of prospective pregnancy outcome data, further large prospective studies are needed.
Modzelewski J et al., 2019·Ginekol Pol·
Open Access
Fetal survival and development is supported by the maternal immune system. Questions regarding those mechanisms have risen from development of transplantation medicine and observation of graft rejection. Initial theories of anatomic division, fetal immune immaturity and maternal immune system inertia were found incorrect. Rejection of fetal "semi-allograft" by maternal immune system could result in pregnancy loss. Two pregnancy losses of any etiology are considered recurrent and effort should be made to name the probable cause. Immune causes of pregnancy loss are probably multifactorial, thus difficult to research and implement findings in clinical practice. Although a full understating of pregnancy loss is not established, new therapies are being developed. This review summarizes the role of lymphocytes in pregnancy development, presents data from studies on recurrent pregnancy loss patients, evidence of new therapies and ESHRE guidelines regarding immunologic investigations.
The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling female reproduction. HPO axis dysfunction leading to ovulation disorders can be classified into three categories defined by the World Health Organization (WHO). Group I ovulation disorders involve hypothalamic failure characterized as hypogonadotropic hypogonadism. Group II disorders display a eugonadal state commonly associated with a wide range of endocrinopathies. Finally, group III constitutes hypergonadotropic hypogonadism secondary to depleted ovarian function. Optimal evaluation and management of these disorders is based on a careful analysis tailored to each patient. This article reviews ovulation disorders based on pathophysiologic mechanisms, evaluation principles, and currently available management options.
Chronic Endometritis · Treatment of Chronic Endometritis
Sfakianoudis K et al., 2019·In vivo (Athens, Greece)·
Open Access
[BACKGROUND/AIM] Patients diagnosed with chronic endometritis (CE) may fail to respond to standard antibiotic treatment. The driver behind the approach reported here was the imperative need for alternative therapeutic solutions. [CASE REPORT] This case report presents a woman with CE and premature ovarian insufficiency having experienced repeated implantation failures following donated embryo transfers. The patient was diagnosed with CE through hysteroscopy, microbiological analysis and scanning electron microscopy. Following the suggested antibiotic treatment, she underwent a new embryo transfer, but with subsequent pregnancy loss. Following a second antibiotic scheme, all diagnostic procedures certified the persistence of CE. The patient underwent autologous, intrauterine platelet-rich plasma treatment and a subsequent embryo transfer. The diagnostic procedures indicated no signs of CE, while the embryo transfer resulted in a twin pregnancy and birth. [CONCLUSION] Platelet-rich plasma may be employed as a first-line CE treatment, especially for patients who fail to respond to conventional antibiotic schemes.
Sharma S et al., 2018·J Hum Reprod Sci·
Open Access
Gonadotropin stimulation is used as the second line of treatment in patients with thin endometrium following clomiphene citrate (CC) administration, which is associated with higher cost, multiple births, and ovarian hyperstimulation syndrome. Tamoxifen (TMX), a selective estrogen receptor modulator, acts as an agonist on the endometrium. The objective of the present study was to compare the efficacy of low-dose CC, TMX, and gonadotropins in women with thin endometrium (<7 mm) following Clomiphene in intrauterine insemination (IUI) cycles. SETTINGS AND A prospective observational study between December 2011 and June 2013 was carried out in a tertiary infertility center. Women (n = 502) undergoing IUI with endometrium <7 mm after 100 mg CC were included in the study and divided into three treatment groups. Women in Group A (n = 182, cycles = 364) received clomiphene (50 mg/day from day 3 to 7), Group B (n = 179, cycles = 342) received TMX (40 mg/day from day 3 to 7), and Group C (n = 141, cycles = 226) received continuous urine-derived follicle-stimulating hormone 75-150 IU from day 3 onward until human chorionic gonadotropin injection. Endometrial thickness (ET), pregnancy rate, and live birth rate were considered as main outcome measures. Multiple comparisons using one-way ANOVA and Schiff's test were performed. Pregnancy and live birth rate were significantly higher (P < 0.004) in TMX and gonadotropin groups compared to clomiphene. A number of follicles in the TMX group were found to be lower (P < 0.001) compared to other two groups. In polycystic ovary syndrome patients, ovulation induction with TMX resulted in inadequate response in more than half of the cycles. TMX can improve ET and live birth rate in patients with thin endometrium after clomiphene.
Fertility and Outcomes · Conception After Excision
To investigate the prevalence of miscarriage in women with endometriosis (WwE) compared with disease-free control women (CW).
Cross-sectional analysis nested in a retrospective observational study (n = 940).
Hospitals and associated private practices. PATIENT(S): Previously pregnant women (n = 268) within reproductive age in matched pairs. INTERVENTION(S): Retrospective analysis of surgical reports and self-administered questionnaires. MAIN OUTCOME MEASURE(S): Rate of miscarriage, subanalysis for fertility status (≤12 vs. >12 months' time to conception), endometriosis stages (revised American Society of Reproductive Medicine classification [rASRM] I/II vs. III/IV) and phenotypic localizations (superficial peritoneal, ovarian, and deep infiltrating endometriosis). RESULT(S): The miscarriage rate was higher in WwE (35.8% [95% confidence interval 29.6%-42.0%]) compared with CW (22.0% [16.7%-27.0%]); adjusted incidence risk ratio of 1.97 (95% CI 1.41-2.75). This remained significant in subfertile WwE (50.0% [40.7%-59.4%]) vs. CW (25.8% [8.5%-41.2%]) but not in fertile WwE (24.5% [16.3%-31.6%]) vs. CW (21.5% [15.9%-26.8%]). The miscarriage rate was higher in women with milder forms (rASRM I/II 42.1% [32.6%-51.4%] vs. rASRM III/IV 30.8% [22.6%-38.7%], compared with 22.0% [16.7%-27.0%] in CW), and in women with superficial peritoneal endometriosis (42.0% [32.0%-53.9%]) compared with ovarian endometriosis (28.6% [17.7%-38.7%]) and deep infiltrating endometriosis (33.9% [21.2%-46.0%]) compared with CW (22.0% [16.7%-27.0%]). CONCLUSION(S): Mild endometriosis, as in superficial lesions, is related to a great extent of inflammatory disorder, possibly leading to defective folliculogenesis, fertilization, and/or implantation, presenting as increased risk of miscarriage. TRIAL NCT02511626.
Pregnancy rates among infertile women have been reported to increase after hysterosalpingography, but it is unclear whether the type of contrast medium used (oil-based or water-soluble contrast) influences this potential therapeutic effect. We performed a multicenter, randomized trial in 27 hospitals in the Netherlands in which infertile women who were undergoing hysterosalpingography were randomly assigned to undergo this procedure with the use of oil-based or water-based contrast. Subsequently, couples received expectant management or the women underwent intrauterine insemination. The primary outcome was ongoing pregnancy within 6 months after randomization. Outcomes were analyzed according to the intention-to-treat principle. A total of 1119 women were randomly assigned to hysterosalpingography with oil contrast (557 women) or water contrast (562 women). A total of 220 of 554 women in the oil group (39.7%) and 161 of 554 women in the water group (29.1%) had an ongoing pregnancy (rate ratio, 1.37; 95% confidence interval [CI], 1.16 to 1.61; P<0.001), and 214 of 552 women in the oil group (38.8%) and 155 of 552 women in the water group (28.1%) had live births (rate ratio, 1.38; 95% CI, 1.17 to 1.64; P<0.001). Rates of adverse events were low and similar in the two groups. Rates of ongoing pregnancy and live births were higher among women who underwent hysterosalpingography with oil contrast than among women who underwent this procedure with water contrast. (Netherlands Trial Register number, NTR3270 .).
The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society.
To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA). The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline. FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation.
Pelvic inflammatory disease (PID) and more specifically salpingitis (visually confirmed inflammation) is the primary cause of tubal factor infertility and is an important risk factor for ectopic pregnancy. The risk of these outcomes increases following repeated episodes of PID. We developed a homogenous discrete-time Markov model for the distribution of PID history in the UK. We used a Bayesian framework to fully propagate parameter uncertainty into the model outputs. We estimated the model parameters from routine data, prospective studies, and other sources. We estimated that for women aged 35-44 years, 33·6% and 16·1% have experienced at least one episode of PID and salpingitis, respectively (diagnosed or not) and 10·7% have experienced one salpingitis and no further PID episodes, 3·7% one salpingitis and one further PID episode, and 1·7% one salpingitis and ⩾2 further PID episodes. Results are consistent with numerous external data sources, but not all. Studies of the proportion of PID that is diagnosed, and the proportion of PIDs that are salpingitis together with the severity distribution in different diagnostic settings and of overlap between routine data sources of PID would be valuable.
The objective of this study was to evaluate the prevalence of cesarean scar defects and its clinical manifestations in reproductive-aged women. We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement using keywords of "cesarean scar defect, uterine scar defect, uterine diverticulum niche, isthmocele, pouch, or sacculation" and their combination. Thirty-two trials met the inclusion criteria. Cesarean scar defects are commonly found on ultrasound examination (24%-88%). Their presence could be asymptomatic or related to postmenstrual spotting, postmenstrual bleeding, or infertility. The prevalence of this condition is related to the number of cesarean deliveries. Hysteroscopic repair of a cesarean scar defect or isthmoplasty is associated with an improvement in uterine bleeding in 59% to 100% of cases and a pregnancy rate of 77.8% to 100%. An improvement in uterine bleeding after vaginal repair occurred in 89% to 93.5% of cases. Laparoscopic repair led to uterine bleeding improvement in 86% of cases and a pregnancy rate of 86%. The association between cesarean scar defect and infertility, pelvic pain, and dysmenorrhea require more studies. Treatment of uterine scar defects should be performed after eliminating other causes of postmenstrual bleeding or infertility. Hysteroscopic isthmoplasty appears to be the most popular treatment. However, in the absence of randomized trials, the efficacy of different surgical approaches remains to be seen. Until we have concrete evidence, the treatment should be reserved for selective cases.
More than 70 million couples suffer from infertility worldwide. The aim of this study was to evaluate the fertility outcomes after laparoscopic fimbrioplasty and neosalpingostomy in female infertility. Laparoscopic distal tuboplasty was carried out for 402 cases at the Gynecological Endoscopic Surgery and Human Reproductive Teaching Hospital in Yaoundé-Cameroon in Central Africa from December 2002 to December 2007. Laparoscopic fimbrioplasty and neosalpingostomy were done using bipolar electrocoagulation and conventional endoscopic instruments. Log-rank test was used to compare cumulative rate curves of intrauterine pregnancy with respect to the tubal stages. P<0.05 was considered statistically significant. The mean age of the patients was 31.6±5.45 years. Secondary infertility was the most frequent type of infertility (70.14%). The laparoscopic tubal surgery done consisted of fimbrioplasty in 185(46%) cases and neosalpingostomy in 217 (54%) cases. Of 260 women followed up after tuboplasty, there were overall 74 (28.48%) pregnancies; 68(26.1%) intrauterine pregnancies and 6(2.3%) ectopic pregnancies. Pregnancy rates were significantly associated to the tubal stage (63% in stage 1, 15% in stage 3 and 00% in stage 4; p<0.001) and the adnexal adhesion scores (73.91% in the absence of adnexal adhesions and 8.8% in the case of a severe adnexal adhesion score). Of the 68 intrauterine pregnancies, there were 60(88%) live births and 8(12%) spontaneous abortions. It is believed that laparoscopic fimbrioplasty and neosalpingostomy should be the preferred choice when faced with tubal distal occlusion in a context of female infertility. This implies that training in endoscopic surgery should be regarded as an important issue in developing countries.
Sterilization and Reversal · Sterilization Reversal
Is bilateral tubotubal anastomosis a successful treatment in an outpatient patient population? For women wanting children after tubal sterilization, bilateral tubotubal anastomosis is an effective outpatient treatment. With the current emphasis in reproductive medicine on high technology procedures, the effectiveness of female surgical sterilization reversal is often overlooked. Previous clinical studies of tubal sterilization reversal have been mostly retrospective analyses of small patient populations. STUDY DESIGN, SIZE, A cohort of women who underwent outpatient bilateral tubotubal anastomosis from January 2000 to June 2013 was followed prospectively until December 2014 to determine the proportions of women undergoing the procedure who became pregnant and who had live births. Data were collected at the time of pregnancy. Differences in pregnancy rates and live birth rates associated with age, race and sterilization method were evaluated. PARTICIPANTS/MATERIALS, SETTING, A total of 6692 women, aged 20-51 years, underwent outpatient bilateral tubotubal anastomosis. MAIN The crude overall pregnancy rate was 69%. The crude overall birth rate was 35%. Results varied according to age at sterilization reversal and the method of sterilization. Women under 30 years of age at reversal of ring/clip sterilizations had an 88% pregnancy rate and 62% birth rate. Pregnancy and birth rates declined as age increased at sterilization reversal. Coagulation sterilization reversals resulted in the lowest rates of pregnancies and births. Ligation/resection reversals had intermediate success rates. LIMITATIONS, Limitations of our study include probable underreporting of pregnancies based on patient-initiated reports; possible errors in the reporting of pregnancies or early miscarriages that may have been based solely on home pregnancy tests; and probable over-reporting of the diagnosis of ectopic pregnancies. We identified age and sterilization method as being associated with subsequent pregnancy, however, in order to be considered predictive, the associations would need to be validated in an independent second prospectively studied group of representative patients. Finally, we also included patients in the study population who had additional surgical procedures performed at the time of tubotubal anastomosis (e.g. uterine myomectomy, fimbrioplasty, ovarian cystectomy and adhesiolysis), factors that could result in differences in pregnancy statistics in our study versus other patient populations. The results of this study can help inform patients and clinicians about this low technology alternative to IVF. None. N/A.
Fertility and Outcomes · Conception After Excision
Were spontaneous miscarriages more frequent in women with histologically proven endometriosis when compared with endometriosis-free controls? Endometriosis-affected women display a significantly higher rate of previous spontaneous miscarriages than endometriosis-free controls. The association between endometriosis and miscarriages has long been debated without reaching a consensus. STUDY DESIGN, SIZE, We conducted a retrospective cohort study comparing exposed women (endometriosis) and control (without endometriosis) regarding the incidence of miscarriages. All study participants underwent surgery for benign gynaecological conditions in a tertiary-care university hospital between January 2004 and March 2013. After thorough surgical examination of the abdominopelvic cavity, 870 women with histologically proven endometriosis were allocated to the endometriosis group and 981 unaffected women to the control group. Only previously pregnant women were finally included for the study analysis: 284 women in the endometriosis group and 466 in the control group. PARTICIPANTS/MATERIALS, SETTING, Data were collected preoperatively using a structured questionnaire. Among women with at least one pregnancy before the surgery, the type and number of the different previous first trimester pregnancies outcomes were studied. Previous history of miscarriage was studied according to the existence of previous infertility history and the disease severity (revised American Fertility Society and surgical classification). MAIN Four hundred and seventy-eight pregnancies in endometriosis-affected women and 964 pregnancies in controls were analysed. The previous miscarriage rate was significantly higher in women with endometriosis compared with the controls (139/478 [29] versus 187/964 [19%], respectively; ITALIC! P < 0.001). After a subgroup analysis, the miscarriage rates of women with endometriosis and the controls were, respectively: 20 versus 12% ( ITALIC! P = 0.003) among women without a previous history of infertility and 53 versus 30% ( ITALIC! P < 0.001) for women with a previous history of infertility. After using a random-effects Poisson regression and adjusting for confounding factors, we found a significantly increased incidence rate ratio (IRR) for miscarriages in women with endometriosis (adjusted 1.70, 95% confidence interval: 1.34-2.16). LIMITATIONS, There is a possible selection bias due to the specificity of the study design which included only surgical patients. In the control group, certain of the surgical gynaecological conditions, such as fibroids, ovarian cysts or tubal pathologies, might be associated with higher spontaneous miscarriage rates. In the endometriosis group, asymptomatic women were less likely to be referred for surgery and might therefore be underrepresented. This study opens the doors to future, more mechanistic studies to establish the exact link between endometriosis and spontaneous miscarriage rates. No external funding was used for this study. The authors have no conflicts of interest to declare.
Flores R, 2016·Scholars Academic Journal of Biosciences·
The latest retrievable data about infertility in the Philippines was made available to the public by Merck Serono, a private pharmaceutical company who commissioned the survey in 2011. The survey was conducted by Synovate in 100 participating households in the Philippines, particularly in key cities located in Luzon, Visayas and Mindanao. The survey results revealed that one out of ten Filipino couples are suffering from infertility. And these couples are not seeking treatment due to the following reasons: (1) financial constraints; (2) time constraints; and (3) the patient’s belief. Of all these, financial constraints, at 86%, is the primary reason why infertile couples are not seeking treatment. In addition to this data, the Chief of The Medical City’s Reproductive Medicine, Infertility and Gynecologic Endoscopy, Dr. Marc Anthony Ancheta, further reveals that “some 35 to 40% of a couple’s inablity to conceive a child are due to female factors; while the other 35 to 40% could be attributed to male factors.” While male factor infertility is also deserving of proper attention, it is the female factor infertility that should receive greater attention and focus in terms of treatment. Why? Because, primarily, the female’s reproductive cycle is very complex and would need months and/or years to partially identify the underlying reason/s of infertility; and second, the female’s ability to conceive naturally will fall by 50% when she reached the age of 35. Therefore, there should be urgency in treating female factor infertility in an efficient, ethical and affordable way. And these conditions can be achieved by the use of NaPro Technology.
Azmoodeh A et al., 2015·Glob J Health Sci·
Open Access
Luteinized unruptured follicle (LUF) syndrome is considered a cause of ovulation failure and a subtle cause of infertility. Preovulatory injection of human chorionic gonadotropin (HCG) prevents or treats LUF syndrome, but it has also occurred after the induction of ovulation with clomiphene/HMG and HCG. This study was designed for evaluation and comparison of LUF incidence in eligible infertile women undergoing two stimulation protocols (clomiphene + HMG and letrozole + HMG) in addition to intrauterine insemination (IUI). Some related factors were compared between LUF and non-LUF cycles as secondary outcomes. The study was designed as a prospective randomized controlled trial. Patients were randomized using a table of random numbers into two equal protocol groups. For group A, (n = 90) clomiphene citrate was administrated orally in doses of 100 mg/day, and group B (n = 90) orally received letrozole 5 mg/day from day 3 to 7 of the menstrual cycle. Then HMG 75IU/day was administered intramuscularly in both groups on day 8 of the menstrual cycle and the dose was adjusted on the basis of ovarian response. The optimum size of preovulatory follicles for the injection of HCG (10,000 IU) was considered 18-23 mm. The number and size of preovulatory follicles were assessed by vaginal ultrasound 12 h before HCG (D0). Endometrial thickness was measured as well. IUI was performed on all patients 38-40 h after HCG. The second ultrasound examination was performed to observe the evidence of oocyte releasing at the time of IUI (D1). If the follicles were unruptured, a third sonography was performed on day 7 after HCG (D7) to observe LUF syndrome. There was a significant difference between clomiphene-HMG and letrozole-HMG in LUF (p = 0.021) and pregnancy (p = 0.041). The complete LUF in letrozole-HMG was lower than the alternative group and the pregnancy rate was higher. The patients in the non-LUF group had higher midluteal progesterone and a thicker endometrium compared to LUF cycles (p = 0.039) and (p < 0.001). The results of our multivariate logistic regression indicate that size 18-19.9 mm leads to the complete LUF less than ≥22 mm [AOR: 0.25, P = 0.005], and in size 20- 21.9 mm as well [AOR: 0.17, P = 0.002]. Letrozole, with lower incidences of LUF, is more effective than clomiphene citrate for the induction of ovulation in IUI cycles. In our study, we illustrated that larger follicles of ≥22 mm diameter were associated with higher incidences of LUF. We recommend that further studies investigate and focus on the relationship between follicular size and/or full hormonal profiles and LUF.
Reproductive Immunology · Autoimmune Conditions and Fertility
Thyroid autoimmunity with normal thyroid function is associated with recurrent miscarriage (RM), but the association with live birth is less clear. Therefore, we determined the association between thyroid peroxidase antibodies (TPO-Ab) and live-birth rate (LBR) in a retrospective cohort of euthyroid women with unexplained RM. We included 202 women of which 28 were TPO-Ab positive (13.9%) and 174 were TPO-Ab negative. TPO-Ab positive women (n = 10) without levothyroxine treatment had a lower LBR (29%) compared to TPO-Ab negative women (51%) (HR 0.23, 0.07-0.72, p = 0.012). The LBR in women with TPO-Ab receiving levothyroxine was not different compared women without TPO-Ab (60% versus 51%, p = 0.50). In conclusion, TPO-Ab are associated with a lower LBR in euthyroid women with unexplained RM and these women may benefit from treatment with levothyroxine.
The aim of the present study was to assess the efficacy of endoscopic repair for secondary infertility caused by post-cesarean scar defect (PCSD). Our investigation focused on the validity of new diagnostic criteria and selection methods. MATERIAL AND The subjects were 22 women with secondary infertility due to PCSD with retention of bloody fluid in the uterine cavity. Women with a residual myometrial thickness of ≥ 2.5 mm and an anteflexed or straight uterus underwent hysteroscopic surgery, while all others underwent laparoscopic repair. Hysteroscopic surgery involved resection and coagulation of scarred areas, whereas laparoscopic surgery involved removal of scarred areas combined with hysteroscopy, followed by resuturing. Fourteen of the 22 women (63.6%) who were followed up for ≥ 1 year after surgery achieved pregnancy. Pregnancies occurred in all four women (100%) who underwent hysteroscopic surgery and in 10 of the 18 women (55.6%) who underwent laparoscopic surgery. Three out of four women who underwent hysteroscopic surgery had term deliveries. Among the women who underwent laparoscopic surgery, five had term deliveries. No cases of uterine rupture were experienced, and the delivery method was cesarean section in all cases. We propose that infertility associated with PCSD, cesarean scar syndrome, is caused by the retention of bloody fluid in the uterine cavity and scarring. Endoscopic treatment, such as hysteroscopy or laparoscopy, was effective for cesarean scar syndrome.
to study the results in patients undergoing infertility treatment with a focus on restorative medicine (NaProTechnology) at a department of obstetrics and gynecology. Methodology: retrospective cohort study conducted by the gynecology and obstetrics department at Universidad de los Andes (Santiago, Chile) in infertility patients from a suburban area of Santiago de Chile, who received treatment between 2006 and 2014. All couples received instructions on how to recognize their fertility period according to a local teaching model based on the Creighton Model FertilityCare System. They also received medical treatment to induce ovulation and/or widen their fertile period, or surgical treatment. The main outcome was the number of pregnancies. 131 patients received instructions. The mean age was 33.6 years. Seventyeight patients (59.5%) consulted due to primary infertility; 53 (40.5%) due to secondary infertility. The duration of group infertility was 4.1 years. The mean use of the method was 12.6 months (median, 9 months). The infertility causes identified included anovulation (50.4%), tubo-peritoneal factors (18.3%), endometriosis (14.5%), uterine factors (9.2%), cervical factors (8.4%) and masculine factors (19.1%). There were 33 pregnancies (25.2 global). The crude proportion of pregnancies at 24 months was 22.9% and the proportion adjusted by the life table at 24 months was 40 per 100 couples. the focus on restorative medicine is effective to achieve pregnancy but it requires a long-term longitudinal treatment. Early discontinuation of fertility charting affects the efficacy of this focus. More research is warranted to optimize medical treatment.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
Practice Committee of the American Society for Reproductive Medicine, 2015·Fertil Steril·
This document reviews surgical options for achieving patency in obstructed fallopian tubes and the factors that must be considered when deciding between surgical repair and IVF. This document replaces the document of the same name, last published in 2012 (Fertil Steril 2012;97:539–45).
Chronic Endometritis · Endometritis and Reproductive Outcomes
Cicinelli E et al., 2015·Human reproduction (Oxford, England)
What is the prevalence of chronic endometritis (CE) in women with repeated unexplained implantation failure (RIF) at IVF, and how does antibiotic treatment affect the reproductive outcome? Chronic endometritis, associated with infection with common bacteria or mycoplasma, is common in women complaining of RIF and antibiotic treatment significantly improves the reproductive outcome at a subsequent IVF cycle. We have reported that CE is a frequent finding in women with repeated pregnancy loss and a significantly higher rate of successful pregnancies was achieved after adequate antibiotic treatment. Moreover, CE was identified in 30.3% of patients with repeated implantation failure at IVF and women diagnosed with CE had lower implantation rates (11.5%) after IVF cycles. In contrast, other authors reported that the clinical implication of CE should be considered minimal and that the reproductive outcome at IVF/ICSI cycles was not negatively affected by CE. STUDY DESIGN, SIZE, A retrospective study was performed from January 2009 through June 2012 on 106 women with unexplained infertility and a history of RIF. PARTICIPANTS/MATERIALS, SETTING, All patients underwent hysteroscopy and endometrial sampling for histology and microbiological investigations. Women diagnosed with CE underwent antibiotic treatment and the effect of treatment was confirmed by hysteroscopy with biopsy. Within 6 months after treatment all women had a further IVF attempt. The IVF outcomes were compared in women without signs of CE (Group 1) and persistent CE (Group 2) after antibiotic treatment. Clinical pregnancy rate (PR), and live birth rate (LBR) were compared at post-treatment IVF attempt. MAIN Seventy (66.0%) women were diagnosed with CE at hysteroscopy. In 61 (57.5%) CE was confirmed by histology and 48 (45.0%) by cultures. Common bacteria and mycoplasma were the most prevalent agents. In 46 (75.4%) out of 61 women, with diagnosis of CE at hysteroscopy and histology, examinations were normal after appropriate antibiotic treatment control (Group 1) while in 15 (24.6%) cases signs of CE were still present (Group 2). At IVF attempt after treatment, a significantly higher PR and LBR was reported in women from Group 1 compared with women from Group 2 (65.2 versus 33.0% P = 0.039; 60.8 versus 13.3%, P = 0.02, respectively). LIMITATIONS, Possible biases related to retrospective studies and to preferential referral of patients with CE, and limited number of cases. A prospective randomized clinical trial is needed to confirm our findings but in women with RIF a hysteroscopic evaluation of the uterine cavity to exclude CE should be considered and appropriate antibiotic treatment should be given before submitting the patient to a further IVF attempt.
Franjoine SE et al., 2015·Minimally invasive surgery·
Open Access
Objective. To study the reproductive outcomes of modified laparoscopic fimbrioplasty (MLF), a surgical technique designed to increase the working surface area of the fimbriated end of the fallopian tube. We postulated that an improvement in fimbrial function through MLF will improve reproductive outcomes. Design. Retrospective cohort study. Setting. Academic tertiary-care medical center. Patients. Women with minimal endometriosis or unexplained infertility, who underwent MLF during diagnostic laparoscopy (n = 50) or diagnostic laparoscopy alone (n = 87). Intervention. MLF involved gentle, circumferential dilatation of the fimbria and lysis of fimbrial adhesions bridging the fimbrial folds. Main Outcome Measures. The primary outcome was pregnancy rate and the secondary outcome was time to pregnancy. Results. The pregnancy rate for the MLF group was 40.0%, compared to 28.7% for the control group. The average time to pregnancy for the MLF group was 13 weeks, compared to 18 weeks for the control group. The pregnancy rate in the MLF group was significantly higher for patients ≤35 ys (51.5% versus 28.8%), but not for those >35 ys (17.6% versus 28.6%). Conclusion. MLF was associated with a significant increase in pregnancy rate for patients ≤35 ys.
Chronic Endometritis · Endometritis and Reproductive Outcomes
To assess the prevalence of chronic endometritis in women with a history of recurrent early pregnancy loss (REPL) and/or fetal demise (FD). Observational cohort study using prospectively collected data. Recurrent pregnancy loss program in an academic medical center. PATIENT(S): Three hundred ninety-five women with a history of two or more pregnancy losses of less than 10 weeks' size or a fetal demise of 10 or more weeks' size. INTERVENTION(S): All women had an endometrial biopsy. Chronic endometritis was treated with antibiotics, and a second endometrial biopsy was recommended as a "test of cure." MAIN OUTCOME MEASURE(S): Subsequent live-birth rate (LBR). RESULT(S): The overall prevalence of chronic endometritis was 9% (35/395) in this cohort; 7% (21/285) in the REPL group, 14% (8/57) in the FD group, and 11% (6/53) in the combined REPL/FD group. The cure rate was 100% after a course(s) of antibiotics. The subsequent cumulative LBR was 88% (21/24) for the treated chronic endometritis group versus 74% (180/244) for the group without chronic endometritis. The per-pregnancy LBR for the treated chronic endometritis group was 7% (7/98) before treatment versus 56% (28/50) after treatment. CONCLUSION(S): There was a high prevalence of chronic endometritis in this cohort. The test of cure was 100% with antibiotics. Subsequent LBRs after treatment were encouraging.
Takasaki A et al., 2013·Journal of ovarian research
Clomiphene citrate (CC) is most commonly used as a first-line treatment of infertility. However, a disturbance of endometrial growth by the adverse effects of the CC has been recognized. Since a thin endometrium is recognized as a critical factor of implantation failure, preventing CC-induced thinning of the endometrium is important. This study was undertaken to investigate whether the modified CC treatments are useful to prevent a thin endometrium in patients undergoing CC treatments. This study is a prospective, randomized controlled study. The study was performed at the Saiseikai Shimonoseki General Hospital during a 4-month period (May 2012 to September 2012). Sixty-six infertile women who had a thin endometrium (< 8 mm) during the standard CC treatment (50 mg/day on days 5-9 of the menstrual cycle) were enrolled. The patients were randomly divided into three groups: 22 patients were given 25 mg/day CC on days 5-9 (half-dose group), 22 patients were given 50 mg/day CC on days 1-5 (early administration group) and 22 patients received a standard CC treatment again (control group). Endometrial thickness at the induction of ovulation was assessed by ultrasonography. The primary endpoint of this study was an endometrial thickness. Half dose administration and early administration improved the endometrial thickness (≥ 8 mm) in 14 patients (70%) and in 19 patients (90%) respectively, while only 3 patients (15%) improved in endometrial thickness in the control group. The mean endometrial thickness was also significantly higher in the half dose group (8.6 ± 1.5 mm) and early administration group (9.4 ± 1.5 mm) compared to the control group (6.7 ± 1.8 mm). No side effect was observed in this study. The modified treatment with a half-dose or early administration of CC significantly increased endometrial thickness in patients with a history of thin endometrium caused by the standard CC regimen. The modified CC treatments in this study can be beneficial for patients with a thin endometrium as a result of standard CC treatment. CLINICAL UMIN000007959.
Chronic Endometritis · Endometritis and Reproductive Outcomes
Recurrent miscarriage (RM) is defined as 3 or more miscarriages before 20 weeks' pregnancy. In recent years, interest has been focused on chronic endometritis (CE), a subtle inflammation thought to be associated with RM. We aimed to evaluate the relationships between CE and RM. The records of 360 women with unexplained RM were retrospectively analyzed. Data from hysteroscopy, endometrial histology, endometrial culture, and polymerase chain reaction for chlamydia, performed before and after antibiotic treatment for CE, were analyzed. The occurrence of successful pregnancies within 1 year after treatment was also evaluated. Results showed that 208 (57.8%) women with RM showed CE at hysteroscopy; 190 (91.3%), positive at hysteroscopy, were also positive at histology, and 142 (68.3%) had positive cultures. Common bacteria were found in 110 (77.5%) patients. Mycoplasma and Ureaplasma were found in 36 (25.3%) patients and Chlamydia in 18 patients (12.7%). In 102 (71%) women, antibiogram-based antibiotic treatment normalized hysteroscopy, histology, and cultures (group 1); while in 40 (28.2%) patients, CE was still present at hysteroscopy (group 2). In 16 of the 66 patients positive at hysteroscopy, but not at cultures, the hysteroscopy becomes normal (group 3) after a Centers for Disease Control and Prevention-based therapy; while in 50 women, CE was still present (group 4). One year after treatment, group 1 showed a significantly higher number of pregnancies (78.4%) compared to group 2 (17.5%; P < .001) and group 4 (15.3%; P = .005). The CE is frequent in women with RM. Antibiotic treatment seems to be associated with an improved reproductive outcome.
Does unilateral volume-adjusted laparoscopic diathermy increase the chances of ovulation in women with polycystic ovary syndrome (PCOS)? Although unilateral laparoscopic ovarian drilling (ULOD) using adjusted thermal doses was more efficient than bilateral laparoscopic ovarian drilling (BLOD) using fixed doses, the chances of ovulation were improved in patients irrespective of the technique used. The adjustment of the thermal dose to ovarian volume in BLOD increases ovulation and pregnancy rates compared with fixed-dose treatment, but BLOD causes the formation of adhesions, particularly on the left ovary, and increases the risk of damage to ovarian tissue. In contrast, ULOD with a fixed thermal dose minimizes the risk of ovarian tissue damage, and can increase the activity in both right and left ovaries, although this varies in humans and in other species. STUDY DESIGN, SIZE, This prospective, longitudinal, study, between September 2009 and January 2013, included 96 infertile women with PCOS who were unresponsive to clomiphene citrate treatment and had underwent either ULOD or BLOD. After surgery, the groups were followed up for 6 months to assess ovulatory response. PARTICIPANTS/MATERIALS, SETTING, Patients were assigned to two groups; one group underwent laparoscopic ovarian drilling of the right ovary alone, while both ovaries were treated in the second group. The ULOD group (n = 49) received thermal doses adjusted to the volume of the right ovary (60 J/cm³). The BLOD group (n = 47) received fixed doses of 600 J per ovary, regardless of its volume. The two treatment groups were matched by the number of participants, age and baseline parameters. MAIN The ovulation rate during the first menstrual cycle after LOD was significantly higher in the ULOD group than in the BLOD group [73 versus 49%; absolute risk reduction (ARR), -0.25; 95% confidence interval (CI), -0.44 to -0.03; P = 0.014]. Treatment with ULOD on the right ovary significantly increased the chances of ovulation in patients with a larger right ovary compared with those who had a smaller right ovary (100 versus 36%; ARR, -0.64; 95% CI, -0.84 to -0.37; P = 0.004). Interestingly, the chances of ovulation were also significantly higher in patients in the BLOD group who had a larger right ovary compared with those who had a smaller right ovary (88 versus 33%; ARR, -0.55; 95% CI, -0.73 to -0.28; P = 0.002). The pregnancy rate was also significantly higher in patients with a larger right ovary compared with those with a smaller right ovary, regardless of the treatment group. LIMITATIONS, The 6-month follow-up was too short to demonstrate any long-term differences in the ovulation rates. Future research should therefore extend the follow-up beyond 6 months. Another limitation is that ULOD was used to treat only the right ovary. Future studies should investigate whether ULOD treatment of the larger ovary, whether left or right, would significantly increase the ovulation rate. This study represents an advance in the determination of the optimal laparoscopic treatment for women with PCOS, as it was shown that improved results can be achieved using less thermal energy in volume-adjusted ULOD.
To determine patterns of usage of clomiphene citrate (CC) by primary care providers (obstetrician-gynecologists, family physicians, and other providers) within University of Utah Community Clinics. We performed a retrospective chart review (n = 79) and followup telephone survey of patients (n = 43) who were prescribed CC in the University of Utah Community Clinics in 2006. Most women who were prescribed CC had appropriate indications for therapy (65% with a diagnosis related to irregular menses and 33% with a diagnosis of female infertility), but there was variable and inconsistent monitoring of ovulation (much of which was apparently initiated by the patients). In the interview, 24 of the women (56%) said they would be fine having twins, and 14 (33%) said they would prefer to have twins if possible. In this primary care setting, clomiphene was prescribed for appropriate indications, but the monitoring of treatment could be improved. The preference of some patients for twin gestations represents a challenge for optimum clinical care and public health.
Robinson L et al., 2012·Human reproduction (Oxford, England)
Is there an association between high levels of sperm DNA damage and miscarriage? Miscarriage rates are positively correlated with sperm DNA damage levels. Most ejaculates contain a subpopulation of sperm with DNA damage, also referred to as DNA fragmentation, in the form of double or single-strand breaks which have been induced in the DNA prior to or following ejaculation. This DNA damage may be particularly elevated in some subfertile men, hence several studies have examined the link between sperm DNA damage levels and conception and miscarriage rates. STUDY DESIGN, SIZE, A systematic review and meta-analysis of studies which examined the effect of sperm DNA damage on miscarriage rates was performed. Searches were conducted on MEDLINE, EMBASE and the Cochrane Library without any language restrictions from database inception to January 2012. PARTICIPANTS/MATERIALS, SETTING, We used the terms 'DNA damage' or 'DNA fragmentation' combined with 'miscarriage', 'abortion' or 'pregnancy' to generate a set of relevant citations. Data extraction was performed by two reviewers. Study quality was assessed using the Newcastle-Ottawa Scale. Meta-analysis of relative risks of miscarriage was performed with a random effects model. Subgroup analyses were performed by the type of DNA damage test, whether the sperm examined were prepared or from raw semen and for pregnancies resulting from IVF or ICSI treatment. MAIN We identified 16 cohort studies (2969 couples), 14 of which were prospective. Eight studies used acridine orange-based assays, six the TUNEL assay and two the COMET assay. Meta-analysis showed a significant increase in miscarriage in patients with high DNA damage compared with those with low DNA damage [risk ratio (RR) = 2.16 (1.54, 3.03), P < 0.00001)]. A subgroup analysis showed that the miscarriage association is strongest for the TUNEL assay (RR = 3.94 (2.45, 6.32), P < 0.00001). LIMITATIONS, There is some variation in study characteristics, including the use of different assays and different thresholds for DNA damage and the definition of pregnancy loss. The use of methods which select sperm without DNA damage for use in assisted conception treatment may reduce the risk of miscarriage. This finding indicates that assays detecting DNA damage could be considered in those suffering from recurrent pregnancy loss. Further research is necessary to study the mechanisms of DNA damage and the potential therapeutic effects of antioxidant therapy. STUDY FUNDING/COMPETING INTEREST(S): None.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
Practice Committee of the American Society for Reproductive Medicine, 2012·Fertil Steril·
The majority of miscarriages are sporadic and most result from genetic causes that are greatly influenced by maternal age. Recurrent pregnancy loss (RPL) is defined by two or more failed clinical pregnancies, and up to 50% of cases of RPL will not have a clearly defined etiology.
To describe the characteristics of women seeking infertility treatment and the types of fertility treatment sought within a population-based sample. We analyzed data from the cross-sectional Pregnancy Risk Assessment Monitoring System (PRAMS) of women with a live birth using data from seven states. Logistic regression was used to determine factors associated with infertility treatment utilization. Infertility treatment was reported by 10.5% of women who were trying to become pregnant. The most common treatment reported was fertility enhancing drugs (29%), followed by assisted reproductive technology including in vitro fertilization (21%), and artificial insemination together with fertility enhancing drugs (15%). Some women reported using other types of treatment (23%). The PRAMS data provide insights into the use of infertility treatment among women giving birth in the United States. Further research is needed to understand the true prevalence of infertility, factors that influence treatment choices, and the longitudinal impact of infertility treatment on outcomes.
Use of selective salpingography (SS) and fallopian tube catheterization (TC) has revolutionized the diagnosis and treatment of proximal tubal infertility. To evaluate results of women treated for proximal tubal obstruction by selective salpingography and tubal catherization. Selective salpingography was performed in women with proximal bilateral tubal obstructions. Follow-up ranged from 4 to 12 months. twelve patients had been shown to have bilateral proximal obstruction of the fallopian tube. After SS/TC, patency was achieved in 8 cases. Spontaneous conceptions occurred in 4 women. SS and TC should be used more widely because it is simple and effective in case of proximal tubal blockage.
To review the treatments of the cesarean-induced isthmocele in restoring infertility, associated techniques, and the risks of complications associated with their use.
Recent Findings: Isthmocele is a reservoir-like pouch defect on the anterior wall of the uterine isthmus located at the site of a previous cesarean delivery scar. The flow of menstrual blood through the cervix may be slowed by the presence of isthmocele, as the blood may accumulate in the niche because of the presence of fibrotic tissue, causing pelvic pain in the suprapubic area. Moreover, persistence of the menstrual blood after menstruation in the cervix may negatively influence the mucus quality and sperm quality, obstruct sperm transport through the cervical canal, interfere with embryo implantation, leading to secondary infertility. The removal of the local inflamed tissue may be performed by laparoscopic, combined laparoscopic-vaginal, or vaginal surgery, and operative hysteroscopy, a minimally invasive approach to improve symptoms and restore fertility.
Isthmocele occurs after cesarean section, a common method of delivery and one of the most frequent surgical procedures, so that its upward incidence appears likely to continue in the near future. Because of its minimal invasiveness, resectoscopy may be the better choice for treatment, yielding good therapeutic results.
Jin LP et al., 2011·American journal of reproductive immunology (New York, N.Y. : 1989)
PROBLEM To evaluate whether the association of the costimulatory signal regulation with T helper 1/T helper 2 (Th1/Th2) bias at maternal-fetal interface in human pregnancy loss. METHOD OF STUDY The expression of CD80 and CD86 in decidual tissues and CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in the decidual T cells was compared between normal early pregnancy and miscarriage by qPCR and Western blot. The cytokine production in decidual T cells was performed by flow cytometry. The correlation of costimulatory molecule expression with Th1/Th2 cytokines was analyzed. RESULTS The CD80 mRNA and protein expression showed no significant difference between normal pregnancy and miscarriage. An increase in the expression of CD28 and CD86 was accompanied by a decrease in the expression of CTLA-4 in miscarriage in comparison with the early pregnancy. The higher expression of interleukin (IL)-2 and interferon-γ (IFN-γ), and lower expression of IL-4 and IL-10 in the decidual T cells were present in miscarriage. A correlation analysis showed a significant positive correlation of CD86 and CD28 expression with the Th1 cytokine production (IL-2 and IFN-γ), a significant negative correlation of CTLA-4 expression with the Th1 cytokine production. CONCLUSION The upregualtion of costimulatory signals on T cells might form an abnormal immune microenvironment, a shift to Th1 responses, at maternal-fetal interface, which leads to human miscarriage.
To assess the clinical effectiveness of falloposcopic tuboplasty in tubal infertility.
Retrospective cohort study (Canadian Task Force classification II-3).
Infertility clinic. Three hundred forty-five infertile patients (≥2y) with a diagnosis of proximal tubal occlusion, either bilateral or unilateral, between January 2005 and January 2011. Falloposcopic tuboplasty. MAIN Medical records for 345 patients with a diagnosis of proximal tubal occlusion were reviewed. Of the 345 patients, 304 underwent falloposcopic tuboplasty, with successful recanalization achieved in 248 patients (81.6%). Ninety-one of the 304 patients (29.9%) became pregnant. Of these, 18 patients (19.8%) miscarried, and 4 (4.4%) had ectopic pregnancies in the recanalized tube. At 1-, 3-, 6-, and 9-month follow-up, the cumulative probability of conception was 23.1%, 50.6%, 73.6%, and 82.4%, respectively. Related complications included postsurgical infection (0.3%), perforation of the fallopian tube (1.3%), and accidental breakage of the catheter (4.9%) or the falloposcope (1.3%). Falloposcopic tuboplasty is safe and effective for treatment of tubal infertility. The pregnancy rate after falloposcopic tuboplasty is comparable to that after in vitro fertilization, which suggests that it can be an alternative to in vitro fertilization in women with tubal infertility.
The diminished role of tubal surgery in infertile women following widespread access to IVF is now being reviewed as more patients and surgeons today consider tubal surgery as an effective alternative to assisted reproduction treatment in certain circumstances. The limitations of and lack of patient acceptance of assisted reproduction treatment for ethical and moral reasons have contributed to this change as well as advances in surgical techniques and instrument technology, notably developments in endoscopic surgery. Strategies in tubal surgery are largely unchanged but the mini-invasive nature of the endoscopic approach has added value because of less tissue trauma, better visualization of the operative field and more rapid healing, which make surgery using today's techniques an integral part of the treatment strategy in infertile couples.
Chronic Endometritis · Endometritis and Reproductive Outcomes
Johnston-MacAnanny EB et al., 2010·Fertility and sterility
To determine the role of endometrial sampling for identification and treatment of chronic endometritis (CE) in patients undergoing IVF-ET who repeatedly failed to conceive despite the transfer of good-quality embryos. Retrospective chart review. University-based tertiary fertility center. PATIENT(S): Thirty-three patients with recurrent implantation failure (RIF) who underwent endometrial sampling and subsequent ET were analyzed based on immunohistochemically confirmed CE: CE present on biopsy (group 1; n = 10) and CE absent on biopsy (group 2; n = 23). Patients with RIF undergoing IVF cycles during the same time period who did not have endometrial sampling were used as controls (group 3; n = 485). INTERVENTION(S): Endometrial sampling for CE and subsequent antibiotic treatment in affected patients followed by another IVF-ET cycle. RESULT(S): Chronic endometritis was identified in 30.3% of patients with RIF. Group 1 had lower implantation rates (11.5%) in the IVF cycle following treatment than did group 2 and group 3 (32.7% and 20.3%, respectively). Clinical pregnancy and ongoing pregnancy rates were similar across groups. CONCLUSION(S): Recurrent implantation failure warrants investigation of CE as a contributing factor. Women demonstrating CE on endometrial sampling have lower implantation rates in a subsequent IVF-ET cycle; however, there were no differences in subsequent clinical pregnancy or ongoing pregnancy rates after successful antibiotic treatment.
Progesterone is essential for endometrial receptivity and successful establishment of pregnancy. Either an insufficient progesterone concentration or an insufficient response to progesterone, therefore can lead to infertility and pregnancy loss. Assessment of the role that either progesterone insufficiency or inadequate progesterone response plays in human reproductive failure has been difficult to assess because serum progesterone concentrations fluctuate markedly, limiting the ability to characterize sufficiency of progesterone, and there are no highly reliable markers of endometrial function available. Recent evidence demonstrates exquisite sensitivity of normal endometrium to very low levels of progesterone stimulation, suggesting that progesterone insufficiency should not be a common cause of reproductive failure. Further evidence suggests that women with endometriosis, and possibly polycystic ovarian syndrome, have an altered progesterone response, which may explain some of the clinical features of these disorders and supports the hypothesis that progesterone resistance underlies some cases of human reproductive failure.
Couples presenting with 3 or more miscarriages fit the definition of recurrent miscarriage which affects 1% of those trying to conceive. Clinics based in Dublin and Galway use a multifactorial approach with NaProTechnology to evaluate and treat such couples. 355 couples with subfertility attended for 2+ consultations during 2010. 50 (14%) had 3+ miscarriages. Of 36 who conceived, 29 (80.6%) had live births, 4 (11.1%) miscarried, 2 (5.6%) had ectopic pregnancies. Average female age 37.5 years. Expected miscarriage rate for this population would be above 30-40%. A total miscarriage and ectopic rate of 16.7% per couple is encouraging. Women with recurrent miscarriage appear to have better than expected outcomes following a multifactorial NaPro treatment approach.
Duffy JM et al., 2009·The Cochrane database of systematic reviews·
Open Access
Hydrotubation with oil-soluble contrast media for unexplained infertility and adhesiolysis for infertility due to peritubal adhesions are primary procedures that are of recognised benefit. It is less clear whether postoperative procedures such as hydrotubation or second-look laparoscopy with adhesiolysis are beneficial following pelvic reproductive surgery. To assess the value of postoperative hydrotubation and second-look laparoscopy with adhesiolysis following female pelvic reproductive surgery. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register (August 2008), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 2), MEDLINE (1966 to August 2008), EMBASE (1980 to August 2008), PsycINFO (1967 to August 2008), Current Contents (1993 to August 2008), Biological Abstracts (1969 to August 2008), CINAHL (1982 to August 2008) and reference lists of identified articles. All randomised controlled trials in which a postoperative procedure was compared with a control group following pelvic reproductive surgery were considered for inclusion in the review. Five randomised controlled trials were identified and included in this updated review. An attempt was made to obtain further information from the authors of all five trials. All trials were assessed for quality. The studied outcomes were pregnancy, live birth, ectopic pregnancy and miscarriage rates, and the rates of tubal patency and procedure-related complications. Review authors extracted the data independently and the odds ratios (OR) were estimated for these dichotomous outcomes. Five randomised controlled trials were identified and included in this review. The odds of pregnancy (OR 1.12, 95% confidence interval (CI) 0.57 to 2.21) and live birth (OR 0.61, 95% CI 0.24 to 1.59) were not significantly different with postoperative hydrotubation versus no hydrotubation. The odds of pregnancy (OR 0.96, 95% CI 0.44 to 2.07) or live birth (OR 0.67, 95% CI 0.19 to 2.32) were also not significantly different with second-look laparoscopy and adhesiolysis versus no second-look laparoscopy. Whether hydrotubation was early or late and whether hydrotubation fluid contained steroid or not had no significant impact on the odds of pregnancy or live birth. Late antibiotic hydrotubation increased the odds of at least one patent fallopian tube when compared with early hydrotubation in women (OR 7.72, 95% CI 2.50 to 8.93). The odds of infective morbidity significantly increased with early hydrotubation when compared with late non-antibiotic hydrotubation (OR 4.72, 95% CI 2.50 to 8.93). When comparing late hydrotubation following tubal stent removal with early hydrotubation in women who had no tubal stenting, there was no significant difference in pregnancy or live birth rates. AUTHORS' There is insufficient evidence to support the routine practice of hydrotubation or second-look laparoscopy following female pelvic reproductive surgery. The studies on which this conclusion is based were either of poor quality or underpowered. These interventions should be performed in the context of a good quality, adequately powered randomised controlled trial. Postoperative hydrotubation with fluid containing antibiotic may offer benefit over hydrotubation fluid without antibiotic following tubal surgery. A randomised controlled trial of postoperative hydrotubation with antibiotic-containing fluid versus no hydrotubation for improving fertility following tubal surgery is justified.
To examine whether thin endometria can be improved by increasing uterine radial artery (uRA) blood flow. A prospective observational study. University hospital and city general hospital. PATIENT(S): Sixty-one patients with a thin endometrium (endometrial thickness [EM] <8 mm) and high radial artery-resistance index of uRA (RA-RI >or=0.81). INTERVENTION(S): Vitamin E (600 mg/day, n = 25), l-arginine (6 g/day, n = 9), or sildenafil citrate (100 mg/day, intravaginally, n = 12) was given. MAIN OUTCOME MEASURE(S): EM and RA-RI were assessed by transvaginal color-pulsed Doppler ultrasound. RESULT(S): Vitamin E improved RA-RI in 18 (72%) out of 25 patients and EM in 13 (52%) out of 25 patients. L-arginine improved RA-RI in eight (89%) out of nine patients and EM in six (67%) patients. Sildenafil citrate improved RA-RI and EM in 11 (92%) out of 12 patients. In the control group (n = 10), who received no medication to increase uRA-blood flow, only one (10%) patient improved in RA-RI and EM. The effect of vitamin E was histologically examined in the endometrium (n = 5). Vitamin E improved the glandular epithelial growth, development of blood vessels, and vascular endothelial growth factor protein expression in the endometrium. CONCLUSION(S): Vitamin E, l-arginine, or sildenafil citrate treatment improves RA-RI and EM and may be useful for the patients with a thin endometrium.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Pregnancy could be associated with a state of oxidative stress that could initiate and propagate a cascade of changes that may lead to pregnancy wastage. This process of oxidative stress may be suppressed by the antioxidant effect of N-acetyl cysteine (NAC). The current study aimed to evaluate the effect of NAC therapy in patients diagnosed with unexplained recurrent pregnancy loss (RPL). The study was a prospective controlled study performed in the Women's Health Centre, Assiut University, Egypt. A group of 80 patients with history of recurrent unexplained pregnancy loss were treated with NAC 0.6 g + folic acid 500 microg/day and compared with an aged-matched group of 86 patients treated with folic acid 500 microg/day alone. NAC + folic acid compared with folic acid alone caused a significantly increased rate of continuation of a living pregnancy up to and beyond 20 weeks [P < 0.002, relative risk (RR) 2.9, 95% confidence interval (CI) 1.5-5.6]. NAC + folic acid was associated with a significant increase in the take-home baby rate as compared with folic acid alone (P < 0.047, RR 1.98, 95% CI 1.3-4.0). In conclusion, NAC is a well-tolerated drug that could be a potentially effective treatment in patients with unexplained RPL.
In 1980, Espey proposed a famous hypothesis that mammalian ovulation is comparable to an inflammatory reaction and many researches have proved the validity of his hypothesis in the last three decades. For example, interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)- alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and other inflammatory cytokines presence was proven in the preovulatory follicle. Since granulocyte is the major leukocyte and it plays a very important role during inflammation, the importance of granulocyte and its related cytokine, granulocyte colony-stimulating factor (G-CSF) in the mechanism of human ovulation is easily predictable. G-CSF is one of the hemopoietic cytokines and it has strong positive effects on granulocytes. G-CSF increases the number of granulocytes and it improves the function of granulocytes. In this review, the participation of leukocytes in the ovulation mechanism is demonstrated first. Second, the participation of G-CSF is shown in comparison with the above mentioned cytokines. Finally, since G-CSF has been used for more than 20 years as a medicine without severe side effects in the field of oncology, the clinical application of G-CSF for the treatment of an ovulation disorder, luteinized unruptured follicle (LUF), will be discussed.
Guidelines by Clinical Area · Fertility and Infertility Guidelines
Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008·Fertility and Sterility
The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. On the basis of the currently available evidence, a group of experts reached a consensus regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counseling should be provided emphasizing the importance of lifestyle, especially weight reduction and exercise in overweight women, smoking, and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotropins is associated with increased chances for multiple pregnancy, and, therefore, intense monitoring of ovarian response is required. Laparoscopic ovarian surgery alone is usually effective in less than 50% of women, and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC-gonadotropin paradigm) is reported to be highly effective with a cumulative singleton live-birth rate of 72%. Recommended third-line treatment is in vitro fertilization (IVF). More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-line, second-line, or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.
Clinically a couple is considered to be infertile after at least one year without contraception and without pregnancy. There was scant knowledge about the prevalences of infertility, involuntary childlessness and the seeking of fertility treatment and only few longitudinal studies about the psychosocial consequences of infertility and its treatment. This thesis is about the epidemiological aspects of infertility; the conceptualization and measurement of important psychosocial aspects of infertility; and a medical sociological analysis of the associations between these psychosocial variables among Danish women and men in fertility treatment. The thesis is based on nine papers. The three main purposes were: (i) to review critically, population based studies of infertility and medical care seeking in industrialised countries. Further, to examine these prevalences and subsequent motherhood among women in former assisted reproduction in a Danish population. (ii) To develop measures of psychosocial consequences of infertility: fertility problem stress, marital benefit, communication, coping strategies, attitudes to and evaluation of fertility treatment. (iii) To examine these phenomena and to analyse their interrelations among Danish women and men in fertility treatment. The thesis is based on four empirical studies: (i) The Women and Health Survey, a cross-sectional population-based study among 15-44 year old women (n=907, 25-44 year old) in Copenhagen County, 1989. (ii) The Psychosocial Infertility Interview Study, a qualitative interview study among 16 couples (n=2 participants) infertility treatment at The Fertility Clinic, Herlev University Hospital,1992. (iii) The Infertility Cohort, a longitudinal cohort study consecutively including all couples (n=250 participants) beginning anew fertility treatment period at one of four public (Braedstrup, Herlev, Odense, Rigshospitalet) and one private fertility clinic (Trianglen),2000-2002. (iv) The Communication and Stress Management Training Programme, an intervention study among couples(n=74 participants) in fertility treatment at The Fertility Clinic, The Juliane Marie Centre, Rigshospitalet, 2001-2003. Included is also a literature review of population-based infertility studies from industrialised countries. Data from (iii) and (iv) are studies from The Copenhagen Multi-centre Psychosocial Infertility (COMPI) Research Programme (www.compipro.dk). Epidemiological and demographic studies investigating the prevalences of infertility differed in how they defined the numerator (the infertile participants) and the denominator (the population at risk). It was important to calculate reliable estimates of the infertility prevalence by including only women who had tried to have at least one child in the population at risk, as a notable proportion of women in the fertile ages had not (yet) attempted to become a mother. The lifetime prevalence of infertility in the representative population-based study was 26.4%. In the age group 35 to 44 years 5.8% were primarily involuntarily in fecund (involuntarily childless). Even in a country with access to fertility treatment in a public health-care system without self-payment lower education was a predictor of lower treatment seeking. In the cohort study (2000-2002)of couples starting a new period of assisted reproduction treatment 62.6% reported a treatment-related pregnancy at the one-year follow-up. In total 32.4% reported a treatment-related delivery. In total 24.2% reported a current continuing pregnancy and spontaneous pregnancies accounted for 2.7% of these. We developed measures of fertility problem stress, marital benefit(that infertility has brought the partners closer together and strengthened their marriage), partner communication, infertility related communication, coping strategies, attitudes to fertility treatment and evaluation of care. The medical sociological analyses showed that the variables of psychosocial consequences of infertility and treatment are interwoven with each others in a complex pattern, a pattern that both differed and was similar when comparing women and men. The infertility-related communication strategy (secrecy, formal, open-minded)identified in the qualitative interviews was later confirmed in the COMPI Infertility Cohort. Using the formal strategy and not talking about the emotional aspects of infertility and its treatment suggested high fertility problem stress. The coping strategies studied showed significant social differences and active-avoidance coping was a significant predictor of high fertility problem stress. A positive effect of infertility on the marriage, marital benefit was common. Men using the secrecy communication strategy had increased risk of low marital benefit. Difficult partner communication was a significant predictor of high fertility problem stress and among men, of low marital benefit. The intervention study showed that it was possible for the participants to change their communication with partner and other people close to them and that participants achieved an increased awareness of what, how much and when to discuss with others. High fertility problem stress and high marital benefit were associated with high importance ratings of patient-centred care and intentions to use professional psychosocial services. Among women, high fertility problem stress was a predictor of lower satisfaction ratings with fertility treatment. High marital benefit was a predictor of high satisfaction ratings of both medical and patient-centred care. In conclusion, infertility is a common experience among couples attempting to become parents. Assisted reproduction in the public health-care system in Denmark has high success rates, i.e. pregnancies,deliveries and high patient satisfaction. A large minority of people in fertility treatment experience high fertility problem stress,and some use communication and coping strategies that predicts high stress. Developing and evaluating different psychosocial interventions are necessary to offer the psychosocial support needed for this minority of fertility patients.
Women with polycystic ovarian syndrome are typically anovulatory and require ovulation induction. Ovarian wedge resection was the first treatment for anovulation but was eventually abandoned because of the increased risk of postsurgical adhesions and as medical ovulation induction with clomiphene and gonadotrophins was introduced. However, with the advent of laparoscopy, there has been a return to surgical approaches. The potential advantages of laparoscopic surgery include avoidance of hyperstimulation and the lowered costs make ovarian surgery an attractive alternative to gonadotrophins.
Recent Findings: Clinical trials in New Zealand and the Netherlands have compared costs of laparoscopic ovarian drilling with gonadotrophins. The total cost of treatment in the Netherlands study for the ovarian drilling group was euro 4664 and for the gonadotrophins group was euro 5418. Without the cost of monitoring and the diagnostic laparoscopy then the difference was euro 2110 in favour of ovarian drilling. It was estimated that the cost per term pregnancy would be euro 14,489 for gonadotrophin and euro 11,301 for ovarian drilling (22% lower). The higher rates of multiple pregnancy in the gonadotrophin group were considered to be responsible for the increased costs. In the New Zealand trial the costs of a live birth were one-third lower in the group that underwent laparoscopic ovarian diathermy compared with those women who received gonadotrophins (NZ$19,640 and 29,836, respectively).
Treating women with clomiphene-resistant polycystic ovarian syndrome with laparoscopic ovarian diathermy results in reduced direct and indirect costs. The reduction in multiple pregnancies makes the alternative of surgery particularly attractive.
The new third generation aromatase inhibitors are extremely potent and specific oral inhibitors of estrogen production. We reported the success of using aromatase inhibitors for induction of ovulation in World Health Organization (WHO) type II anovulatory patients. Promising pregnancy rates were associated with the use of aromatase inhibitors for induction of ovulation in these women. In addition, the use of aromatase inhibition in conjunction with gonadotropin injection was associated with a significant reduction in the gonadotropin dose required for optimum controlled ovarian hyperstimulation. We believe that these oral agents are efficient and safe and have many advantages compared with clomiphene citrate (CC). We propose that aromatase inhibitors will replace CC in the future as the new primary treatment for ovulation induction. In this review, we present an update on the use of aromatase inhibitors for induction of ovulation and we discuss several new areas of potential interest regarding the use of aromatase inhibitors, either alone or together with recombinant follicle-stimulating hormone (FSH) for infertility treatment. Further research in these areas may demonstrate an expanded role in assisted reproductive technologies.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Proximal tubal occlusion at the uterotubal junction, whether from salpingitis isthmica nodosa, fibrosis, or prior sterilization, requires cornual resection and microsurgical tubal reimplantation to re-establish luminal continuity. NaProTECHNOLOGY treats this as a reconstructive procedure rather than a reason to defer to IVF, and outcomes data support intrauterine pregnancy rates comparable to assisted reproduction in appropriately selected patients.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Distal tubal occlusion — including hydrosalpinx, fimbrial agglutination, and peritubal adhesions — is a correctable cause of tubal-factor infertility amenable to salpingoneostomy, fimbrioplasty, and adhesiolysis under PEARS principles. Restoration of distal tubal patency and normal fimbrial architecture allows natural conception and avoids the bypassing of physiological fertilization that characterizes assisted reproductive technology.
Dunson DB et al., 2004·Obstetrics & Gynecology·
To estimate the effects of aging on the percentage of outwardly healthy couples who are sterile (completely unable to conceive without assisted reproduction) or infertile (unable to conceive within a year of unprotected intercourse).
A prospective fecundability study was conducted in a sample of 782 couples recruited from 7 European centers for natural family planning. Women aged 18-40 years were eligible. Daily intercourse records were used to adjust for timing and frequency of intercourse when estimating the per-menstrual-cycle probability of conception. The number of menstrual cycles required to conceive a clinical pregnancy and the probability of sterility and infertility were derived from the estimated fecundability distributions for men and women of different ages.
Sterility was estimated at about 1%; this percent did not change with age. The percentage infertility was estimated at 8% for women aged 19-26 years, 13-14% for women aged 27-34 years and 18% for women aged 35-39 years. Starting in the late 30s, male age was an important factor, with the percentage failing to conceive within 12 cycles increasing from an estimated 18-28% between ages 35 and 40 years. The estimated percentage of infertile couples that would be able to conceive after an additional 12 cycles of trying varied from 43-63% depending on age.
Increased infertility in older couples is attributable primarily to declines in fertility rates rather than to absolute sterility. Many infertile couples will conceive if they try for an additional year.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Laser adhesiolysis protocols address peritubal, periovarian, and cul-de-sac adhesions using CO2 laser energy applied under direct near-contact visualization, with attention to underlying anatomy and vascular proximity. Restoration of normal adnexal mobility and tubo-ovarian relationships is a prerequisite for improved cycle-based fertility after surgical NaProTECHNOLOGY intervention.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Selective hysterosalpingography combined with transcervical fallopian tube catheterization allows both precise diagnosis and non-surgical correction of proximal tubal occlusion, distinguishing true anatomical obstruction from tubal spasm or mucous plugging. In NaProTECHNOLOGY practice, this minimally invasive approach restores tubal patency without laparotomy, preserving natural conception potential in appropriately selected patients.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Three-dimensional ultrasound enables volumetric assessment of uterine architecture, endometrial morphology, and ovarian follicular dynamics with greater anatomical precision than conventional 2D imaging, facilitating detection of septate uteri, submucosal fibroids, and endometriotic lesions that affect implantation. Integration of 3D ultrasound into NaProTECHNOLOGY evaluation protocols enhances the pre-treatment structural workup and informs targeted surgical planning for uterine factor infertility.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Pelvic adhesions from prior infection, surgery, or endometriosis restrict tubal motility, occlude the fimbriae, and distort ovarian-tubal relationships, constituting a primary mechanical barrier to natural conception. Microsurgical adhesiolysis performed under NaProTECHNOLOGY protocols achieves tubal patency and restores anatomical relationships, enabling natural pregnancy in a substantial proportion of cases that would otherwise be directed to IVF.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Uterine fibroids contribute to abnormal uterine bleeding, dysmenorrhea, recurrent pregnancy loss, and implantation failure, making myomectomy a central NaProTECHNOLOGY surgical intervention for women seeking conception. PEARS myomectomy technique prioritizes uterine preservation, meticulous layered closure of the myometrial defect, and hemostasis strategies that minimize adhesion formation and support subsequent pregnancy.
Adhesion Prevention · Surgical Technique and Adhesions
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Extensive pelvic adhesions — often the sequela of prior surgeries, infection, or undertreated endometriosis — distort tubo-ovarian relationships and impair fertility through mechanical obstruction and altered pelvic microenvironment. PEARS adhesiolysis principles emphasize meticulous sharp dissection, copious irrigation, and anti-adhesion adjuncts to restore normal anatomy and optimize postoperative fertility outcomes.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Recurrent spontaneous abortion is examined through a systematic NaProTECHNOLOGY diagnostic framework that includes hormonal, anatomical, immunological, and infectious etiologies identified via CrMS cycle charting and targeted laboratory evaluation. Correcting underlying pathology—particularly luteal phase deficiency and uterine structural abnormalities—achieves live birth rates substantially higher than expectant management alone.
The third-generation aromatase inhibitors were initially introduced to treat postmenopausal breast cancer. We now realize that many other potential indications for aromatase inhibitors exist, especially in the field of gynecology. Preliminary data were suggestive that aromatase inhibitors could be used to treat endometriosis and uterine leiomyomata and induce or augment ovulation.
Aromatase inhibitors promote ovulation, most likely by increasing endogenous FSH production owing to decreased estrogen biosynthesis in the ovary and extraovarian tissues, including the brain. Aromatase inhibitors differ from the estrogen antagonist clomiphene citrate in that they do not exert a direct unfavorable effect on endometrial growth and development during the menstrual cycle.
Healey et al. (1) report important findings on the effects of the addition of an aromatase inhibitor to gonadotropin injections for superovulation. A relatively large number of patients and a control group were studied, and several clinically useful outcomes including pregnancy rates were reported.
The addition of letrozole to an ovulation induction regimen using injectable gonadotropins in a mixed population of patients with infertility does not seem to offer any benefits over gonadotropin-only cycles, because the decreased gonadotropin dose (the only apparent benefit) was offset by increased complexity of the treatment. Further randomized clinical trials using a similar design and patient sample may not provide clinically useful data. On the other hand, optimization of this regimen (gonadotropin plus aromatase inhibitor) in poor responders may offer an alternative in this subset of women (2).
From the existing literature, it appears that use of an aromatase inhibitor alone to induce or augment ovulation will continue to be an exciting area of research future (3, 4). In particular, the dosing and timing of administration (late luteal versus early follicular) of an aromatase inhibitor for ovulation induction should be optimized. Defining the hormonal profiles of the women who will benefit the most from aromatase inhibition may further increase the success of treatment.
In summary, Healey et al. (1) should be congratulated for conducting this interesting work. Carefully designed randomized studies on the use of aromatase inhibitors for ovulation induction or augmentation are warranted.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome. Systematic review and meta-analysis. Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent. 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence. Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome. Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance. Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.
To evaluate the effects of laparoscopic ovarian wedge resection on hormonal and metabolic parameters of polycystic ovary syndrome (PCOS) and to compare profiles of women who achieved pregnancy with those who did not.
Prospective study.
University hospital. PATIENT(S): Thirty-three women with PCOS. INTERVENTION(S): Laparoscopic ovarian wedge resection using harmonic scalpel. MAIN OUTCOME MEASURE(S): Pregnancy; levels of testosterone, DHEAS, gonadotropins, sex hormone-binding globulin (SHBG), and glucose and insulin during 2-hour glucose tolerance test; lipid profile; body mass index; and waist-to-hip ratio. RESULT(S): Twenty-two women (67%) achieved clinical pregnancy within the mean of 4.9 months after surgery. Baseline parameters of women who became pregnant differed from those who did not: those who became pregnant were less obese, had lower levels of total cholesterol, low-density lipoprotein, and triglycerides; higher levels of SHBG; lower levels of fasting insulin; lower insulin area under the curve; and higher insulin sensitivity index. Subjects not pregnant by 12 weeks after surgery underwent repeat endocrine and metabolic evaluations. In these women, wedge resection was followed by declines in testosterone, LH, and insulin sensitivity index. Wedge resection had no significant effect on SHBG, DHEAS, or lipid profile. CONCLUSION(S): Laparoscopic wedge resections are associated with the highest pregnancy rates among less obese subjects with favorable lipid profiles and lower insulin. In this study, the postoperative decline of serum testosterone and LH is not attributable to improvement of insulin sensitivity.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
To review the effectiveness of metformin in restoring regular menstrual cycles and ovulation and achieving pregnancy in women with polycystic ovary syndrome (PCOS). Systematic review of pertinent studies identified using the bibliographic databases MEDLINE and EMBASE. References of selected articles identified were hand-searched for additional relevant citations. PATIENT(S): Women with PCOS undergoing treatment with metformin alone, metformin combined with other methods of ovulation induction such as clomiphene citrate (CC) or gonadotropin injections, or metformin combined with in vitro fertilization (IVF). RESULT(S): Thirty published studies were included in the overall review. Studies consisted of 12 randomized controlled trials, two cohort studies, and 16 uncontrolled descriptive studies. Due to a strong variability in the use of metformin according to study population, exposure, and outcome of interest, it was not possible to combine the data of the 12 randomized controlled trials to perform a meta-analysis. Limited data on predominately obese PCOS patients demonstrate that metformin alone improves both restoration of regular menses and spontaneous ovulation, but there are no data supporting an improvement in pregnancy rate. The addition of metformin to CC results in an improved ovulation and pregnancy rate in both unselected and CC-resistant PCOS women. There are insufficient data to make any conclusions on the effect of metformin on FSH ovulation induction or IVF. CONCLUSION(S): The effectiveness and role of metformin in the treatment of PCOS anovulatory infertility in clinical practice is difficult to assess from currently available research. Further well-designed prospective, perhaps multicenter, randomized controlled trials with the primary end point of pregnancy or live-birth rate are required.
To evaluate the effect of an antifibrotic treatment by a combination of pentoxifylline (PTX) and tocopherol (vitamin E) in patients with a thin endometrium who were enrolled in an oocyte donation programme. Eighteen oocyte recipients who failed to develop a pre-ovulatory endometrial thickness of at least 6 mm after receiving vaginal micronized estradiol were enrolled in the study. The patients received a combination of PTX (800 mg/day) and vitamin E (1000 IU/day) for 6 months. The main outcome measurements were the change in endometrial thickness and the pregnancy and delivery rates after treatment. Endometrial thickness increased significantly (P <0.001), with a mean of (+/-SD) 4.9 +/-0.6 mm before and 6.2 +/- 1.4 mm after treatment, with 72% (13/18) of patients being good responders. Five patients either did not respond to the treatment or responded only slightly. Three patients, of which two had received previous radiotherapy, became spontaneously pregnant, and two became pregnant after embryo transfer. Three patients did not have embryo transfer. A total of four babies were delivered. The pregnancy rate was thus 33% and the delivery rate 27%. Treatment by combination of PTX and vitamin E appears to improve the pregnancy rate in patients with a thin endometrium by increasing the endometrial thickness and improving ovarian function. This was especially noticeable in patients who had previously received total body irradiation.
Gleicher N et al., 2001·Early Pregnancy (Cherry Hill)·
Innumerable studies have attempted to demonstrate that hormonal support of the luteal phase during ovulation induction cycles improves pregnancy rates. None has, however, so far been able to confirm the validity of such treatment conclusively, possibly because most studies only utilized progesterone substitution. Since luteal phase endometrium also requires estradiol support, this study attempted to investigate whether hormone substitution with progesterone and estradiol would be more successful in improving pregnancy rates. Amongst approximately 7500 consecutive ovulation induction cycles were identified prospectively which were characterized by a precipitous drop of luteal phase serum estradiol levels by more than 50% over a 48 hour period within 10 days from hCG administration. Those cycles were prospectively randomized to oral micronized estradiol substitution (Group I) or not (Group II), while both groups received routine progesterone substitution of the luteal phase. Cycles were then evaluated in regards to the occurrence of chemical, ectopic and clinical pregnancies. One hundred sixty-three Group I cycles resulted in 34 pregnancies (20.9%), which compared favorably to 21 pregnancies in 167 Group II patients (12.6%) (x2[1] = 4.06; p < 0.04). The advantage for Group I cycles (29/95 pregnancies, 31%) vs. Group II cycles (16/105, 15%) became even more pronounced when only women up to age 35 years were evaluated. Estradiol substitution maintained a significant advantage until age 38 (x2 [1] = 6.87; p < 0.009). While gravidity did not affect pregnancy success, estradiol substitution in Group I benefited nulliparous (23% pregnancy rate) over multiparous women (12% pregnancy rate) (x2 [2] = 6.86; p< 0.03). This association was, however, age-dependent. A combined estradiol and progesterone substitution of the luteal phase of ovulation induction cycles increases the overall pregnancy rate. Since estradiol substitution was initiated in this study only once a precipitous drop in serum estradiol levels had already taken place, an even larger improvement in pregnancy rates could conceivably be possible if earlier estradiol substitution of the luteal phase is initiated. A further expansion of investigations of similar protocols for routine ovulation induction and in vitro fertilization (IVF) cycles may be indicated, especially in women below age 38 years and in nulliparous females.
To compare the rates of ovulation and pregnancy after tamoxifen citrate (TMX) or clomiphene citrate (CC) among anovulatory women with infertility. Prospective randomized trial. Infertility clinic in a university teaching hospital. PATIENT(S): Eighty-six anovulatory women under 40 years of age undergoing ovulation induction. INTERVENTION(S): The women were assigned randomly to receive either TMX or CC on cycle days 5-9. MAIN OUTCOME MEASURE(S): Rates of ovulation and pregnancy for the two treatment modalities. RESULTS(S): The overall rate of ovulation in the TMX group was 50 of 113 (44.2%) and in the CC group, 41 of 91 (45.1%). There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group. The cycle fecundity per ovulatory cycle was 20.0% in the TMX group and 14.6% in the CC group. CONCLUSION(S): The overall rate of ovulation and pregnancy were similar with TMX and CC. TMX is a suitable alternative agent to CC in the management of anovulatory infertility.
The present study was designed to evaluate the prognostic value of salpingoscopy in patients undergoing tubal laparoscopic surgery for infertility due to periadnexal adhesion or distal tubal occlusion. In addition, the clinical value of salpingoscopy was compared with a current classification system of adnexal adhesions and distal tubal occlusion. A total of 51 patients with either adnexal adhesions (24 patients) or hydrosalpinx (27 patients) were prospectively evaluated. Salpingoscopy was performed concomitantly with salpingo-ovariolysis or salpingoneostomy at the time of operative laparoscopy. There was no significant correlation between salpingoscopic classes and the classification system used for both the salpingo-ovariolysis and the salpingoneostomy groups of patients. The patients had a mean follow-up of 33 months. Patients with a normal tubal mucosa (salpingoscopic classes I and II) had a 71% cumulative term pregnancy rate in the salpingo-ovariolysis group and a 64% cumulative term pregnancy rate in the salpingoneostomy group. No intrauterine pregnancies were obtained in patients with intratubal damage (salpingoscopic classes III to V). There was a statistically significant correlation between the occurrence of a term pregnancy and the salpingoscopic classes, but not with the classification system used. These results suggest that patients with tubal infertility should be offered operative laparoscopy with salpingoscopy as the first step of treatment.
To assess the intratubal pressure (ITP) and patency status of the fallopian tubes before and after transcervical catheterization of the fallopian tubes (TCFT). Prospective procedural assessment. Pope Paul VI Institute for the Study of Human Reproduction. PATIENT(S): Two hundred thirty-four women with either primary or secondary infertility. INTERVENTION(S): Patients underwent selective hysterosalpingography and, in some cases, TCFT with measurement of the ITP before and after the procedure. MAIN OUTCOME MEASURE(S): The ITP before and after TCFT. RESULT(S): The mean (+/-SD) ITP in freely patent tubes was 0.53 +/- 0.06 atm, that in partially obstructed tubes was 1.23 +/- 0.52 atm, and that in completely obstructed tubes was 2.79 +/- 1.40 atm. After TCFT, the mean (+/-SD) ITP in partially obstructed tubes decreased to 0.64 +/- 0.31 atm and that in completely obstructed tubes decreased to 1.86 +/- 1.35 atm. The ITP was normalized in 76% of partially obstructed tubes and in 29.5% of completely obstructed tubes. In all cases of complete obstruction in which surgical correction was attempted, organic pathology was identified. CONCLUSION(S): The procedure described is a safe and easy means of obtaining reliable and significant information on the status of the proximal fallopian tube.
Outcomes and Effectiveness · Outcomes by Diagnosis
This meta-analysis was intended to evaluate differences in pregnancy rates after in-vitro fertilization (IVF) in tubal fertility with and without hydrosalpinx. It examined nine published retrospective comparative series and five series published as abstracts for which additional information was obtained. In all, these studies involved 5592 patients (1004 with hydrosalpinx and 4588 with tubal infertility without hydrosalpinx). The main outcome measures were rates of pregnancy, implantation, live delivery, and early pregnancy loss. Pregnancy rates were significantly lower in the presence of hydrosalpinx: 31.2% for the tubal sterility group without hydrosalpinx and 19.7% for the group with hydrosalpinx (odds ratio: 0.64; 95% confidence interval: 0.56, 0.74). Similarly, the implantation rate and the delivery rate per transfer in the hydrosalpinx group were only slightly more than half those of the non-hydrosalpinx group (implantation: 8.5 and 13.7%, respectively; delivery: 13.4 and 23.4%). The incidence of early pregnancy loss was also higher in the hydrosalpinx group (43.7%) than in the control group (31.1%). This meta-analysis makes it clear that hydrosalpinx present during IVF-embryo transfer has negative consequences on the rates of pregnancy, implantation, live delivery, and early pregnancy loss. It would be premature, nonetheless, to conclude that routine salpingectomy should be performed on all patients with hydrosalpinx.
To review the physiology, pathology, and treatment of proximal tubal disease. Relevant reports on the pathophysiology of proximal tubal disease were reviewed. All studies in English of microsurgery and macrosurgery, and of radiographic and hysteroscopic cannulation in women with proximal tubal blockage were identified through MEDLINE searches. All studies of therapy for proximal blockage that included pregnancy rates were considered. Series of sterilization reversals, series of unilateral or combined procedures, and series in which the location of tubal blockage was not given were excluded from the data analyses. Raw data were assessed for homogeneity, then standardized and pooled. Total and ongoing pregnancy rates after microsurgery and macrosurgery, as well as radiographic and hysteroscopic transcervical cannulation, were compared by the chi2 test. Relative risks for total and ongoing pregnancies were calculated for all treatment methods. RESULT(S): This meta-analysis suggests that, overall, microsurgical anastomosis results in higher total and ongoing pregnancy rates than macrosurgery or radiographic tubal cannulation. However, pregnancy rates in selected series of transcervical tubal cannulation are similar to those reported for microsurgery. CONCLUSION(S): Ongoing intrauterine pregnancy rates near 50% can be achieved in patients with proximal blockage of the fallopian tube. Selective salpingography and transcervical cannulation under fluoroscopic guidance are effective at establishing patency in appropriately selected patients and are less invasive and costly than the surgical alternatives.
To investigate whether the timing of administration of clomiphene citrate (CC) affects hormone levels, follicular recruitment, reproductive end organs, and pregnancy rates. Prospective, randomized, double-blind trial. Academic center. PATIENT(S): Twenty-three patients with unexplained infertility. INTERVENTION(S): Twenty-three patients with unexplained infertility underwent 45 cycles of CC and IUI. For each cycle, patients were randomized either to receive 100 mg of CC on days 1-5 and placebo on days 5-9 (study group), or placebo on days 1-5 and CC on days 5-9 (control group). MAIN OUTCOME MEASURE(S): The difference in uterine artery PI, number of follicles, endometrial thickness, and pregnancy rates. RESULT(S): Gonadotropins and E2 levels, as well as uterine artery pulsatility index, were significantly higher in the study group on day 5. In addition, in the study group, a longer time interval existed between finishing CC and IUI (8 versus 6 days; MD = 2 days; 95% CI = 1-3) and the pregnancy rate was higher than in the control group (6 versus 0; OR = 15.1; 95% CI = 1.1-72.4). CONCLUSION(S): Clomiphene citrate commenced on day 1 of the menstrual cycle, rather than day 5, results in more rapid follicular growth, a longer CC-free period before IUI, and higher pregnancy rates. Although methodologically sound, our results should be taken with some degree of caution because they are based on a relatively small number of patients.
Audebert AJ et al., 1998·Human reproduction (Oxford, England)
The aim of this prospective study was to assess the value of laparoscopic treatment of severe fimbrial occlusions. During a period of 52 months infertile patients with fimbrial lesions were treated by operative laparoscopy. Only those patients requiring incision of the tubal serosa (salpingostomy) were included, representing the most severe lesions. The most frequent cases, those patients requiring simple adhesiolysis and deagglutination of the fringes, were excluded. All tubal lesions were documented carefully. Positive Chlamydia trachomatis (CT) serology was found in 65.7% of the patients. All the patients were followed up for at least 2 years. Three patients lost to follow-up were defined as failures. The global conception rate was 74.3%. The intrauterine pregnancy rate was 51.4%, and the 'take home baby rate' was 37.1% (only the first pregnancy being taken into account). The ectopic pregnancy rate was 22.9%. A positive CT serology was found to have a significant influence on the outcome. It can be concluded that the laparoscopic approach provides results similar to those obtained by microsurgery for the treatment of severe fimbrial occlusions, and represents an acceptable alternative to in-vitro fertilization (IVF) in selected cases.
Kasia JM et al., 1997·European journal of obstetrics, gynecology, and reproductive biology
OBJECTIVE(S): To study the fertility results after laparoscopic distal tuboplasty and compare them with the data in the literature. 194 laparoscopic distal tuboplasties were carried out from May 1992 to May 1994 in the Yaounde General Hospital (Cameroon). The results were analysed according to the age of the patients, the type and duration of infertility, past history of abortion, laparotomy and Chlamydia trachomatis infection, the tube and adhesion scores, surgical procedures and achievement of pregnancy. The fertility rates were calculated according to Cramer's method [11]. The cumulative pregnancy rate curves were drawn up from the life table [12] and compared using the Log-Rank test. 53 patients obtained pregnancy (27.3%) of which 45 were inter-uterine (23.2%) and 8 ectopic (4.1%). Of the 45 intra-uterine pregnancies (IUP), 36 were obtained after fimbrioplasty (33.3%) and 9 after neosalpingostomy (10.5%). The monthly fertility rate at one year was 1.4%. The rate of IUP for tube stages I and II is significantly higher than that for stages III and IV (p<0.001). However the rate of ectopic pregnancies (EP) is proportional to damage to the tubes. Infection with Chlamydia trachomatis, and residual inflammation could have an effect on the achievement of pregnancy. CONCLUSION(S): Our results are similar to those found in the literature. The tube stage thus remains the decisive factor in terms of fertility (Cox: p<0.001). Operative laparoscopy is the best alternative in our countries compared with laparotomy for distal tubal pathology.
To evaluate effectiveness and safety of a regimen of extended clomiphene citrate (CC) and prednisone for patients who fail treatment with CC alone. Retrospective observational analysis. University-based tertiary infertility center. PATIENT(S): Twenty-four anovulatory patients who failed to ovulate after CC 150 mg administered for 5 days. INTERVENTION(S): Treatment consisted of CC given on cycle days 3 through 9 (extended) at a starting dose of 100 to 150 mg/d. Additionally, patients were given prednisone 5 mg orally each night throughout the cycle. MAIN OUTCOME MEASURE(S): Ovulation was confirmed by luteal serum P. Pregnancy was confirmed by rising hCG levels and transvaginal ultrasound. RESULT(S): A total of 60 cycles were available for review. Forty-four of these cycles were ovulatory (73%) and 11 patients (46%) conceived on this therapy. Logistic (two-parameter) pregnancy occurrence over time (cycles) revealed a maximum pregnancy probability of 0.66 and a cycle fecundity of 0.36. No complications of therapy were noted. CONCLUSION(S): Clomiphene citrate-resistant anovulatory patients have high rates of ovulation and pregnancy after treatment with extended CC and prednisone. This therapy offers a potential reduction in cost and risk and should be considered in this group of patients before gonadotropin stimulation or surgery.
To determine pregnancy rates (PR) after fimbrioplasty and salpingostomy in nonocclusive distal tubal disease. To evaluate the relative impact of various factors using contemporary statistical analysis. Prospective cohort. Tertiary institutional infertility clinic. PATIENTS(S): Infertility patients. INTERVENTION(S): Fimbrioplasty and salpingostomy. MAIN OUTCOME MEASURE(S): Cumulative PR, monthly fecundity rates, monthly probability of pregnancy, crude PR, and cure rates. RESULTS(S): Thirty-five percent of patients conceived with a cure rate of 72.2%, monthly probability of pregnancy of 3.9%, and monthly fecundity rate of 3.9%. Cumulative PRs were 22%, 35%, and 58% at 6, 12, and 24 months, respectively. Pairwise comparisons (unilateral, bilateral, or either) failed to detect any statistical difference between the salpingostomy and fimbrioplasty groups. Salpingostomy patients initially may have a higher tendency to become pregnant but appear to lose that advantage after the first few months. When patients with tubo-ovarian adhesions are excluded from the analysis, patients who underwent a bilateral salpingostomy as their sole procedure had better outcome compared with those who only underwent bilateral fimbrioplasty. There was no significant association between pregnancy outcome and the presence of endometriosis, other infertility factors, or tubo-ovarian adhesions. The staging of adnexal adhesions and endometriosis did not predict pregnancy outcome. CONCLUSION(S): Laparoscopic fimbrioplasty and salpingostomy are clinically efficacious for the treatment of nonocclusive distal tubal disease. After accounting for statistical interactions of various factors among them, no particular association with pregnancy outcome could be identified. This illustrates the need for a revision of the classification of patients with distal tubal disease.
Recurrent miscarriage remains an enigma. The main aetiologies are endocrinological, immunological and unexplained. With the growth in molecular biology, it is now possible to look at the effect of these aetiologies in more detail, allowing greater understanding of the underlying pathogenesis.
To investigate whether luteal and endometrial abnormalities occur more frequently in an infertile population and thus contribute to infertility. Prospective controlled clinical study. Outpatient clinic in an academic research institution. Thirty-three fertile controls and 31 infertile women without ovulatory disorders, tubal disease, or male factors. All women underwent an endometrial biopsy 9 days after the LH surge followed by an IM injection of 5,000 IU hCG. Blood samples were drawn immediately before hCG administration for serum P and placental protein 14 (PP14) measurements, at 6 hours after hCG stimulation for serum P concentrations, and on day 5 after hCG administration for serum PP14 levels. Histologic dating of the endometrium and serum P and PP14 measurements. Abnormal endometrial biopsies occurred more frequently in infertile (43%) than in fertile women (9%). Except for one case, these specimens were not associated with low hCG-stimulated P levels. Serum PP14 measurements varied widely and did not discriminate subjects with abnormal endometrial development. Disruption of endometrial maturation without a concomitant defect of the corpus luteum occurs more frequently in an infertile population and thus may contribute to infertility.
The pulsatile release pattern of LH during the entire menstrual cycle is well defined; however, the response of corpora lutea to these LH pulses in patients suffering from corpus luteum insufficiencies (CLI) is largely unknown. Patients suffering from CLI were selected from infertile patients on the basis of low progesterone (P < 25 nmol/L) in a blood sample withdrawn during a monitoring cycle. During the next cycle, nine blood samples were collected during the follicular and luteal phase and follicular development was assessed by vaginal sonography. Of 109 patients who had a CLI in the monitoring cycle, 55 had a CLI again, and 38 women agreed to undergo assessment of pulsatile hormone secretion. These women again had P < 25 nmol/L at days 6 and 7 of the luteal phase and blood samples were withdrawn through antecubital vein catheters from 0900-1700 h at 10-min intervals on days 7, 8, or 9 following ovulation. From 38 patients with such defined CLI, 16 (42%) had no LH episode and significantly lower basal LH levels in comparison with 14 control subjects. Thirteen (34%) of the patients had normal appearing LH episodes despite too low P and E2 concentrations, but their CL did not react to the LH episodes. The remaining 9 patients (24%) had normal LH episodes; their CL reacted to these episodes, but their basal P levels were too low. In all blood samples LH was not only determined using an immunoassay but also by the mouse Leydig cell testosterone production bioassay. It could be established that no CLI exists, which is due to the release of bioinactive LH. It is anticipated that the differentiation of three different types of CLI, one of hypothalamic and two of ovarian origin, may allow the development of differential diagnostic and therapeutic tools in the future.
To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test.
Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients were divided into two groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule. Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels. The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.
To compare the prognostic value of salpingoscopy with a current classification system of adnexal adhesions and distal tubal occlusion in patients with tubal infertility undergoing reconstructive tubal surgery. Prospective clinical study. Department of Obstetrics and Gynecology of the Catholic University, a tertiary care University Center in Rome, Italy. Fifty-five infertile patients with either adnexal adhesions (29 patients) or hydrosalpinx (26 patients) undergoing reconstructive tubal surgery. Salpingoscopy performed concomitantly to salpingo-ovariolysis or salpingoneostomy at the time of either operative laparoscopy or laparotomy using microsurgical techniques. Salpingoscopic findings were compared with a current classification system of adnexal adhesions and distal tubal occlusion. The patients were followed for a mean follow-up of 49 months; the pregnancy rates achieved were correlated with the salpingoscopic findings and the classification system used. There was a significant correlation between the salpingoscopic grade and the occurrence of a term pregnancy for both the salpingo-ovariolysis and salpingoneostomy groups of patients. There was no significant correlation between the classification system used and the occurrence of a term pregnancy for both groups of patients. Salpingoscopy plays an important role in selecting the patients who may benefit the most from reconstructive tubal surgery.
Valle RF, 1995·Obstetrics and Gynecology Clinics of North America
While uterotubal chromopertubations were performed early in the 1970s with the introduction of hysteroscopy, cornual cannulation was extended and adapted to fluoroscopy. The disadvantages of fluoroscopy include the difficulty in ruling out tubal spasm, inability to evaluate distal tubal disease, and other pelvic abnormalities. Tubal cannulation has emerged as an excellent alternative to treat patients with cornual obstruction. Only those patients in whom cannulation fails should be subjected to microsurgical reconstruction. While cannulation with coaxial catheters began under fluoroscopy, the use of the hysteroscope simplifies the technique. With laparoscopy the hysteroscopic approach enables tubal cannulation and evaluation of the entire pelvis. Treatment of additional problems affecting the fallopian tubes, particularly adhesions and endometriosis, is possible. Laparoscopy helps in monitoring the procedure and visual assessment of tubal patency. The ability to observe the uterotubal junctions directly by hysteroscopy provides an excellent approach for tubal cannulation. There are two techniques to cannulate the fallopian tubes, either with coaxial catheters or catheters with distal balloons, but the result obtained with these two techniques is similar. The simplicity of coaxial catheters makes this approach more appealing, and with the hysteroscope one can avoid exposure to radiation. The results obtained with tubal cannulation are encouraging and this procedure should be offered as the initial method to attempt treatment of tubal cornual obstruction. Often it can represent an excellent alternative to microsurgical tubal anastomosis, avoiding a laparotomy and extended disability.
Outcomes and Effectiveness · Cumulative Versus Per Cycle Reporting
The last decade has transformed the physician's approach to infertility. The development of IVF for its treatment has so improved our capacity to overcome this most distressing of disabilities that we now need to revise many of our working ideas on how it can come about. This is not because new causes have been discovered. Rather, an appreciation has been gained of how apparently minor disturbances can combine to cause a major disruption in the expectation of pregnancy.
At the best of times-and sometimes, no doubt, at the worst of times getting pregnant is a matter of chance. The parameter that describes this chance is the monthly probability of conception, known among epidemiologists as fecundability (f) (probability of achieving pregnancy in one menstrual cycle), and is similar to "monthly fecundity" (monthly probability of a live birth in one cycle exposed to the risk of pregnancy) (1). Like every statistic in biology, fecundability has a wide distribution of values in the population (modeled in Fig. 1). Figure 1 also illustrates a group of couples with a fecundability value of zero-meaning complete infertility, or sterility, which affects perhaps 5% of couples attempting to achieve a pregnancy.
To determine whether the diagnostic accuracy and prognostic value of hysterosalpingography (HSG) could be improved if routine spot films were replaced by an on-line recorded gynecoradiologic study.
Medical school-affiliated private infertility center.
In 1992, a review of 152 infertile women with infertility who demonstrated a normal HSG, by standard criteria of spot film evaluation, in 117 (77%). They were further investigated by gynecoradiologic study if the HSG revealed asymmetrical tubal filling, an increased perfusion pressure, and/or evidence for abnormal tubal spill. In 1993, 47 women with normal HSG by spot film criteria underwent bilateral selective salpingography and were subdivided into those with normal (group I, n = 23) and abnormal (group II, n = 24) tubal perfusion pressures. Patients in both study groups then were treated for their infertility independently of pressure perfusion measurements.
Clinical pregnancy rates (PRs) over the ensuing 6 to 10 months. Among 117 women with apparently normal spot film HSG, 64 (55%) demonstrated asymmetrical tubal filling, 32 (27%) demonstrated abnormal spillage into the peritoneal cavity, and 55 (47%) demonstrated abnormally elevated injection pressures. Among 98 women who underwent bilateral selective salpingography, 43 (44%) demonstrated bilaterally normal tubal perfusion pressures and 55 (56%) showed an abnormally elevated pressure in at least one oviduct. Of 47 women that were followed prospectively in 1993, patients with normal perfusion pressure (group I) demonstrated a significantly higher PR than women with elevated tubal pressure (group II) from 2 months and on after the procedure. Routine spot film HSG is of limited value in assessing tubal status beyond the determination of tubal patency. Especially with regard to fertility potential, HSG should be replaced by gynecoradiologic study.
To assess uterine receptivity in women with unexplained infertility using integrin cell adhesion molecules as markers. Prospective, controlled study design. Eighty-seven nulliparous women with unexplained infertility and 32 fertile and infertile parous controls. Immunohistochemical staining for alpha 1, alpha 4, and beta 3 integrin subunits in endometrial biopsies obtained during the window of implantation (days 20 to 24), using the semiquantitative HSCORE by two observers in a blinded fashion. All endometrial biopsies from parous controls contained positive immunostaining for the alpha 1, and beta 3 integrin subunits in glandular epithelium. Some samples from parous controls were missing the alpha 4 subunit. In contrast, compared with parous controls, biopsies from women with unexplained infertility had reduced significantly beta 3 expression, with similar expression of alpha 1 and alpha 4. Two distinct defects in integrin expression were identified: "out-of-phase" samples that lacked beta 3 because of histologic lag (type I defects) and "in-phase" endometrium that still failed to express this integrin (type II defects). These subclassifications accounted for 26% and 39% of the total unexplained infertility group, respectively. Abnormal endometrial integrin expression was a frequent finding in women with unexplained infertility. These data suggest that defective uterine receptivity may be an unrecognized cause of infertility in this population of women.
Women with hyperandrogenic disorders represent a unique group among those with infertility due to anovulation. Although antiestrogens are effective in restoring ovulation in most women, it remains unclear whether these treatments restore fecundability per ovulatory cycle and the ability to maintain pregnancy in these individuals. Moreover, antiestrogens are ineffective in restoring ovulation in some hyperandrogenic anovulatory women, whose condition poses unique and vexing challenges for the infertility therapist. Gonadotropin treatment in antiestrogen-resistant women often leads to ovarian hyperstimulation syndrome, which has been addressed by modification of dosing schedules (e.g., low-dose administration), pretreatment with gonadotropin-releasing hormone (GnRH) analogs, and elimination of luteinizing hormone from the administered gonadotropins. Surgical reduction in ovarian volume has met with some success, although there may be a risk of inducing surgical adhesions of the adnexa. The second major reproductive adversity facing these patients is their elevated risk of endometrial cancer. Unopposed estrogen exposure probably contributes to this risk, but hyperandrogenicity and hyperinsulinism may act independently or in concert with estrogen to amplify the risk in these women. While the risks and strategies for preventive care in these women need to be better defined, reproductive health specialists are urged to continue using presently accepted measures, including education, to maintain these women's reproductive health.
To characterize ampullary endosalpingeal findings in women with occlusive or nonocclusive salpingitis isthmica nodosa. Prospective case study. Obstetrics and Gynecology Department of a University Hospital. Twenty women (38 tubes) with occlusive or nonocclusive salpingitis isthmica nodosa were studied. Salpingoscopy was performed during diagnostic laparoscopy in 20 women (38 tubes) with hysterosalpingographic evidence of salpingitis isthmica nodosa. Salpingoscopic findings were recorded and the patients were managed accordingly. Of the 38 tubes 10 appeared radiographically and laparoscopically normal. Two tubes were occluded distally. Of the 26 tubes with occlusive or nonocclusive salpingitis isthmica nodosa, 5 (19.2%) showed varying degrees of endosalpingeal abnormality. Patients with abnormal salpingoscopy were regarded as having bipolar tubal disease and were referred for assisted conception. The remaining patients were scheduled for microsurgical tubal reconstruction. One in five patients with proximal tubal disease may have ampullary endosalpingeal damage of varying degrees. However, the significance of this finding in relation to subsequent management strategies and fertility outcome is yet to be characterized.
To evaluate further the safety and efficacy of selective ostial salpingography combined with transcervical wire recanalization for the diagnosis and treatment of proximal tubal obstruction. Prospective study. Division of Reproductive Endocrinology and Department of Radiology at Harbor-University of California Los Angeles (UCLA) Medical Center, a tertiary care academic institution. Twenty-eight infertile patients diagnosed with proximal tubal obstruction by hysterosalpingogram (HSG) or by chromopertubation at laparoscopy (total of 46 obstructed tubes). After antibiotic prophylaxis and IV analgesia a conventional HSG was performed. If proximal tubal obstruction was confirmed, selective salpingography was done under fluoroscopic guidance. If proximal tubal obstruction was still present, wire recanalization using a new prototype cannula was then performed. If recanalization was successful, contrast media was injected to confirm tubal patency. Proximal tubal patency, complete tubal patency, pregnancies. Eleven of 46 tubes (23.9%) were patent by HSG. Ostial salpingography of the remaining 35 tubes revealed 6 patent tubes (13%). Nine of the 29 obstructed tubes (31%) had successful wire recanalization, and 8 of these were patent distally. There were 4 intrauterine pregnancies (IUPs) and 1 ectopic pregnancy after recanalization and 2 IUPs after ostial salpingography. Selective salpingography should be considered at the time of an HSG showing proximal tubal obstruction. If indicated, wire recanalization can also be attempted. Selective ostial salpingography combined with wire recanalization is a safe and effective procedure for the diagnosis and treatment of PTO.
Mårtensson O et al., 1993·Acta Obstet Gynecol Scand·
In 25 women with primary or secondary infertility, primary hysterosalpingography (HSG) or laparoscopy with chromopertubation indicated 33 proximal and 2 distal tubal obstructions. Four salpingectomies had been performed earlier. All patients were considered for transcervical catheter salpingoplasty (TCSP) to reconstruct tubal patency. Secondary examination with repeat HSG or selective osteal salpingography confirmed 26 proximal and 3 distal tubal occlusions while 17 tubes were patent. Selective osteal salpingography was performed successfully in 32 of 33 (97%) tubes. Sixteen of 26 (61.5%) proximally occluded tubes were successfully recanalized by coaxial catheter and guidewire technique while two of three distally occluded tubes were reopened by forceful flushing of contrast medium. So far, one ectopic and five intrauterine pregnancies were achieved in ten patients with observation time more than four months. Three patients have had normal deliveries. The favorable results, lack of complications and low costs seem to justify the recommendation to use selective salpingography and fallopian tube recanalization as the first intervention in patients with obstruction of the proximal fallopian tube.
To evaluate publications that introduced novel diagnostic and therapeutic transcervical procedures on the fallopian tubes. Major studies that conceptually changed the therapeutic approach to the fallopian tubes were reviewed. Minor publications were also included if they introduced a new concept or contributed to the topic. Clinical publications were selected if they involved transcervical diagnosis and treatment of fallopian tubes. Transcervical tubal catheterization procedures for diagnosis of tubal disease, tubal obliteration, tubal recanalization, and tubal medication are minimally invasive procedures that can improve our understanding and diagnostic accuracy of tubal disease. These procedures allow transcervical treatment of proximal tubal occlusion. Further improvements in equipment and methodology are promising. Transcervical tubal occlusion, gamete and embryo deposition, and treatment of ectopic pregnancy may all be performed using the transcervical approach. Transcervical tubal catheterization can replace microsurgery and IVF in selected patients with proximal tubal occlusion, improve the diagnostic accuracy of tubal disease, and deliver medications to the fallopian tubes. Cumulative knowledge suggests that transcervical tubal catheterization should become a universally accepted, taught, and practiced approach in the diagnosis and treatment of the fallopian tubes.
To assess the endocrinologic and clinical outcome after laparoscopic ovarian electrocautery because of polycystic reaction to ovarian stimulation in anovulatory infertility patients. Between 1986 and 1989, 133 patients with polycystic ovarian disease underwent laparoscopic electrocoagulation of the ovarian surface in an outpatient clinic after conventional ovarian stimulation had led to polycystic reaction. All patients were referred to our outpatient clinic affiliated with the university hospital. The reduction of androgen levels and normalization of cycle length were highly significant. The overall pregnancy rate was 70% (73 of 104), ranging from 27% in smokers to 94% in nonsmoking couples. In 26 second-look operations de novo adhesions were found in 26.9% of the patients. Laparoscopic coagulation of the ovarian surface is an effective tool to reduce elevated androgen levels and to improve the intraovarian mechanism of selecting a dominant follicle. A postoperative complication may be adhesion formation.
Induction of ovulation is indicated for anovulatory and amenorrheic women as well as for women who have an inadequate luteal phase. It is also indicated as a strategy for recruiting multiple follicles for women with unexplained infertility and those who are undergoing assisted reproductive technologies. The use of various agents and detection of ovulation are described. This includes a discussion of clomiphene citrate, bromocriptine, human menopausal gonadotropins, urinary follicle stimulating hormone and pulsatile gonadotropin releasing hormone therapy. Regimens, success rates and potential complications of each form of therapy are reviewed. Also discussed is the use of combination therapy and partial ovarian destruction.
Ovarian laparoscopic resection was applied to 23 sterile patients affected with polycystic ovarian disease (PCOD) resistant to different pharmacological treatments, in order to induce ovulation. After resection, 56% of the patients had spontaneous ovulatory cycles and 13 pregnancies arose. Ten of the pregnancies were spontaneous and three followed treatment with clomiphene. Hormone changes were assessed in 15 patients, including five with spontaneous menstruation but without ovulation and five with persistent amenorrhoea for 3 months after resection. A significant decrease in both androstenedione and testosterone levels occurred in all patients. These decreases were not related to the clinical results of resection. Luteinizing hormone (LH) did not vary greatly in any group after resection. Mean values and mean pulsatility of follicle stimulating hormone (FSH) increased significantly only in pregnant patients or those with spontaneous ovulatory cycles. The results of gonadotrophin-releasing hormone (GnRH) assays did not change after resection. The mechanisms involved in the resumption of cyclic function of the hypophyseal-ovarian axis after resection are discussed briefly.
Cervical mucus is produced throughout the menstrual cycle. Sperm migration, however, is possible only during the periovulatory period of the cycle. Cervical mucus is also produced during the amenorrhoeic post-partum period. Post-partum mucus is very similar to luteal phase mucus except that it can allow sperm migration. In this study, mucus samples obtained from all these periods were classified according to their capacity to allow sperm migration. The biochemical characteristics of mucus samples that did (peri-ovulatory and 40% of post-partum samples) and did not (luteal and 60% of post-partum samples) allow sperm migration were then compared. Mucus samples with positive sperm migration showed the highest percentage of water and lowest protein and glycoprotein concentration (per ml of mucus). In addition, post-partum mucus samples with positive sperm migration showed lower concentrations of proteins and glycoproteins than post-partum mucus samples that did not allow sperm migration. However, the amount of glycoproteins per mg of protein was similar between post-partum samples that were positive and negative for sperm migration. These data suggest that the carbohydrate composition of the glycoproteins is playing a key role in the ability of cervical mucus to accept spermatozoa.
From 1960 10 1984, 2,501 women underwent diagnostic laparoscopy (index laparoscopy) because of a clinical suspicion of acute pelvic inflammatory disease (PID). Of these women, 1,844 had abnormal laparoscopic findings (patients) and 657 had normal findings (control subjects). The reproductive events after index laparoscopy of 1,732 patients and 601 control subjects were followed. The patients and control subjects were followed for a total of 13,400 and 3,958 woman-years, respectively. During the follow-up period, 1,309 (75.6%) of the patients and 451 (75.0%) of the control subjects attempted to conceive. Of these women, 209 (16.0%) of the patients and 12 (2.7%) of the control subjects failed to conceive. A total of 141 (10.8%) of the patients and 0 (0%) of the control subjects had confirmed tubal factor infertility, 21 (1.6%) of the patients and 3 (0.7%) control subjects had other causes of infertility, and 47 (3.6%) patients and 9 (2.0%) control subjects did not have a complete infertility evaluation. Additional information on tubal morphology (hysterosalpingography, laparoscopy, or laparotomy) in women from couples for whom evaluation was incomplete indicated that 165 (12.2%) patients and 4 (0.9%) of the control subjects had abnormal tubal function or morphology after index laparoscopy. Tubal factor infertility after PID was associated with number and severity of PID episodes. The ectopic pregnancy rate for first pregnancy after index laparoscopy was 9.1% among the patients and 1.4% among control subjects.
To review, evaluate, and synthesize current published reports assessing the value of abdominal myomectomy in infertile women and those desiring to preserve fertility potential. Major studies dealing with myomectomy were identified through Medline Searches. Those papers reporting the results of myomectomy, factors influencing them, and potential future innovations were obtained. More than half of women not previously pregnant and undergoing myomectomy to preserve childbearing capacity for treatment of recurrent pregnancy wastage or previous infertility conceive. The long duration of infertility before surgery, absence of other factors to explain their not conceiving, and short time interval subsequent to surgery in which conception occurs suggests myomectomy has value in treatment of patients with leiomyomata and otherwise unexplained infertility. The operation carries acceptable risk. Approximately 25% of women undergoing myomectomy have recurrent leiomyomata, but most recurrences are sufficiently delayed to allow adequate opportunity for conception. Abdominal myomectomy is an appropriate alternative to hysterectomy for most women who wish to preserve childbearing potential or enhance it. For the future, myomectomy by endoscopic techniques may hold similar potential.
Clomiphene citrate therapy has been found to improve the infertility rate in women suffering from polycystic ovarian disease (PCOD). However, there still exists a group of women with PCOD who fail to respond to clomiphene citrate or human menopausal gonadotropin/human chorionic gonadotropin or urofollitropin/chorionic gonadotropin treatment, an ovarian wedge resection by laparotomy approach which has been known for 50 years. Within the last decade, translaparoscopic electrocautery and laser drilling techniques have been utilized. In 1986, a translaparoscopic carbon dioxide laser ovarian wedge resection was introduced for resistant PCOD. This paper describes the surgical principle of a translaparoscopic carbon dioxide laser ovarian wedge resection. This type of treatment results in a 75% crude conception rate, with a 67% rate of healthy live birth. There was an 8% postsurgical adhesion rate among 12 cases that were incorporated into the study. This mode of therapy may prove to be very useful, safe, easy to perform, and cost effective as a second-line therapy for resistant PCOD in cases where medical inductions fail to achieve ovulation.
To determine possible etiologies of unsuccessful fluoroscopically guided tubal canalization, we studied the histology of tubal segments in cases of failed canalization for proximal tubal obstruction. Factors contributing to cases of unsuccessful fluoroscopically guided tubal canalization remain unclear. Prospective. Reproductive Endocrinology Clinic. Twenty-seven cornual and/or isthmic tubal segments from 15 patients who underwent proximal tubal surgery after fluoroscopically guided tubal canalization were studied. Specimens were prepared with hemotoxylin-eosin and Masson trichrome stains. Histologic examination of excised cornual and isthmic tubal segments revealed abnormalities in 93% of specimens. Obliterative fibrosis (61%), chronic salpingitis (57%), and salpingitis isthmica nodosa (42%) were the most commonly found histologic tubal abnormalities. One case of complete tubal occlusion and tubal schistosomiasis was also detected. These data suggest that cases of failed fluoroscopically guided tubal canalization may be secondary to severe intrinsic tubal disease and tubal occlusion and not to the technique. Fluoroscopically guided tubal canalization may provide a means of differentiating a functional obstruction amenable to conservative management from true occlusion requiring management by microsurgical techniques or in vitro fertilization.
To test a sonoscopic technique developed for transvaginal catheterization and recanalization of the fallopian tube. In a feasibility study, catheterization was performed with the use of laparoscopic control. Patients with bilateral proximal tubal obstruction underwent fallopian tube recanalization under ultrasonic observation. This study represents patients evaluated for primary or secondary infertility at Humboldt University Hospital. PATIENTS, Proximal tubal obstruction had been diagnosed on previous hysterosalpingogram and with laparoscopy. None. Tubal patency was assessed by hydrotubation under ultrasonic observation. Transvaginal catheterization was successful in 31 (91.2%) of the 34 tubes. In 19 patients with proximal tubal obstruction, patency of both or at least one tube was achieved in 16 (84.2%) women. Five (31.6%) of 16 patients successfully recanalized were found to have an intrauterine pregnancy at a 6-month follow-up interval. This catheterization technique should be investigated for possible use in diagnostic schedule early in the evaluation of the infertile patient. Also, the transvaginal recanalization of proximally obstructed tubes calls into question the application of microsurgical treatment of a selected group of patients.
Evaluation of selective salpingography for diagnosis and treatment of tubal injection failure during hysterosalpingography (HSG). Prospective study. Obstetrics and Gynecology Department, University of Genoa (Italy)--tertiary care. One hundred eighty infertile women with unilateral or bilateral proximal tubal injection failure during HSG were submitted to the procedure. Under fluoroscopy, a 4.5-F nylon catheter (3-F tip) was inserted into the ostium with or without the aid of a J-shaped, coaxial, angiographic guide wire, and 2 to 3 mL of contrast medium were injected. The procedure lasts 20 to 30 sec/tube. Of 155 tubal ostia, 145 (94.2%) were catheterized. Of the 146 catheterized tubes, 110 (75%) were rendered patent. Of the others, 21 (14.3%) presented hydrosalpinx or distal obstructions, and isthmic obstruction was present in 5 (3.4%). Patency of at least one tube was achieved in 82 (81.2%) of the 101 catheterized women; 8 conceived spontaneously and 11 after gamete intrafallopian transfer to the recanalized tube. During HSG, selective salpinography can be performed when proximal injection failure is observed to determine its cause or to restore patency.
In this study we have evaluated the score, sperm migration and ultrastructural characteristics of cervical mucus present in amenorrhoeic women under exclusive breastfeeding at 30, 60, 90, 120, 150 and 180 days post-partum. Periovulatory mucus samples from seven normally cycling women were used as a control. The average scores of post-partum and periovulatory mucus were 4.6 +/- 0.4 and 14.1 +/- 0.5 respectively. Twenty-one (39%) of the 54 post-partum cervical mucus samples and all (100%) periovulatory mucus samples allowed sperm migration. Positive sperm migration into post-partum mucus was observed at all time intervals studied. The only parameter that correlated with sperm migration into post-partum mucus was ferning formation. Sperm migration was obtained in all post-partum mucus samples with a score greater than 8, but samples with scores between 2 and 7 also showed sperm penetration. Scanning electron microscopic studies showed the characteristic spongy appearance of periovulatory mucus. Post-partum mucus was formed by a dense mesh (rocky appearance), when samples were generally unable to sustain sperm migration, but samples where sperm migration occurred showed small areas of spongy mucus mixed with areas in which a dense mesh and high cellularity was observed.
Women with luteal phase deficiency have been shown to have an increased frequency of luteinizing hormone pulses in the early follicular phase of the menstrual cycle. Because progesterone is known to modulate luteinizing hormone secretion, it has been hypothesized that the decreased progesterone secretion in a previous luteal phase deficiency cycle could lead to the abnormal luteinizing hormone secretory pattern in the ensuing early follicular phase. With the possibility that the higher luteinizing hormone pulse frequency might lead to another deficient luteal phase, it becomes conceivable that luteal phase deficiency could be self-perpetuating. To test this hypothesis, luteal phase deficiency was induced in six normal women by decreasing luteinizing hormone support of the corpus luteum with a gonadotropin-releasing hormone antagonist Nal-Glu, administered twice daily beginning in the midluteal phase after a control cycle. During the antagonist-treated luteal phase, each subject met the predetermined criteria for induced luteal phase deficiency: a 33% or greater decrease in integrated progesterone from the control cycle and an integrated progesterone level less than 100 ng/ml per day. Luteinizing hormone secretion patterns were determined by frequent blood sampling performed every 10 minutes for 12 hours in the early follicular phase of the control cycle and the cycle after antagonist administration. Daily luteal progesterone levels were measured in the control, treatment, and posttreatment cycles. Each volunteer served as her own control. Standard parameters were compared between the control and posttreatment pulse studies in the early follicular phase: (1) luteinizing hormone pulse frequency was 9.5 +/- 1.0 vs 10.0 +/- 0.9 pulses/12 hours, control vs posttreatment, respectively, p = 0.5; (2) luteinizing hormone pulse amplitude was 11.0 +/- 1.3 vs 12.0 +/- 2.2 ng/ml, p = 0.6; and (3) luteinizing hormone mean level was 19.4 +/- 2.3 vs 22.2 +/- 3.3 ng/ml, p = 0.1. Corpus luteum function was also compared between the control and posttreatment cycles. Luteal phase length was 13.7 +/- 0.6 vs 12.7 +/- 0.6 days, p = 0.08. Integrated progesterone values were 136.9 +/- 12.9 vs 130.5 +/- 11.3 ng/ml per day, p = 0.5. Therefore no discernible abnormalities in early follicular luteinizing hormone secretions or corpus luteum secretion of progesterone occurred after an induced luteal phase deficiency cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
Obstruction of the uterine (proximal) end of the fallopian tube is noted on up to 20% of hysterosalpingograms and has a variety of underlying causes. Definitive diagnosis and treatment in the past have required laparoscopy or laparotomy with tubal resection. Selective salpingography and fallopian tube recanalization with fluoroscopically guided catheters has emerged as an improved method both for diagnosis and treatment in these patients. Technical success rates for overcoming the obstruction and visualizing distal tubal anatomy range from 76% to 95%. Pregnancy rates after the procedure vary depending on the patient populations studied; however, early results indicate a greater than 50% intrauterine pregnancy rate by 1 year. The rate of ectopic pregnancy is approximately 10% and that of early tubal reocclusion is less than 30%. Selective salpingography and fallopian tube recanalization is recommended as the first intervention in patients with obstruction of the proximal fallopian tube.
Selective salpingography and transvaginal catheter dilatation were performed in 157 women with infertility to diagnose, localize, and classify obstructive diseases of the fallopian tubes and to correct obstruction of the proximal (uterine-end) tube. In 61 (39%) of the patients, the selective salpingograms showed patent tubes despite the fact that two previous hysterosalpingograms showed obstruction of the proximal (uterine-end) tube. Transvaginal catheter dilatation successfully recanalized the proximal portion of the tubes in 79 (82%) of 96 patients with obstructed tubes. In 18 of 25 with successful transvaginal catheter dilatation and 6-month follow-up salpingography, the tubes remained patent. Coexisting disease of the distal (ovarian-end) tubes was diagnosed in 29 (18%) of the patients. Pregnancy was achieved in 11 of the 157 patients (six in whom obstructions were corrected by transvaginal catheter dilatation and five in whom selective salpingograms showed patent tubes). There were no complications due to the procedure. The excellent diagnostic and therapeutic yield, lack of complications, and low cost justify the use of these percutaneous techniques to investigate female infertility and to treat obstruction of the uterine end of the fallopian tube.
Proximal tubal obstruction, either unilateral or bilateral, is a frequent finding on hysterosalpingogram (HSG). Approximately two-thirds of the fallopian tubes resected for proximal tubal obstruction reveal an absence of luminal occlusion. The distinction between true pathologic occlusion and either spasm or plugging is crucial in determining therapy. We combined hysteroscopic cannulation of the proximal fallopian tube with laparoscopy in 11 patients with proximal tubal obstruction diagnosed by HSG and confirmed at laparoscopy. Hysteroscopic cannulation was able to be performed in 72% of the fallopian tubes attempted, and there was a postcannulation patency rate by HSG of 73%. Six of the 11 patients became pregnant after tubal cannulation and adjunctive distal tubal surgery. Hysteroscopic cannulation of the fallopian tube is a safe diagnostic procedure that can be used to identify those patients with true proximal occlusion, and may also serve as a therapeutic procedure in some of these patients.
Borenstein R et al., 1989·Aust N Z J Obstet Gynaecol·
Fourteen pregnancies were achieved with tamoxifen therapy in 12 women who failed to conceive with clomiphene citrate. There were no side-effects and fewer treatment cycles were required than with clomiphene citrate treatment. Ovulation and cervical score with tamoxifen therapy were significantly higher (p less than 0.005).
Ultrasound (US) has been demonstrated to be the method of choice for diagnosing luteinized unruptured follicle syndrome and to be a valuable adjuvant in the assessment of luteal phase defect. In this prospective study, the use of US with postcoital testing (PCT) is evaluated. Fifty control infertility patients were examined with serial US for follicle dynamics in conjunction with PCT. Standard curves for follicle dynamics versus cervical mucus quality (Insler score) were calculated. Eighteen patients referred for abnormal mucus underwent similar evaluation. Their follicle dynamics versus mucus quality were compared with those of the controls. The findings were: (1) there is a predictable relationship between follicle size and mucus quality, (2) the majority of patients with abnormal mucus have normal follicular dynamics, and (3) a minority of patients with abnormal mucus have either a narrow mucus window or abnormal follicular dynamics. In addition, US was found to be cost-effective in the overall fertility evaluation.
Traditional therapies for abnormal cervical mucus, other than timed intrauterine insemination, are noteworthy for being ineffectual. Patients (n = 27) with documented abnormal Insler scores in repetitive cycles and failure to conceive with traditional treatments were screened with conjugated equine estrogens (CEE) for estrogen responsiveness of the cervix. Only 5 patients were found unresponsive. Seventeen patients with CEE-responsive cervices then were treated with human gonadotropins (hMG), initially 1 ampule days 5 to 11. If the mucus failed to improve, the hMG was increased to standard doses. Eight patients responded to 1 ampule hMG with improved mucus and conception. The remainder required 2 ampules hMG. In patient cycles with corrected cervical mucus, the viable fecundibility (fv) was 0.35. This is significantly higher than predicted for this population (fv = 0.09; P less than 0.01). In all, 14 of 17 patients conceived viable pregnancies during hMG treatment. It is concluded that graduated hMG is efficacious in treating patients with abnormal cervical mucus responsive to CEE. It is preferable to either in vitro fertilization or gamete intrafallopian transfer, based on both cost and efficacy for most patients.
Fertility and Outcomes · Conception After Excision
Pregnancy outcomes were evaluated retrospectively in 350 women to investigate the relationship between endometriosis and spontaneous abortions. The frequency of spontaneous abortions in women with endometriosis was significantly higher than in both a fertile nonendometriosis group and an infertile group with tubal disease. There was no correlation between the severity of the endometriosis and the frequency of spontaneous abortions. After treatment, the frequency of spontaneous abortions was significantly decreased in both the endometriosis and the tubal disease group, but these values were not significantly different from each other. We conclude that high spontaneous abortion rates are a characteristic of other subgroups of women with secondary infertility and not just in women with endometriosis, and that the majority of spontaneous abortions associated with endometriosis are not caused by the condition.
Diagnostic Criteria and Classification · Staging and Classification Systems
Pulsatile administration of gonadotrophin releasing hormone (GnRH) is a very effective treatment for induction of ovulation in hypothalamic amenorrhoea (HA). Thirty-seven women have been treated for a total of 117 cycles which resulted in 42 pregnancies--four treatment failures occurred. If these cycles are excluded, the 42 pregnancies were obtained within 2.3 cycles. One twin pregnancy occurred and no hyperstimulation was observed. The treatment was administered intravenously with a dosage schedule based on the grading of HA. We concluded that pulsatile GnRH was safe and very successful in induction of pregnancy in HA. Other indications (polycystic ovary syndrome and luteal phase defect) remain much less suitable for this treatment.
A deficiency in follicle stimulating hormone (FSH) levels during the early follicular phase of the menstrual cycle has been shown to result in luteal phase defect (LPD). A short course of human urinary FSH (uFSH) (Metrodin, Serono Laboratories) was given for a maximum of six cycles to 18 women with endometrial-biopsy-proven (EBX-proven) LPD. Adjunctive therapy in the form of midcycle human chorionic gonadotropin was given after the third therapy cycle. The uFSH therapy reduced the mean EBX lag time (2.0 +/- 0.6 days with therapy vs. 4.1 +/- 0.4 pretherapy, P less than .01), normalized the follicular phase length (15 +/- 0.4 days vs. 17.2 +/- 0.8 pretherapy, P less than .25) and increased the luteal phase length (12.7 +/- 0.4 days vs. 10.8 +/- 0.2 pretherapy, P less than .001). Twelve of 46 cycles (26%) in which uFSH was given without adjunctive therapy were anovulatory. Seven patients conceived; the result was seven viable pregnancies, all delivered at term. The cumulative pregnancy rate approached 48% by the sixth therapy cycle. uFSH therapy is useful for the correction of LPD and yields an acceptable pregnancy rate.
Attempts to induce ovulation have been made since the early 1920s, but the major breakthrough came in the early 1960s with the introduction of clomiphene citrate and the gonadotropins. Additional progress was made in the early 1970s with the introduction of bromocriptine and in the early 1980s with the introduction of pulsatile GnRH. At the present, 'pure' FSH and GnRH agonists are being evaluated as adjuncts to HMG for induction of ovulation. As more insight is gained in the neuroendocrine control of the ovulating cycle, we may soon be able to induce ovulation by direct manipulation of the central nervous system.
A technique of translaparoscopic salpingoscopy is utilized to evaluate the ampullary segment of the Fallopian tube in patients suffering from infertility. Comparison of this technique with hysterosalpingography in a series of 32 patients with hydrosalpinges demonstrates its superiority in the evaluation of the tubal mucosa. This new diagnostic approach allows a more accurate selection of patients for either microsurgical repair, in-vitro fertilization (IVF) or gamete intra-Fallopian transfer (GIFT).
The nature and incidence of normal and abnormal spontaneous ovarian cycles, identified with ultrasound and endocrine tracking, were examined in 45 regularly cycling infertile women with no definitive cause and 15 women who were apparently normal and were receiving donor insemination because of clearly infertile partners. In 136 cycles, four apparently distinct abnormal patterns were detected. The total incidence in the infertile group was 58% compared with 23% in the donor insemination group (P less than 0.005). Twelve of 26 subjects who had at least three cycles tracked showed two different abnormalities, and 1 subject had three different abnormalities in five abnormal cycles. These results suggest that abnormal cycles are a significant factor in unexplained infertility and that diagnosis and treatment cannot be based on the study of a single cycle.
Endocervical gland estrogen receptor (ER) deficiency has been proposed as a possible cause for the poor cervical mucus (CM) in some infertile women with cervical factor. Cytosol ERs were measured in endocervical tissue obtained by biopsy within 3 days of ovulation (determined by the endogenous luteinizing hormone [LH] surge) in five infertile women with persistent poor preovulatory CM (group 1) and in endocervical tissue obtained in the late follicular phase in eight ovulatory women with excellent CM (group 2). ER concentrations were measured in Fmol/mg protein by the dextran-coated charcoal separation method (New England Nuclear Kit, Boston, MA). CM score evaluation and measurement of serum estradiol (E2) and progesterone (P) levels were performed concomitantly. Serum E2 levels of 123.4 +/- 29.3 pg/ml (mean +/- standard error of the mean [SEM]) in group 1 were comparable to E2 levels of 123.3 +/- 15.0 pg/ml in group 2. Serum P concentrations of 0.9 +/- 0.27 ng/ml in group 1 were comparable to 0.79 +/- 0.29 in group 2. A CM score of 4.6 +/- 0.69 in group 1 was significantly lower than 11.6 +/- 0.53 in group 2 (P less than 0.01). The cytosol ER was negative in four of five women in group 1, whereas in group 2, ER was positive in six, borderline in one, and negative in one subject. This study suggests that cytosol ER may be deficient in some women with cervical factor.
The effectiveness of ovulation induction with clomiphene citrate or human menopausal gonadotropins was evaluated in 52 infertile women with stage I or stage II endometriosis and ovulatory dysfunction: anovulation or luteinized unruptured follicle (LUF) syndrome before (group I) and after (group II) danazol treatment. The incidence of anovulation and LUF in the endometriosis population was 9% and 34%, respectively. In group I, 10 of 36 patients (27.8%) conceived, with an average of 17.6 induction cycles per pregnancy. In group II, 21 of 30 patients (70%) conceived, with an average of 4.5 cycles per pregnancy (difference significant at P less than 0.001). There was no difference in the average number of ovulation induction cycles per patient between groups I and II (4.9 and 3.1, respectively). Of 14 patients who did not conceive in group I and crossed over to group II, 9 (64.3%) conceived (not different from group II). Spontaneous abortion rates were 20% in group I and 14% in group II. These results indicate that mild endometriosis may interfere with conception through mechanisms other than ovulatory dysfunction and that treatment with danazol appears to more than double the fertility rate.
An examination was made of the possibility that 100 to 200 ml of intraperitoneal 32% dextran 70 and/or 0.5% hydrocortisone sodium succinate (randomized independently with similar volumes of Ringer's lactate solution) might help to lessen the postoperative formation of adhesions among patients undergoing surgical procedures for peritubal adhesions (n = 76), endometriosis (n = 27), or midtubal occlusion (n = 61). Patients in the first two groups who were given intraperitoneal corticosteroids were also given systemic steroids. Nonparametric comparison of median adhesion scores at operation and at subsequent laparoscopy showed that there was a poorer outcome with dextran than when dextran was not used in every subgroup except one (repeat salpingolysis after previous operation for adhesions), including first operations for adnexal adhesions (Mann-Whitney U = 200, m = 23, n = 26; p less than 0.05). The probability was small (p beta less than 0.002) that an important beneficial effect of dextran was overlooked. Systemic corticosteroids were associated with a consistent trend toward improved outcome, especially in patients who initially had few or no adhesions, such as those operated on for endometriosis (U = 2, m = 7, n = 4; p less than 0.025), but among patients with tubal resections and anastomoses with adnexal adhesions the use of intraperitoneal hydrocortisone alone was associated with a worse outcome (U = 15, m = 12, n = 8; p less than 0.02). Life-table analysis of the accumulating probability of pregnancy showed that no significant difference resulted from adjunct use in any group. The conclusion is that no empiric basis supports the use of intraperitoneal 32% dextran 70 or 0.5% hydrocortisone in the attempt to prevent peritoneal adhesions, but further investigations on the systemic administration of corticosteroids to decrease the formation of adhesions would be useful.
More than 100 years after the first description of endometriosis, the pathophysiology of the disorder still remains an enigma. In addition to infertility, an increased frequency of clinically apparent spontaneous abortions (32% vs. 8-15% in the normal population and 19% in the infertile one) has been found in women with endometriosis and secondary infertility. Treatment of endometriosis with conservative surgery, danazol or both results in a frequency of spontaneous abortion within the range of the normal population's. Although the factors involved in the pathophysiology of endometriosis are probably multiple, abnormal corpus luteum function is a common mechanism that might explain both the infertility and the spontaneous abortions. Several studies suggested a relationship between endometriosis and corpus luteum function, which may be mediated by prostaglandins. However, not all the data have been supportive. We developed a hypothetical scheme (modified from Drake) that outlines possible mechanisms of endometriosis mediated by the adverse effects of increased prostaglandins. Further investigation of this scheme may provide new information about the pathophysiology of endometriosis.
Pittaway DE et al., 1984·The Journal of reproductive medicine
More than 100 years after the first description of endometriosis, the pathophysiology of the disorder still remains an enigma. In addition to infertility, an increased frequency of clinically apparent spontaneous abortions (32% vs. 8-15% in the normal population and 19% in the infertile one) has been found in women with endometriosis and secondary infertility. Treatment of endometriosis with conservative surgery, danazol or both results in a frequency of spontaneous abortion within the range of the normal population's. Although the factors involved in the pathophysiology of endometriosis are probably multiple, abnormal corpus luteum function is a common mechanism that might explain both the infertility and the spontaneous abortions. Several studies suggested a relationship between endometriosis and corpus luteum function, which may be mediated by prostaglandins. However, not all the data have been supportive. We developed a hypothetical scheme (modified from Drake) that outlines possible mechanisms of endometriosis mediated by the adverse effects of increased prostaglandins. Further investigation of this scheme may provide new information about the pathophysiology of endometriosis.
Interesting data on infertile human membranous mucus compared with infertile filamentous mucus have emerged from previous studies using scanning electron microscopy (SEM). The aim of this study was to obtain more information about the infertility of membranous mucus being independent of ovarian hormone stimulus. All different types of mucus, progressively secreted during the menstrual cycle by endocervical muciparous cells, were collected from the cervical canal of a fertile woman with a long menstrual cycle and specifically with a long infertile preovulatory period. The most significant results concern the identification of the cycle phase characterized by the presence of membranous mucus alone, i.e. the infertile preovulatory phase and the hormonal bases of membranous mucus infertility. The conclusion is reached that each ovarian hormone pattern stimulates the secretion of a specific type of mucus during the menstrual cycle.
Normal probability plots were used to assess the homogeneity of a population of 327 luteal phases from apparently ovulatory menstrual cycles. The length of the luteal phase was defined as the interval (in days) following but not including, the luteinizing hormone peak, up to and including the day before onset of menstruation. A small sub-set of the population consisted of cycles with abnormally short luteal phases but the majority of the data followed a normal frequency distribution which gave a mean (+/- SD) for normal luteal phase length of 14.13 (+/- 1.41) days. It was estimated that all cycles with a luteal phase less than or equal to 9 days were abnormal, and that 74%, 22% and 2% respectively of cycles with luteal phases of 10, 11 and 12 days were also abnormal. The total incidence of short luteal phases defined as above was 5.2%.
There seems to be an association of first-trimester spontaneous abortion and untreated endometriosis. In this report, 52% of an untreated group of patients with endometriosis aborted. However, 12% of a second group of surgically treated patients and 7% of a third group of patients treated with danazol aborted. Therefore, either medical or surgical therapy for endometriosis lowers the abortion rate significantly.
Diagnosis, choice of therapy, and pregnancy outcome were analyzed in 79 women evaluated for luteal phase inadequacy. Criteria for the diagnosis were established, and groups at risk for luteal inadequacy were identified. Treatment choices, tailored to the suspected cause, included progesterone suppositories in 54 women, with 23 pregnancies and 19 deliveries; clomiphene citrate in 6 women, with 2 pregnancies and deliveries; and combined treatment in 7 women, with 5 pregnancies and 4 deliveries. Eight women received no treatment, including three who underwent endometrial biopsy in the cycle of conception and who subsequently delivered. These data suggest that careful diagnosis and the proper choice of treatment are important, and that progesterone supplementation may result in improved pregnancy outcome for patients with infertility and pregnancy wastage who have luteal phase inadequacy.
Twenty-two infertile women with repeated deficient results in the postcoital test received clomiphene citrate or tamoxifen. The patterns of luteinizing hormone, follicle-stimulating hormone, prolactin, 17 beta-estradiol (E2), and progesterone were examined during the follicular and periovulatory phases of the menstrual cycle, as were the cervical mucus characteristics. Under clomiphene treatment, an overproduction of E2 was observed (P less than 0.01), which did not result in an improvement of the cervical mucus characteristics. The pH of the endocervical mucus was lower (P less than 0.01). Under tamoxifen treatment, the serum E2 levels were higher (P less than 0.05) and normalized. Higher spermatozoa penetration meter scores were observed during the preovulatory and periovulatory periods, whereas the pH of the endocervical mucus was not lowered. These data support that tamoxifen may be preferential to clomiphene in treating this kind of infertile woman.
In some series the most appropriate therapy for luteal phase defects is supplemental progesterone in the luteal phase. Clomiphene's efficacy is more controversial since in one series only 8% achieved a successful pregnancy versus 45% in another study. Pelvic sonography was used to evaluate follicular development and release of the ovum in 50 infertile women with luteal phase defects. The results showed that only 40% had "pure" luteal phase defects whereas 52% had immature follicles and 8% had unruptured follicles. Sixty-two percent of the patients had previous therapy for a luteal phase defect and failed to conceive. Sixty-eight percent of this group did conceive when ultrasound was used to determine the appropriate therapy. Thus ultrasound can be employed to determine if the women with a luteal phase defect should be treated with a fertility drug, e.g., clomiphene or just with luteal phase progesterone support. Supplemental progesterone might still be needed with clomiphene based on repeat endometrial biopsy results.
During the five years ending on December 31, 1981, 159 anovulatory and oligomenorrheic patients were treated with clomiphene citrate for induction of ovulation. Overall, 86% of these patients ovulated, and 49% of the patients who ovulated conceived. Life table analysis was employed to investigate factors contributing to reduced conception rates, including abnormal semen analysis, pelvic or tubal abnormalities, and poor cervical mucus. Elevated serum testosterone levels did not affect conception rates. The most significant factor contributing to reduced overall pregnancy rates was patient discontinuation of therapy. Cumulative pregnancy rates corrected for discontinuation approach 100% after ten cycles of therapy. During this period, the monthly probability of pregnancy (monthly fecundability) remained constant. Optimal pregnancy rates are attained if other infertility factors are corrected and treatment is continued for ten to 12 ovulatory cycles.
The cause of infertility has remained obscure in women with endometriosis in whom the tuboovarian relationship is unaltered. Abnormal corpus luteum function has been one mechanism implicated in the pathophysiology of endometriosis in infertilityl-3 and may also be a possible explanation for the high frequency of spontaneous abortions among women with untreated endometriosis.4 However, we have observed only an occasional occurrence of luteal phase deficiency in women with an ultimate diagnosis of endometriosis. In order to verify this observation, we examined the incidence of luteal phase defects (LPDs) in. our infertility population.
The incidence of luteal phase defects in 366 infertility patients was 12.7%. Life-table analysis was used for determination of the conception rate with clomiphene citrate therapy, and with this method, evidence was found for the presence of two subgroups with respect to response. The crude conception rate was 40.9%. In a group of patients with a luteal phase defect and no other infertility factors, those that conceived had a significantly larger mean biopsy delay than those who did not (6.28 days versus 4.32; P less than 0.02). In a group with a histologic delay of 5 days or more, the conception rate was 79%, while the rate was only 8.9% in those with a less severe deficit (P less than 0.001). Theoretic considerations for clomiphene citrate therapy are discussed.
Sixty-nine infertile women with a midluteal serum progesterone level of 4 to 14 ng/ml were treated with a graduated dosage schedule of clomiphene citrate until the progesterone level on day 21 was greater than 20 ng/ml. Thirty-one pregnancies occurred, 58% during the first adequate treatment cycle and 19% during the second cycle. The abortion rate was 23%. After 6 adequate treatment cycles, laparoscopic evaluation was performed on 28 of 39 patients who did not conceive. Pathology was noted in 57%. Seven of 17 patients with intraperitoneal causes of infertility conceived after alternative therapy. The corrected pregnancy rate was 60%. Results of this study suggest that low luteal phase progesterone levels may compromise fertility and that clomiphene citrate enhances pregnancy rates.
Messinis IE et al., 1982·Acta Obstet Gynecol Scand·
The effectiveness of tamoxifen and clomiphene in inducing ovulation was compared in 46 women with anovulatory infertility. All the women were given both the drugs in an alternate way. If one cycle was treated by tamoxifen the next was treated by clomiphene and vice versa. Forty-one out of the 46 women (89.1%) ovulated at least once during the study. Similar ovulation rates were achieved by tamoxifen (56.2%) and clomiphene (62.9%). The lengths of the ovulatory cycles and their luteal phases and the mid-luteal phase serum progesterone levels did not differ significantly between the two compounds. Nor did the occurrence of luteal phase defects during the tamoxifen and clomiphene treatment cycles differ. Thirty-seven of the 46 women (80.4%) responded similarly to both drugs. Thus, tamoxifen is just as effective as clomiphene in inducing ovulation in women with anovulation.
Three hundred and ninety-six patients were evaluated for primary and secondary infertility between December 1976 and May 1979 at a large referral center. Timed late luteal endometrial biopsies were routinely obtained as part of the work-up and were repeated for confirmation if subsequent menses did not occur within 2 days of the expected date. If both biopsies were abnormal, a diagnosis of luteal phase defect (LPD) was made and patients were treated with vaginal progesterone suppositories for a minimum of 6 months. LPD was discovered in 32 of 396 patients (8.1%); among those patients whose infertility was not complicated by other abnormalities, 9 of 13 conceived (70%) and 7 of 13 carried to term (54%). These data suggest an incidence higher than generally recognized and a very encouraging response to replacement therapy.
Twenty-five women scheduled for hysterectomy for nonmalignant disease participated in the study. Sperm storage in endocervical crypts was examined in three groups of nine women pretreated with estrogen and inseminated with normal semen, nine women pretreated with gestagen and inseminated with normal semen, and seven women pretreated with estrogen and inseminated with abnormal semen. The number of crypts containing spermatozoa (colonized crypts) and the sperm density per crypt were examined in serially sectioned cervices. In estrogen-pretreated cervices both the percentage of colonized crypts and the sperm density were significantly higher than in gestagen-pretreated cervices. Large and giant crypts proved to be the main storage facility for spermatozoa. The localization of crypts along the endocervical canal did not influence sperm storage. The quality of semen appeared to be of critical importance to sperm storage. The percentage of colonized crypts and sperm density were severly reduced in patients inseminated with abnormal semen.
Tubal abrasions were surgically induced in 25 rhesus monkeys following demonstration of tubal patency. Five monkeys received dexamethasone, promethazine, and ampicillin perioperatively, five received intraperitoneal 10% dextran 40, five received intraperitoneal 32% dextran 70, and 10 received no additional therapy. Fimbrial biopsies were obtained from two additional monkeys treated with 32% dextran 70 before and postoperatively on days 2, 5, and 7. Only those treated with 32% dextran 70 retained tubal patency and avoided development of adhesions, involving fimbria, omentum, ovary, uterus, and bladder. Histologic examination of fimbrial biopsies demonstrated sufficient epithelial repair to have occurred during the 5 days 32% dextran 70 remained in the pelvin cavity to prevent adhesion formation.
Pelvic adhesion formation represents a major problem following fallopian tube surgery for infertility. Intraperitoneal dextran may prevent pelvic adhesions. Extensive personal clinical experience (W. H. U.) with intraperitoneal dextran organ-flotation on completion of tubal and ovarian surgery has appeared to limit adhesions. A specific study was designed to test the validity of this theory. Four randomized groups of rabbits were subjected to bilateral tubocornual division and microsurgical reanastomosis with total hemostasis and pelvic lavage. Routine peritoneal closure was performed on one group, but followed instillation of 30 to 50 ml of normal saline into the peritoneal cavities of the second group, and 30 to 50 ml of 6% dextran 70 into those of the third. Study of fourth group, which received 32% dextran 70 in the peritoneal cavity, was discontinued because of complications. A second laparotomy was performed 4 weeks later for precise assessment and photography of adhesion formation. Each animal was mated 4 weeks after the second operation in order to determine fertility rates. Reduced adhesion formation and increased fertility rates following the instillation of dextran are reported. A role for dextran 70 in infertility surgery is recommended.
Salpingostomy for hydrosalpinx was carried out using a microsurgical technique. The postoperative patency rate was over 90%. Among the 41 patients followed for more than 1 year, 29% have had one or more intrauterine pregnancies and 27% have had live births. The ectopic gestation rate was 12%. All of the tubal gestations occurred in the 1st postoperative year whereas 60% of the intrauterine pregnancies occurred after the 1st year, suggesting a degree of restoration in the mucosa and the musculature of the oviduct with the re-establishment of patency and the passage of time.
A clinical description of luteinized unruptured follicles is presented. This abnormality in ovulation is characterized by normal endocrinologic presumptive signs of ovulation: biphasic basal body temperature curves, secretory endometrium, and laboratory evidence of progesterone production by elevated urinary pregnanediol or plasma progesterone levels. In a group of 102 such infertile women, laparoscopy performed 3 to 5 days after apparent ovulation revealed the absence of a corpus hemorrhagicum in 30 women, and the absence of a sigma on a corpus hemorrhagicum in an additional 32 women. These findings were evidence that a follicle had not ruptured and an ovum had not escaped. Of 28 patients undergoing follicular stimulation with clomiphene citrate or human menopausal gonadotropin after this diagnosis, 15 conceived.
In summary, the luteal phase defect is a deficiency of corpus luteum progesterone steroidogenesis, either in amount or duration, or both. The clinical manifestations include either primary infertility or repeated first trimester abortions. The diagnosis can only be made clinically on the basis of a well-timed endometrial biopsy that is read histologically as 2 or more days out of phase with the next period in at least two cycles.
In an effort to diminish the incidence of multiple pregnancy, ovarian hyper-stimulation syndrome, and the excessive cost of human menopausal gonadotropin (HMG) administration, a sequence of Clomid-HMG-human chorionic gonadotropin (HCG) was used in 80 patients with infertility due to prolonged amenorrhea. Criteria for this therapeutic regimen were: (1) normal seminal fluid analysis and postcoital test; (2) lack of withdrawal bleeding from progesterone following amenorrhea of more than 6 months' duration; (3) normal x-ray of the sella turcica and visual fields; (4) low serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels; (5) normal endoscopic examination; and (6) lack of response to clomiphene in excessive dose (200 mg daily for 5 days) or prolonged dose (100 mg daily for 10 days) with or without HCG, or apparent ovulatory response to the above sequence for five or six consecutive cycles without pregnancy. Clomiphene was administered in a dose of 100 mg daily for 7 days. HMG was then given in the following manner: two ampules daily for 4 days, then one ampule daily for 2 days (75 IU of FSH and 75 IU of LH/ampule). After a 24-hour interval without treatment, 10,000 IU of HCG were given and 2000 IU of HCG 4 days later. Twenty-three pregnancies occurred in 80 patients. However, 15 of the first 25 patients became pregnant--in these patients the only abnormality noted was lack of ovulation. Six additional pregnancies occurred subsequent to one or more unsuccessful cycles. Multiple pregnancies occurred in only two patients (twins delivered at 32 weeks in one and an abortion of five fetuses at 20 weeks in another). However, multiple pregnancy did not occur in any patient whose urinary estrogen level was monitored and in whom the level was 100 mug or less when the HCG was given. The ovarian hyperstimulation syndrome did not occur in any patient.
The use of clomiphene in gradually increasing doses, in cases of infertility due to anovulation, oligo-ovulation and inadequate luteal phase, led to a high pregnancy rate, particularly in the initial stages of treatment. Although clomiphene is a relatively safe and inexpensive drug, there is a possibility that high doses in repeated cycles may adversely affect fertility by its anti-oestrogenic effect. It is therefore suggested that therapy be commenced with a lower dosage than that generally recommended.
Eighty-six women reached at least 20 weeks' pregnancy in 96 instances, after ovulation induced by clomiphene citrate. Although 37 of the women had 44 previous pregnancies, there had been a high pregnancy wastage (70.5%) producing only 13 live infants prior to the successful clomiphene therapy. After clomiphene therapy, pregnancies were normal except for a high incidence of toxemia (16.7%) and a possibly increased incidence of prediabetes. The pregnancies resulted in 88 single and 8 twin births. The total fetal and neonatal loss was 6.7%. The loss of single births (3.1%) included two stillbirth infants of prediabetic mothers. The twin loss of 25% was due to prematurity. The incidence of congenital malformations was within normal limits.