Vitagliano A et al., 2022·Diagnostics (Basel)·
Open Access
This systematic review and meta-analysis aims to evaluate the impact of chronic endometritis (CE) and its therapy on in vitro fertilization (IVF) outcome. Additionally, we aim to investigate whether various degrees of CE severity may exert a different effect on IVF outcome. Ongoing-pregnancy rate/live-birth-rate (OPR/LBR), clinical-pregnancy rate (CPR), and miscarriage rate (MR) were calculated. A total number of 4145 patients (from ten studies) were included. Women with CE had lower OPR/LBR (OR 1.97, p = 0.02) and CPR (OR 2.28, p = 0.002) compared to those without CE. CE cure increased OPR/LBR (OR 5.33, p < 0.0001) and CPR (OR 3.64, p = 0.0001). IVF outcome was comparable between women with cured CE and those without CE (OPR/LBR, CPR and MR: p = ns). Women with severe CE had lower OPR/LBR (OR 0.43, p = 0.003) and CPR (OR 0.40, p = 0.0007) compared to those mild CE. Mild CE showed no influence on the IVF outcome as compared to women without CE (OPR/LBR, CPR and MR: p = ns). Based on this data analysis, CE significantly reduces OPR/LBR and CPR in women undergoing IVF. Importantly, CE resolution after antibiotic therapy may improves IVF outcome, leading to similar OPR/LBR and CPR as compared to unaffected patients. The negative effects of CE on IVF outcome may be restricted to severe disease, whereas mild CE may have no influence on IVF success.
Chronic Endometritis · Diagnosis of Chronic Endometritis
Chronic endometritis is a persistent inflammation of the endometrial mucosa caused by bacterial pathogens such as Enterobacteriaceae, Enterococcus, Streptococcus, Staphylococcus, Mycoplasma, and Ureaplasma. Although chronic endometritis can be asymptomatic, it is found in up to 40% of infertile patients and is responsible for repeated implantation failure and recurrent miscarriage. Diagnosis of chronic endometritis is based on hysteroscopy of the uterine cavity, endometrial biopsy with plasma cells being identified histologically, while specific treatment is determined based on microbial culture. However, not all microorganisms implicated are easily or readily culturable needing a turnaround time of up to 1 week. We sought to develop a molecular diagnostic tool for chronic endometritis based on real-time polymerase chain reaction equivalent to using the 3 classic methods together, overcoming the bias of using any of them alone. Endometrial samples from patients assessed for chronic endometritis (n = 113) using at least 1 or several conventional diagnostic methods namely histology, hysteroscopy, and/or microbial culture, were blindly evaluated by real-time polymerase chain reaction for the presence of 9 chronic endometritis pathogens: Chlamydia trachomatis, Enterococcus, Escherichia coli, Gardnerella vaginalis, Klebsiella pneumoniae, Mycoplasma hominis, Neisseria gonorrhoeae, Staphylococcus, and Streptococcus. The sensitivity and specificity of the molecular analysis vs the classic diagnostic techniques were compared in the 65 patients assessed by all 3 recognized classic methods. The molecular method showed concordant results with histological diagnosis in 30 samples (14 double positive and 16 double negative) with a matching accuracy of 46.15%. Concordance of molecular and hysteroscopic diagnosis was observed in 38 samples (37 double positive and 1 double negative), with an accuracy of 58.46%. When the molecular method was compared to microbial culture, concordance was present in 37 samples (22 double positive and 15 double negative), a matching rate of 56.92%. When cases of potential contamination and/or noncultivable bacteria were considered, the accuracy increased to 66.15%. Of these 65 patients, only 27 patients had consistent histological + hysteroscopic diagnosis, revealing 58.64% of nonconcordant results. Only 13 of 65 patients (20%) had consistent histology + hysteroscopy + microbial culture results. In these cases, the molecular microbiology matched in 10 cases showing a diagnostic accuracy of 76.92%. Interestingly, the molecular microbiology confirmed over half of the isolated pathogens and provided additional detection of nonculturable microorganisms. These results were confirmed by the microbiome assessed by next-generation sequencing. In the endometrial samples with concordant histology + hysteroscopy + microbial culture results, the molecular microbiology diagnosis demonstrates 75% sensitivity, 100% specificity, 100% positive and 25% negative predictive values, and 0% false-positive and 25% false-negative rates. The molecular microbiology method describe herein is a fast and inexpensive diagnostic tool that allows for the identification of culturable and nonculturable endometrial pathogens associated with chronic endometritis. The results obtained were similar to all 3 classic diagnostic methods together with a degree of concordance of 76.92% providing an opportunity to improve the clinical management of infertile patients with a risk of experiencing this ghost endometrial pathology.
Chronic Endometritis · Diagnosis of Chronic Endometritis
To evaluate the association between endometriosis end chronic endometritis (CE) diagnosed by hysteroscopy, conventional histology, and immunohistochemistry. Case-control study. University hospital. PATIENT(S): Women with and without endometriosis who have undergone hysterectomy. INTERVENTION(S): Retrospective evaluation of 78 women who have undergone hysterectomy and were affected by endometriosis and 78 women without endometriosis. MAIN OUTCOME MEASURE(S): CE diagnosed based on conventional histology and immunohistochemistry with anti-syndecan-1 antibodies to identify CD138 cells. RESULT(S): The prevalence of CE was statistically significantly higher in the women with endometriosis as compared with the women who did not have endometriosis (33 of 78, 42.3% vs. 12 of 78, 15.4% according to hysteroscopy; and 30 of 78, 38.5% vs. 11 of 78, 14.1% according to histology). The women were divided into two groups, 115 patients without CE and 41 patients with CE. With univariate analysis, parity was associated with a lower risk for CE, and endometriosis was associated with a statistically significantly elevated risk of CE. Using multivariate analysis, parity continued to be associated with a lower incidence of CE, whereas endometriosis was associated with a 2.7 fold higher risk. CONCLUSION(S): The diagnosis of CE is more frequent in women with endometriosis. Although no etiologic relationships between CE and endometriosis can be established, this study suggests that CE should be considered and if necessary ruled out in women with endometriosis, particularly if they have abnormal uterine bleeding. Identification and appropriate treatment of CE may avoid unnecessary surgery.
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.
Chapron C et al., 2011·Human reproduction (Oxford, England)
The relationship between the use of oral contraception (OC) and endometriosis remains controversial. We therefore compared various characteristics of OC use and the surgical diagnosis of endometriosis histologically graded as superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) or deep infiltrating endometriosis (DIE). This cross-sectional study included 566 patients without visible endometriosis at surgery as controls, and 410 patients with histologically proven endometriosis, categorized by their worst lesions as SUP n = 47, OMA n = 120 and DIE n = 243. Personal data, including on OC use, were prospectively collected during standardized interviews. Statistical analysis was performed using unconditional logistic regression. Past OC users had an increased incidence of endometriosis (adjusted odd ratios (OR) = 2.79, 95% confidence interval (CI) 1.74-5.12, P = 0.002) of any revised American Fertility Society stage. Women who had previously used OC for severe primary dysmenorrhea were even more frequently diagnosed with endometriosis (adjusted OR = 5.6, 95% CI 3.2-9.8), especially for DIE (adjusted OR = 16.2, 95% CI 7.8-35.3). Women who had previously used OC for other reasons also had an increased risk of endometriosis, but to a lesser extent (adjusted OR = 2.6, 95% CI 1.8-4.1). The age at which OC was initiated, duration of OC use and free interval from last OC use were not significantly different between control and endometriosis women, irrespective of histological grading. Current OC users did not show an increased prevalence of endometriosis (OR = 1.22, 95% CI 0.6-2.52). Our data indicate that a history of OC use for severe primary dysmenorrhea is associated with surgical diagnosis of endometriosis, especially DIE, later in life. However, this does not necessarily mean that use of OC increases the risk of developing endometriosis. Past use of OC for primary dysmenorrhea may serve as a marker for women with endometriosis and DIE.
Chronic Endometritis · Diagnosis of Chronic Endometritis
To evaluate the type and etiopathogenic role of infectious agents detected in endometrial cultures obtained from women with chronic endometritis (CE). Prospective controlled study. University hospital. PATIENT(S): 2190 women undergoing hysteroscopy for different indications. INTERVENTION(S): Vaginal and endometrial samples were collected from 438 women with a CE diagnosis at hysteroscopy and 100 women with no signs of CE (controls). MAIN OUTCOME MEASURE(S): Histology and cultures for common bacteria, Neisseria gonorrhoeae and Mycoplasma, and molecular biology testing for Chlamydia were performed. RESULT(S): We compared results of vaginal and intrauterine cultures obtained from women with and without CE. Histologic results were positive in 388 of these cases (88.6%), and at least one microorganism was found in 320 endometrial samples (73.1%). In the control group, histologic results and endometrial culture were positive in only 6% and 5% of cases, respectively. The most frequent infectious agents detected at the endometrial level were common bacteria (58% of cases). Ureaplasma urealyticum was detected in 10% and Chlamydia in only 2.7% of positive endometrial cultures. In only 143 (32.6%) cases were the same infectious agent isolated in endometrial and vaginal cultures. CONCLUSION(S): More than 70% of CE cases resulted from nongonococcal, nonchlamydial infections. Common bacteria and Mycoplasma were the most frequent etiologic agents. Vaginal cultures have low concordance with endometrial cultures.
Human chorionic gonadotropin (hCG) is widely used as a surrogate to luteinizing hormone (LH) to trigger ovulation in controlled ovarian hyperstimulation (COH). Yet this molecule may exert direct effects on the endometrium. These effects, not mediated by ovarian hormones, are probably a consequence of stimulation of endometrial hCG/LH receptors. Because the half-life of hCG differs markedly from that of LH, possible pharmacological effects of hCG on the endometrium could alter endometrial receptivity in COH. Arguments supporting a clinical action of gonadotropins, and hCG in particular, on the endometrium abound. Notably, evidence has been reported of decidualization of stromal cells of the human endometrium in vitro as a result of exposure to gonadotropins, including hCG. The present article discusses, from a clinical standpoint, the main basis supporting the hypothesis that hCG administration as commonly used in infertility treatments may exert direct effects in vivo on endometrial histology and partake in endometrial transformations of the luteal phase. Preliminary results suggest that endometrial effects of hCG exist in vivo and should be taken into account when assessing the endometrial effects of hormones.
To investigate whether uterine contractility at the time of embryo transfer (ET) can be reduced by early onset of luteal support with progesterone administered vaginally. Prospective analysis. Assisted reproduction unit. PATIENT(S): Eighty-four women undergoing 84 GnRH-a and FSH/hCG cycles for IVF-ET were studied. INTERVENTION(S): Vaginal progesterone was randomly started on the day of oocyte retrieval (group A, n = 43) or on the evening of ET (group B, n = 41). On the day of hCG administration and just before ET, 2-minute sagittal uterine scans were obtained by ultrasound and digitized with an image analysis system for assessing uterine contraction frequency. MAIN OUTCOME MEASURE(S): Uterine contraction frequency. RESULT(S): Whereas uterine contraction frequency was similar in both groups on the day of hCG (4.6 +/- 0.3 and 4.5 +/- 0.3 contractions per minute, respectively), only women in group A showed decreased uterine contraction frequency on the day of ET (2.8 +/- 0.2 vs. 4.2 +/- 0.3 contractions per minute). CONCLUSION(S): Vaginal progesterone administration starting on the day of oocyte retrieval induced a decrease in uterine contraction frequency on the day of ET as compared with preovulatory values. Uterine relaxation before ET is likely to improve IVF-ET outcome by avoiding the displacement of embryos from the uterine cavity.
We sought to compare the effects of estrogen/transvaginal progesterone gel with estrogen/medroxyprogesterone acetate (MPA) on exercise-induced myocardial ischemia in postmenopausal women with coronary artery disease or previous myocardial infarction, or both. Estrogen therapy beneficially affects exercise-induced myocardial ischemia in postmenopausal women; however, women with an intact uterus also take progestin to protect against uterine malignancies. The effects of combination estrogen/progestin therapy on myocardial ischemia are unknown. Eighteen postmenopausal women (mean +/- SD age 59+/-7 years) were given 17-beta-estradiol in single-blinded manner for four weeks (1 mg/day for three weeks then 2 mg/day for one week). Estradiol (2 mg/day) was then continued, and the patients were randomized (double-blind) for 12 days to either transvaginal progesterone gel (90 mg on alternate days) and oral MPA placebo (10 mg/day), or vice versa. After another two weeks on estradiol alone, the patients crossed over to progestin treatment and repeated the protocol on the opposite treatment. Patients underwent treadmill exercise testing after each estradiol phase and at day 10 of each progestin phase. Exercise time to myocardial ischemia increased after the first estrogen phase as compared with baseline (mean difference with 95% confidence interval [CI]: 72 s [34 to 110], p = 0.001), and was increased by combination estradiol/progesterone therapy as compared with estradiol/MPA therapy (92 s [35 to 149], p = 0.001)). Two patients (11%) were withdrawn while taking estradiol/MPA owing to unstable angina. Combination estrogen/transvaginal progesterone gel increases exercise time to myocardial ischemia, as compared with estrogen/MPA. These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration.
Bulletti C et al., 2000·Human reproduction (Oxford, England)
The non-pregnant uterus shows different patterns of contractility during the menstrual cycle. A renewed interest in uterine contractility has resulted from reports of non-invasive ultrasound (US) based studies. To clarify the changes in uterine contractility occurring throughout the menstrual cycle, we prospectively studied uterine contractions (UC) at six representative stages with US and intrauterine pressure (IUP) based approaches in 30 cycling volunteers. Results showed UC frequency could be measured by either US or IUP. UC amplitude and resting pressure tone could only be assessed by IUP. Conversely, direction of UC displacement could only be assessed by US. UC frequency increased at mid-cycle and decreased throughout the luteal phase suggesting oestradiol and progesterone exert positive and negative actions on uterine contractility, respectively. UC amplitude increased throughout the menstrual cycle to maximum values in the late luteal phase. Retrograde UC were most frequent at mid-cycle and convergent ('opposing') UC predominated during the luteal phase. While the former pattern ensures sperm transport, the latter may facilitate embryo implantation. In conclusion, UC changes throughout the menstrual cycle assessed by US and IUP emphasize the hormonal dependence of uterine contractility. Although UC patterns favouring sperm transport appear regulated by oestradiol, uterine quiescence and the dominance of convergent UC prevailing at the time of implantation are linked to progesterone. These data will serve to identify and treat possible dyskinetic changes in uterine contractility, particularly in women suffering from infertility, endometriosis, and dysmenorrhea.
To examine the endometrial effects of three different doses of progesterone administered vaginally. Forty women 25-41 years old deprived of ovarian function received estradiol (E2) for 28 days. From days 15 to 27, a new mucus-like vaginal gel of progesterone was administered every other day, randomly, dosed at 45 mg (group A, n = 14), 90 mg (group B, n = 13), or 180 mg (group C, n = 13). Plasma gonadotropins, estrone, E2, and progesterone were measured. An endometrial biopsy was performed on day 20 (n = 20) or 24 (n = 20) for endometrial dating and for estrogen and progesterone receptor determinations. Plasma estrogen levels were in the menstrual cycle range. Mean progesterone levels were lower in group A (2.4 +/- 0.2 ng/mL) than in group B (3.6 +/- 0.2 ng/mL) or C (3.4 +/- 0.4 ng/mL) (P < .005). Plasma FSH and LH decreased significantly during progesterone treatment. In all groups, we observed secretory transformation in the glands (day 20) and stroma (day 24) and the distribution of estrogen and progesterone receptors seen in normal menstrual cycles. Transvaginal administration of progesterone induced normal secretory transformation of the endometrium despite low plasma levels, suggesting a direct transit into the uterus or "first uterine pass effect."
The objective was to verify the hypothesis of a 'first uterine pass effect' or direct preferential vagina-to-uterus transport, suggested by the evidence of higher than expected uterine tissue concentrations after vaginal administration of progesterone; we used a human ex-vivo uterine perfusion model. A mixture of tritiated (3H) and unlabelled progesterone was applied to the cuff of vaginal tissue remaining attached to the cervix after hysterectomy. At the end of the perfusion period (up to 12 h), 3H and 14C radioactivity was measured in samples of uterine tissue. Tritiated water and [14C]dextran were tested to determine the extent of non-specific vagina-to-uterus transport (leaks). Finally, sections of uterine tissue exposed only to [3H]progesterone were prepared for autoradiography. By 4-5 h after application progesterone had diffused to the entire uterus and had reached a steady state; 4 h after application, progesterone concentrations reached 185 +/- 155 and 254 +/- 305 ng/100 mg of endometrial and myometrial tissue respectively. Endometrial extraction of progesterone was higher when the experiment was performed on uteri obtained during the luteal phase (280 +/- 156 ng/100 mg of endometrial tissue) than those removed during the proliferative phase of the menstrual cycle (74 +/- 28 ng/100 mg of endometrial tissue). These data demonstrate that a 'first uterine pass effect' occurs when drugs are delivered vaginally, thereby providing an explanation for the unexpectedly high uterine concentrations relative to the low serum concentration observed after vaginal administration. Hence, the vaginal route permits targeted drug delivery to the uterus, thereby maximizing the desired effects while minimizing the potential for adverse systemic effects.
To analyze the effects of clomiphene citrate (CC) on cervical mucus (CM) and endometrial morphology independently of hormonal changes encountered when CC is administered for ovulation induction. Volunteers whose ovarian functions were temporarily suppressed (n = 18) by a long-acting GnRH agonist and 6 women of similar age suffering from premature ovarian failure (POF) received E2 and P. Half of the women also received CC (50 mg/d, days 2 to 6). Tertiary University Institution, Hôpital A. Béclère. PATIENTS, Eighteen volunteers suffering from infertility not related to a uterine cause and 6 women of similar age suffering from POF. Plasma gonadotropins, E2, and P were measured at baseline to confirm that the ovaries were inactive and twice weekly during physiological E2 and P replacement. Cervical mucus was analyzed on day 14 and scored from 0 to 15. Endometrial biopsies were obtained on replacement days 20 and 24 for conventional histology and immunocytochemistry analysis of estrogen receptors and progesterone receptors (PR). Premature ovarian failure women whose results have been previously published served as controls for day 20 biopsies. Cervical mucus scored lower in women who received CC (5.5 +/- 3.2) than in controls (13.6 +/- 4.7, mean +/- SEM). On day 20, endometrial findings were similar in women treated with CC and in controls. On day 24, specimens showed a significant delay in endometrial maturation in women treated with CC. On day 24, only staining for PR selectively persisted in endometrial stroma, and no difference was observed between women who received CC and controls. Our results indicate that CC significantly alters CM quality and late luteal phase endometrial morphology despite physiological levels of plasma E2 and P. Hence, clinicians should monitor E2 levels when using CC, and caution should be exerted when supraphysiological levels of E2 are not present to counterbalance the effects of CC on the CM and the endometrium.