Safety concerns and health benefits associated with oral contraception

Ronald Burkman

Department of Obstetrics/Gynecology, Baystate Medical Center, Springfield, MA 01199, USA. rtb@bhs.org

Abstract: Since the introduction of hormonal contraceptives in the 1960s, there have been a variety of both health benefits and safety concerns attributed to their use. In most instances, the noncontraceptive benefits of oral contraceptives (OCs) outweigh the potential cardiovascular risks. In fact, the probability of a patient experiencing a cardiovascular event while taking a low-dose OC is very low. However, smoking, hypertension, obesity, and diabetes are risk factors that must be taken into account when prescribing OCs. The neoplastic effects of hormonal contraceptives have been extensively studied, and recent meta-analyses indicate that there is a reduction in the risk of endometrial and ovarian cancer, a possible small increase in the risk for breast and cervical cancer, and an increased risk of liver cancer. Finally, many women will experience noncontraceptive health benefits with OCs that expand far beyond pregnancy prevention. Some of these benefits include reduction in menstrual-related symptoms, fewer ectopic pregnancies, a possible increase in bone density, and possible protection against pelvic inflammatory disease.

American Journal of Obstetrics and Gynecology


Aromatase inhibitors in ovulation induction

Mohamed F Mitwally

Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lununfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.

Abstract: 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.


Obesity, obstetric complications and cesarean delivery rate--a population-based screening study

Abstract:
OBJECTIVE: This study was undertaken to determine whether obesity is associated with obstetric complications and cesarean delivery.

METHODS: A large prospective multicenter database was studied. Subjects were divided into 3 groups: body mass index (BMI) less than 30 (control), 30 to 34.9 (obese), and 35 or greater (morbidly obese). Groups were compared by using univariate and multivariable logistic regression analyses.

RESULTS: The study included 16,102 patients: 3,752 control, 1,473 obese, and 877 morbidly obese patients. Obesity and morbid obesity had a statistically significant association with gestational hypertension (odds ratios [ORs] 2.5 and 3.2), preeclampsia (ORs 1.6 and 3.3), gestational diabetes (ORs 2.6 and 4.0), and fetal birth weight greater than 4000 g (ORs 1.7 and 1.9) and greater than 4500 g (ORs 2.0 and 2.4). For nulliparous patients, the cesarean delivery rate was 20.7% for the control group, 33.8% for obese, and 47.4% for morbidly obese patients.

CONCLUSION: Obesity is an independent risk factor for adverse obstetric outcome and is significantly associated with an increased cesarean delivery rate.

American journal of obstetrics and gynecology


Association of bioavailable, free, and total testosterone with insulin  resistance: influence of sex hormone-binding globulin and body fat

Abstract:
Objective: Previous reports of an association between low testosterone levels and diabetes risk were often confounded by covariation of sex hormone-binding globulin (SHBG) and testosterone measurements. Measurements of bioavailable and free testosterone, more reliable indexes of biologically active testosterone, were examined for their associations with markers of insulin resistance and body fat measures in 221 middle-aged nondiabetic men. RESEARCH DESIGN AND

Methods: Bioavailable and free testosterone were calculated from the concentrations of total testosterone, SHBG, and albumin, and they were not significantly correlated with SHBG (r = 0.07-0.1). In contrast, total testosterone correlated significantly with SHBG (r = 0.63). We evaluated the relationship between these measures of circulating testosterone and markers for insulin resistance (i.e., fasting insulin, C-peptide, and homeostasis model assessment for insulin resistance [HOMA-IR]) as well as total body fat (assessed by dual-energy X-ray absorptiometry [DEXA]) and abdominal fat distribution (assessed by single-slice computed tomography [CT]).

Results: Bioavailable, free, and total testosterone and SHBG all correlated significantly with fasting insulin (age-adjusted r = -0.15 [P = 0.03], -0.14 [P = 0.03], -0.32 [P < 0.0001], and -0.38 [P < 0.0001], respectively), fasting C-peptide (r = -0.18 [P = 0.009] to -0.41 [P < 0.0001]), HOMA-IR (r = -0.15 [P = 0.03] to - 0.39 [P < 0.0001]), and body fat measures (r = -0.17 [P = 0.008] to -0.44 [P < 0.0001]). Only SHBG and total testosterone were significantly associated with fasting glucose (r = -0.20 [P = 0.003] to -0.21 [P = 0.002]). In multivariate analysis, bioavailable or free testosterone was significantly and inversely associated with insulin, C-peptide, and HOMA-IR, but this was not independent of total body or abdominal fat. SHBG was a significant determinant of insulin, C-peptide, and HOMA-IR, independent of body fat. The associations between total testosterone and insulin resistance were confounded by SHBG.

Conclusions: The inverse association between testosterone and insulin resistance, independent of SHBG, was mediated through body fat.


More than one fertile ovulation per cycle?

Petra Frank-Herrmann

Department of Gynaecological Endocrinology and Fertility Disorders, University of Heidelberg, Vossstrasse 9, 69115 Heidelberg, Germany. petra.frank-herrmann@med.uni-heidelberg.de

Abstract: Baerwald et al. (1) proposed a new model for ovarian follicular development in the human menstrual cycle. They showed additional waves of follicular development in the follicular and luteal phase of normal ovulatory cycles. Although no additional ovulation was observed, the authors speculated that the anovulatory follicles from the additional waves of follicular development may be able to ovulate in the presence of an additional LH surge.


S28.3: Validity of methods used to estimate the effectiveness of Emergency Contraception


Mucus observations in the fertile window: a better predictor of conception than timing of intercourse

Jamie L Bigelow

University of North Carolina at Chapel Hill

Bernardo Colombo

National Institute of Environmental Health Sciences

Abstract:
BACKGROUND: Intercourse results in a pregnancy essentially only if it occurs during the 6-day fertile interval ending on the day of ovulation. The strong association between timing of intercourse within this interval and the probability of conception typically is attributed to limited sperm and egg life times.

METHODS: A total of 782 women recruited from natural family planning centres in Europe contributed prospective data on 7288 menstrual cycles. Daily records of intercourse, basal body temperature and vaginal discharge of cervical mucus were collected. Probabilities of conception were estimated according to the timing of intercourse relative to ovulation and a 1-4 score of mucus quality.

RESULTS: There was a strong increasing trend in the day-specific probabilities of pregnancy with increases in the mucus score. Adjusting for the mucus score, the day-specific probabilities had limited variability across the fertile interval.

CONCLUSIONS: Changes in mucus quality across the fertile interval predict the observed pattern in the day-specific probabilities of conception. To maximize the likelihood of conception, intercourse should occur on days with optimal mucus quality, as observed in vaginal discharge, regardless of the exact timing relative to ovulation.


Epigenetics and assisted reproductive technology: a call for investigation

Abstract: A surprising set of recent observations suggests a link between assisted reproductive technology (ART) and epigenetic errors--that is, errors involving information other than DNA sequence that is heritable during cell division. An apparent association with ART was found in registries of children with Beckwith-Wiedemann syndrome, Angelman syndrome, and retinoblastoma. Here, we review the epidemiology and molecular biology behind these studies and those of relevant model systems, and we highlight the need for investigation of two major questions: (1) large-scale case-control studies of ART outcomes, including long-term assessment of the incidence of birth defects and cancer, and (2) investigation of the relationship between epigenetic errors in both offspring and parents, the specific methods of ART used, and the underlying infertility diagnoses. In addition, the components of proprietary commercial media used in ART procedures must be fully and publicly disclosed, so that factors such as methionine content can be assessed, given the relationship in animal studies between methionine exposure and epigenetic changes.


Contributions of infertility treatment to very-low-birth-weight multiple birth infants receiving neonatal intensive care

Christopher J Lindsell

Cincinnati Children's Hospital Medical Center

Abstract:
OBJECTIVE: This study was undertaken to determine proportions of very-low-birth-weight (VLBW) multiple birth infants receiving neonatal intensive care whose mothers received various types of infertility treatment and to evaluate infertility treatment-associated morbidity and mortality.

STUDY DESIGN: Study infants were multiples with birth weight 401 to 1500 g cared for in Cincinnati neonatal intensive care units from January 1996 to December 2000. Data were obtained retrospectively from the National Institute for Child Health and Human Development Neonatal Research Network registry. Use of infertility treatment (in vitro fertilization, injection or oral ovulation, and intrauterine insemination) was determined by maternal interview or chart review. The generalized estimating equation approach to logistic regression was used.

RESULTS: The study included 382 infants of 212 mothers: 201=spontaneous conception (53%), 93=in vitro fertilization (24%), 55=injection (14%), 15=oral (4%), and 18=intrauterine insemination (5%). Neither gestational age nor birth weight differed between groups. More female (58%, P=.003) and white infants (95%, P<.001) resulted from infertility treatment-induced pregnancies than from spontaneous pregnancies. Advancing gestational age significantly decreased odds for all outcomes.

CONCLUSION: Of VLBW multiples receiving neonatal intensive care, 47% are associated with infertility treatment. Infertility treatment does not influence outcomes in VLBW multiples.


The future of professional education in natural family planning

Abstract: Nurses and other health care professionals often have little knowledge of methods of natural family planning (NFP) and do not readily prescribe natural methods for their patients. One reason for this is that little or no information on NFP is provided in nursing or medical schools. The holistic, informational, and integrative nature of NFP fits well with professional nursing practice. A university online distance education NFP teacher training program, which offers academic credit and includes theory, practice, and the latest developments in fertility monitoring, has been developed for health care professionals. Professional NFP services in the United States need to meet worldwide standards and include documenting and assessing pregnancy outcomes, tailoring NFP services to the client or couple, and simplifying them for ease of use in a standard health care practice.

Journal of Obstetric, Gynecologic, and Neonatal Nursing : JOGNN


Women's sexual experience during the menstrual cycle: identification of the sexual phase by noninvasive measurement of luteinizing hormone

Abstract: Imprecise measures of ovulation obscure the relationship between women's sexuality and the menstrual cycle, as does studying women with different contraceptive goals in different social contexts. Here we present a novel noninvasive method to precisely pinpoint the preovulatory surge of Luteinizing Hormone (LH), demarcating hormonally distinct cycle phases with greater than 95% reliability. Women were more sexually active on days prior to and including the preovulatory (LH) surge. This pattern was evident only when women initiated sexual activity and not when their partners did, indicating an increase in women's sexual motivation rather than attractiveness. A second study replicated the 6-day increase in sexual activity beginning 3 days before the LH surge, accompanied by stronger sexual desire and more sexual fantasies. We propose the term 'sexual phase' of the cycle, since follicular phase is over inclusive and ovulatory phase is not sufficient. These findings are striking because the women were avoiding pregnancy and were kept blind to the hypotheses, preventing expectation bias. The sexual phase was more robust in women with regular sexual partners, although the increase in sexual desire was just as great in nonpartnered women, who also reported feeling less lonely at this time. We use these results to evaluate potential neuroendocrine mechanisms underlying women's sexual motivation and activity.


Prognostic value of placental growth factor in patients with acute chest pain

Abstract:
CONTEXT: Experimental data suggest that placental growth factor (PlGF), a member of the vascular endothelial growth factor family, acts as a primary inflammatory instigator of atherosclerotic plaque instability and thus may be useful as a risk-predicting biomarker in patients with acute coronary syndromes (ACS).

OBJECTIVE: To determine whether blood levels of PlGF predict risk for death or nonfatal myocardial infarction in patients with acute chest pain.

DESIGN, SETTING, AND

PATIENTS: Measurement of PlGF levels as well as levels of markers of myocardial necrosis (troponin T [TnT]), platelet activation (soluble CD40 ligand [sCD40L]), and inflammation (high-sensitivity C-reactive protein [hsCRP]) in an inception cohort of 547 patients with angiographically validated ACS participating in the CAPTURE (c7E3 Fab Anti-Platelet Therapy in Unstable Refractory Angina) trial and in a heterogeneous cohort of 626 patients presenting with acute chest pain to an emergency department in Germany between December 1996 and March 1999.

MAIN OUTCOME MEASURE: Risk for death or nonfatal myocardial infarction after 30 days.

RESULTS: In patients with ACS, elevated PlGF levels (>27.0 ng/L; 40.8% of patients) indicated a markedly increased risk of events at 30 days (14.8% vs 4.9%; unadjusted hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.79-6.24; P<.001). In a multivariable model, elevated levels of TnT (HR, 1.83; 95% CI, 1.05-3.86; P =.03), sCD40L (HR, 2.65; 95% CI, 1.41-4.99; P =.002), and PlGF (HR, 3.03; 95% CI, 1.54-5.95; P<.001) were independent predictors, while elevated hsCRP level was not (HR, 0.98; 95% CI, 0.53-1.98; P =.94). In patients with acute chest pain, elevated levels of PlGF predicted risk (21.2% vs 5.3%) (unadjusted: HR, 4.80; 95% CI, 2.81-8.21; P<.001; adjusted: HR, 3.00; 95% CI, 1.68-5.38; P<.001). Patients negative for all 3 markers (TnT, sCD40L, and PlGF) were at very low cardiac risk (7 days: no event; 30 days: 2.1% event rate).

CONCLUSIONS: Plasma PlGF levels may be an independent biomarker of adverse outcome in patients with suspected ACS. A single initial measurement of plasma PlGF appears to extend the predictive and prognostic information gained from traditional inflammatory markers.


Neuromorbidity in preterm twins in relation to chorionicity and discordant birth weight

Abstract:
OBJECTIVE: The purpose of this study was to determine the incidence of neurologic morbidity in preterm monochorionic (MC) and dichorionic (DC) twins.

STUDY DESIGN: We collected perinatal, neonatal, and infant follow-up data of 76 MC and 78 DC twins born between 24 and 34 weeks of gestation (295 infants). Risks of neuromorbidity in the surviving infants were evaluated in relation to chorionicity, discordant birth weight (>20%), twin-twin transfusion syndrome (TTTS), and cotwin death.

RESULTS: The overall incidence of cerebral palsy and minor neurologic disabilities in surviving twins was 4% and 9%, respectively. MC infants had a higher incidence of cerebral palsy (8% vs 1%, P<.05) and neurologic morbidity (15% vs 3%, P<.05) than DC infants. The risk of impaired neurodevelopment was higher in MC infants with discordant birth weight (42%, P<.01), TTTS (37%, P<.01), and cotwin death (60%, P<.01) than those with concordant birth weight (8%). In MC pregnancies, the cerebral palsy risk was higher in infants with discordant birth weight than those with chronic TTTS (19% vs 4%, P<.05). Similarly, discordant DC infants had higher neuromorbidity than concordant group (5% vs 1%, P<.05). In both MC and DC discordant infants, neurologic morbidity was independent of growth restriction.

CONCLUSION: Neurologic morbidity in the preterm MC infants was 7-fold higher than DC infants because of chronic TTTS, discordant birth weight, and cotwin death in utero.

American Journal of Obstetrics and Gynecology


Sexually transmitted diseases

Sexually transmitted diseases

Abstract: Sexually transmitted diseases (STDs) constitute a major health burden in the United States, causing pelvic inflammatory disease, ectopic pregnancy, infertility, chronic pelvic pain, genital lesions, genital neoplasms, adverse pregnancy outcomes, immune system dysfunction, liver disease, and even death. STDs disproportionately affect adolescents and young adults. Of the estimated 15 million STDs that occur annually each year in the United States, 4 million are among adolescents and 6 million among young adults. The current epidemic is complicated by the high asymptomatic carrier state associated with most STDs and the inadequate protection of condoms in preventing transmission. Sexually active individuals, particularly adolescents, must be educated on the ramifications of early onset of sexual activity and the health consequences of multiple sexual partners.


A comparison of the fertile phase as determined by the Clearplan Easy Fertility  Monitor and self-assessment of cervical mucus

Abstract: The purpose of this study was to compare the fertile phase of the menstrual cycle as determined by the Clearplan Easy Fertility Monitor (CPEFM) with self-monitoring of cervical mucus. One-hundred women (mean age = 29.4 years) observed their cervical mucus and monitored their urine for estrogen and luteinizing hormone metabolites with the CPEFM on a daily basis for 2-6 cycles and generated 378 cycles of data; of these, 347 (92%) had a CPEFM peak. The beginning of the fertile window was, on average, day 11.8 (SD = 3.4) by the monitor and day 9.9 (SD = 3.0) by cervical mucus (r = 0.43, p < 0.001). The average first day of peak fertility by the monitor was 16.5 (SD = 3.6) and by cervical mucus 16.3 (SD = 3.7) (r = 0.85, p < 0.001). The mean length of the fertile phase by the monitor was 7.7 days (SD = 3.1) and by cervical mucus 10.9 days (SD = 3.7) (t = 12.7, p < 0.001). The peak in fertility as determined by the monitor and by self-assessment of cervical mucus is similar but the monitor tends to underestimate and self-assessment of cervical mucus tends to overestimate the actual fertile phase.


Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group

Abstract: Since the 1990 National Institutes of Health-sponsored conference on polycystic ovary syndrome (PCOS), it has become appreciated that the syndrome encompasses a broader spectrum of signs and symptoms of ovarian dysfunction than those defined by the original diagnostic criteria. The 2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome, and as such no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events.


Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome

Abstract:
OBJECTIVE: To evaluate the effects of metformin administration on spontaneous LH episodic release in a group of nonobese polycystic ovary (PCOS) patients.

DESIGN: Controlled clinical study.

SETTING: PCOS patients in a clinical research environment.

PATIENT(S): Twenty nonobese PCOS patients were enrolled after informed consent.

INTERVENTION(S): All patients underwent hormonal evaluations and a pulsatility study (sampling every 10 minutes for 4 hours) before and at the sixth month of therapy (metformin, 500 mg, p.o. b.i.d.). Ultrasound examinations and Ferriman-Gallwey scoring were also performed.

MAIN OUTCOME MEASURE(S): Measurements of plasma LH, FSH, estradiol (E(2)), androstenedione (A), 17-hydroxy-progesterone (17-OHP), and testosterone (T), glucose, insulin, and C-peptide concentrations.

RESULT(S): After 6 months of metformin administration, the plasma LH, 17-OHP, A, and T levels and LH/FSH ratio were significantly reduced. Insulin sensitivity, expressed as the glucose-to-insulin ratio, was significantly improved under glucose load after 6 months of treatment. Spontaneous LH episodic release showed a significant reduction in pulse amplitude with no changes in pulse frequency. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic women. The ovarian volume and Ferriman-Gallwey scores also were significantly reduced.

CONCLUSION(S): Metformin administration improves reproductive axis functioning in hyperandrogenic nonobese PCOS patients. By acting on the ovary and restoring normal ovarian activity, metformin positively modulates the reproductive axis (namely GnRH-LH episodic release).


Survival and long-term neurodevelopmental outcome of extremely premature infants born at 23-26 weeks' gestational age at a tertiary center

Robert J Couser

Division of Neonatology, Children’s Hospitals and Clinics of Minneapolis, Minneapolis, Minnesota

Abstract:
OBJECTIVE: Long-term outcome, including school-age function, has been infrequently reported in infants born at ages as young as 23-26 weeks' gestation. The objective of this study is to report outcome on a large cohort of these infants to understand better the risks and factors that affect survival and long-term prognosis.

METHODS: Records from 1036 infants who were born between January 1, 1986, and December 31, 2000, were analyzed retrospectively by logistic regression to correlate multiple factors with both survival and long-term outcome. A total of 675 surviving infants were analyzed at a mean age of 47.5 months for developmental outcome. A subset of 147 surviving infants who were born before 1991 were followed through school-age years using the University of Vermont Achenbach Child Behavioral Checklist and Teachers Report Form. Longitudinal follow-up was performed comparing 1-year outcome with school-age performance.

RESULTS: Gestational age and recent year of birth correlated highly with survival. Maternal nonwhite race, female sex, inborn status, surfactant therapy, single gestation, and secondary sepsis also correlated positively with survival. Normal cranial ultrasound results, absence of chronic lung disease, female sex, cesarean delivery, and increased birth weight correlated favorably with long-term outcome. Infants who were born at 23 weeks were more likely to have severe impairments compared with those who were born at 24-26 weeks. Early follow-up identified most subsequent physical impairments but correlated poorly with school-age function.

CONCLUSIONS: Survival continues to improve for infants who are born at extremely early gestational ages, but long-term developmental concerns continue to be prevalent. Early outcomes do not reliably predict school-age performance. Strategies that reduce severe intraventricular hemorrhage and chronic lung disease will likely yield the best chances to improve long-term outlook.


Chapter 15: Scientific Foundations of the CrMS

Thomas W Hilgers

Pope Paul VI Institute for the Study of Human Reproduction, Omaha, Nebraska.

Abstract: The CREIGHTON MODEL FertilityCare System (CrMS) rests on a decades-long body of research demonstrating that cervical mucus functions as a physiologically regulated biological valve, opening predictably at the periovulatory estrogen rise and closing in the post-Peak phase. Chapter 15 of Hilgers (2004) synthesizes hormonal, ultrasound, cytologic, and biophysical evidence to establish that a woman's external observation of her Peak Day reliably identifies the fertile window, and documents the system's effectiveness data for both achieving and avoiding pregnancy across a five-study meta-analysis of nearly 1,900 couples.

The Medical and Surgical Practice of NaProTECHNOLOGY


Chapter 43: Polycystic Ovarian Disease

Chapter 43: Polycystic Ovarian Disease

Abstract: PCOS (polycystic ovary syndrome), increasingly designated PMOS (polycystic metabolic ovary syndrome) to reflect its metabolic complexity, is far more prevalent than its classic presentation suggests, affecting roughly six percent of reproductive-age women and carrying systemic consequences well beyond fertility disruption. This chapter from the foundational NaProTECHNOLOGY textbook maps the hormonal architecture of the condition, its ovulatory defect patterns, its frequent co-occurrence with endometriosis, and the restorative surgical and cycle-tracking approaches developed at the Pope Paul VI Institute.


Chapter 47: Male Infertility: Evaluation and Treatment

Abstract: Male infertility plays a clinically significant role in a large share of couples who struggle to conceive, yet standard laboratory criteria for semen analysis were designed primarily to predict success with assisted reproduction, not natural fertility. NaProTECHNOLOGY approaches male factor as a diagnosable condition with identifiable root causes, applying medical and surgical options aimed at restoring sperm function and combining that work with fertility-awareness charting to maximize the couple's chances of natural conception.


Chapter 55: Using Progesterone Support During Pregnancy

Abstract: Luteal phase and early pregnancy progesterone supplementation protocols are detailed, including indications derived from Creighton Model hormone profiles and dosing regimens for intramuscular and vaginal routes. Targeted progesterone support addresses a correctable physiological deficit identified through CrMS-guided monitoring, reducing early pregnancy loss in women with documented luteal insufficiency.


Chapter 56: Prevention of Preterm Birth

Chapter 56: Prevention of Preterm Birth

Abstract: Preterm birth remains a leading cause of perinatal mortality, with rates in the United States rising significantly over the latter half of the twentieth century despite decades of awareness. NaProTechnology's integrated prevention approach, developed at the Pope Paul VI Institute, addresses this problem through systematic risk stratification, hormonal support, infection surveillance, and cervical monitoring across the full course of pregnancy.


Chapter 6: Introductory Presentation of the CrMS

Abstract: This 2004 textbook chapter by Thomas W. Hilgers outlines the structure and content of the formal introductory session used to enroll couples in the Creighton Model FertilityCare System (CrMS). It covers the biological foundation of fertility charting, the role of cervical mucus as a biomarker of the reproductive cycle, and the educational framework designed to train couples in systematic, real-time cycle observation.


Chapter 85: NaProTECHNOLOGY Nursing

Chapter 85: NaProTECHNOLOGY Nursing

Abstract: Nursing within the NaProTECHNOLOGY practice encompasses preoperative preparation, intraoperative assistance, postoperative monitoring, hormone administration protocols, and patient education on cycle-based treatment timing. Nurses fluent in CrMS charting language and NaProTECHNOLOGY biomarker systems function as clinical integrators, ensuring that laboratory and treatment protocols are executed in alignment with the individualized menstrual cycle data driving each patient's care plan.


Chapter 86: Summary of NaProTECHNOLOGY Biomarkers

Abstract: NaProTECHNOLOGY utilizes a defined panel of cycle-phase-specific biomarkers — including targeted progesterone, estradiol, LH, FSH, and prolactin drawn at CrMS-standardized cycle days — to characterize the hormonal profile underlying each patient's reproductive dysfunction. This biomarker summary consolidates reference ranges, collection timing rules, and clinical interpretation frameworks that govern diagnosis and treatment decisions across infertility, endometriosis, recurrent pregnancy loss, and cycle irregularity.


Chapter 87: Summary of Medical Protocols

Abstract: Medical protocols in NaProTECHNOLOGY are cycle-phase-targeted regimens — covering ovulation induction, luteal phase hormonal support, hyperprolactinemia management, thyroid optimization, and pre-conceptual supplementation — derived from the biomarker-defined diagnosis rather than empirical stimulation. Consolidating these protocols in a single reference enables practitioners to apply evidence-based, individualized treatment sequences that address root hormonal pathology while supporting natural conception.


Chapter 88: Cost-Effectiveness of NaProTECHNOLOGY

Abstract: An economic analysis of NaProTECHNOLOGY compares the total treatment costs and cost-per-live-birth outcomes against assisted reproductive technologies, including IVF, drawing on outcome data from the Pope Paul VI Institute to demonstrate that NaPro's higher per-cycle success rates yield a favorable cost-effectiveness ratio despite comparable or lower upfront expenditures. Because NaProTECHNOLOGY identifies and corrects underlying pathology rather than bypassing it, its resource utilization model supports long-term gynecological health benefits that IVF cannot provide, making the economic case inseparable from the clinical one.


Chapter 89: Research End-notes

Chapter 89: Research End-notes

Abstract: A comprehensive, thematically organized compendium of citations documents the evidentiary foundations for every clinical protocol and outcome claim presented across the preceding 88 chapters, spanning foundational cervical mucus research through contemporary reproductive endocrinology and surgical outcomes literature. Consolidating this reference architecture in a dedicated chapter provides practitioners and researchers a structured pathway to primary literature, reinforcing that NaProTECHNOLOGY is grounded in a reproducible, peer-reviewed evidence base rather than institutional convention.


Chapter 90: The Future of NaProTECHNOLOGY

Abstract: Hilgers articulates a programmatic vision for the global expansion of NaProTECHNOLOGY through the continued development of FertilityCare Centers International, advanced medical consultant training, and integration of longitudinal hormonal research into evolving clinical protocols. Establishing a roadmap for research priorities, practitioner education infrastructure, and broader medical acceptance positions NaProTECHNOLOGY as a scalable, restorative alternative to the prevailing ART-centered paradigm in reproductive medicine.


Chapter 13: Achieving- and Avoiding-Related Behavior (Use)

Abstract: Chapter 13 of Hilgers' NaProTECHNOLOGY textbook establishes a clinical behavioral taxonomy unique to the Creighton Model FertilityCare System, distinguishing between achieving-related and avoiding-related use based on whether a couple's actions increase or decrease the probability of conception. The chapter argues that a "taking a chance" mindset is inherently contraceptive in psychology and must be replaced with intentional, education-grounded behavior that reflects a couple's genuine family planning goals.


Chapter 34: Cancer: NaProTECHNOLOGY and Early Detection

Abstract: Chapter 34 of Hilgers (2004) examines how NaProTechnology cycle charting may identify women at elevated risk for three gynecologic cancers: endometrial, breast, and ovarian. The chapter presents clinical case series and a small prospective study suggesting that observable cycle biomarkers, particularly patterns indicating suboptimal luteal-phase function, may precede diagnosis and could inform earlier evaluation, while calling explicitly for further research to validate these findings.


Chapter 5: Standardization of Teaching

Chapter 5: Standardization of Teaching

Abstract: The structured protocols used to train and certify FertilityCare Practitioners (FCPs) in the uniform delivery of CrMS instruction are detailed, covering the sequence of follow-up sessions, the use of standardized teaching aids, and quality-control mechanisms that ensure inter-instructor consistency. Standardization is essential to the scientific validity of CrMS data, because chart comparability across practitioners and study populations depends on identical observation and recording conventions.


Positive predictive value of clinical diagnosis of endometriosis

B R Carr

The University of Texas Southwestern Medical Center

Abstract:
Objective: To determine the positive predictive value of the combined symptoms of severe dysmenorrhea with the sign of tenderness and/or nodularity of the cul-de-sac and/or uterosacral ligament(s) in diagnosing endometriosis clinically. Material and Method: In this prospective study, 116 patients with severe dysmenorrhea, after excluding urinary and gastrointestinal disease, underwent pelvic examination by the same investigator. Women having adnexal mass on pelvic examination were excluded Tenderness, and also nodularity, of the cul-de-sac, right and left uterosacral ligament were recorded separately. The laparoscopist did not know the findings of the pelvic examination. The diagnosis of endometriosis was made visually when lesions were typical and all other lesions were biopsied.

Results: The prevalence of endometriosis was 78.4%. Tenderness, nodularity, tenderness and nodularity, and also tenderness or nodularity of cul-de-sac and/or uterosacral ligament(s) were all statistically significantly associated with the presence of endometriosis (P = .048, .005, .004, and .004 respectively). The positive predictive values were 85.5%, 94.0%, 94.6% and 86.7%, respectively.

Conclusion: The positive predictive value of severe dysmenorrhea with nodularity of the cul-de-sac and/or uterosacral ligament(s) was 94.0%.

Journal of the Medical Association of Thailand = Chotmaihet thangphaet


Chapter 64: Visual Appearance of Endometriosis

Abstract: Endometriotic implants are catalogued across their full morphological spectrum—classic powder-burn lesions, red flame lesions, clear vesicles, white fibrotic plaques, and subtle vascular changes—with photographic documentation guiding surgical recognition. Familiarity with atypical implant appearances is essential because underrecognition of non-pigmented lesions leads to incomplete excision and persistent symptomatology.


Chapter 58: Early Pregnancy Loss

Chapter 58: Early Pregnancy Loss

Abstract: Early pregnancy loss encompasses biochemical pregnancy, embryonic demise, and missed abortion, each distinguished by specific hormonal profiles and ultrasound criteria within the NaProTECHNOLOGY surveillance model. CrMS-based cycle identification enables recognition of pregnancy at the earliest stages, allowing timely hormonal intervention when progesterone or estradiol deficits are detected.


Chapter 9: Basic CrMS Instructions

Chapter 9: Basic CrMS Instructions

Abstract: The content and sequence of the introductory and follow-up instructional sessions that constitute the formal CrMS education series are outlined, covering observation technique, recording conventions, and the practitioner-client interaction model. Consistent delivery of these core instructions establishes the behavioral competence required for both family planning use and the medical monitoring applications that NaProTECHNOLOGY depends upon.


Chapter 62: What is Surgical NaProTECHNOLOGY?

Abstract: Surgical NaProTECHNOLOGY is defined as a cooperative surgical discipline that corrects reproductive pathology identified through CrMS monitoring and targeted diagnostic workup, employing microsurgical and laser techniques that maximize tissue preservation and minimize adhesion formation. The philosophical and technical distinctions from conventional gynecologic surgery are established, emphasizing restorative intent and anatomical precision as core principles.


Chapter 53: Dating the Beginning of Pregnancy

Thomas W Hilgers

Pope Paul VI Institute for the Study of Human Reproduction, Omaha, Nebraska.

Abstract: NaProTECHNOLOGY uses the Peak Day of the Creighton Model chart — the last day of the most fertile-type cervical mucus — as the reference point for dating conception, providing a biologically grounded alternative to last menstrual period dating that remains accurate across irregular cycles. Precise cycle-based dating improves the clinical interpretation of early pregnancy hormone levels, ultrasound findings, and obstetric gestational age assignments, reducing unnecessary interventions triggered by apparent growth discordance.

The Medical and Surgical Practice of NaProTECHNOLOGY


Chapter 35: Follicular and Luteal Phase Deficiencies: Advancing Concepts and New Terminology

Abstract: Hilgers presents a refined classification of follicular and luteal phase deficiencies grounded in the integration of CrMS mucus pattern characteristics, cycle-phase-targeted estradiol and progesterone profiles, ultrasound folliculometry, and endometrial histology, introducing terminology that links specific chart signatures to defined endocrine subtypes and treatment protocols. Follicular deficiencies -- marked by short or poor-quality mucus phases and suboptimal estradiol -- and luteal deficiencies -- marked by a post-Peak phase under nine days, premenstrual spotting, or blunted serial progesterone curves -- are treated with tailored ovulation induction, cooperative progesterone replacement, and correction of contributing systemic disorders including thyroid dysfunction, hyperprolactinemia, and insulin resistance.


Chapter 51: Effectiveness of NaProTECHNOLOGY

Abstract: Cumulative pregnancy and live birth data from the Pope Paul VI Institute document NaProTECHNOLOGY outcomes across diagnostic categories including unexplained infertility, endometriosis, PCOD, and tubal disease, with multi-year follow-up that captures pregnancies occurring after continued treatment — a metric not captured in per-cycle ART statistics. These outcomes provide the evidence base for positioning NaProTECHNOLOGY as a first-line rather than last-resort reproductive medicine strategy.


Chapter 41: Hypothalamic-Pituitary-Ovarian Dysfunction

Abstract: Disruptions along the hypothalamic-pituitary-ovarian axis — including luteal phase deficiency, inadequate LH surges, and follicular maturation failure — are among the most common and underdiagnosed contributors to infertility and recurrent pregnancy loss. Targeted hormone supplementation guided by cycle-specific progesterone and estradiol assays, timed to CrMS biomarkers, restores functional ovulatory and luteal competence without suppressing the axis.


Chapter 21: Disorders of Human Ovulation: Endocrine Validation of the Sonographic Classification System

Abstract: The sonographic ovulation classification is validated against targeted hormone profiles -- estradiol, LH, and serial post-Peak progesterone (P+3 through P+11) -- drawn at CrMS Peak-anchored time points rather than fixed calendar days. Hormone patterns corresponding to each sonographic category (e.g., absent LH surge in anovulation, progesterone rise without follicle rupture in LUF) confirm that ultrasound morphology reliably reflects the underlying endocrine disorder, establishing the biochemical legitimacy of the classification for clinical diagnosis.


Chapter 78: Management of Ectopic Pregnancies

Abstract: Ectopic pregnancy demands prompt diagnosis and intervention to prevent life-threatening hemorrhage, and NaProTECHNOLOGY's CrMS-guided cycle monitoring enables earlier detection compared to symptom-driven presentations. Surgical management favors salpingotomy with tube preservation when feasible, aligned with the NaProTECHNOLOGY commitment to maintaining reproductive anatomy and future fertility potential.


Chapter 84: Role of FertilityCare Practitioner

Abstract: The FertilityCare Practitioner (FCP) is the trained educator and coach who teaches the Creighton Model FertilityCare System to clients, standardizes charting methodology, and serves as the primary data interface between the patient and the NaProTECHNOLOGY physician. Accurate, consistent chart data from FCPs directly determines the quality of biomarker interpretation, targeted intervention timing, and longitudinal outcome assessment throughout medical and surgical care.


Chapter 2: What is NaProTECHNOLOGY?

Chapter 2: What is NaProTECHNOLOGY?

Abstract: NaProTECHNOLOGY (Natural Procreative Technology) is defined as a women's health science that monitors and cooperates with the menstrual and fertility cycles to identify, evaluate, and treat gynecologic and reproductive disorders at their root cause. Unlike suppressive approaches such as hormonal contraception or ART, NaProTECHNOLOGY maintains procreative potential and treats underlying pathology while preserving the human ecology of reproduction.


Chapter 68: Laparoscopic Laser Vaporization of Endometrial Implants

Abstract: CO2 laser vaporization technique for peritoneal and superficial ovarian endometriotic implants is described in detail, covering power density settings, spot size, vaporization depth control, and recognition of adequate treatment endpoints. Complete destruction of all visible implants, facilitated by the near-contact survey, is necessary to achieve durable symptom relief and improvement in fertility outcomes.


Chapter 63: Diagnostic Laparoscopy: "Near Contact" Approach


Chapter 29: Premenstrual Syndrome: Evaluation and Treatment

Abstract: Premenstrual syndrome in NaProTECHNOLOGY is defined by a recurrent cluster of symptoms -- including irritability, breast tenderness, bloating, depression, and carbohydrate craving -- beginning at least four days before menses, and is associated with late-luteal deficiencies in progesterone, estrogen, and beta-endorphin identified through CrMS-anchored hormone profiling. Treatment with cycle-synchronized bioidentical progesterone, targeted HCG injections to stimulate endogenous corpus luteum function, and low-dose naltrexone to modulate opioid dynamics produces superior symptom resolution compared to SSRI therapy in Hilgers' comparative data, without suppressing ovulation.


"Chapter 59: Fertility, Conception, and Childbirth in Women of Mature Reproductive Age"

Abstract: Reproductive outcomes in women aged 35 and older are analyzed using CrMS-monitored cycles, documenting that natural conception remains achievable when ovulatory function and hormonal sufficiency are maintained and underlying pathology is treated. NaProTECHNOLOGY's restorative approach offers an alternative to assisted reproduction for mature-age patients by identifying and correcting specific endocrine or anatomical barriers.


Chapter 3: NaProTECHNOLOGY and the New Humanism

Renee Mirkes

Pontifical John Paul II Institute for Studies on Marriage and Family

Abstract: The philosophical and ethical foundation of NaProTECHNOLOGY is examined through the lens of a "new humanism" that affirms the dignity of women, couples, and the unborn by working within — rather than against — natural reproductive processes. Hilgers and contributing author Sr. Renee Mirkes situate NaProTECHNOLOGY within a broader critique of technologized reproductive medicine and articulate a coherent framework for procreative ethics applicable to clinical practice.


Chapter 48: Fecundity and Mucus Cycle Score

Abstract: The Mucus Cycle Score, derived from the standardized CrMS daily observations, quantifies cervical mucus quality and quantity across a cycle and correlates with measured estrogen levels and fecundity rates, providing a non-invasive index of reproductive potential. Declining mucus scores are clinically actionable, directing investigation into hypoestrogenism, cervical pathology, or medication effects that reduce cycle fecundity and can be corrected before ART is considered.


Chapter 77: PEARS for the Fallopian Tubes: Proximal Tubal Occlusion with Tubal Reimplantation

Abstract: 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.


Chapter 18: Professional and Academic Infrastructure of the CrMS

Thomas W Hilgers

Pope Paul VI Institute for the Study of Human Reproduction, Omaha, Nebraska.

Abstract: The institutional architecture supporting the CrMS — including the FertilityCare Centers of America network, the American Academy of FertilityCare Professionals (AAFCP), training and certification pathways, and the research programs of the Pope Paul VI Institute — is described. This infrastructure is what distinguishes NaProTECHNOLOGY from informal fertility awareness methods, providing the professional standards, peer accountability, and ongoing research capacity required for clinical credibility.

The Medical and Surgical Practice of NaProTECHNOLOGY


Chapter 20: Disorders of Human Ovulation: Sonographic Classification System

Abstract: Serial transvaginal ultrasound monitoring of follicular dynamics -- growth, rupture, corpus luteum formation, and free fluid -- forms the basis of a systematic classification of human ovulation disorders, including anovulation, luteinized unruptured follicle (LUF), follicular arrest, premature luteinization, and PCOS-type patterns. Anchoring sonographic findings to the CrMS Peak day allows precise correlation between ultrasound events and cervical mucus biomarkers, creating a reproducible diagnostic taxonomy that drives targeted medical and surgical treatment within the NaProTECHNOLOGY framework.


Chapter 50: Pregnancy Following Failed ART

Phil C Boyle

NeoFertility Clinic, Suite 7, 1st Floor, Beacon Mall, Sandyford, Dublin 18, Ireland. Phil.Boyle@NeoFertility.ie.

Abstract: 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.


Chapter 10: Special Instructions and Applications

Abstract: Adaptations of CrMS instruction for physiologically distinct reproductive states — including breastfeeding, post-hormonal contraceptive use, long or irregular cycles, and premenopause — are described with specific observational guidance for each context. These special protocols extend the clinical reach of the CrMS to all phases of a woman's reproductive life and ensure that charting remains interpretable even when cycle dynamics are atypical.


Chapter 82: Postoperative Care and Complications

Abstract: Structured postoperative management following PEARS procedures addresses wound care, pain control, early ambulation, hormonal support, and surveillance for complications including bleeding, infection, urinary injury, and bowel complications. NaProTECHNOLOGY postoperative protocols integrate CrMS-guided hormonal monitoring to optimize the healing environment and time the resumption of targeted fertility treatment.


Chapter 61: Preconceptional Care and the CREIGHTON MODEL System

Abstract: Preconceptional optimization using CrMS cycle data establishes hormonal baselines, identifies correctable pathologies, and guides targeted supplementation before conception is attempted. Systematic preconceptional evaluation reduces early pregnancy loss and improves obstetric outcomes by ensuring the endocrine environment supports implantation and early embryonic development.


Chapter 42: Endometriosis and Effects on Fertility

Abstract: Endometriosis impairs fertility through direct mechanical distortion of pelvic anatomy, peritoneal inflammatory mediators, and hormonal micro-environment alterations that reduce implantation potential, making thorough surgical excision critical to restoring fertility rather than bypassing it. The PEARS classification system, used in NaProTECHNOLOGY surgical practice, enables standardized documentation of endometriotic disease extent and correlates operative findings with postoperative reproductive outcomes.


Chapter 32: Unusual Bleeding: Evaluation and Treatment

Abstract: Unusual uterine bleeding -- including premenstrual spotting, tail-end brown bleeding, mid-cycle intermenstrual bleeding, and heavy menses -- is evaluated in NaProTECHNOLOGY through prospective CrMS charting combined with cycle-phase-targeted estradiol and serial post-Peak progesterone profiles, which typically reveal luteal phase deficiency, follicular estradiol insufficiency, or anovulation as the primary etiology. Treatment is etiology-directed and cycle-synchronized: cooperative progesterone replacement for luteal defects, follicular support or ovulation induction for follicular phase insufficiency, and fertility-sparing surgical correction for structural pathology such as endometriosis, polyps, or fibroids, without routine recourse to contraceptive suppression.


"Chapter 1: Disturbing Trends in the Health Care of Women, Children and Families"

Abstract: Escalating rates of contraceptive use, abortion, divorce, child abuse, teenage pregnancy, and out-of-wedlock births over the preceding four decades are documented as interconnected indicators of systemic failure in women's and family healthcare. Hilgers argues these trends reflect a prevailing medical culture that suppresses or bypasses reproductive function rather than supporting it, establishing the clinical and moral imperative for a restorative alternative.


Chapter 71: PEARS for Bowel Endometriosis: Surgical Techniques for the Gynecologist

Abstract: Deep infiltrating endometriosis involving the rectosigmoid, appendix, and small bowel is addressed through gynecologist-performed PEARS techniques that include superficial disc excision, appendectomy, and coordinated bowel resection when full-thickness involvement requires it. Recognition of intestinal endometriosis at laparoscopy and command of the relevant surgical steps allow the NaProTECHNOLOGY surgeon to treat the complete disease burden in a single operative setting.


Chapter 25: Chronic Discharges and CrMS

Chapter 25: Chronic Discharges and CrMS

Abstract: The Creighton Model's standardized daily vulvar observation system -- recording discharge color, consistency, quantity, and sensation -- allows chronic pathological discharges (persistent yellow or cloudy mucus, continuous post-Peak discharge, premenstrual brown bleeding, or refractory vulvovaginitis) to be distinguished from normal cyclical mucus patterns and tracked longitudinally as a diagnostic tool. NaProTECHNOLOGY uses chronic discharge patterns as biomarkers that prompt organism-specific cultures, targeted hormonal evaluation, ultrasound, and etiology-directed treatment -- including antimicrobials, cooperative hormone replacement, or fertility-sparing surgery -- rather than empirical cycle suppression.


Chapter 79: Recurrence of Endometriosis after PEARS

Abstract: Endometriosis recurrence after surgical excision remains a clinical reality driven by residual ectopic implants, persistent hormonal milieu favoring re-seeding, and incomplete initial resection. NaProTECHNOLOGY addresses recurrence risk through postoperative hormone normalization guided by CrMS biomarkers, with repeat PEARS reserved for symptomatic or fertility-impairing recurrence confirmed by clinical and laparoscopic assessment.


Chapter 26: Isomolecular Hormones vs Heteromolecular Artimones

Abstract: Hilgers distinguishes isomolecular hormones -- molecules structurally identical to endogenous estradiol and progesterone -- from heteromolecular artimones, his term for synthetic analogues such as medroxyprogesterone acetate, norethindrone, and ethinyl estradiol, which differ in receptor binding, metabolic pathways, and systemic effects. NaProTECHNOLOGY restricts hormone therapy to isomolecular compounds administered in cycle-synchronized, physiologic doses because artimones suppress the hypothalamic-pituitary-ovarian axis, mask underlying pathology, and produce non-physiologic metabolite profiles incompatible with a restorative reproductive medicine approach.


Chapter 16: Measuring Effectiveness and Pregnancy Rates of the CrMS

Abstract: Methodologically rigorous effectiveness data for the CrMS are presented, including method-effectiveness and use-effectiveness rates for pregnancy avoidance drawn from prospective cohort studies, demonstrating rates comparable to or exceeding hormonal contraception. Standardized outcome measurement is necessary to establish the CrMS's scientific credibility and to provide practitioners and patients with accurate, evidence-based counseling on system performance.


Chapter 19: Targeted Hormone Assessment of the Menstrual Cycle

Abstract: A CrMS-synchronized hormone sampling protocol is detailed in which progesterone, estradiol, and other reproductive hormones are drawn at cycle-phase-specific time points defined by the charted Peak Day rather than by fixed cycle day, producing a targeted hormone profile that accurately reflects luteal and follicular function. This Peak Day-referenced approach substantially improves the diagnostic sensitivity for luteal phase deficiency, follicular dysfunction, and other endocrine abnormalities that fixed-day sampling routinely misclassifies.


Chapter 39: Medical Risks of Infertility

Thomas W Hilgers

Pope Paul VI Institute for the Study of Human Reproduction, Omaha, Nebraska.

Abstract: Infertility is not merely a reproductive inconvenience but frequently signals systemic or hormonal pathology — including polycystic ovarian disease, endometriosis, thyroid dysfunction, and immune abnormalities — each carrying independent health risks beyond failure to conceive. Identifying and treating these underlying conditions reduces long-term morbidity and reframes infertility evaluation as a form of preventive medicine rather than a terminal bypass decision.

The Medical and Surgical Practice of NaProTECHNOLOGY


Chapter 80: Chronic Pelvic Pain and Dysmenorrhea

Abstract: Chronic pelvic pain and dysmenorrhea in reproductive-age women most commonly reflect undertreated endometriosis, adenomyosis, ovarian dysfunction, or pelvic adhesive disease rather than psychosomatic pathology. NaProTECHNOLOGY evaluates these symptoms through a structured diagnostic pathway integrating CrMS biomarker profiles, hormonal assays, and targeted laparoscopy, directing restorative surgical and medical interventions rather than suppressive hormonal therapy.


Chapter 37: Role of Compounding Pharmacist

Abstract: Compounding pharmacists prepare individualized hormone formulations — including HCG, progesterone, and thyroid preparations — that are central to NaProTECHNOLOGY treatment protocols, where standardized commercial doses are often inadequate for patient-specific needs. Collaborative prescribing between NaPro practitioners and licensed compounding pharmacists ensures consistent bioidentical formulation quality, dosing precision, and regulatory compliance within fertility and reproductive endocrine management.


Chapter 33: Osteoporosis and Role of CrMS

Abstract: Chronic anovulation and progesterone or estradiol deficiency identified through CrMS charting represent periods of suboptimal bone accrual in women of reproductive age, because both estradiol and progesterone contribute to skeletal maintenance -- estradiol through suppression of osteoclast activity and progesterone through osteoblast stimulation. NaProTECHNOLOGY uses longitudinal CrMS records of ovulatory status and hormone profiles as a bone-health risk screen, guiding cycle-synchronized bioidentical hormone replacement to restore normal estrogen-progesterone balance and potentially mitigate progression toward osteoporosis in women with chronic cycle-based endocrine deficiencies.


Pregnancy during the use of levonorgestrel intrauterine system

Abstract:
OBJECTIVES: This study was undertaken to evaluate the pregnancy rate with the levonorgestrel intrauterine system (LNG IUS) and to analyze the outcome of pregnancies with the LNG IUS in situ in regular use.

STUDY DESIGN: Questionnaires from 17,360 users of the LNG IUS were analyzed. With the consent of women reporting pregnancy during the use of the LNG IUS, related hospital records were reviewed concerning the pregnancies.

RESULTS: Originally 132 pregnancies were reported. Medical records were reviewed from 108 of these women. In 64 pregnancies, conception occurred with the LNG IUS in situ. Thirty-three pregnancies were ectopic. The 5-year cumulative pregnancy rate per 100 users was 0.5 and the 5-year Pearl rate was 0.11.

CONCLUSION: Pregnancy with the LNG IUS in situ is rare. Ectopic pregnancies constitute 53% of all pregnancies. Typical pregnancy symptoms occur during pregnancies with the LNG IUS. The importance to counsel about the risk of pregnancy before insertion is emphasized.

American journal of obstetrics and gynecology


Infant Deaths up in US for First Time Since 1958: Premature Birth is a Leading Cause


Chapter 76: PEARS for the Fallopian Tubes: Distal Occlusions and Other Applications

Abstract: 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.


Chapter 30: Postpartum Depression: Evaluation and Treatment

Abstract: Postpartum depression in susceptible women is linked to abrupt postpartum progesterone withdrawal following the high-progesterone state of pregnancy, particularly in those with prior PMS, luteal phase defects, or recurrent miscarriage, and NaProTECHNOLOGY evaluates this through serum progesterone, thyroid function, and prolactin assessment in the postpartum period. Treatment uses bioidentical progesterone -- preferably intramuscular for reliable absorption -- with serum levels monitored every two weeks for dose titration, and once cycles resume, dosing is resynchronized to the CrMS Peak day; Hilgers reports no increase in congenital anomalies in over 2,000 progesterone-supported pregnancies in the Pope Paul VI Institute series.


Increased infertility with age in men and women

D D Baird

Epidemiology Branch, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA

Bernardo Colombo

Abstract:
OBJECTIVE: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.


Chapter 23: Differences Between Laboratories

Abstract: Serum estradiol and progesterone assays vary substantially across laboratories because of differences in antibody specificity, calibration standards, detection platforms, and quality-control practices, meaning that a value within one laboratory's generic reference range may represent a clinically significant deficiency when interpreted against NaPro Peak-day-specific norms. NaProTECHNOLOGY requires consistent use of a single reference laboratory and interpretation relative to cycle-phase-specific NaPro standards rather than broad lab-generated reference intervals, to avoid missing subtle follicular or luteal phase defects that standard reporting would classify as normal.


Chapter 22: Disorders of Human Ovulation: Clinical Validation of the Sonographic Classification System

Abstract: CrMS charting features -- Peak day definition, pre-Peak mucus quality and duration, post-Peak phase length, and premenstrual spotting -- are systematically compared against sonographic and endocrine findings to demonstrate that prospective cycle observations reliably identify specific ovulation disorder categories. This clinical validation shows that the CrMS chart functions as a non-invasive biomarker map capable of directing targeted ultrasound and hormonal investigation, and that treatment guided by the classification improves ovulatory and fertility outcomes.


Chapter 83: Family Physician's Experience

Abstract: Family physicians trained in NaProTECHNOLOGY serve as primary coordinators of medical management — prescribing targeted hormone support, monitoring biomarker trends, and triaging surgical referrals — within a collaborative care model. Their longitudinal relationship with patients and ability to integrate reproductive medicine into whole-person primary care is a structural advantage of the NaProTECHNOLOGY delivery system over specialist-only models.


Chapter 60: Lethal Congenital Anomalies: Prenatal Diagnosis and the Management of Pregnancy

Thomas W Hilgers

Pope Paul VI Institute for the Study of Human Reproduction, Omaha, Nebraska.

Abstract: Management of pregnancies complicated by lethal fetal anomalies is addressed within an ethical framework that provides perinatal palliative care, parental support, and medical management without recourse to induced abortion. The chapter outlines clinical protocols for continuing care that respect fetal life while attending to maternal physical and psychological wellbeing through delivery and bereavement.

The Medical and Surgical Practice of NaProTECHNOLOGY


Chapter 69: Laparoscopic Laser Lysis of Adhesions

Abstract: 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.


Chapter 4: Introduction to the CREIGHTON MODEL System

Abstract: The Creighton Model FertilityCare System (CrMS) is introduced as a standardized, scientifically grounded method for observing and recording cervical mucus biomarkers and bleeding patterns across the menstrual cycle. Its development from earlier natural family planning methods into a fully systematized fertility monitoring tool is traced, establishing the CrMS as the observational substrate for all subsequent NaProTECHNOLOGY medical applications.


Chapter 27: Cooperative Progesterone and Estrogen Replacement

Abstract: Cooperative progesterone and estrogen replacement therapy administers bioidentical hormones in precise synchrony with the woman's CrMS-identified Peak day -- beginning progesterone at P+2 or P+3 and continuing through the luteal phase -- to augment deficient corpus luteum output rather than override the cycle with suppressive dosing. Serial serum progesterone across post-Peak days guides dose titration, and the approach is applied to luteal phase deficiency, recurrent miscarriage, premenstrual syndrome, and postpartum depression while preserving ovulatory function and fertility.


Chapter 65: Atlas of Findings in Diagnostic Laparoscopy

Abstract: 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.


Chapter 66: Selective Hysterosalpingography and Transcervical Catheterization of the Fallopian Tubes

Abstract: 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.


Chapter 11: Case Management

Chapter 11: Case Management

Abstract: A systematic framework for managing patient cases within the CrMS-NaProTECHNOLOGY system is presented, addressing how FCPs and medical consultants collaborate to identify abnormal chart patterns, initiate medical referral, and coordinate ongoing care. Structured case management is the operational bridge between fertility monitoring and clinical intervention, ensuring that biomarker observations are translated into timely diagnostic and therapeutic action.


Chapter 28: Effects of Stress

Chapter 28: Effects of Stress

Abstract: Physiological and psychological stress disrupts hypothalamic GnRH pulsatility via CRH-cortisol pathways, producing downstream impairments in LH and FSH secretion that manifest as anovulation, delayed ovulation, follicular phase prolongation, or luteal phase deficiency -- all of which are documented cycle-by-cycle on the CrMS chart. NaProTECHNOLOGY addresses stress-induced HPO axis dysfunction by identifying the specific cycle-level disorder through charting and targeted hormone profiling, then applying cycle-appropriate ovulation induction and cooperative hormone support alongside correction of the underlying physical or psychological stressor.


Chapter 52: Three-dimensional Ultrasound

Abstract: 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.


Chapter 45: Amenorrhea and Anovulation

Chapter 45: Amenorrhea and Anovulation

Abstract: Amenorrhea and anovulation represent a spectrum of hypothalamic, pituitary, ovarian, and end-organ etiologies that must be differentiated through systematic hormonal and anatomical evaluation before treatment is initiated. NaProTECHNOLOGY integrates CrMS mucus charting with targeted biochemical testing to identify the level of dysfunction and guide ovulation induction or hormonal restoration appropriate to the specific cause.


Chapter 12: Decision Making in the CrMS

Chapter 12: Decision Making in the CrMS

Abstract: Clinical and instructional decision trees guide practitioners through the interpretation of chart findings and the selection of appropriate responses — ranging from continued observation to medical referral — based on pattern recognition and established CrMS criteria. Systematic decision-making protocols reduce practitioner variability, support evidence-based care, and define the threshold at which observed abnormalities warrant further NaProTECHNOLOGY medical evaluation.


Chapter 46: Medical Treatment of Ovarian Dysfunction

Abstract: Ovarian dysfunction — encompassing luteal insufficiency, abnormal folliculogenesis, and anovulation — is treated in NaProTECHNOLOGY with cycle-timed interventions including HCG trigger, progesterone supplementation, clomiphene, and thyroid optimization, guided by prospective CrMS charting rather than protocol-driven stimulation. This approach normalizes endogenous hormonal patterns rather than overriding them, preserving uterine receptivity and reducing multiple gestation risk.


Chapter 72: PEARS for Bowel Endometriosis: Surgical Techniques for the General Surgeon

Abstract: Bowel endometriosis involving the rectosigmoid, appendix, and small intestine requires specialized resection and repair techniques that fall within the competency of a general surgeon collaborating with the NaProTECHNOLOGY surgical team. Addressing bowel involvement is essential to achieving complete excision of endometriotic disease, which underpins the PEARS philosophy of restoring normal pelvic anatomy and maximizing reproductive potential.


DIR Jahrbuch 2003 (Deutsches IVF-Register Annual Report 2003)

Abstract: Annual report (Jahrbuch) of the Deutsches IVF-Register (DIR) for treatment year 2003. DIR is the German national IVF/ICSI registry, founded 1982 — the oldest continuously operating ART registry. Voluntary professional-society database with high de-facto coverage of German fertility centres. Reports cycles, transfers, pregnancies and clinical outcomes by treatment type (IVF, ICSI, frozen embryo transfer, donor). German-language registry document. Used as a Phase B historical-archive source for the ART Registry Comparison study (cross-registry classification by reporting completeness on 7 framework dimensions).


Chapter 44: Pelvic Adhesive Disease

Chapter 44: Pelvic Adhesive Disease

Abstract: 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.


Chapter 67: Fundamental Anti-Adhesion Surgical Techniques

Abstract: Core microsurgical principles for adhesion prevention—continuous peritoneal irrigation, meticulous hemostasis, minimal thermal spread, avoidance of foreign material, and precise tissue approximation—are detailed as non-negotiable standards in every NaProTECHNOLOGY procedure. Postoperative adhesion formation is the primary cause of surgical failure in pelvic reconstruction, making preventive technique as important as the corrective intervention itself.


Chapter 38: Trends and Deficiencies in Infertility

Abstract: 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.


Chapter 49: Family Physician's Approach

Chapter 49: Family Physician's Approach

Phil C Boyle

NeoFertility Clinic, Suite 7, 1st Floor, Beacon Mall, Sandyford, Dublin 18, Ireland. Phil.Boyle@NeoFertility.ie.

Abstract: Family physicians are optimally positioned to introduce NaProTECHNOLOGY to patients presenting with infertility, irregular cycles, or recurrent pregnancy loss during routine primary care, enabling early evaluation and restorative treatment before referral to subspecialists. Familiarity with CrMS charting interpretation, basic hormone panels timed to identified cycle phases, and the range of treatable NaPro diagnoses allows the family physician to substantially expand reproductive care at the primary care level.


Chapter 75: PEARS for Polycystic Ovaries: Ovarian Wedge Resection

Abstract: Ovarian wedge resection reduces androgen-producing stromal tissue in women with polycystic ovary syndrome who have failed medical ovulation induction, restoring spontaneous or treatment-responsive ovulatory cycles. Within NaProTECHNOLOGY, the procedure is performed with precise tissue economy and anti-adhesion technique to preserve ovarian reserve while correcting the underlying hormonal dysfunction identified through CrMS biomarker monitoring.


Chapter 24: Establishing Normal Hormone Levels

Abstract: Normal estradiol and progesterone reference ranges in NaProTECHNOLOGY are derived from fertile, ovulatory cycles with confirmed CrMS Peak days and sonographic ovulation, with blood sampling timed to Peak-anchored days (pre-ovulatory P-days for estradiol, P+3 through P+11 for luteal hormones) rather than to calendar cycle days. These day-specific normative values allow detection of subtle deficiencies -- such as a blunted progesterone rise at P+5 or inadequate pre-ovulatory estradiol -- that are clinically actionable for diagnosing follicular and luteal phase disorders but are invisible to standard mid-luteal or phase-independent reference intervals.


Chapter 40: NaProTECHNOLOGY in Infertility

Thomas W Hilgers

Pope Paul VI Institute for the Study of Human Reproduction, Omaha, Nebraska.

Abstract: NaProTECHNOLOGY applies the standardized biomarkers of the Creighton Model FertilityCare System to identify the specific pathophysiological causes of infertility in each couple, then directs targeted medical or surgical intervention against those causes. Published pregnancy rates demonstrate outcomes comparable to or exceeding IVF in many diagnostic categories, without the ethical, financial, or obstetric risks associated with assisted reproduction.

The Medical and Surgical Practice of NaProTECHNOLOGY


Chapter 17: Achieving-Related Pregnancy Rate and Its Natural Adaptability

Abstract: Pregnancy achievement rates among couples using the CrMS to target fertile days are analyzed by cycle type, reproductive history, and duration of use, demonstrating the system's capacity to accommodate irregular and abnormal cycles without reducing its fertility-targeting utility. These data are foundational to NaProTECHNOLOGY's application in infertility management, establishing that the CrMS identifies fertile windows even in subfertile populations with disrupted cycle parameters.


Chapter 31: Ovarian Cysts: Evaluation and Treatment

Abstract: Ovarian cysts in NaProTECHNOLOGY are classified as functional (follicular cysts, luteinized unruptured follicle, corpus luteum cysts) or pathological (endometriomas, neoplasms) through serial cycle-timed transvaginal ultrasound correlated with CrMS Peak day observations and post-Peak progesterone and estradiol profiles. Management of functional cysts uses cooperative progesterone replacement and targeted HCG injections to normalize corpus luteum function and reduce cyst recurrence without contraceptive suppression, while pathological or persistent cysts are addressed through fertility-sparing laparoscopic surgery with anti-adhesion technique.


Chapter 14: Objective Classification of the Mucus Cycle

Abstract: A quantitative taxonomy for classifying the cervical mucus cycle is established, using standardized descriptors for mucus type, quantity, consistency, and Peak Day timing to produce objectively comparable cycle profiles across patients and study populations. This classification system is indispensable to NaProTECHNOLOGY research and clinical correlation, as it enables the linkage of specific mucus pattern anomalies to underlying endocrine pathology.


The Medical & Surgical Practice of NaProTechnology


Chapter 7: Basic Charting and Chart Reading

Abstract: The CrMS charting system is explained in full, including the stamp-based notation for recording mucus characteristics, bleeding, and dry days on the standardized chart, and the conventions for identifying the Peak Day. Accurate chart reading is the foundational clinical skill for NaProTECHNOLOGY practitioners, as the chart provides the biomarker timeline against which hormone profiles and pathology are interpreted.


Chapter 70: PEARS: Peritoneal and Ovarian Endometriosis

Abstract: The PEARS (Pelvic Endoscopic Adhesion-Related Surgery) procedure for peritoneal and ovarian endometriosis combines near-contact laser vaporization, adhesiolysis, and ovarian cystectomy under strict anti-adhesion protocols to achieve comprehensive disease eradication while preserving ovarian reserve. Outcomes data demonstrate superior fertility and pain resolution compared to incomplete surgical approaches, establishing PEARS as the operative standard within NaProTECHNOLOGY.


Chapter 74: PEARS for Uterine Leiomyomata: Myomectomy

Abstract: 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.


Clinical trial: Progesterone reduces postpartum depression in Naprotechnology patients


Chapter 73: PEARS for Extensive Pelvic Adhesive Disease

Abstract: 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.


Chapter 81: Preventing Pelvic Adhesions

Chapter 81: Preventing Pelvic Adhesions

Abstract: Postoperative pelvic adhesions are a leading cause of secondary infertility, chronic pain, and bowel obstruction following gynecologic surgery, making adhesion prevention a primary surgical quality metric in NaProTECHNOLOGY. PEARS technique integrates continuous peritoneal irrigation, meticulous tissue handling, avoidance of foreign-body contamination, and selective use of barrier agents to minimize the fibrinous cascade that initiates adhesion formation.


Chapter 8: Charting Continuous Discharges

Abstract: Women with persistent or continuous vaginal discharges — including those from chronic cervicitis, hormonal imbalance, or other gynecologic sources — present a distinct charting challenge, and this chapter provides CrMS-specific protocols for distinguishing pathologic discharge from fertile-quality cervical mucus. Correct identification is clinically critical because misclassification distorts cycle interpretation, effectiveness calculations, and the hormone-assessment timeline.


Chapter 36: Thyroid System Dysfunction

Chapter 36: Thyroid System Dysfunction

Abstract: Both overt and subclinical thyroid dysfunction are recognized in NaProTECHNOLOGY as significant causes of cycle-level reproductive abnormalities -- including oligomenorrhea, anovulation, luteal phase deficiency, heavy bleeding, and recurrent early pregnancy loss -- detectable through CrMS charting before standard screening would prompt thyroid evaluation. The chapter advocates comprehensive thyroid assessment (TSH, free T4, free T3, and thyroid antibodies) with fertility-optimized reference thresholds in women presenting with cycle disorders or infertility, followed by reassessment of CrMS patterns and hormone profiles after thyroid correction to identify and treat any residual follicular or luteal phase defects.


Chapter 57: Recurrent Spontaneous Abortion

Abstract: 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.


Chapter 54: Assessing Progesterone During Pregnancy

Abstract: Serial progesterone measurement timed to the luteal phase and early pregnancy using CrMS Peak Day-referenced protocols reveals luteal insufficiency and early placental progesterone inadequacy that are associated with miscarriage risk and preterm labor. Progesterone supplementation guided by these standardized assessments has been associated with reduced pregnancy loss in NaProTECHNOLOGY-managed pregnancies, and the chapter details the specific drawing protocols, reference ranges, and supplementation decision thresholds used in clinical practice.


Aromatase Inhibitors in Ovulation Induction. In: Aromatase: Update and New Roles in Reproductive Disease. Carr BR, Bulun SE (Eds)

Mohamed F Mitwally

Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lununfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.


Assisted reproductive technology surveillance--United States, 2001

Laura A Schieve

Centers for Disease Control and Prevention

Gary Jeng

National Center for Chronic Disease Prevention and Health Promotion

Abstract: Wright VC(1), Schieve LA, Reynolds MA, Jeng G, Kissin D.

Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002)


Methodologic and statistical approaches to studying human fertility and environmental exposure

David B Dunson

National Institute of Environmental Health Sciences

Abstract: Although there has been growing concern about the effects of environmental exposures on human fertility, standard epidemiologic study designs may not collect sufficient data to identify subtle effects while properly adjusting for confounding. In particular, results from conventional time to pregnancy studies can be driven by the many sources of bias inherent in these studies. By prospectively collecting detailed records of menstrual bleeding, occurrences of intercourse, and a marker of ovulation day in each menstrual cycle, precise information on exposure effects can be obtained, adjusting for many of the primary sources of bias. This article provides an overview of the different types of study designs, focusing on the data required, the practical advantages and disadvantages of each design, and the statistical methods required to take full advantage of the available data. We conclude that detailed prospective studies allowing inferences on day-specific probabilities of conception should be considered as the gold standard for studying the effects of environmental exposures on fertility.


Prospective pregnancy study designs for assessing reproductive and developmental toxicants

Germaine M Buck Louis

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Anne Sweeney

United States Department of Health and Human Services

Germaine M Buck

Epidemiology Branch, National Institute of Child Health and Human Development, National Institutes of Health/DHHS, 6100 Executive Boulevard, Rm. 7B03, Rockville, MD 20852, USA. gb156i@nih.gov

Abstract: The determinants of successful human reproduction and development may act as early as periconceptionally, underscoring the need to capture exposures during these critical windows when assessing potential toxicants. To identify such toxicants, couples must be studied longitudinally prior to conception without regard to a couple's ability to ascertain a clinically recognized pregnancy. We examined the utility and feasibility of prospective pregnancy study designs by conducting a systematic review of the literature to summarize relevant information regarding the planning, implementation, and success of previously published prospective pregnancy studies. Information concerning design elements and participation was abstracted from 15 eligible studies (from a total of 20 identified studies) using a standardized form. The primary author of each study was contacted to review our summary of their work and obtain missing information. Our findings confirm the ability to recruit women/couples from diverse populations using a variety of recruitment strategies. Among the studies we reviewed, 4-97% of eligible individuals were successfully contacted, with enrollment rates ranging from 42 to 100%. Length of follow-up varied from 3 to 12 months. A high percentage of women provided urine (57-98%) and blood (86-91%) specimens and most male partners (94-100%) provided semen samples. These data support the feasibility of this design.


ACOG Committee Opinion. Use of progesterone to reduce preterm birth

Abstract: Preterm birth affects 12% of all births in the United States. Recent studies support the hypothesis that progesterone supplementation reduces preterm birth in a select group of women (ie, those with a prior spontaneous birth at <37 weeks of gestation). Despite the apparent benefits of progesterone in this high-risk population, the ideal progesterone formulation is unknown. The American College of Obstetricians and Gynecologists Committee on Obstetric Practice believes that further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, such as multiple gestations, short cervical length, or positive test results for cervicovaginal fetal fibronectin. When progesterone is used, it is important to restrict its use to only women with a documented history of a previous spontaneous birth at less than 37 weeks of gestation because unresolved issues remain, such as optimal route of drug delivery and long-term safety of the drug.


Ovulation induction is not the same as superovulation: the effect of selective  estrogen receptor modulators and aromatase inhibitors


Comparison of the effects of letrozole and clomiphene citrate on ovarian follicles, endometrium, and hormone levels in the rat

Abstract:
OBJECTIVE: To compare the effects of letrozole and clomiphene citrate in the rat in terms of number of ovarian follicles; endometrial thickness; and serum levels of E2, FSH, LH, and T.

DESIGN: Controlled prospective study.

SETTING: University research laboratory.

ANIMAL(S): Thirty sexually mature female Wistar-Albino rats that were 20 weeks of age.

INTERVENTION(S): Letrozole, 5 mg/kg of body weight daily (10 rats); clomiphene citrate, 100 microg/kg daily (10 rats); or saline solution, 2 mL/d (10 rats). After 2 days, rats were euthanized and ovariectomized.

MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness, and serum levels of hormones.

RESULT(S): Mean levels of FSH, LH, E2, and T; number of mature follicles; and ovary size differed among the groups, whereas the mean endometrial thickness did not differ.

CONCLUSION(S): In rats, the effect of letrozole on follicular maturation is similar to that of clomiphene citrate.


Ovulation induction in women with infertility: a new indication for aromatase inhibitors

Abstract:
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.


Classification and pharmacology of progestins

Johannes Huber

Arbeitsgemeinschaft für Klinische Ernährung

Abstract: Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.


Letrozole: ovulation or superovulation?

Letrozole: ovulation or superovulation?


Minimal surgery for the twisted ischaemic adnexa can preserve ovarian function

Abstract:
BACKGROUND: Recently detorsion has replaced salpingo-oophorectomy as treatment for the twisted ischaemic adnexa. This paper asssess whether the ovary resumes normal function after preservation by detorsion.

METHODS: The results of detorsion performed between January 1988 and December 2001 were retrospectively analysed. Post-operative complications and subsequent ovarian function were assessed including: ultrasound monitoring of follicular development, adnexal appearance during subsequent surgery, and the outcome of IVF.

RESULTS: A total of 102 detorsions were performed; 67 by laparoscopy, 35 by laparotomy. No patient developed thromboembolism. Post-operative fever occurred in 15% of patients after laparoscopy and 29% after laparotomy (P < 0.01). Patients were hospitalized for a mean (+/- SD) of 2.1 +/- 1.2 and 7.4 +/- 1.5 days after laparoscopy and laparotomy respectively (P < 0.001). Ultrasound showed normal follicular development in 93 and 91% of patients after detorsion by laparoscopy and laparotomy respectively. At subsequent surgery, the adnexa appeared normal in nine out of nine patients after laparoscopy and in four out of five patients after laparotomy. Four patients of the laparoscopy group and two patients of the laparotomy group underwent subsequent IVF. In all six patients oocytes retrieved from the previously ischaemic ovary were fertilized.

CONCLUSIONS: Detorsion with adnexal sparing is the treatment of choice for twisted ischaemic adnexa, and preferably performed by laparoscopy.


Letrozole and gonadotropins: what is the ideal patient protocol?


The Enigma of Chronic Pelvic Pain: Systematically Tracing the Cause


Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination

Abstract:
OBJECTIVE: To investigate the effects of letrozole in patients undergoing superovulation with gonadotropins and IUI.

DESIGN: Retrospective analysis.

SETTING: Academic teaching hospital.

PATIENT(S): Women younger than 40 years of age with patent fallopian tubes and infertility of more than 1 year in duration who were undergoing IUI and gonadotropin therapy.

INTERVENTION(S): Gonadotropins alone administered from day 3 or a combination of letrozole, 5 mg/d on day 3 to 7, and gonadotropins starting on day 5 of the menstrual cycle. Ultrasonography was performed before initiation of treatment, on day 9 of menstrual cycle, and as required thereafter until the dominant follicle reached 18 mm in diameter. Ovulation was triggered with 10,000 IU of hCG, and IUI was performed 24 and 48 hours later.

MAIN OUTCOME MEASURE(S): Gonadotropin requirements, endometrial thickness, number of follicles, and pregnancy rate.

RESULT(S): All 205 IUI treatment cycles conducted from March 2001 to March 2002 were included. Gonadotropins alone were used in 145 cycles and combination therapy was used in 60 cycles. Patients cotreated with letrozole required fewer gonadotropin administrations (median difference, 300 IU [95% confidence interval (CI), 225-375 IU]), developed more follicles larger than 14 mm (median difference, 1 follicle [95% CI, 1-2 follicles), and had a thinner endometrium (median difference, 1 mm [95% CI, 0.4-1.6 mm]). The pregnancy rate did not differ between patients using gonadotropin alone and those using gonadotropin plus letrozole (20.9% vs. 21.6%).

CONCLUSION(S): The addition of letrozole to gonadotropins decreases gonadotropin requirements, increases the number of pre-ovulatory follicles and decreases endometrial thickness, without a negative effect on pregnancy rates.


Extraperitoneal endometriosis with catamenial pneumothoraces: a review of the literature

Lisa M Roberts

Advanced Gynecology Endoscopic Surgery, Kingston, Pennsylvania, USA.

Abstract:
OBJECTIVE: To present a case of recurrent catamenial pneumothorax and diaphragmatic endometriosis that was managed thoracoscopically. A review of the literature is also presented.

METHODS: A-28-year-old woman presented with bloody stools, chronic constipation, and chest pain. A review of systems was positive for monthly chest pain associated with her menses. A preoperative chest x-ray revealed a right pneumothorax. Colonoscopy revealed biopsy proven endometriosis of the sigmoid colon. A pelvic computed tomography scan revealed bilateral complex, cystic and solid adenexal lesions.

RESULTS: A right thoracoscopy was performed. A lesion on the right hemidiaphragm was excised and confirmed to be endometriosis. A wedge section of lung tissue containing a bleb was resected and also contained endometriosis. Three months later, the patient underwent laparoscopic excision of her pelvic endometriosis, including a low anterior rectal resection. Five months later, she presented again with right-sided chest pain. A thoracoscopic right total pleurectomy was performed for recurrent pneumothorax.

CONCLUSION: Pullmonary endometriosis may present as chest pain, shortness of breath, or hemoptysis associated with menstrual cycles. This case emphasizes the importance of a careful review of systems in patients with known endometriosis. Management now includes an endoscopic alternative and all of its known benefits.

JSLS : Journal of the Society of Laparoendoscopic Surgeons


Ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome

Practice Committe of the American Society for Reproductive Medicine

The Practice Committee of the American Society for Reproductive Medicine


Use of clomiphene citrate in women

Use of clomiphene citrate in women

Practice Committee of the American Society for Reproductive Medicine