Chlamydial Pgp3 Seropositivity and Population-Attributable Fraction Among Women With Tubal Factor Infertility.

BACKGROUND: Chlamydial infection is associated with tubal factor infertility (TFI); however, assessment of prior chlamydial infection and TFI is imperfect. We previously evaluated a combination of serological assays for association with TFI. We now describe the chlamydial contribution to TFI using a newer Chlamydia trachomatis Pgp3-enhanced serological (Pgp3) assay. METHODS: In our case-control study of women 19 to 42 years old with hysterosalpingogram-diagnosed TFI (cases) and non-TFI (controls) in 2 US infertility clinics, we assessed possible associations and effect modifiers between Pgp3 seropositivity and TFI using adjusted odds ratios with 95% confidence intervals (CIs) stratified by race. We then estimated the adjusted chlamydia population-attributable fraction with 95% CI of TFI. RESULTS: All Black (n = 107) and 618 of 620 non-Black women had Pgp3 results. Pgp3 seropositivity was 25.9% (95% CI, 19.3%-33.8%) for non-Black cases, 15.2% (95% CI, 12.3%-18.7%) for non-Black controls, 66.0% (95% CI, 51.7%-77.8%) for Black cases, and 71.7% (95% CI, 59.2%-81.5%) for Black controls. Among 476 non-Black women without endometriosis (n = 476), Pgp3 was associated with TFI (adjusted odds ratio, 2.6 [95% CI, 1.5-4.4]), adjusting for clinic, age, and income; chlamydia TFI-adjusted population-attributable fraction was 19.8% (95% CI, 7.7%-32.2%) in these women. Pgp3 positivity was not associated with TFI among non-Black women with endometriosis or among Black women (regardless of endometriosis). CONCLUSIONS: Among non-Black infertile women without endometriosis in these clinics, 20% of TFI was attributed to chlamydia. Better biomarkers are needed to estimate chlamydia TFI PAF, especially in Black women.

Host Genetic Risk Factors for Chlamydia trachomatis-Related Infertility in Women.

BACKGROUND: Chlamydia trachomatis (Ct) infection ascending to the upper genital tract can cause infertility. Direct association of genetic variants as contributors is challenging because infertility may not be diagnosed until years after infection. Investigating the intermediate trait of ascension bridges this gap. METHODS: We identified infertility genome-wide association study (GWAS) loci using deoxyribonucleic acid from Ct-seropositive cisgender women in a tubal factor infertility study and Ct-infected cisgender women from a longitudinal pelvic inflammatory disease cohort with known fertility status. Deoxyribonucleic acid and blood messenger ribonucleic acid from 2 additional female cohorts with active Ct infection and known endometrial infection status were used to investigate the impact of infertility single-nucleotide polymorphisms (SNPs) on Ct ascension. A statistical mediation test examined whether multiple infertility SNPs jointly influenced ascension risk by modulating expression of mediator genes. RESULTS: We identified 112 candidate infertility GWAS loci, and 31 associated with Ct ascension. The SNPs altered chlamydial ascension by modulating expression of 40 mediator genes. Mediator genes identified are involved in innate immune responses including type I interferon production, T-cell function, fibrosis, female reproductive tract health, and protein synthesis and degradation. CONCLUSIONS: We identified Ct-related infertility loci and their potential functional effects on Ct ascension.

Tubal Factor Infertility, In Vitro Fertilization, and Racial Disparities: A Retrospective Cohort in Two US Clinics.

BACKGROUND: Nearly 14% of US women report any lifetime infertility which is associated with health care costs and psychosocial consequences. Tubal factor infertility (TFI) often occurs as a result of sexually transmitted diseases and subsequent pelvic inflammatory disease. We sought to evaluate for and describe potential racial disparities in TFI and in vitro fertilization (IVF) prevalence. METHODS: Records of women aged 19 to 42 years in our retrospective cohort from 2 US infertility clinics were reviewed. We calculated TFI prevalence, IVF initiation prevalence, and prevalence ratios (PRs), with 95% confidence intervals (CIs) for each estimate, overall and by race. RESULTS: Among 660 infertile women, 110 (16.7%; 95% CI, 13.8-19.5%) had TFI which was higher in Black compared with White women (30.3% [33/109] vs 13.9% [68/489]; PR, 2.2 [95% CI, 1.5-3.1]). For women with TFI, IVF was offered to similar proportions of women by race (51.5% [17/33] vs 52.9% [36/68] for Black vs White women); however, fewer Black than White women with TFI started IVF (6.7% [1/15] vs 31.0% [9/29]; PR, 0.2 [95% CI, 0-1.0]), although the difference was not statistically different. CONCLUSIONS: Tubal factor infertility prevalence was 2-fold higher among Black than White women seeking care for infertility. Among women with TFI, data suggested a lower likelihood of Black women starting IVF than White women. Improved sexually transmitted disease prevention and treatment might ameliorate disparities in TFI.

Population-attributable fraction of tubal factor infertility associated with chlamydia.

BACKGROUND: Chlamydia trachomatis infection is highly prevalent among young women in the United States. Prevention of long-term sequelae of infection, including tubal factor infertility, is a primary goal of chlamydia screening and treatment activities. However, the population-attributable fraction of tubal factor infertility associated with chlamydia is unclear, and optimal measures for assessing tubal factor infertility and prior chlamydia in epidemiological studies have not been established. Black women have increased rates of chlamydia and tubal factor infertility compared with White women but have been underrepresented in prior studies of the association of chlamydia and tubal factor infertility. OBJECTIVES: The objectives of the study were to estimate the population-attributable fraction of tubal factor infertility associated with Chlamydia trachomatis infection by race (Black, non-Black) and assess how different definitions of Chlamydia trachomatis seropositivity and tubal factor infertility affect population-attributable fraction estimates. STUDY DESIGN: We conducted a case-control study, enrolling infertile women attending infertility practices in Birmingham, AL, and Pittsburgh, PA, during October 2012 through June 2015. Tubal factor infertility case status was primarily defined by unilateral or bilateral fallopian tube occlusion (cases) or bilateral fallopian tube patency (controls) on hysterosalpingogram. Alternate tubal factor infertility definitions incorporated history suggestive of tubal damage or were based on laparoscopic evidence of tubal damage. We aimed to enroll all eligible women, with an expected ratio of 1 and 3 controls per case for Black and non-Black women, respectively. We assessed Chlamydia trachomatis seropositivity with a commercial assay and a more sensitive research assay; our primary measure of seropositivity was defined as positivity on either assay. We estimated Chlamydia trachomatis seropositivity and calculated Chlamydia trachomatis-tubal factor infertility odds ratios and population-attributable fraction, stratified by race. RESULTS: We enrolled 107 Black women (47 cases, 60 controls) and 620 non-Black women (140 cases, 480 controls). Chlamydia trachomatis seropositivity by either assay was 81% (95% confidence interval, 73-89%) among Black and 31% (95% confidence interval, 28-35%) among non-Black participants (P < .001). Using the primary Chlamydia trachomatis seropositivity and tubal factor infertility definitions, no significant association was detected between chlamydia and tubal factor infertility among Blacks (odds ratio, 1.22, 95% confidence interval, 0.45-3.28) or non-Blacks (odds ratio, 1.41, 95% confidence interval, 0.95-2.09), and the estimated population-attributable fraction was 15% (95% confidence interval, -97% to 68%) among Blacks and 11% (95% confidence interval, -3% to 23%) among non-Blacks. Use of alternate serological measures and tubal factor infertility definitions had an impact on the magnitude of the chlamydia-tubal factor infertility association and resulted in a significant association among non-Blacks. CONCLUSION: Low population-attributable fraction estimates suggest factors in addition to chlamydia contribute to tubal factor infertility in the study population. However, high background Chlamydia trachomatis seropositivity among controls, most striking among Black participants, could have obscured an association with tubal factor infertility and resulted in a population-attributable fraction that underestimates the true etiological role of chlamydia. Choice of chlamydia and tubal factor infertility definitions also has an impact on the odds ratio and population-attributable fraction estimates.

Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype.

STUDY QUESTION: Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking? SUMMARY ANSWER: Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment. WHAT IS KNOWN ALREADY: Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction. STUDY DESIGN, SIZE, DURATION: Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case-control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS, age 18-40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, self-report of smoking in the nested case-control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels <15 ng/ml compared with 90% of past smokers and 6% of current smokers). There were minor changes in smoking status as determined by serum cotinine levels over time, with the greatest change found in the smoking groups (past or current smokers). In the larger cohort, hirsutism scores at baseline were lower in the never smokers compared with past smokers. Total testosterone levels at baseline were also lower in the never smokers compared with current smokers. At end of study follow-up insulin levels and homeostatic index of insulin resistance increased in the current smokers (P < 0.01 for both) compared with baseline and with non-smokers. The chance for ovulation was not associated with smoking status, but live birth rates were increased (non-significantly) in never or past smokers. LIMITATIONS, REASONS FOR CAUTION: The limitations include the selection bias involved in our nested case-control study, the possibility of misclassifying exposure to second hand smoke as smoking and our failure to capture self-reported changes in smoking status after enrollment in the trial. WIDER IMPLICATIONS OF THE FINDINGS: Because self-report of smoking is accurate, further testing of smoking status is not necessary in women with PCOS. Because smoking status is unlikely to change during infertility treatment, extra attention should be focused on smoking cessation in current or recent smokers who seek or who are receiving infertility treatment. STUDY FUNDING/COMPETING INTERESTS: Sponsored by the Eugene Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov numbers, NCT00068861 and NCT00719186.

High throughput, cell type-specific analysis of key proteins in human endometrial biopsies of women from fertile and infertile couples.

BACKGROUND: Although histological dating of endometrial biopsies provides little help for prediction or diagnosis of infertility, analysis of individual endometrial proteins, proteomic profiling and transcriptome analysis have suggested several biomarkers with altered expression arising from intrinsic abnormalities, inadequate stimulation by or in response to gonadal steroids or altered function due to systemic disorders. The objective of this study was to delineate the developmental dynamics of potentially important proteins in the secretory phase of the menstrual cycle, utilizing a collection of endometrial biopsies from women of fertile (n = 89) and infertile (n = 89) couples. METHODS AND RESULTS: Progesterone receptor-B (PGR-B), leukemia inhibitory factor, glycodelin/progestagen-associated endometrial protein (PAEP), homeobox A10, heparin-binding EGF-like growth factor, calcitonin and chemokine ligand 14 (CXCL14) were measured using a high-throughput, quantitative immunohistochemical method. Significant cyclic and tissue-specific regulation was documented for each protein, as well as their dysregulation in women of infertile couples. Infertile patients demonstrated a delay early in the secretory phase in the decline of PGR-B (P < 0.05) and premature mid-secretory increases in PAEP (P < 0.05) and CXCL14 (P < 0.05), suggesting that the implantation interval could be closing early. Correlation analysis identified potential interactions among certain proteins that were disrupted by infertility. CONCLUSIONS: This approach overcomes the limitations of a small sample number. Protein expression and localization provided important insights into the potential roles of these proteins in normal and pathological development of the endometrium that is not attainable from transcriptome analysis, establishing a basis for biomarker, diagnostic and targeted drug development for women with infertility.

Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.

BACKGROUND: The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. METHODS: We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. RESULTS: The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combination-therapy group (46.0%, P<0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group. CONCLUSIONS: Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861 [ClinicalTrials.gov].).

Extended-release metformin does not reduce the clomiphene citrate dose required to induce ovulation in polycystic ovary syndrome.

CONTEXT: When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS). OBJECTIVE: Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS. DESIGN: A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed. SETTING: Study volunteers at multiple academic medical centers were included. PARTICIPANTS: Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study. INTERVENTIONS: Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy. MAIN OUTCOME MEASURES: Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1-2 wk. RESULTS: The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups. CONCLUSION: Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS.

Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene.

CONTEXT: Clomiphene and insulin sensitizers such as metformin are used to induce ovulation in polycystic ovary syndrome (PCOS), but the ovulatory response is variable, and the causes of this variation are poorly understood. OBJECTIVE: Our objective was to identify predictive genetic polymorphisms and other determinants of ovulatory response. DESIGN: This was a substudy of a multicenter randomized clinical trial. SETTING: This study was performed at academic medical centers and their affiliates. PARTICIPANTS: A total of 312 women with PCOS were included in the study. MAIN OUTCOME MEASURES: Historical, biometric, biochemical, and genetic parameters were performed. RESULTS: We found that the C allele of a single nucleotide polymorphism in the STK11 gene (expressed in liver; also known as LKB1) was associated with a significantly decreased chance of ovulation in PCOS women treated with metformin. In an analysis of ovulation per cycle, the adjusted odds ratio (OR) comparing the C/C genotype to the G/G genotype was 0.30 [95% confidence interval (CI) 0.14, 0.66], and the OR for the C/G genotype vs. the G/G genotype was also 0.30 (95% CI 0.14, 0.66). In an analysis of metformin-treated subjects, we found that the percentage of women who ovulated increased with the number of G alleles present: 48% (10 of 21) of C/C women, 67% (32 of 48) of C/G women, and 79% (15 of 19) of G/G women ovulated. We also found that increased frequency of ovulation was associated with lower body mass index (BMI) [adjusted OR of 2.36 (95% CI 1.65, 3.36) and 2.05 (95% CI 1.46, 2.88), respectively, for comparisons of BMI less than 30 vs. BMI equal to or more than 35, BMI 30-34 vs. BMI equal to or more than 35, in the analysis of ovulation per cycle], a lower free androgen index (FAI) [adjusted OR of 1.59 (95% CI 1.17, 2.18) for FAI<10 vs. FAI>or=10], and a shorter duration of attempting conception [adjusted OR of 1.63 (95% CI 1.20, 2.21) for<1.5 vs.>or=1.5 yr]. CONCLUSIONS: We have demonstrated that a polymorphism in STK11, a kinase gene expressed in liver and implicated in metformin action, is associated with ovulatory response to treatment with metformin alone in a prospective randomized trial. The interaction with the effects of changes in modifiable factors (e.g. BMI or FAI) requires further study.

Statins improve human coronary atherosclerotic plaque morphology.

Statin treatment markedly reduces the incidence of acute coronary events in patients with coronary atherosclerosis. Although imaging studies have indirectly shown the beneficial effects of statins on plaque morphology, there has to our knowledge been no reported histologic comparison of the morphology of coronary plaque in statin-treated versus untreated patients who had substantial coronary artery atherosclerosis. We retrospectively studied arterial sections from the native hearts of patients who had experienced end-stage ischemic heart disease and subsequent cardiac transplantation. Of 44 qualified patients, 33 study patients had received pre-transplantation statin therapy, and 11 control patients had not. Pathologic examination of each explanted heart confirmed coronary artery disease and previous myocardial infarction in all patients. Diabetes mellitus was more prevalent in the study group. The groups were similar in levels of total and low-density lipoprotein cholesterol, and in the available number of arterial cross-sections per patient. All patients had plaques. High-grade lesions were found in 66.3% of cross-sections in the control group, and in 34.6% in the study group (P=0.011). Conversely, the degree of inflammation was markedly lower in the study group: low-grade fibrous plaques occurred in 45.7% of cross-sections in the study group, versus 11.3% in the control group (P=0.006). The study group had significantly fewer high-grade plaques and more fibrous plaques than did the control group at the time of transplantation. Our findings show that statin therapy substantially enhances plaque stabilization. We further suggest that reduction of plaque inflammation is an important aspect of this stabilization.

Vitamin D Status Relates to Reproductive Outcome in Women With Polycystic Ovary Syndrome: Secondary Analysis of a Multicenter Randomized Controlled Trial.

CONTEXT: Experimental evidence supports a relevance of vitamin D (VitD) for reproduction; however, data in humans are sparse and inconsistent. OBJECTIVE: To assess the relationship of VitD status with ovulation induction (OI) outcomes in women with polycystic ovary syndrome (PCOS). DESIGN: A retrospective cohort. SETTING: Secondary analysis of randomized controlled trial data. PARTICIPANTS: Participants in the Pregnancy in PCOS I (PPCOS I) randomized controlled trial (n = 540) met the National Institutes of Health diagnostic criteria for PCOS. INTERVENTIONS: Serum 25OHD levels were measured in stored sera. MAIN OUTCOME MEASURES: Primary, live birth (LB); secondary, ovulation and pregnancy loss after OI. RESULTS: Likelihood for LB was reduced by 44% for women if the 25OHD level was < 30 ng/mL (<75 nmol/L; odds ratio [OR], 0.58 [0.35-0.92]). Progressive improvement in the odds for LB was noted at thresholds of ≥38 ng/mL (≥95 nmol/L; OR, 1.42 [1.08-1.8]), ≥40 ng/mL (≥100 nmol/L; OR, 1.51 [1.05-2.17]), and ≥45 ng/mL (≥112.5 nmol/L; OR, 4.46 [1.27-15.72]). On adjusted analyses, VitD status was an independent predictor of LB and ovulation after OI. CONCLUSIONS: In women with PCOS, serum 25OHD was an independent predictor of measures of reproductive success after OI. Our data identify reproductive thresholds for serum 25OHD that are higher than recommended for the nonpregnant population.

Effect of spontaneous pregnancy reduction on obstetric outcome.

OBJECTIVE: To determine if obstetric outcome is compromised in pregnancies in which a spontaneous pregnancy reduction (SPR) occurred in the first trimester. STUDY DESIGN: Case-control study. RESULTS: First-trimester SPR was diagnosed in 29 (27.8%) of 104 twin pregnancies, 14 (28.6%) of 49 triplet pregnancies and 10 (28.6%) of 35 quadruplet pregnancies. Of these 53 patients, 15 were excluded from the analysis. In the remaining 38 women with SPR, vaginal bleeding occurred in 2 (5.3%) as compared to 7 (8.3%) of the controls. Pregnancy-induced hypertension occurred in 4 (10.5%) of SPR pregnancies as compared to 9 (10.7%) of control pregnancies. When compared to respective controls, there were no significant differences in the birth weights or gestational age at delivery of pregnancies spontaneously reduced to singletons (SPR, 38.5 weeks; controls, 38.2 weeks), twins (SPR, 36.2 weeks; controls, 34.4 weeks) or triplets (SPR, 31.0 weeks; controls, 32.0 weeks). CONCLUSION: SPR can be recognized in >25% of multiple pregnancies diagnosed in the early first trimester. Our data suggests that SPR is not associated with decreased gestational age at delivery, reduced birth weight or increased incidence of pregnancy-induced hypertension.

Gestational hypothyroidism: development of mild hypothyroidism in early pregnancy in previously euthyroid women.

OBJECTIVE: To determine the proportion of euthyroid women attending a fertility practice who develop hypothyroidism in very early pregnancy (gestational hypothyroidism [GHT]), and to examine the association of GHT with exogenous gonadotropin treatment. DESIGN: Retrospective cohort study. SETTING: A private reproductive medicine practice. PATIENT(S): All healthy women (N = 94) with infertility or recurrent pregnancy loss, TSH level <2.5 mIU/L, negative thyroid peroxidase antibodies at initial evaluation, and not taking thyroid medication, who conceived during an 18-month period. INTERVENTION(S): Usual fertility care; 30 women who had received exogenous gonadotropins. MAIN OUTCOME MEASURE(S): Serum TSH level at the time of pregnancy detection. RESULT(S): Gestational hypothyroidism (TSH ≥ 2.5 mIU/L) developed in 23 of 94 women (24%). The mean increase in serum TSH level from initial evaluation to early pregnancy was 0.45 ± 0.08 [SE] mIU/L. There was a trend toward the association of GHT with use of exogenous gonadotropins. Gestational hypothyroidism was positively associated with initial prepregnancy TSH level. CONCLUSION(S): Euthyroid women may develop mild hypothyroidism in early pregnancy, especially after exogenous gonadotropin treatment. Appropriate vigilance will allow for timely levothyroxine treatment.

Highly purified human-derived follicle-stimulating hormone (Bravelle) has equivalent efficacy to follitropin-beta (Follistim) in infertile women undergoing in vitro fertilization.

BACKGROUND: These data compare the efficacy and safety of highly purified human-derived follicle-stimulating hormone (Bravelle) and recombinant follitropin-beta (Follistim) in women undergoing in vitro fertilization. METHODS: This report describes the pooled data from two, nearly identical, randomized, controlled, parallel-group, multicenter studies conducted in a total of 19 academic and private IVF-ET centers in the United States. Infertile premenopausal women underwent pituitary down-regulation using leuprolide acetate followed by a maximum of 12 days of subcutaneous Bravelle (n = 120) or Follistim (n = 118), followed by administration of human chorionic gonadotropin, oocyte retrieval and embryo transfer. The primary efficacy measure was the mean number of oocytes retrieved; secondary efficacy measures included the total dose and duration of gonadotropin treatment; peak serum estradion levels; embryo transfer and implantation rates; chemical, clinical and continuing pregnancies; and live birth rates. All adverse events were recorded and injection site pain was recorded daily using a patient, self-assessment diary. RESULTS: Similar efficacy responses were observed for all outcome parameters in the two treatment groups. Although patients receiving Bravelle consistently reported a greater number of chemical, clinical and continuing pregnancies, as well as an increased rate of live birth, the data did not attain statistical significance (P > 0.05). The overall incidence of adverse events was similar in both groups, but compared to Follistim, injections of Bravelle were reported by patients to be significantly less painful (P < 0.001). CONCLUSIONS: Bravelle and Follistim had comparable efficacy in controlled ovarian hyperstimulation in women undergoing IVF-ET. There were no differences in the nature or number of adverse events between the treatment groups although Bravelle injections were reported to be significantly less painful.

An accessory uterine cavity as a cause of pelvic pain.

BACKGROUND: Pelvic pain is a common gynecologic problem. We report a case of a noncommunicating accessory uterine cavity as a cause of pelvic pain in a young adolescent. CASE: A 17-year-old nulligravida presented with worsening pelvic pain. Transvaginal ultrasound revealed a 3-cm cavity within the myometrium. Hysteroscopy revealed a normal uterine cavity. Surgical excision of the accessory cavity just lateral to the normal uterine cavity was achieved through laparotomy. Pathology confirmed endometrial tissue in the accessory cavity. Pelvic pain resolved after surgery. CONCLUSION: A noncommunicating uterine cavity should be considered in the differential diagnosis of pelvic pain.

Thalidomide-induced amenorrhea: case report and literature review.

OBJECTIVE: To report on a patient with thalidomide-induced amenorrhea and review the literature on the effect of thalidomide on ovarian function. DESIGN: Case report and literature review. SETTING: University medical center. PATIENT(S): A twenty-eight-year-old woman referred for a 2-year history of amenorrhea. INTERVENTION(S): History, physical examination, laboratory evaluation of the patient, and subsequent medical therapy. Literature review performed by using OVID/Medline and PubMed search strategies. MAIN OUTCOME MEASURE(S): Diagnosis and appropriate management of thalidomide-induced amenorrhea. RESULT(S): Elevated pituitary gonadotropins, other labs normal. All known causes of hypergonadotropic amenorrhea were excluded. CONCLUSION(S): Thalidomide induces hypergonadotropic amenorrhea. Although this effect appears to be reversible, the long-term effect of thalidomide on ovarian reserve is unclear.

Assisted reproduction in patients with early-stage ovarian malignancies.

OBJECTIVE: To determine the outcome of women with early-stage ovarian malignancies who subsequently underwent assisted reproductive technologies (ART). DESIGN: Retrospective study. SETTING: Academic assisted reproductive technology program. PATIENT(S): Four infertile women who were previously diagnosed with early-stage ovarian malignancies. INTERVENTION(S): Controlled ovulation hyperstimulation, IVF, and/or gamete intrafallopian transfer treatments using clomiphene citrate and/or gonadotropins. MAIN OUTCOME MEASURE(S): Development of tumor recurrence and disease-free interval. RESULT(S): All four women remain free of disease for up to 15 years after treatment. Three of the four women achieved pregnancy. CONCLUSION(S): In patients with early-stage ovarian malignancies, conservative therapy followed by ovarian stimulation for assisted reproduction is an acceptable strategy.

Monozygotic twins discordant for vaginal agenesis and bilateral tibial longitudinal deficiency.

OBJECTIVE: To report the first case of monozygotic twins with discordant congenital anomalies. DESIGN: Descriptive case report. SETTING: University hospital. PATIENT(S): A 20-year woman with complete vaginal agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) and right renal agenesis presented for creation of a neovagina. She had a monozygous twin confirmed by DNA testing using short tandem repeat (STR) loci; the twin had normal mullerian/mesonephric development but isolated bilateral tibial longitudinal deficiency. INTERVENTION(S): The complete history, physical, and laboratory data of both the patient and her twin. Also, operative laparoscopy with creation of a neovagina in the patient. MAIN OUTCOME MEASURE(S): Diagnosis and appropriate treatment of Mayer-Rokitansky-Kuster-Hauser syndrome and DNA testing with STR loci for monozygosity. RESULT(S): The surgical resection of the bilateral uterine remnants, creation of a neovagina in the patient, and the demonstration of monozygosity with her twin with bilateral tibial longitudinal deficiency. CONCLUSION(S): This case report suggests a link between developmental abnormalities of the genital and skeletal system.

Infertility from female circumcision.

OBJECTIVE: To present a case report of a patient with primary infertility from female circumcision, the management of the patient, and a review of the literature. DESIGN: Case report and literature review. SETTING: University hospital. PATIENT(S): A 31-year-old woman referred for a history of primary infertility. INTERVENTION(S): Complete history and physical exam of the patient and subsequent deinfibulation. MAIN OUTCOME MEASURE(S): Diagnosis, surgical management, and postoperative sexual function and pregnancy. RESULT(S): Resolution of dyspareunia, satisfactory postoperative sexual function, and pregnancy. CONCLUSION(S): Awareness of this type of female circumcision and familiarity with its surgical management may prevent delays and any subsequent complications.

Laparoscopic evaluation following failure to achieve pregnancy after ovulation induction with clomiphene citrate.

OBJECTIVE: To assess the value of laparoscopic evaluation of the pelvis after failure to achieve pregnancy with clomiphene citrate-induced ovulation and to determine whether predictors for significant pelvic pathology can be isolated. DESIGN: Retrospective study. SETTING: Tertiary care academic medical center. PATIENT(S): Ninety-two patients failing to conceive after four ovulatory cycles with clomiphene citrate with a normal hysterosalpingogram who underwent laparoscopic evaluation of the pelvis. INTERVENTION(S): Laparoscopy. MAIN OUTCOME MEASURE(S): Presence of pelvic pathology and predictors of pelvic disease. RESULT(S): Of the 92 patients studied, 32 patients (34.8%) had a "positive" laparoscopy (i.e., stages III and IV endometriosis, an endometrioma, pelvic adhesions, and/or tubal disease), 27 patients (29.3%) had stage I or II endometriosis, and 30 patients (32.6%) had a normal pelvis. The predictors for intrapelvic disease were a history of dyspareunia, no prior use of oral contraceptive pills, and no prior use of any form of contraception. Almost 40% of women with predictors had a "positive" laparoscopy, compared with only 12.5% of patients without predictors; however, the majority of patients (91.3%) had at least one predictor. CONCLUSION(S): More than one third of the patients failing to conceive after four ovulatory cycles of clomiphene citrate had significant intrapelvic pathology. Although predictors for intrapelvic disease were isolated, their high prevalence reduced their predictive value.