Lower prevalence of non-cavity-distorting uterine fibroids in patients with polycystic ovary syndrome than in those with unexplained infertility.

OBJECTIVE: To study whether there is a difference in the prevalence of non-cavity-distorting uterine fibroids between infertile patients with polycystic ovary syndrome (PCOS) and those with unexplained infertility (UI). DESIGN: A secondary analysis of data from three randomized clinical trials. SETTING: Academic health centers. PATIENT(S): A total of 2,249 patients with normal uterine cavities. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The presence or absence of non-cavity-distorting fibroids. RESULT(S): Compared with women with UI, those with PCOS were younger, had a higher body mass index, and were more likely to be Hispanic or African American, with a lower percentage of previous conception and live birth, a higher percentage of current smokers, a lower percentage of current alcohol users, and higher total testosterone, fasting insulin, and homeostasis-model-assessment insulin resistance. The prevalence of women with non-cavity-distorting uterine fibroids was lower in women with PCOS than in those with UI (6.7% vs. 12.4%); this result held after patients were divided into Black and non-Black or into three different body mass index groups. After adjustment for all the other variables in the final model, patients with PCOS had a significantly lower prevalence of fibroids than those with UI (odds ratio 0.54). No differences in the prevalence of non-cavity-distorting fibroids with any dimensions ≥4 cm or the volume of the largest fibroid was found between the two groups. CONCLUSION(S): A lower prevalence of non-cavity-distorting uterine fibroids was found in infertile women with PCOS than in those with UI.

Major depression, antidepressant use, and male and female fertility.

OBJECTIVE: To determine if maternal major depression (MD), antidepressant use, or paternal MD are associated with pregnancy outcomes after non-IVF fertility treatments. DESIGN: Cohort study. SETTING: Clinics. PATIENT(S): Participants in two randomized trials: PPCOS II (clomiphene citrate versus letrozole for polycystic ovary syndrome), and AMIGOS (gonadotropins versus clomiphene citrate versus letrozole for unexplained infertility). INTERVENTION(S): Female and male partners completed the Patient Health Questionnaire (PHQ-9). Female medication use was collected. PHQ-9 score ≥10 was used to define currently active MD. MAIN OUTCOME MEASURE(S): Primary outcome: live birth. SECONDARY OUTCOMES: pregnancy, first-trimester miscarriage. Poisson regression models were used to determine relative risks after adjusting for age, race, income, months trying to conceive, smoking, and study (PPCOS II versus AMIGOS). RESULT(S): Data for 1,650 women and 1,608 men were included. Among women not using an antidepressant, the presence of currently active MD was not associated with poorer fertility outcomes (live birth, miscarriage), but rather was associated with a slightly increased likelihood of pregnancy. Maternal antidepressant use (n = 90) was associated with increased risk of miscarriage, and male partners with currently active MD were less likely to achieve conception. CONCLUSION(S): Currently active MD in the female partner does not negatively affect non-IVF treatment outcomes; however, currently active MD in the male partner may lower the likelihood of pregnancy. Maternal antidepressant use is associated with first-trimester pregnancy loss, which may depend upon the type of antidepressant. CLINICAL TRIAL REGISTRATION NUMBERS: NCT00719186 and NCT01044862.

Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS.

CONTEXT: In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown. OBJECTIVE: We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18-40 years of age who were overweight/obese and infertile with PCOS. INTERVENTION: We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142). MAIN OUTCOME MEASURES: Live birth, pregnancy loss, and ovulation were measured. RESULTS: In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45% [67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1-1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2-1.8; P < .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.8; P = .01). CONCLUSIONS: These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment.

Baseline AMH Level Associated With Ovulation Following Ovulation Induction in Women With Polycystic Ovary Syndrome.

CONTEXT: Anti-Müllerian hormone (AMH) reduces aromatase activity and sensitivity of follicles to FSH stimulation. Therefore, elevated serum AMH may indicate a higher threshold for response to ovulation induction in women with polycystic ovary syndrome (PCOS). OBJECTIVE: This study sought to determine the association between AMH levels and ovulatory response to treatment among the women enrolled into the Pregnancy in PCOS II (PPCOS II) trial. DESIGN AND SETTING: This was a secondary analysis of data from a randomized clinical trial in academic health centers throughout the United States Participants: A total of 748 women age 18-40 years, with PCOS and measured AMH levels at baseline, were included in this study. MAIN OUTCOME MEASURES: Couples were followed for up to five treatment cycles to determine ovulation (midluteal serum progesterone > 5 ng/mL) and the dose required to achieve ovulation. RESULTS: A lower mean AMH and AMH per follicle was observed among women who ovulated compared with women who never achieved ovulation during the study (geometric mean AMH, 5.54 vs 7.35 ng/mL; P = .0001; geometric mean AMH per follicle, 0.14 vs 0.18; P = .01) after adjustment for age, body mass index, T, and insulin level. As AMH levels increased, the dose of ovulation induction medication needed to achieve ovulation also increased. No associations were observed between antral follicle count and ovulation. CONCLUSIONS: These results suggest that high serum AMH is associated with a reduced response to ovulation induction among women with PCOS. Women with higher AMH levels may require higher doses of medication to achieve ovulation.

Cost Implications for Subsequent Perinatal Outcomes After IVF Stratified by Number of Embryos Transferred: A Five Year Analysis of Vermont Data.

BACKGROUND: In states in the USA without in vitro fertilzation coverage (IVF) insurance coverage, more embryos are transferred per cycle leading to higher risks of multi-fetal pregnancies and adverse pregnancy outcomes. OBJECTIVE: To determine frequency and cost of selected adverse perinatal complications based on number of embryos transferred during IVF, and calculate incremental cost per IVF live birth. METHODS: Medical records of patients who conceived with IVF (n = 116) and delivered at >20 weeks gestational age between 2007 and 2011 were evaluated. Gestational age at delivery, low birth weight (LBW) term births, and delivery mode were tabulated. Healthcare costs per cohort, extrapolated costs assuming 100 patients per cohort, and incremental costs per infant delivered were calculated. RESULTS: The highest prematurity and cesarean section rates were recorded after double embryo transfers (DET), while the lowest rates were found in single embryo transfers (SET). Premature singleton deliveries increased directly with number of transferred embryos [6.3 % (SET), 9.1 % (DET) and 10.0 % for ≥3 embryos transferred]. This trend was also noted for rate of cesarean delivery [26.7 % (SET), 36.6 % (DET), and 47.1 % for ≥3 embryos transferred]. The proportion of LBW infants among deliveries after DET and for ≥3 embryos transferred was 3.9 and 9.1 %, respectively. Extrapolated costs per cohort were US$718,616, US$1,713,470 and US$1,227,396 for SET, DET, and ≥3 embryos transferred, respectively. CONCLUSION: Attempting to improve IVF pregnancy rates by permitting multiple embryo transfers results in sharply increased rates of multiple gestation and preterm delivery. This practice yields a greater frequency of adverse perinatal outcomes and substantially increased healthcare spending. Better efforts to encourage SET are necessary to normalize healthcare expenditures considering the frequency of very high cost sequela associated with IVF where multiple embryo transfers occur.

Chlamydia trachomatis immunoglobulin G3 seropositivity is a predictor of reproductive outcomes in infertile women with patent fallopian tubes.

OBJECTIVE: To determine if Chlamydia trachomatis (C. trachomatis) seropositivity, as detected by the C. trachomatis elementary body (EB)-based enzyme-linked immunosorbent assay [EB ELISA] predicts pregnancy and pregnancy outcome among infertile women with documented tubal patency. DESIGN: Cohort study. SETTING: Outpatient clinics. PATIENT(S): In all, 1,250 infertile women with documented tubal patency enrolled in 1 of 2 randomized controlled trials: Pregnancy in Polycystic Ovary Syndrome II; and the Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. INTERVENTION(S): Sera were analyzed for anti-C. trachomatis immunoglobulin G (IgG)1 and IgG3 antibodies, using a research C. trachomatis EB ELISA. The optical density (OD)405 readings of ≥ 0.35 and ≥ 0.1 were considered positive for IgG1 and IgG3, respectively. MAIN OUTCOME MEASURE(S): Primary outcomes included pregnancy, live birth, and ectopic pregnancy. Log-linear regression was used to determine the relative risk after adjusting for age, race, treatment medication, smoking status, and current alcohol use. RESULT(S): A total of 243 (19%) women were seropositive for anti-C. trachomatis IgG3. They tended to be nonwhite and smokers. Anti-C. trachomatis IgG3 seropositive women were significantly less likely to conceive (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.52-0.83) or to have a live birth (RR 0.59, 95% CI 0.43-0.80); these associations were weakened after adjusting for number of hysterosalpingography-documented patent tubes (RR 0.73, 95% CI 0.56-0.97) and (RR 0.73, 95% CI 0.50-1.04), respectively. Anti-C. trachomatis IgG3 seropositive women who conceived had a ×2.7 risk (95% CI 1.40-5.34) of ectopic pregnancy. CONCLUSION(S): Even in the presence of tubal patency, anti-C. trachomatis IgG3 seropositivity is associated with a lower likelihood of pregnancy. Anti-C. trachomatis IgG3 seropositive women have as high as 3 times the risk of ectopic pregnancy. CLINICAL TRIAL REGISTRATION NUMBER: PPCOSII: NCT00719186 and AMIGOS: NCT01044862.

Impact of Male and Female Weight, Smoking, and Intercourse Frequency on Live Birth in Women With Polycystic Ovary Syndrome.

CONTEXT: Obese men with normal semen parameters exhibit reduced fertility but few prospective data are available. OBJECTIVE: This study aimed to determine the effect of male factors and body mass among the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) participants. METHODS: This is a secondary analysis of the PPCOS II trial. A total of 750 infertile women with polycystic ovary syndrome (PCOS) were randomly assigned to up to receive five cycles of letrozole or clomiphene citrate. Females were 18-39-years-old and had a male partner with sperm concentration of at least 14 million/mL who consented to regular intercourse. Analysis was limited to couples with complete male partner information (n = 710). RESULTS: Male body mass index (BMI) was higher in couples who failed to conceive (29.5 kg/m(2) vs 28.2 kg/m(2); P = .039) as well as those who did not achieve a live birth (29.5 kg/m(2) vs 28.1 kg/m(2); P = .047). At least one partner was obese in 548 couples (77.1%). A total of 261 couples were concordant for obesity (36.8%). After adjustment for female BMI, the association of male BMI with live birth was no longer significant (odds ratio [OR] = 0.85; 95 % confidence interval [CI], 0.68-1.05; P = .13). Couples in which both partners smoked had a lower chance of live birth vs nonsmokers (OR = 0.20; 95 % CI, 0.08-0.52; P = .02), whereas there was not a significant effect of female or male smoking alone. Live birth was more likely in couples with at least three sexual intercourse attempts over the previous 4 weeks (reported at baseline) as opposed to couples with lesser frequency (OR = 4.39; 95 % CI, 1.52-12. 4; P < .01). CONCLUSIONS: In this large cohort of obese women with PCOS, effect of male obesity was explained by female BMI. Lower chance of success was seen among couples where both partners smoked. Obesity and smoking are common among women with PCOS and their partners and contribute to a decrease in fertility treatment success.

Effects of testosterone on cardiomyocyte calcium homeostasis and contractile function in female rats.

The role of testosterone (T) in the regulation of cardiovascular function in females is not well understood. Our goal was to examine the effect of T on cardiomyocyte biology by measuring sarcomere shortening/relaxation and intracellular calcium cycling in adult female Sprague-Dawley rats. The rats were divided into the following four groups: (1) sham operated; (2) ovariectomized (OVX); (3) OVX plus T; and (4) OVX + T plus an aromatase inhibitor (AI). The final group was added to rule out effects from bioconversion of T to oestradiol. Sarcomere/calcium dynamics were measured after 4 weeks at 2 and 6 Hz, then at 6 Hz following exposure to 300 nm isoprenaline. Additionally, the acute (i.e. non-genomic) effects of T were evaluated in sham-operated and OVX + T + AI rats. There were no group differences, nor was there evidence for an effect of T on frequency or isoprenaline response. Additionally, there were no findings to indicate an acute, non-genomic T effect. Moreover, the relative α- and ß-myosin heavy chain isoform complement was unchanged by OVX or T replacement. Our results argue against acute or chronic effects of T on cardiomyocyte shortening dynamics, calcium cycling or myosin heavy chain expression, arguing against any direct effect of T on cardiomyocyte function in adult females.

The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome.

Polycystic Ovary Syndrome (PCOS) is a common cause of female infertility and first line treatment is currently oral clomiphene citrate, a selective estrogen receptor modulator, which results in both a high nonresponse rate and multiple pregnancy rate. Aromatase inhibitors such as letrozole may have more favorable ovarian and endometrial effects. The goal of the Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) study is to determine the safety and efficacy of clomiphene citrate (CC) compared to letrozole, in achieving live birth in infertile women with PCOS. The population will consist of 750 infertile women with PCOS. Additionally, the couple will have no other major infertility factor. This will be a multi-center, prospective, double-blind clinical trial of CC vs. letrozole for 5 treatment cycles (or approximately up to 25 weeks). The randomization scheme will be coordinated through the central data coordinating center (DCC) and the randomization is stratified by each participating site. After progestin withdrawal as needed, 750 women will be equally randomized to two different treatment arms: A) CC 50mg every day for 5 days (days 3-7 of cycle), or B) letrozole 2.5mg every day for 5 days (days 3-7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day (×5 days) or 7.5mg of letrozole a day (×5 days). The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms.

Recruitment challenges of a multicenter randomized controlled varicocelectomy trial.

OBJECTIVE: To review reasons for suboptimal recruitment for a randomized controlled trial (RCT) of varicocelectomy versus intrauterine insemination (IUI) for treatment of male infertility and to suggest means for improving future study recruitment. DESIGN: Survey of Reproductive Medicine Network (RMN) participating sites. SETTING: Reproductive Medicine Network. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ascertain reasons for inadequate recruitment and suggest improvements for future varicocelectomy trails. RESULT(S): This study screened seven and enrolled three couples, with the first couple randomized on June 30, 2010. The study was subsequently stopped on March 30, 2011. The following themes were cited most frequently by sites and therefore determined to be most likely to have played a role in suboptimal recruitment: [1] men must be screened at the beginning of a couple's infertility evaluation, [2] inclusion of infertile women who had failed previous fertility interventions appeared to be associated with the couple's intolerance of a placebo arm, and [3] an apparent bias against the use of unstimulated IUI cycles indicated a prejudicial preference for surgical intervention in the male partner. CONCLUSION(S): Improved recruitment may be realized through screening infertile men as early as possible while minimizing study-related time commitments. Focused patient education may promote improved equipoise and acceptance of a placebo arm in male infertility studies. Creative approaches to implementing varicocelectomy trials must be considered in addition to having a network of motivated researchers who carry a high volume of possible study participants because very large numbers may need to be screened to complete the clinical trial enrollment.

Establishing a biologic specimens repository for reproductive clinical trials: technical aspects.

The individual research group or independent investigator often requires access to samples from a unique well characterized subject population. Cohorts of such samples from a well-defined comparative population are rare and limited access can impede progress. This bottleneck can be removed by accessing the samples provided by biorepositories such as the NIH/NICHD Cooperative Reproductive Medicine Network (RMN) Biorepository (detailed in the preceeding manuscript in this issue. In those cases where the individual research group or independent investigator already has access to a unique population, comparisons between well-defined groups are often sought to contextualize the data. In both cases seamless integration of data resources associated with the samples is required to ensure optimal comparisons. At the most basic level this requires standardization of sample collection and storage, as well as a de-identified data base containing demographic, clinical, and laboratory values. To facilitate such interoperability, the reagents and protocols that have been adopted by the RMN Biorepository for the collection and storage of serum, blood, saliva and sperm are described.

Proactively establishing a biologic specimens repository for large clinical trials: an idea whose time has come.

Large randomized clinical trials are becoming more costly, and resources to support them increasingly scarce. Biologic materials, such as blood, DNA, body fluids, or tissue samples collected and stored as a component of these studies represent an invaluable resource, to answer immediate secondary hypotheses, but also as archived material, linked to the study data, for the use of investigators long into the future. The regulatory climate surrounding the storage and future unconstrained utilization of biologic materials is evolving quickly. It is no longer acceptable simply to store samples and use them in an unbridled and unregulated fashion. Thus, to fully utilize the tremendous potential of biologic samples generated from large clinical trials and their related databases, investigators should consider proactively creating a biologic specimen repository, or biorepository. A repository likely assures appropriate subject consent, sample provenance, secure storage, and codified procedures for sample and data retrieval and sharing that protect the subject's confidentiality, the investigator's need for accurate data, and the limited resource. Importantly, the biorepository specimens/samples are typically collected in addition to local and core specimens obtained for the parent study that provide baseline assessments for safety and efficacy outcomes.

Relationship of androgens to body composition, energy and substrate metabolism and aerobic capacity in healthy, young women.

OBJECTIVE: To evaluate the role of physiologic levels of androgens and their precursors in the regulation of body composition, energy and substrate metabolism and aerobic capacity in healthy, cycling, premenopausal women. EXPERIMENTAL: We evaluated 30 young (27±1 year) premenopausal, non-obese (23±0.5 kg/m(2)), normally-cycling women, without clinical or chemical evidence of hyperandrogenism or hyperinsulinemia, for parameters of total and regional body composition, glucose tolerance, aerobic capacity and resting energy expenditure and substrate oxidation. Serum was assayed for androgens and androgen precursors by techniques optimized to assess the low androgen levels in this population. RESULTS: Higher serum testosterone levels correlated with greater fat mass (r=0.377; p=0.04), but not abdominal adiposity or other metabolic/physiologic variables. Additionally, dehydroepiandrosterone (DHEA) was negatively related to visceral fat content (r=-0.569; p=0.02). Other serum androgens did not correlate with total or regional adiposity, skeletal muscle mass, aerobic capacity, glucose tolerance, or resting energy and substrate metabolism. CONCLUSION: In this group of non-obese, premenopausal women with no clinical or chemical evidence of hyperandrogenemia, serum testosterone levels were positively related with fat mass, but not with abdominal adiposity; whereas, DHEA was negatively related to visceral adiposity. Our data suggest that within the normal physiologic range, testosterone is a predictor of overall adiposity, but that this effect does not appear to be associated with concomitant alterations in resting energy or substrate metabolism that could predispose to weight gain.

Increasing burden of institutional review in multicenter clinical trials of infertility: the Reproductive Medicine Network experience with the Pregnancy in Polycystic Ovary Syndrome (PPCOS) I and II studies.

UNLABELLED: Many clinical investigators think that the burden of Institutional Review Board (IRB) requirements has been consistently increasing over recent years, although there are few objective data describing these trends. Over a period of 7 years, the Reproductive Medicine Network observed a significant increase in the size and requirements of IRB submissions and significant variability of IRB performance in reviewing multicenter trials. These additional regulatory and administrative demands represent substantial burdens to researchers and to the IRBs themselves. It is timely to consider whether these changes better protect the interests and safety of human research participants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00068861 and NCT00719186.

Total testosterone assays in women with polycystic ovary syndrome: precision and correlation with hirsutism.

CONTEXT: There is no standardized assay of testosterone in women. Liquid chromatography mass spectrometry (LC/MS) has been proposed as the preferable assay by an Endocrine Society Position Statement. OBJECTIVE: The aim was to compare assay results from a direct RIA with two LC/MS. DESIGN AND SETTING: We conducted a blinded laboratory study including masked duplicate samples at three laboratories--two academic (University of Virginia, RIA; and Mayo Clinic, LC/MS) and one commercial (Quest, LC/MS). PARTICIPANTS AND INTERVENTIONS: Baseline testosterone levels from 596 women with PCOS who participated in a large, multicenter, randomized controlled infertility trial performed at academic health centers in the United States were run by varying assays, and results were compared. MAIN OUTCOME MEASURE: We measured assay precision and correlation and baseline Ferriman-Gallwey hirsutism scores. RESULTS: Median testosterone levels were highest with RIA. The correlations between the blinded samples that were run in duplicate were comparable. The correlation coefficient (CC) between LC/MS at Quest and Mayo was 0.83 [95% confidence interval (CI), 0.80-0.85], between RIA and LC/MS at Mayo was 0.79 (95% CI, 0.76-0.82), and between RIA and LC/MS at Quest was 0.67 (95% CI, 0.63-0.72). Interassay variation was highest at the lower levels of total testosterone (≤50 ng/dl). The CC for Quest LC/MS was significantly different from those derived from the other assays. We found similar correlations between total testosterone levels and hirsutism score with the RIA (CC=0.24), LC/MS at Mayo (CC=0.15), or Quest (CC=0.17). CONCLUSIONS: A testosterone RIA is comparable to LC/MS assays. There is significant variability between LC/MS assays and poor precision with all assays at low testosterone levels.

Decision trees for identifying predictors of treatment effectiveness in clinical trials and its application to ovulation in a study of women with polycystic ovary syndrome.

BACKGROUND: Double-blind, randomized clinical trials are the preferred approach to demonstrating the effectiveness of one treatment against another. The comparison is, however, made on the average group effects. While patients and clinicians have always struggled to understand why patients respond differently to the same treatment, and while much hope has been held for the nascent field of predictive biomarkers (e.g. genetic markers), there is still much utility in exploring whether it is possible to estimate treatment efficacy based on demographic and baseline variables. METHODS: The pregnancy in polycystic ovary syndrome (PPCOS) study was a prospective, multi-center, randomized clinical trial comparing three ovulation induction regimens: clomiphene citrate (CC), metformin and the combination of the two. There were 446 women who ovulated in response to the treatments among the entire 626 participants. In this report, we focus on the 418 women who received CC (alone or combined with metformin) to determine if readily available baseline physical characteristics and/or easily obtainable baseline measures could be used to distinguish treatment effectiveness in stimulating ovulation. We used a recursive partitioning technique and developed a node-splitting rule to build decision tree models that reflected within-node and within-treatment responses. RESULTS: Overall, the combination of CC plus metformin resulted in an increased incidence of ovulation compared with CC alone. This is particularly so in women with relatively larger left ovarian volumes (≥ 19.5 cubic cm), and a left ovarian volume <19.5 cubic cm was related to treatment outcomes for all subsequent nodes. Women who were older, who had higher baseline insulin, higher waist-to-hip circumference ratio or higher sex hormone-binding globulin levels had better ovulatory rates with CC alone than with the combination of CC plus metformin. CONCLUSIONS: Polycystic ovary syndrome (PCOS) is a phenotypically diverse condition. Both baseline laboratory and clinical parameters can predict the ovulatory response in women with PCOS undergoing ovulation induction. Without a priori hypotheses with regard to any predictors, the observation regarding left ovary volume is novel and worthy of further investigation and validation.

Correlation of serum androgens with anthropometric and metabolic indices in healthy, nonobese postmenopausal women.

OBJECTIVE: The role of testosterone in the regulation of metabolic and physiological function in men is well defined, but its role in women remains enigmatic. Thus, the present study sought to assess the contribution of endogenous circulating androgens to the regulation of metabolic function, body morphometry, and physical function in normal naturally postmenopausal women. METHODS: Using a cross-sectional design, we measured serum androgens in a cohort of 29 naturally postmenopausal women and correlated the results with metabolic, morphometric, and functional outcome parameters. These included insulin sensitivity, whole-body fat and lean body mass, visceral/abdominal fat areasm and aerobic capacity. RESULTS: Higher serum testosterone levels were related to greater maximal aerobic capacity and reduced adiposity. Additionally, higher serum dihydrotestosterone, dehydroepiandrosterone sulfate, androstenedione, and androstenetriol glucuronidate levels were correlated to greater insulin sensitivity. CONCLUSION: In naturally postmenopausal women, endogenous androgens may play a role in the maintenance of beneficial patterns of metabolic, morphometric, and functional parameters.

An investigation of the visual disturbances experienced by patients on clomiphene citrate.

OBJECTIVE: To evaluate the impact of clomiphene citrate on vision. DESIGN: Observational study. SETTING: Patients were referred to the University of Ottawa Eye Institute ophthalmology clinic from the Department of Obstetrics and Gynaecology of the Ottawa Hospital-General Campus. PATIENT(S): Eight adult females taking clomiphene citrate and experiencing visual disturbances. INTERVENTION(S): Patients received a comprehensive visual evaluation twice: once during a washout period, and once during an active clomiphene citrate treatment. MAIN OUTCOME MEASURE(S): Ophthalmologic examination, color vision, visual acuity, contrast sensitivity, visual fields using standard automated perimetry, and foveal flicker sensitivity at high (32 Hz) and low (8 Hz) temporal frequencies. RESULT(S): We found no differences between the washout and clomiphene citrate conditions for color vision, visual acuity, contrast sensitivity, and visual fields. The only statistically significant difference was found for foveal flicker sensitivity at 32 Hz in the right eye, with a similar trend in the left eye and at 8 Hz in both eyes. CONCLUSION(S): The effect of clomiphene citrate on vision was minimal, and the visual disturbances were reversible in all patients. A bilateral reduction in flicker sensitivity was the only observed visual disturbance. Women who experience visual symptoms associated with clomiphene citrate should be monitored, but therapy can usually be maintained.

Effect of ovarian suppression with gonadotropin-releasing hormone agonist on glucose disposal and insulin secretion.

Several lines of evidence suggest that ovarian hormones influence glucose homeostasis, although their exact role in humans has not been clearly defined. In the present study, we sought to test the hypothesis that ovarian hormones regulate glucose homeostasis by examining the effect of pharmacologically induced ovarian hormone deficiency on glucose disposal and insulin secretion. Young, healthy women with regular menstrual patterns were studied during the follicular and luteal phases of their cycle at baseline and after 2 mo of treatment with gonadotropin-releasing hormone agonist (GnRHa; n = 7) or placebo (n = 6). Using hyperglycemic clamps, in combination with stable isotope-labeled (i.e., (13)C and (2)H) glucose tracers, we measured glucose disposal and insulin secretion. Additionally, we assessed body composition and regional fat distribution using radiologic imaging techniques as well as glucoregulatory hormones. Ovarian hormone suppression with GnRHa did not alter body composition, abdominal fat distribution, or thigh tissue composition. There was no effect of ovarian suppression on total, oxidative, or nonoxidative glucose disposal expressed relative to plasma insulin level. Similarly, no effect of ovarian hormone deficiency was observed on first- or second-phase insulin secretion or insulin clearance. Finally, ovarian hormone deficiency was associated with an increase in circulating adiponectin levels but no change in leptin concentration. Our findings suggest that a brief period of ovarian hormone deficiency in young, healthy, eugonadal women does not alter glucose disposal index or insulin secretion, supporting the conclusion that ovarian hormones play a minimal role in regulating glucose homeostasis. Our data do, however, support a role for ovarian hormones in the regulation of plasma adiponectin levels.

Ovarian suppression with a gonadotropin-releasing hormone agonist does not alter insulin-stimulated glucose disposal.

OBJECTIVE: Aging is associated with reduced tissue sensitivity to insulin. In women, these age-related changes may be accelerated by menopause. The effect of ovarian hormone deficiency on tissue insulin sensitivity in humans, however, has not been defined clearly. Thus, the goal of this study was to evaluate the effect of suppression of endogenous ovarian hormone production on insulin-stimulated glucose disposal. DESIGN: Randomized, single-blind, placebo-controlled trial. SETTING: General clinical research center. PATIENTS: Thirteen healthy, nonobese premenopausal women. INTERVENTION(S): Insulin-stimulated glucose disposal was determined by hyperinsulinemic (40 mU/m(2)/min) clamp during the early to midfollicular and midluteal phase of the menstrual cycle. Volunteers then received 2 months of treatment with the GnRH agonist (GnRHa) leuprolide acetate (n = 6) or placebo (n = 7) and were retested. MAIN OUTCOME MEASURE(S): Total, oxidative, and nonoxidative insulin-stimulated glucose disposal. RESULT(S): Because no effect of cycle phase was found on total, oxidative, or nonoxidative glucose disposal, pretreatment follicular and luteal phase values were averaged. Treatment with GnRHa had no effect on total glucose disposal (GnRHa: 10.6 +/- 0.9 to 10.8 +/- 0.9 vs. placebo: 10.2 +/- 0.7 to 10.4 +/- 1.0 mg/kg fat-free mass/min, P = .99). Similarly, there was no effect of GnRHa administration on oxidative (GnRHa: 2.77 +/- 0.58 to 3.89 +/- 0.58 vs. placebo: 2.74 +/- 0.42 to 3.33 +/- 0.62 mg/kg fat-free mass/min, P = .52; n = 6 and 6, respectively) or nonoxidative (GnRHa: 7.82 +/- 0.68 to 6.91 +/- 0.66 vs. placebo: 7.94 +/- 0.72 to 7.79 +/- 0.99 mg/kg fat-free mass/min, P = .59; n = 6 and 6, respectively) components of glucose disposal. CONCLUSION(S): Our results suggest that endogenous ovarian hormones do not regulate tissue responsiveness to insulin or intracellular pathways of glucose disposal.