Ovarian response to follicle-stimulating hormone in women with polycystic ovary syndrome is diminished compared to ovulatory controls.

OBJECTIVE: The mechanisms underlying ovarian dysfunction in polycystic ovary syndrome (PCOS) have not been definitively established. Our objective was to perform a detailed examination of ovarian responses to recombinant follicle-stimulating hormone (rFSH) in women with PCOS and controls. DESIGN: This prospective, crossover, dose-response study included three rFSH stimulation periods. Each stimulation period involved three consecutive, daily, subcutaneous injections of rFSH administered at a single dose. Low, medium and high rFSH doses were weight-adjusted, corresponding to 0.5, 1.1 and 2.2 IU/kg/d, respectively. Stimulation periods occurred in randomized order and were separated by 8-week washouts. PATIENTS: Thirty participants (8 PCOS and 22 controls) were studied. PCOS was defined by oligomenorrhea and clinical or biochemical androgen excess, excluding other aetiologies of ovulatory dysfunction. MEASUREMENTS: Blood samples were obtained for hormone measurements before and 24 h after each rFSH injection. RESULTS: Participants with PCOS had significantly greater body mass index, antral follicle count and circulating testosterone, anti-mullerian hormone (AMH) and luteinizing hormone concentrations compared with controls participants. Baseline estradiol (E2) concentrations were similar in both groups. At the lowest dose of rFSH, PCOS participants did not demonstrate E2 increments, whereas a significant increase occurred in controls. rFSH-induced E2 production per follicle was significantly reduced in PCOS participants compared with controls at all rFSH doses. Increasing T and decreasing AMH concentrations were associated with augmented E2 production per follicle. COONCLUSIONS: Women with PCOS exhibited diminished initial E2 responses to rFSH compared with controls. These findings suggest that the mechanism of anovulation in PCOS may involve altered ovarian response to gonadotropins.

Effect of the spatial-temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse.

BACKGROUND: In the ovarian follicle, the Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. TCs express the essential enzyme 17α-hydroxylase/17,20-desmolase (CYP17), which permits the conversion of pregnenolone and progesterone into androgens. Dysregulation of CYP17 enzyme activity due to an intrinsic ovarian defect is hypothesized to be a cause of hyperandrogenism in women. Androgen excess is observed in women with polycystic ovary syndrome (PCOS) resulting from excess endogenous androgen production, and in transgender males undergoing exogenous testosterone therapy after female sex assignment at birth. However, the molecular and morphological effects of Cyp17 overexpression and androgen excess on folliculogenesis is unknown. METHODS: In this work, seeking a comprehensive profiling of the local outcomes of the androgen excess in the ovary, we generated a transgenic mouse model (TC17) with doxycycline (Dox)-induced Cyp17 overexpression in a local and temporal manner. TC17 mice were obtained by a combination of the Tet-dependent expression system and the Cre/LoxP gene control system. RESULTS: Ovaries of Dox-treated TC17 mice overexpressed Cyp17 specifically in TCs, inducing high testosterone levels. Surprisingly, TC17 ovarian morphology resembled the human ovarian features of testosterone-treated transgender men (partially impaired folliculogenesis, hypertrophic or luteinized stromal cells, atretic follicles, and collapsed clusters). We additionally assessed TC17 fertility denoting a perturbation of the normal reproductive functions (e.g., low pregnancy rate and numbers of pups per litter). Finally, RNAseq analysis permitted us to identify dysregulated genes (Lhcgr, Fshr, Runx1) and pathways (Extra Cellular Matrix and Steroid Synthesis). CONCLUSIONS: Our novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.

Elevation of markers of endotoxemia in women with polycystic ovary syndrome.

STUDY QUESTION: Is polycystic ovary syndrome (PCOS) associated with an elevation of markers of endotoxemia? SUMMARY ANSWER: In women with PCOS serum levels of lipopolysaccharides (LPS), the LPS to high-density lipoprotein (HDL) ratio and LPS-binding protein (LBP) are significantly greater than those of normal control subjects. WHAT IS KNOWN ALREADY: Mononuclear cells from women with PCOS respond excessively to LPS by releasing pro-inflammatory cytokines. In rat ovarian theca-interstitial cell cultures LPS stimulates androgen production. STUDY DESIGN, SIZE, DURATION: Cross-sectional study comparing markers of endotoxemia in women with PCOS (n = 62), healthy ovulatory women with polycystic ovary morphology (PCOM, n = 39) and a control group of healthy ovulatory women without PCOM [normal (NL), n = 43]. PARTICIPANTS/MATERIALS, SETTING, METHODS: LPS was measured using a chromogenic assay. LBP was measured by ELISA. Total cholesterol and lipids were measured using a homogeneous enzyme colorimetric method. Androgens, gonadotrophins, prolactin, insulin, high-sensitivity C-reactive protein (hs-CRP) and sex hormone-binding globulin were determined by electrochemiluminescence assays. Glucose was measured using an enzymatic reference method with hexokinase. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS, when compared with NL subjects, had a significantly higher mean LPS (P = 0.045), LPS/HDL ratio (P = 0.007) and LBP (P = 0.01). Women with PCOM had intermediate levels of markers of endotoxemia. Comparison among all groups revealed that markers of endotoxemia correlated positively with testosterone level, ovarian volume, number of antral follicles and hirsutism score, but negatively with the number of spontaneous menses per year. In multiple regression analysis, all measures of endotoxemia correlated independently and positively with hs-CRP and with ovarian volume. LIMITATIONS, REASONS FOR CAUTION: This cross-sectional study reveals that markers of endotoxemia are associated with several clinical features observed in women with PCOS. However, responsible mechanisms and causation remain unknown. Steroid quantification was carried out by electrochemiluminescence assays and not by the current gold standard: liquid chromatography-mass spectrometry. Hence, the relationship of endotoxemia with features of PCOS and the extent to which endotoxemia contributes to reproductive and metabolic dysfunction warrants further investigation. WIDER IMPLICATIONS OF THE FINDINGS: This study reveals the novel observation that markers of endotoxemia are elevated in young and otherwise healthy women with PCOS without significant metabolic dysfunction. Moreover, the association of clinical and endocrine markers of PCOS with those of endotoxemia may represent a pathophysiologic link to reproductive dysfunction as well as metabolic and long-term cardiovascular risks associated with this disorder. STUDY FUNDING/COMPETING INTEREST(S): Intramural funding from Poznan University of Medical Sciences. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Androgens Modulate Rat Granulosa Cell Steroidogenesis.

Paracrine interactions between ovarian theca-interstitial cells (TICs) and granulosa cells (GCs) play an important role in the regulation of follicular steroidogenesis. Androgens serve as substrates for aromatization as well as affect GC function. This study evaluated the effects of co-culture of GC with TICs and the role of testosterone (T) and 5-alpha-dihydrotestosterone (DHT), and estradiol (E2) in modulation of GC expression of genes involved in the production of progesterone: 3ß-hydroxysteroid dehydrogenase/Δ5-4 isomerase (Hsd3b) and cholesterol side-chain cleavage (Cyp11). GCs obtained from immature Sprague-Dawley rats and were cultured in chemically defined media without or with TICs, DHT, or T. Hsd3b and Cyp11 transcripts were analyzed by qt-PCR. Co-culture of GCs with TICs stimulated Hsd3b and CYP11 expression in GCs. DHT and T induced a concentration-dependent upregulation of Hsd3b and CYP11 expression, as well as increased progesterone concentrations in spent media. E2 also increased expression of Hsd3b, and Cyp11. Effects of androgens were abrogated in the presence of an anti-androgen bicalutamide and the antiestrogen ICI 182780 (ICI). In conclusion, present findings demonstrate that androgens upregulate production of progesterone in GCs; these effects are likely due to a combination of direct action on androgen receptors and effects mediated by estrogen receptors.

Inflammatory Stimuli Trigger Increased Androgen Production and Shifts in Gene Expression in Theca-Interstitial Cells.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by theca cell hyperplasia and excessive androgen production. An increasing body of evidence has pointed to a close association between PCOS and low-grade chronic systemic inflammation. However, the mechanistic basis for this linkage is unknown. Therefore, we evaluated the effects of the inflammatory agents lipopolysaccharide (LPS) and IL-1ß on rat theca-interstitial cells (TICs). We found that incubation with either LPS or IL-1ß elicited a dose-dependent increase in both TIC viability and androgen production. Using RNA sequencing analysis, we found that both of these inflammatory agents also triggered profound and widespread shifts in gene expression. Using a stringent statistical cutoff, LPS and IL-1ß elicited differential expression of 5201 and 5953 genes, respectively. Among the genes upregulated by both LPS and IL-1ß were key regulatory genes involved in the cholesterol and androgen biosynthesis pathways, including Cyp17a1, Cyp11a1, Hsd3b, and Hmgcr. This provides a molecular explanation for the mechanism of action of inflammatory agents leading to increased androgen production. Gene ontology and pathway analysis revealed that both LPS and IL-1ß regulated genes highly enriched for many common functions, including the immune response and apoptosis. However, a large number of genes (n = 2222) were also uniquely regulated by LPS and IL-1ß, indicating that these inflammatory mediators have substantial differences in their mechanism of action. Together, these findings highlight the potential molecular mechanisms through which chronic low-grade inflammation contributes to the pathogenesis of androgen excess in PCOS.

The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline.

Objective: To update the "Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline," published by the Endocrine Society in 2008. Participants: The participants include an Endocrine Society-appointed task force of seven medical experts and a methodologist. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: Group meetings, conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees, members, and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. Conclusion: We suggest testing for elevated androgen levels in all women with an abnormal hirsutism score. We suggest against testing for elevated androgen levels in eumenorrheic women with unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score). For most women with patient-important hirsutism despite cosmetic measures (shaving, plucking, waxing), we suggest starting with pharmacological therapy and adding direct hair removal methods (electrolysis, photoepilation) for those who desire additional cosmetic benefit. For women with mild hirsutism and no evidence of an endocrine disorder, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral combined estrogen-progestin contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For most women who choose hair removal therapy, we suggest laser/photoepilation.

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence.

This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.

Activation of Endoplasmic Reticulum Stress in Granulosa Cells from Patients with Polycystic Ovary Syndrome Contributes to Ovarian Fibrosis.

Recent studies report the involvement of intra-ovarian factors, such as inflammation and oxidative stress, in the pathophysiology of polycystic ovary syndrome (PCOS), the most common endocrine disorder of reproductive age women. Endoplasmic reticulum (ER) stress is a local factor that affects various cellular events during a broad spectrum of physiological and pathological conditions. It may also be an important determinant of pro-fibrotic remodeling during tissue fibrosis. In the present study, we showed that ER stress was activated in granulosa cells of PCOS patients as well as in a well-established PCOS mouse model. Pharmacological inducers of ER stress, tunicamycin and thapsigargin, were found to increase the expression of pro-fibrotic growth factors, including transforming growth factor (TGF)-ß1, in human granulosa cells, and their expression also increased in granulosa cells of PCOS patients. By contrast, treatment of PCOS mice with an ER stress inhibitor, tauroursodeoxycholic acid or BGP-15, decreased interstitial fibrosis and collagen deposition in ovaries, accompanied by a reduction in TGF-ß1 expression in granulosa cells. These findings suggest that ER stress in granulosa cells of women with PCOS contributes to the induction of pro-fibrotic growth factors during ovarian fibrosis, and that ER stress may serve as a therapeutic target in PCOS.

The effect of estradiol on granulosa cell responses to FSH in women with polycystic ovary syndrome.

BACKGROUND: The influence of estradiol (E2) on granulosa cell (GC) function has not been tested clinically in women with polycystic ovary syndrome (PCOS). The objective of this study is to determine if E2 influences GC responses to FSH in women with PCOS. METHODS: This is a two phase, single cohort study conducted over a 2-year period at a single academic center. Nine women with PCOS according to NIH criteria. In Phase 1, FSH stimulation of GC responses as measured by E2 and Inhibin B (Inh B) were assessed before and at 5 and 6 weeks after GnRH agonist administration. In Phase 2, the same protocol was employed with the addition of an aromatase inhibitor (letrozole, LET) administered daily beginning at week 4 for 2 weeks. RESULTS: In Phase 1, recovery of FSH, E2 and Inh B from ovarian suppression occurred at 5 and 6 weeks after GnRH agonist injection and preceded resumption of LH and androgen secretion. In Phase 2, hormone recovery after GnRH agonist was characterized by elevated FSH and suppressed E2 levels whereas recovery of LH and androgen levels were unchanged. In Phase 1, FSH stimulated E2 and Inh B responses were unaltered during recovery from ovarian suppression. In Phase 2, E2 and Inh B fold changes after FSH were significantly reduced at weeks 5 (p < 0.04) and 6 (p < 0.01), respectively. CONCLUSION: In anovulatory women with PCOS, chronic, unopposed E2 secretion may contribute, at least in part, to enhanced ovarian responsiveness to FSH. TRIAL REGISTRATION: NCT02389088.

Androgen responses to adrenocorticotropic hormone infusion among individual women with polycystic ovary syndrome.

OBJECTIVE: To compare androgen responses during ACTH infusion among women with polycystic ovary syndrome (PCOS) and healthy women. DESIGN: Cross-sectional study. SETTING: Academic medical center. PATIENT(S): Women with PCOS (n = 13) and healthy controls (n = 15). INTERVENTION(S): Blood samples were obtained frequently during a 6-hour dose-response ACTH infusion. MAIN OUTCOME MEASURE(S): Comparison of basal and stimulated levels of 17α-hydroxyprogesterone (17-OHP), androgens, and cortisol (F) during ACTH infusion with those after hCG injection within individual subjects. RESULT(S): In women with PCOS increased 17-OHP, androstenedione (A), and DHEA responses during ACTH infusion were comparable to those observed in healthy controls. The magnitude of responses was highly variable among women with PCOS. Within individual women with PCOS adrenal responses to ACTH and ovarian responses to hCG were significantly correlated. Cortisol responses to ACTH were similar in women with PCOS and healthy controls. CONCLUSION(S): Within individual women with PCOS, enhanced androgen responses to ACTH are accompanied by comparable androgen responsiveness to hCG. These findings suggest that dysregulated steroidogenesis leading to hyperandrogenemia in this disorder is likely present in both adrenal and ovarian tissues. CLINICAL TRIAL REGISTRATION NUMBER: NCT00747617.

17-Hydroxyprogesterone responses to human chorionic gonadotropin are not associated with serum anti-Mullerian hormone levels among adolescent girls with polycystic ovary syndrome.

BACKGROUND: In adult women with polycystic ovary syndrome (PCOS) 17-OHP responses to human chorionic gonadotropin (hCG) stimulation are highly variable and inversely correlated with serum anti-Mullerian hormone (AMH) levels. The objective of this study was to determine whether adolescents with PCOS exhibit similar variable 17-OHP responsiveness to hCG and whether these responses are correlated to AMH levels. METHODS: In a prospective study, adolescent PCOS (n=14) and normal controls (n=10) received 25 µg of hCG, intravenously. Blood samples were obtained before and 24 h afterwards for measurement of 17-OHP and basal AMH. RESULTS: Variable 17-OHP responses to hCG were observed among PCOS girls similar to that observed in adults. There was no correlation between AMH and 17-OHP responses to hCG. CONCLUSIONS: Among adult and adolescent individuals with PCOS variable 17-OHP production appears to be characteristic of the disorder. In adolescent PCOS, 17-OHP responsiveness to hCG is not correlated to AMH.

Relationship between 17-hydroxyprogesterone responses to human chorionic gonadotropin and markers of ovarian follicle morphology in women with polycystic ovary syndrome.

CONTEXT: Women with polycystic ovary syndrome (PCOS) have increased 17-hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation although individual variability is substantial, as reflected by exaggerated as well as normal responses. The relationship between 17-OHP responses to gonadotropin stimulation and markers of ovarian function has not been assessed. OBJECTIVE: To determine whether 17-OHP responses are associated with antral follicle count (AFC), anti-Mullerian hormone (AMH), or inhibin B (Inh B) levels in PCOS and normal women. DESIGN: Prospective study. SETTING: Research center at an academic medical center. PARTICIPANTS: Women with PCOS (n = 18) and normal controls (n = 18). INTERVENTIONS: Blood samples were obtained before and 24 hours after administration of 25 µg recombinant-human chorionic gonadotropin. Ovarian imaging was conducted with three-dimensional pelvic ultrasound. MAIN OUTCOME MEASURES: Basal and stimulated levels of 17-OHP, androgens, estrogen, AMH, Inh B, and AFC. RESULTS: In women with PCOS, 17-OHP responses were heterogeneous and inversely correlated with AMH and Inh B levels, but not AFC. In a subgroup of PCOS women with exaggerated 17-OHP responses, AMH levels were equivalent to that of normal women. In PCOS women with normal 17-OHP responses, AMH levels were markedly elevated. CONCLUSION: Based on heterogeneous 17-OHP responses to human chorionic gonadotropin in women with PCOS, AMH levels are inversely linked to ovarian androgen production while positively correlated with AFC. These findings suggest that in PCOS, AMH production may reflect redistribution of the follicle population or regulation by intraovarian mechanisms.

Lack of Serum anti-Mullerian hormone responses after recombinant human chorionic gonadotropin stimulation in women with polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is an anovulatory disorder characterized by excess androgen production and increased LH secretion. Serum anti-Mullerian hormone (AMH) is also elevated in this disorder. Women with PCOS exhibit a positive correlation between AMH and LH levels and recent in vitro data demonstrate that LH can directly stimulate AMH production by granulosa cells from women with PCOS. OBJECTIVE: The objective of the study was to directly test whether LH increases AMH production in women with PCOS in vivo by assessing responses after recombinant human chorionic gonadotropin (r-hCG) stimulation. DESIGN: This was a prospective study. SETTING: The study was conducted at a research center at an academic medical center. PARTICIPANTS: Women with PCOS (n = 28) and normal controls (n = 29) participated in the study. INTERVENTIONS: Blood samples were obtained before and 24 hours after iv administration of 25 µg r-hCG. MAIN OUTCOME MEASURES: Basal and stimulated serum AMH, androstenedione, T, and 17-hydroxyprogesterone levels were measured. RESULTS: Baseline AMH levels in women with PCOS were greater than in normal controls and correlated with levels of LH as well as androstenedione, T, and 17-hydroxyprogesterone. A rise of serum AMH levels was not observed after r-hCG administration in women with PCOS or normal ovaries. CONCLUSION: These findings are in contrast to in vitro evidence demonstrating that AMH secretion by granulosa cells of PCOS women in response to LH stimulation and suggest AMH regulation in vivo is complex and that the elevated serum AMH in women with PCOS is not a direct effect of the excess LH production characteristic of PCOS.

Anti-Mullerian hormone may be a useful adjunct in the diagnosis of polycystic ovary syndrome in nonobese adolescents.

OBJECTIVES: This study aimed to [1] confirm that nonobese adolescents with polycystic ovary syndrome (PCOS) have higher anti-Mullerian hormone (AMH) than controls; [2] examine the relationship of AMH with PCOS features and hormonal profile; and [3] approximate an AMH value that discriminates between adolescents with PCOS and controls. DESIGN: Case-control study. SETTING: Subspecialty ambulatory clinic. PATIENTS: Thirty-one nonobese adolescent girls (age 13-21 years), 15 with PCOS diagnosed using the National Institutes of Health (NIH) criteria and 16 healthy control subjects. Subjects and controls were comparable for body mass index z-score, age and ethnicity. MAIN OUTCOME MEASURE(S): AMH in PCOS subjects and control groups, correlation of AMH with hormonal parameters. RESULTS: AMH was higher in PCOS subjects (4.4±3.4 ng/mL) than in controls (2.4±1.3 ng/mL), when adjusted for menstrual age. In the entire group (PCOS and controls), AMH correlated with androgens, ovarian size and the presence of polycystic ovary (PCO) appearance. There was no difference in average ovarian size between PCOS (7.1±2.6 cm³) and controls (6.7±1.8 cm³). PCOS subjects were 1.49 times more likely to have AMH >3.4 ng/mL (confidence interval 0.98-2.26 ng/mL). CONCLUSIONS: Our data suggest that AMH may be a useful adjunct in the diagnosis of PCOS in adolescents.

Decreased inhibin B responses following recombinant human chorionic gonadotropin administration in normal women and women with polycystic ovary syndrome.

OBJECTIVE: To determine whether granulosa cells contribute to excess androgen production, by assessing inhibin B (Inh B) responses to hCG in women with polycystic ovary syndrome (PCOS) and in normal women. DESIGN: Prospective study. SETTING: Academic medical center. PATIENT(S): Twenty women with PCOS and 16 normal women. INTERVENTION(S): Blood samples obtained before and 24 hours after injection of 25 µg recombinant hCG (r-hCG). MAIN OUTCOME MEASURE(S): Basal and stimulated Inh B, E2, androstenedione (A), and T responses after r-hCG administration. RESULT(S): In normal and PCOS women, r-hCG induced a significant reduction of Inh B levels. Lowered Inh B responses were not related to body mass index, PCOS status, or age by multivariate regression. Recombinant hCG significantly increased serum A and E2 in both normal and PCOS women. CONCLUSION(S): In normal and PCOS women, Inh B production was decreased following r-hCG administration. These findings strongly suggest that in PCOS women androgen excess is not enhanced by LH-stimulated Inh B production. CLINICAL TRIAL REGISTRATION NUMBER: NCT00747617.

The impact of depot GnRH agonist on AMH levels in healthy reproductive-aged women.

CONTEXT: GnRH agonists (GnRHa) are being used experimentally in an attempt to preserve fertility in young female cancer patients undergoing chemotherapy. Anti-Müllerian hormone (AMH) produced by ovarian granulosa cells may serve as a marker of ovarian reserve, but it is not clear whether this marker is useful during GnRHa treatment. OBJECTIVE: The purpose of this study was to determine the effect of a depot GnRHa on AMH levels. DESIGN: Depot leuprolide (3.75 mg) was administered in the midluteal phase (MLP) in healthy women. Assessments of AMH, FSH, LH, estradiol, and progesterone were performed in the early follicular phase (EFP) and MLP before GnRHa treatment and approximately 7, 14, and 30 days after GnRHa administration. SETTING: The study was conducted in a university research center. PATIENTS: Participants were 33 healthy, premenopausal women aged 18 to 45 years old with regular menses. RESULTS: EFP and MLP AMH levels were similar before GnRHa administration. Relative to MLP AMH levels, AMH decreased 7 days after GnRHa administration by a median of 24% (P < .001) and then increased above pretreatment levels 14 and 30 days after GnRHa by 13% and 32%, respectively (P < .001). Changes in AMH levels did not correlate with changes in gonadotropins, estradiol, or progesterone. CONCLUSIONS: Significant changes in AMH levels occur in the first 4 weeks after depot leuprolide administration, suggesting that AMH may not be a reliable marker of ovarian reserve during this interval. Changes in AMH occurred independent of gonadotropin levels, supporting a direct effect of GnRHa on granulosa cell expression of AMH or an indirect effect of GnRHa on the development and/or dynamics of the follicle pool.

Paracrine regulation of theca androgen production by granulosa cells in the ovary.

OBJECTIVE: To test whether and to what extent inhibin mediates Cyp17 messenger RNA (mRNA) expression in theca cells (TCs) in response to FSH stimulation of granulosa cells (GCs). DESIGN: Ex vivo and in vitro experimental study. SETTING: University. ANIMAL(S): Immature female Sprague Dawley rats. INTERVENTION(S): Ovarian tissue explants and isolated theca cell preparations with or without GCs were treated with FSH, inhibin, inhibin antibody, or ß-glycan antibody. MAIN OUTCOME MEASURE(S): As a key enzyme in androgen production, Cyp17 mRNA levels were measured by real-time reverse transcription-polymerase chain reaction. RESULT(S): After 24 hours, Cyp17 mRNA expression was dose-dependently increased by FSH in ovarian tissue explants and theca cells, suggesting that paracrine factor(s) secreted from GCs in response to FSH mediates Cyp17 mRNA expression in TCs. Antibodies against inhibin and inhibin coreceptor, ß-glycan, blocked the stimulatory effect of FSH on Cyp17 mRNA expression. However, inhibin alone did not increase Cyp17 mRNA level to the same extent. CONCLUSION(S): These findings suggest a role for inhibin in the paracrine regulation of TC Cyp17 mRNA expression by GCs influenced by FSH; however, other paracrine factors produced by GCs by virtue of FSH seem to be required.

Future Directions in Oncofertility and Fertility Preservation: A Report from the 2011 Oncofertility Consortium Conference.

Fertility impairment and loss due to cancer or its treatment is a significant survivorship consideration for many pediatric, adolescent, and young adult cancer survivors. Chemotherapeutics, radiation, and surgery can impact the future fertility of men, women, and children with cancer. The field of oncofertility, founded to ensure the reproductive future of cancer survivors, gained momentum with 5 years of funding through a 2007 National Institutes of Health Roadmap Grant for Biomedical Research. This report from working group meetings at the fifth annual Oncofertility Consortium Conference speaks to the present state of oncofertility research and clinical care, existing gaps, and future directions for the field. This summary from conference participants and leaders in the field addresses the science, clinical specialties, and academic scholarship that can guide the field as the Roadmap Grant funding comes to a close.

Ovarian imaging by magnetic resonance in adolescent girls with polycystic ovary syndrome and age-matched controls.

PURPOSE: To compare ovarian morphology in adolescent girls with and without polycystic ovary syndrome (PCOS) using magnetic resonance imaging (MRI). MATERIALS AND METHODS: In 21 adolescent girls (age 12-18 years) without and 19 adolescents with PCOS (diagnosis based on excessive hair growth and irregular menstrual cycles) ovarian volume, antral follicle count (AFC) per ovary, and follicle size were evaluated. MRI was performed at 1.5 T or 3 T and axial or angled-axial single-shot echo-train spin echo images of 6 mm slice thickness were acquired. In a subset of subjects, 2-mm images were also obtained. PCOS and non-PCOS groups were compared using mixed affects regression. RESULTS: Mean AFC per ovary and ovarian volume were substantially greater in PCOS subjects compared to non-PCOS subjects. Mean follicle size was similar between groups. Follicles exceeding 10 mm were seen in 2/19 PCOS subjects versus 9/21 non-PCOS subjects. Consistently higher follicle counts were detected in images obtained at 2 mm compared to 6-mm slice thickness. CONCLUSION: In adolescence, MRI of the ovary reveals distinct differences between girls with and without PCOS. MRI may help evaluate young patients in whom transvaginal ultrasound is contraindicated.