Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ-induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double-blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12-day washout. Twenty-four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18-49 years) and 22.6 +/- 2.2 kg/m(2), respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor-I (PAI-I), leptin, and tumor necrosis factor-alpha (TNF-alpha) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short-term perturbations in IS.

We greatly appreciate Dr. Acién's interest in the Task Force's report (1Azziz R. Carmina E. Dewailly D. Diamanti-Kandarakis E. Escobar-Morreale H.F. Futterweit W. et al.The Androgen Excess and PCOS Society Criteria for the Polycystic Ovary Syndrome: The Complete Task Force Report.Fertil Steril. 2009; 91: 456-488Abstract Full Text Full Text PDF PubMed Scopus (1319) Google Scholar). He first suggests that “more stress should have been put on the criteria to define each symptom and analytical data instead of widely analyzing their prevalence.” We fully agree that while much emphasis has been made on arriving at a uniform definition of polycystic ovary syndrome (PCOS), of equal or even greater importance is the need to clearly and accurately define the specific phenotypic features used in the definitions. Although not the aim of our Task Force, we did make an effort to discuss throughout the pitfalls and limitations of each of the diagnostic criteria discussed (e.g., assessment of ovulatory dysfunction, measures of androgen levels, exclusion of related disorders). Further details on these important questions were discussed elsewhere (2Azziz R. Diagnosing the diagnosis: Why we must standardize the defining features of PCOS.Ann Clin Biochem. 2008; 45: 3-5Crossref PubMed Scopus (10) Google Scholar). Second, Dr. Acién notes that the assessment of ovarian morphology by “transabdominal echography is of little utility; therefore, it should be done transvaginally.” Although transvaginal ultrasonography is clearly superior to transabdominal imaging, we should note that not all patients tolerate a vaginal or rectal examination, and are able to tolerate a transabdominal exam. The results of transabdominal sonography greatly depend on the degree of the patient's obesity and are superior for assessment of ovarian size than follicle number. Although it is true that it is preferable that the ultrasound examination is performed by the examining physician, this is not always practical or possible. In fact, the results of the evaluation will primarily depend on the skill of the sonographer, be it a radiologic technician, radiologist, or clinician. Therefore, whereas we agree that transvaginal sonography has a greater value than transabdominal imaging, we cannot agree that the latter is “of little utility.” Likewise, we respectfully disagree that PCOS is a gynecologic pathology. Polycystic ovary syndrome is a life-long reproductive-metabolic disorder, whose impact is felt and should be understood and managed by a broad spectrum of practitioners. Third, the correspondent notes that in his opinion all features of PCOS must be present for the diagnosis to be made (i.e., hirsutism, hyperandrogenemia, oligoanovulation, polycystic ovaries, and alteration of the relation FSH/LH in day 3–4 of the cycle). Surprisingly he feels that need for “the exclusion of other related disorders is even more imperative” when “any of these criteria is missing.” We disagree. Polycystic ovary syndrome clearly has a heterogeneous presentation, and exclusion of related disorders should be made in all patients suspected of the disorder, regardless of their phenotypic presentation. The correspondent is referred to the text of the report for further responses to this statement (1Azziz R. Carmina E. Dewailly D. Diamanti-Kandarakis E. Escobar-Morreale H.F. Futterweit W. et al.The Androgen Excess and PCOS Society Criteria for the Polycystic Ovary Syndrome: The Complete Task Force Report.Fertil Steril. 2009; 91: 456-488Abstract Full Text Full Text PDF PubMed Scopus (1319) Google Scholar). We apologize that we did not include the correspondent's own publication in our task force report. However, we should note that many other reports were not included, particularly if they did not report the prevalence of the features of PCOS being evaluated (e.g., menstrual or ovulatory dysfunction, hirsutism, hyperandrogenemia). Of note, a “total of 527 articles were initially available for this review, although additional studies (cross-references and those published in 2006) were also considered” and only a fraction of these were actually included. We appreciate Dr. Acién's interest in the report. Criteria for the polycystic ovary syndromeFertility and SterilityVol. 92Issue 1PreviewTo the Editor: Full-Text PDF Open Archive

OBJECTIVE:To review all available data and recommend a definition for polycystic ovary syndrome (PCOS) based on published peer-reviewed data, whether already in use or not, to guide clinical diagnosis and future research. DESIGN:Literature review and expert consensus. SETTING:Professional society. PATIENTS:None. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):A systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. RESULT(S):The Task Force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the Androgen Excess and PCOS (AE-PCOS) Society AE-PCOS Board of Directors. No section was finalized until all members were satisfied with the contents, and minority opinions noted. Statements were not included that were not supported by peer-reviewed evidence. CONCLUSION(S):Based on the available data, it is the view of the AE-PCOS Society Task Force that PCOS should be defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries), and the exclusion of related disorders. However, a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism, but recognized that more data are required before validating this supposition. Finally, the Task Force recognized and fully expects that the definition of this syndrome will evolve over time to incorporate new research findings.

Objective: To test the hypothesis that an acute reduction in circulating insulin affects LH secretion in women with polycystic ovary syndrome (PCOS).Design: Prospective study in normal and PCOS women.Setting: General Clinic Research Centers at the University of Virginia, the Medical College of Virginia and the Massachusetts General Hospital.Patient(s): Six normal women and five women with PCOS.Intervention(s): Administration of diazoxide to lower circulating insulin concentrations.Main Outcome Measure(s): Characteristics of LH secretion as appraised by multiparameter deconvolution and estimation of approximate entropy.Result(s): Short-term administration of diazoxide had no effect on the secretion of LH in women with PCOS.Conclusion(s): Hyperinsulinemia resulting from insulin resistance in women with PCOS may not have a direct effect on gonadotropin secretion.

The goals of the clinical evaluation of women with possible polycystic ovary syndrome (PCOS) include: (1) making the proper diagnosis (excluding other more serious diagnoses); (2) determining whether to screen for associated health complications of PCOS in the patient and/or her family members; (3) determining the appropriate current treatment; and (4) discussing a long-term management plan for the patient.The clinical evaluation begins with a complete medical history and physical examination. Although the evaluation will naturally focus on those areas of greatest concern to the patient, the clinician must remember the myriad associated health abnormalities that can occur with PCOS and has a responsibility to evaluate all the health impacts of the condition on the patient, whether or not intervention is currently requested or required.

Gonadotropin abnormalities are common in women with polycystic ovary syndrome. Interpretation of LH values depends on body weight, time of last ovulation, assay used, and the precision of the normative data against which a value is compared.

OBJECTIVEThe Androgen Excess Society (AES) charged a task force to review all available data and recommend an evidence-based definition for polycystic ovary syndrome (PCOS), whether already in use or not, to guide clinical diagnosis and future research.PARTICIPANTSParticipants included expert investigators in the field.EVIDENCEBased on a systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, we tried to identify studies evaluating the epidemiology or phenotypic aspects of PCOS.CONSENSUS PROCESSThe task force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the AES Board of Directors. No section was finalized until all members were satisfied with the contents and minority opinions noted. Statements that were not supported by peer-reviewed evidence were not included.CONCLUSIONSBased on the available data, it is the view of the AES Task Force on the Phenotype of PCOS that there should be acceptance of the original 1990 National Institutes of Health criteria with some modifications, taking into consideration the concerns expressed in the proceedings of the 2003 Rotterdam conference. A principal conclusion was that PCOS should be first considered a disorder of androgen excess or hyperandrogenism, although a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism but recognized that more data are required before validating this supposition. Finally, the task force recognized, and fully expects, that the definition of this syndrome will evolve over time to incorporate new research findings.

Recent studies have demonstrated the presence of ovarian follicular development in up to 78% of women with premature ovarian failure (POF). The purpose of this study was to examine the control of FSH by estradiol and inhibin secretion from these follicles. Weekly blood samples were collected in conjunction with assessment of ovarian follicle development by ultrasound for at least 12 wk in 49 subjects with POF. Results were compared with those of 44 normal cycling women. Ovulatory cycles occurred in 24 subjects (49%) with POF. These ovulatory cycles were characterized by higher FSH and lower inhibin B and inhibin A levels, whereas estradiol levels were higher compared with those in normal women. Follicles developed in the absence of ovulation in 18 women (37%) with POF, whereas the ovaries were inactive in seven women (14%). FSH levels were lower in POF women with ovulatory or anovulatory follicle development compared with levels in women with inactive ovaries. These findings demonstrate that ovulatory cycles in women with POF are characterized by a persistent elevation in FSH compared with levels in normal cycling women. The association of increased FSH with lower levels of inhibin B and inhibin A, but higher estradiol levels provides additional evidence for an important physiological role of the inhibins in the negative feedback control of FSH. These data also demonstrate the variability in FSH levels as a function of underlying follicular development in women with POF.

This study was an attempt to determine whether polycystic ovarian morphology (PCOM) is an important factor in the development of polycystic ovarian syndrome (PCOS). Among the 68 women studied, all of whom had regular ovulatory menstrual cycles and lacked clinical signs of hyperandrogenism, 39 had PCOM and 29 had morphologically normal ovaries. Ovarian morphology was examined by ultrasonography, usually performed transvaginally. Hormone levels were estimated at baseline in the early follicular phase (EFP) of the cycle and, in 36 women, studies were repeated each day during a complete cycle. Body mass index did not differ in women with PCOM and those with normal ovaries. Ovarian volume was twice as great in the PCOM group, and these women had higher numbers of follicles than did those with normal ovaries (8–15 vs. 4–8 per ovary). Baseline EFP levels of testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) were higher in women with PCOM, and levels of sex hormone-binding globulin (SHBG) were lower. Four PCOM women had elevated testosterone levels. The difference in DHEAS levels was independent of age. Sampling across the cycle disclosed no significant group differences in luteinizing hormone, follicle-stimulating hormone, progesterone, or estradiol. In EFP and also at midcycle, women with PCOM had significantly higher testosterone levels compared with those with normal ovaries. SHBG levels tended to be lower in women with PCOM across the cycle, but not significantly so. Levels of free testosterone were higher in women with PCOM, especially in the EFP. Fasting insulin and insulin resistance were higher in women with PCOM; both parameters correlated inversely with SHBG. No group differences were found in blood pressure or serum lipid levels. Women with PCOM had greater androstenedione, testosterone, and 17-hydroxyprogesterone responses to human chorionic gonadotropin compared with women with normal ovaries. These findings indicate that PCOM is the mildest form of ovarian hyperandrogenism. Whether PCOM favors the development of PCOS remains to be determined.

Context: Previous studies suggest that inhibin subunit expression is decreased in granulosa cells of women with polycystic ovary syndrome ( PCOS).Objective: The objective of this study was to test the hypothesis that inhibin A and inhibin B protein concentrations are also decreased in PCOS follicles.Design: The design was a parallel study.Setting: The study was performed at an in vitro fertilization suite.Participants: We studied women with regular cycles (n = 36) and women with PCOS (n = 8).Interventions: Follicular fluid was aspirated from the follicles of women with PCOS (n = 14 follicles) and from women with regular cycles at various times during the follicular phase (n = 50 follicles).Main Outcome Measure: Inhibin A and B concentrations from PCOS follicles were compared with those in size-matched follicles, dominant follicles (>= 10 mm), and subordinate follicles from regularly cycling women.Results: Inhibin A(220 +/- 38 vs. 400 +/- 72 IU/ml; P < 0.05) and inhibin B (75.4 +/- 10.4 vs. 139 +/- 26 ng/ml; P < 0.05) concentrations were lower in the follicular fluid of PCOS follicles compared with those of size-matched follicles from regularly cycling women. Inhibin A was also lower in the follicular fluid of PCOS compared with subordinate follicles from normal women (577 +/- 166 IU/ml; P < 0.05). Inhibin A concentrations increased with increasing follicle size, resulting in significantly higher follicular fluid concentrations in dominant follicles from normal women compared with PCOS follicles ( 2298 +/- 228 IU/ml; P < 0.05).Conclusions: These data demonstrate that inhibin A and inhibin B concentrations are significantly reduced in the follicular fluid of women with PCOS compared with those in the follicular fluid of size-matched follicles from normal women, consistent with the decreased inhibin subunit mRNA expression in previous studies. These findings point to the potential importance of inhibins in normal follicle development and suggest that inhibin deficiency may play a role in the follicle arrest associated with PCOS.

We describe the clinical course of three women with presumptive autoimmune oophoritis who developed multiple follicles but very low to undetectable estradiol levels. Multiple follicles developed spontaneously in all subjects and during pulsatile GnRH treatment for ovulation induction in subject 1. The development of multiple dominant follicles was accompanied by LH levels in the postmenopausal range and FSH levels at the upper limit for premenopausal women. Serum inhibin B levels were elevated appropriately in the setting of multifollicular development, but estradiol levels remained low. Measurement of estradiol precursors demonstrated androstenedione and estrone levels below the 95th percentile in normal women. Adrenal cortical antibodies, and antibodies to 21-hydroxylase and P450 side chain cleavage enzymes were identified in all subjects. All subjects met the criteria for premature ovarian failure during follow-up. Subject 1 later developed adrenal failure, whereas subject 3 had adrenal failure at the time of the study. These subjects elucidate the hormonal pattern in autoimmune oophoritis, before the full criteria for premature ovarian failure are met. The elevated inhibin A and B levels, which accompany the development of multiple small and dominant follicles in these women, suppress FSH relative to LH levels, virtually independent of estradiol. These data provide further evidence for an important role of inhibin B and inhibin A in the negative feedback control of FSH. In addition, the normal inhibin A and inhibin B production in the absence of estradiol precursors and estradiol provide insight into the selective dysfunction of the theca cells in autoimmune oophoritis.

Up to 28% of female fragile X premutation carriers develop premature ovarian failure. To test the hypothesis that fragile X premutation carriers with ovulatory menstrual cycles exhibit hormone changes characteristic of early ovarian aging, 11 regularly cycling fragile X premutation carriers, 24-41 yr old (34.5 +/- 5.7 yr, mean +/- sd), drew daily blood samples across one menstrual cycle. LH, FSH, estradiol, progesterone (P4), inhibin A, and inhibin B levels were compared with levels in 22 age-matched, regularly cycling women, 23-41 yr old (34.6 +/- 5.8 yr), at each cycle stage. Total cycle (26.1 +/- 1.0 vs. 28.2 +/- 0.4 d; P < 0.05) and follicular phase length (12.9 +/- 0.8 vs. 14.5 +/- 0.4 d; P < 0.05) were decreased in fragile X premutation carriers compared with age-matched controls, whereas luteal phase length was similar (13.2 +/- 0.5 vs. 13.7 +/- 0.3 d; P = not significant). FSH was elevated across the follicular (21.9 +/- 3.5 vs. 11.2 +/- 0.5 IU/liter; P < 0.001) and luteal phases (14.6 +/- 3.9 vs. 7.9 +/- 0.5 IU/liter; P < 0.05) in fragile X premutation carriers compared with age-matched controls. Inhibin B in the follicular phase (77 +/- 11 vs. 104 +/- 6 pg/ml; P < 0.05) and inhibin A (3.4 +/- 0.7 vs. 5.8 +/- 0.5 IU/ml; P < 0.01) and P4 [7.3 +/- 1.0 vs. 10.1 +/- 0.7 ng/ml (23.2 +/- 3.0 vs. 32.1 +/- 2.3 nmol/liter); P < 0.05] in the luteal phase were decreased in fragile X premutation carriers compared with age-matched controls, whereas there was no difference in estradiol or LH. In summary, despite regular ovulatory cycles, FSH was increased in fragile X premutation carriers compared with age-matched controls. The increased FSH was accompanied by decreased inhibin B in the follicular phase and inhibin A and P4 in the luteal phase. These hormonal changes suggest that fragile X premutation carriers exhibit early ovarian aging despite regular menstrual cycles. Early ovarian aging in fragile X premutation carriers likely results from decreased follicle number and function, as reflected by lower inhibin B, inhibin A, and P4 levels.

To determine the relevance of polycystic ovarian morphology (PCOM) to the pathophysiology of polycystic ovarian syndrome (PCOS), biochemical features associated with PCOS were examined in 68 women with an established history of regular ovulatory cycles and no clinical evidence of hyperandrogenism. Ovarian morphology was objectively assessed by pelvic ultrasound. LH, FSH, estradiol (E(2)), testosterone (T), androstenedione (Delta(4)A), SHBG, and dehydroepiandrosterone sulfate (DHEAS) were measured at baseline in the early follicular phase (EFP) in all subjects. LH, FSH, E(2), and progesterone (P(4)) were then measured daily for a complete menstrual cycle in 16 women with normal ovarian morphology and in 26 women with PCOM. T, Delta(4)A, SHBG, and DHEAS levels were measured in pools of three daily samples in each of the EFP, midcycle, and midluteal phases. An additional 26 normal women (13 with normal ovarian morphology and 13 with PCOM) were studied in the EFP to assess pulsatile LH secretion, insulin and glucose levels, and the ovarian response to human chorionic gonadotropin. At baseline, there were no differences in body mass index or hirsutism scores between women with PCOM and normal ovaries. In daily samples across the menstrual cycle LH, FSH, E(2), and P(4) did not differ between women with PCOM and those with normal ovaries, and there was no difference in LH pulse amplitude or frequency in the EFP frequent sampling studies. In women with PCOM, T (P < 0.01), free T (P < 0.005), and DHEAS (P < 0.01) levels were higher at baseline in the EFP, and SHBG was lower (P < 0.05). Differences in Delta(4)A did not reach significance (P = 0.14). T, free T, Delta(4)A, and DHEAS were also increased in PCOM across the menstrual cycle (P < 0.05). In addition, 17-hydroxyprogesterone (P < 0.02), Delta(4)A (P < 0.01), and T (P < 0.01) responses to human chorionic gonadotropin were greater in women with PCOM. Fasting glucose was not different between the two groups, but fasting insulin was higher (P < 0.02) in PCOM women as was insulin resistance calculated from homeostatic model assessment (P < 0.01). These studies demonstrate that PCOM in nonhirsute women with documented ovulatory cycles is associated with normal E(2), P(4), and gonadotropin dynamics, but higher androgen and insulin levels and lower SHBG levels. Taken together, these findings suggest that PCOM with ovulatory cycles exists as a discrete entity, represents the mildest form of ovarian hyperandrogenism, and is associated with greater insulin resistance than in women with normal ovarian morphology. The absence of any neuroendocrine abnormality in women with PCOM and ovulatory cycles suggests that gonadotropin dysfunction is not required for increased androgen secretion, but may be critical for development of the anovulatory disorder associated with PCOS.

Joffe, Hadine MD, MSc; Hall, Janet E. MD; Cohen, Lee S. MD; Taylor, Ann E. MD; Baldessarini, Ross J. MD Author Information

Background: Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain.Objective and Methods: This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle, (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy (n = 119) with those on valproate monotherapy (n = 103) for <5 years.Results: Mean total serum testosterone and androstenedione levels were higher (P < 0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher (P < 0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels (P < 0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg,Conclusions: Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility. (C) 2003 Elsevier Science B.V. All rights reserved.

Purpose. Although interest in supporting clinical investigators is increasing, information regarding the quantity, spectrum, and specific types of clinical research performed in academic health centers (AHCs) is generally not available. The authors report on an instrument to quantify the National Institutes of Health (NIH)-funded component of clinical research at one institution.Method. A systematic review of all NIH grants awarded to Massachusetts General Hospital (MGH) in fiscal year (FY) 1997-98 was performed using public information from two NIH Internet sources. Research abstracts from all 487 grants were reviewed and the percentage and type of clinical research activity within each was estimated and compared with estimates provided by a subset of principal investigators.Results. During FY 1997-98, the NIGH received $134 million in total NIH funding; $39.9 million (30%) supported the broadest definition of clinical research (that using human materials). When the definition of clinical research was narrowed to direct interaction between investigator and patient for investigative purposes (patient-oriented research), the total for clinical research was $18.2 million. These numbers significantly exceeded the institution's previous estimates of $.6 million for NIH-sponsored clinical trials and $2.2 million for population-based studies.Conclusions. Clinical investigation is an important component of AHCs' research portfolios from several perspectives, not the least of which is financial. Data on the clinical component of an institution's research effort should be collected prospectively and nationally to inform the optimal allocation of research resources and the alignment of the AHC's infrastructure.

Inhibin B is a product of the granulosa cells of growing preantral and antral follicles. Despite the large ovarian volume and increased follicle number typically detected in women with polycystic ovary syndrome (PCOS), previous studies demonstrate that inhibin B is not elevated as would be expected in PCOS, but is inversely correlated with body mass index (BMI). We therefore hypothesized that inhibin B levels in women with PCOS are regulated by a factor related to BMI. Thus, LH, sex steroids, and metabolic parameters were measured in 50 anovulatory PCOS subjects in pools constituted from equal aliquots of serum drawn every 10 min for 4 h and were correlated with inhibin B. Based on the results of these correlative studies, inhibin B regulation by human chorionic gonadotropin (hCG) and insulin was tested directly. In PCOS subjects, inhibin B correlated inversely with BMI (r = -0.413; P < 0.004) and fasting insulin (r = -0.409; P < 0.004). Inhibin B also correlated directly with pool LH (r = 0.419; P < 0.003), LH pulse amplitude (r = 0.512; P < 0.0001), and SHBG (r = 0.429; P < 0.003). The relationships demonstrated for inhibin B were not demonstrated for inhibin A, nor were they evident in normal subjects. To determine whether the correlations represent regulation of inhibin B, i.e. stimulation of inhibin B by LH or suppression by insulin, two interventional studies were performed. In the first study hCG (5000 U) was administered to PCOS subjects (n = 15) to mimic the effects of LH. Inhibin B was not increased, but was significantly reduced 24 h after hCG administration (223.8 +/- 21.3 vs. 152.4 +/- 15.9 pg/ml; P < 0.0005). In the second study, diazoxide (100 mg every 8 h) was administered for 3 d to PCOS subjects (n = 9). Inhibin B increased (85.4 +/- 12.4 to 136.6 +/- 18.8 pg/ml; P < 0.05) in association with a decrease in the insulin area under the curve (104 +/- 29 to 83 +/- 22 nmol/liter.min; P < 0.05) induced by diazoxide. In PCOS subjects, inhibin B demonstrated significant relationships with BMI and factors related to BMI, including LH, insulin, and SHBG. Although LH was associated with inhibin B, hCG administration suppressed inhibin B secretion after 24 h, whereas short-term insulin suppression increased inhibin B. These findings suggest that both increased LH and insulin may account for the relative suppression of inhibin B in patients with PCOS.