Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. OBJECTIVE: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. RESULTS: The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. CONCLUSION: The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.

Navigating Complexities: Vitamin D, Skin Pigmentation, and Race.

Vitamin D plays a critical role in many physiological functions, including calcium metabolism and musculoskeletal health. This commentary aims to explore the intricate relationships among skin complexion, race, and 25-hydroxyvitamin D (25[OH]D) levels, focusing on challenges the Endocrine Society encountered during clinical practice guideline development. Given that increased melanin content reduces 25(OH)D production in the skin in response to UV light, the guideline development panel addressed the potential role for 25(OH)D screening in individuals with dark skin complexion. The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants' skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations. Lessons learned from the guideline development process emphasize the necessity of clarity when incorporating race and ethnicity into clinical guidelines. Such clarity is an essential step toward improving health outcomes and ensuring equitable healthcare practices.

Vitamin D Insufficiency and Epistemic Humility: An Endocrine Society Guideline Communication.

A long-held precept is that vitamin D supplementation primarily, if not exclusively, benefits individuals with low circulating 25-hydroxyvitamin D (25[OH]D) concentrations at baseline. However, the most appropriate 25(OH)D threshold to distinguish unacceptably low vs reliably adequate concentrations remains controversial. Such threshold proposals have largely been based on observational studies, which provide less robust evidence compared to randomized clinical trials (RCTs). Since the Endocrine Society's first vitamin D-related guideline was published in 2011, several large vitamin D-related RCTs have been published, and a newly commissioned guideline development panel (GDP) prioritized 4 clinical questions related to the benefits and harms of vitamin D supplementation in generally healthy individuals with 25(OH)D levels below a threshold. The GDP determined that available clinical trial evidence does not permit the establishment of 25(OH)D thresholds that specifically predict meaningful benefit with vitamin D supplementation. The panel noted important limitations in the available evidence, and the panel's overall certainty in the available evidence was very low. Nonetheless, based on the GDP's analyses and judgments, the Endocrine Society no longer endorses its previously proposed definition of vitamin D "sufficiency" (ie, at least 30 ng/mL [75 nmol/L]) or its previously proposed definition of vitamin D "insufficiency" (ie, greater than 20 ng/mL [50 nmol/L] but lower than 30 ng/mL [75 nmol/L]). The Endocrine Society's rationale for such is the subject of this Guideline Communication.

Spironolactone metabolite causes falsely increased progesterone in the Abbott Architect immunoassay.

BACKGROUND: Immunoassays are important for routine clinical testing and medical diagnosis. However, they are limited by cross-reactivity especially at low analyte concentrations. There is a critical need to investigate compounds that can interfere with immunoassays. Herein, we describe the identification of canrenone, a spironolactone metabolite that falsely increases progesterone concentrations on the Abbott Architect i2000 Immunoassay. METHODS: Serum samples and assay diluents were spiked with spironolactone or canrenone and progesterone concentrations were measured on the Architect i2000 and Immulite XPi immunoassay platforms. Blood samples from patients taking spironolactone were analyzed with liquid chromatography-tandem mass spectrometry to evaluate the intrinsic response of progesterone concentrations to the presence of canrenone. RESULTS: We measured approximately 10-fold higher progesterone concentrations on the Abbott Architect i2000 compared to reference immunoassay analyzers (Siemens Immulite XPi and Roche Cobas e601/602), suggesting an analytical error which is unique to the Architect i2000 antibody and/or assay conditions. By measuring serum progesterone after addition of spironolactone or canrenone to serum samples, we found that canrenone falsely increased progesterone on the Architect i2000 immunoassay. However, this interference was more pronounced at low serum progesterone concentrations. Moreover, a strong positive correlation was seen between canrenone and measured serum progesterone concentrations. CONCLUSIONS: Our investigations are important for individuals who require progesterone measurements using the Architect i2000 immunoassay, especially because it is unlikely for clinicians to order canrenone measurements alongside progesterone measurements for individuals taking spironolactone. Further research is needed to determine whether canrenone can influence progesterone measurements on other immunoassay systems.

Enhancing the Trustworthiness of the Endocrine Society's Clinical Practice Guidelines.

In an effort to enhance the trustworthiness of its clinical practice guidelines, the Endocrine Society has recently adopted new policies and more rigorous methodologies for its guideline program. In this Clinical Practice Guideline Communication, we describe these recent enhancements-many of which reflect greater adherence to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to guideline development-in addition to the rationale for such changes. Improvements to the Society's guideline development practices include, but are not limited to, enhanced inclusion of nonendocrinologist experts, including patient representatives, on guideline development panels; implementation of a more rigorous conflict/duality of interest policy; a requirement that all formal recommendations must be demonstrably underpinned by systematic evidence review; the explicit use of GRADE Evidence-to-Decision frameworks; greater use and explanation of standardized guideline language; and a more intentional approach to guideline updating. Lastly, we describe some of the experiential differences our guideline readers are most likely to notice.

Acute progesterone feedback on gonadotropin secretion is not demonstrably altered in estradiol-pretreated women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) demonstrate gonadotropin-releasing hormone (GnRH) pulse generator resistance to suppression with 7 days of progesterone and estradiol administration. It remains unknown whether such women demonstrate impairments in acute progesterone negative feedback on LH pulse frequency or progesterone positive feedback on gonadotropin release. This was a randomized, double-blind, placebo-controlled crossover study designed to test the hypothesis that acute, progesterone-related suppression of LH pulse frequency and progesterone-related augmentation of gonadotropin release are impaired in PCOS. Twelve normally cycling women and 12 women with PCOS completed study. Volunteers were pretreated with transdermal estradiol (0.2 mg/day) for 3 days and then underwent a frequent blood sampling study (20:00-20:00 h), during which they received micronized progesterone (100 mg) or placebo at 06:00 h. In a second study admission, volunteers received the intervention they did not receive during the first admission, but the protocol was otherwise identical. The primary outcome measures were LH secretory characteristics and circulating gonadotropin concentrations. Exogenous progesterone did not reduce LH pulse frequency in either group. Mean LH, pulsatile LH secretion, LH pulse mass, and mean FSH increased more with progesterone compared to placebo in both groups. Although trends toward less pronounced changes in LH pulse mass and pulsatile LH secretion were observed in the PCOS group, these differences were not statistically significant. In summary, exogenous progesterone did not suppress LH pulse frequency within 12 hours in estradiol-pretreated women, and the positive feedback effect of progesterone on gonadotropin release was not demonstrably impaired in PCOS. NEW & NOTEWORTHY: This study indicated that exogenous progesterone does not reduce LH pulse frequency within 12 h in women with PCOS, but progesterone acutely increased gonadotropin in these women. This study suggested that progesterone-related augmentation of gonadotropin release may be impaired in PCOS compared to normally cycling women, but this finding was not statistically significant.

Non-PCOS Hyperandrogenic Disorders in Adolescents.

Hyperandrogenism-clinical features resulting from increased androgen production and/or action-is not uncommon in peripubertal girls. Hyperandrogenism affects 3 to 20% of adolescent girls and often is associated with hyperandrogenemia. In prepubertal girls, the most common etiologies of androgen excess are premature adrenarche (60%) and congenital adrenal hyperplasia (CAH; 4%). In pubertal girls, polycystic ovary syndrome (PCOS; 20-40%) and CAH (14%) are the most common diagnoses related to androgen excess. Androgen-secreting ovarian or adrenal tumors are rare (0.2%). Early pubic hair, acne, and/or hirsutism are the most common clinical manifestations, but signs of overt virilization in adolescent girls-rapid progression of pubic hair or hirsutism, clitoromegaly, voice deepening, severe cystic acne, growth acceleration, increased muscle mass, and bone age advancement past height age-should prompt detailed evaluation. This article addresses the clinical manifestations of and management considerations for non-PCOS-related hyperandrogenism in adolescent girls. We propose an algorithm to aid diagnostic evaluation of androgen excess in this specific patient population.

The role of gonadotropin-releasing hormone neurons in polycystic ovary syndrome.

Given the critical central role of gonadotropin-releasing hormone (GnRH) neurons in fertility, it is not surprising that the GnRH neural network is implicated in the pathology of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility. Although many symptoms of PCOS relate most proximately to ovarian dysfunction, the central reproductive neuroendocrine system ultimately drives ovarian function through its regulation of anterior pituitary gonadotropin release. The typical cyclical changes in frequency of GnRH release are often absent in women with PCOS, resulting in a persistent high-frequency drive promoting gonadotropin changes (i.e., relatively high luteinizing hormone and relatively low follicle-stimulating hormone concentrations) that contribute to ovarian hyperandrogenemia and ovulatory dysfunction. However, the specific mechanisms underpinning GnRH neuron dysfunction in PCOS remain unclear. Here, we summarize several preclinical and clinical studies that explore the causes of aberrant GnRH secretion in PCOS and the role of disordered GnRH secretion in PCOS pathophysiology.

Polycystic Ovary Syndrome: Ontogeny in Adolescence.

The pathophysiology of symptomatic polycystic ovary syndrome (PCOS) often unfolds across puberty, but the ontogeny of PCOS is difficult to study because, in general, its pathophysiology is well entrenched before the diagnosis can be confirmed. However, the study of high-risk groups (daughters of women with PCOS, girls with premature pubarche, and girls with obesity) can offer insight in this regard. Available data support the hypothesis that the pubertal development of PCOS involves various combinations of genetic predisposition, intrauterine programming, hyperinsulinism, and numerous other abnormalities that provoke reproductive symptoms (eg, hyperandrogenism, ovulatory dysfunction) in response to the pubertal increase in gonadotropin secretion.

Abnormal GnRH Pulsatility in Polycystic Ovary Syndrome: Recent Insights.

Although the fundamental symptoms of polycystic ovary syndrome (PCOS) relate most directly to ovarian dysfunction, central neuroendocrine systems play a prominent role in its pathophysiology. Gonadotropin-releasing hormone (GnRH) pulse generator resistance to negative feedback contributes to rapid GnRH pulse secretion, which promotes gonadotropin abnormalities that foster ovarian hyperandrogenemia and ovulatory dysfunction. The causes of GnRH neuron dysfunction, however, have remained enigmatic. In this review, we highlight a number of recent preclinical and clinical studies pertinent to the neuroendocrine abnormalities of PCOS, including those that have provided important insights into the relevance of animal models with PCOS-like features, the potential roles of kisspeptin and γ-aminobutyric acid (GABA)-ergic neurons, and the potential role of anti-Müllerian hormone.

Conflicts of Interest in Clinical Practice Guidelines: Accelerating an Evolution. An Endocrine Society Consensus Statement.

An analysis of the Endocrine Society's clinical practice guidelines (CPGs) published from 2010 to 2017-presented by Irwig et al. in the current issue of The Journal of Endocrinology and Metabolism-suggested that the Endocrine Society met five of seven National Academy of Medicine (NAM) standards concerning financial conflicts of interest in CPGs. As current contributors to the Endocrine Society's CPG efforts, we offer additional context related to the 2011 NAM standards and the current environment concerning industry support in medicine, and we comment on the nature of industry support received by the Society's CPG authors according to Irwig and colleagues' analysis of the Centers for Medicare and Medicaid Services' Open Payments database. Perhaps most importantly, we outline the Society's recent and ongoing efforts to enhance the value of its CPGs. Such efforts include a 2016 revision of CPG author conflict of interest rules-a change that was invisible to the investigatory methods used by Irwig et al.-in addition to other processes designed to enhance CPG objectivity. We conclude our commentary by recognizing that good-faith attempts to enhance transparency and to reduce conflicts of interest (real or apparent) in CPGs will ultimately serve the best interests of patients and providers; we confirm the Endocrine Society's resolute commitment to providing high-quality, evidence-based clinical guidance via a CPG development process that faithfully accords with current CPG best practices.

Estimating testosterone concentrations in adolescent girls: Comparison of two direct immunoassays to liquid chromatography-tandem mass spectrometry.

CONTEXT: The appropriate role of direct total testosterone (T) immunoassays in reproductive research is controversial. OBJECTIVE: To assess the concordance between two direct immunoassays and a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for total T in adolescent girls with measured concentrations < 50 ng/dl. DESIGN: Cross-sectional analysis. SETTING: Academic medical center. PARTICIPANTS: Adolescent girls (age 8.4-18.1 years) participating in clinical research protocols. INTERVENTION: Paired blood samples were obtained for total T by LC-MS/MS (n = 66; Mayo Clinic Laboratory) and by direct immunoassay (Center for Research in Reproduction)-either radioimmunoassay (RIA; n = 31) or chemiluminescence immunoassay (CLIA; n = 35). At the time of assay, laboratories were unaware that results would be compared. MAIN OUTCOME MEASURE: Measurement agreement between immunoassay and LC-MS/MS. RESULTS: Measured T concentrations (LC-MS/MS) were <7 to 44 ng/dl. The average difference between RIA and LC-MS/MS was 0.84 [-0.89, 2.56] ng/dl (mean [95% confidence interval]). RIA correlated very strongly with LC-MS/MS (r = 0.899; p < 0.0001); and both Deming regression and Bland-Altman analysis suggested no bias. The average difference between chemiluminescence and LC-MS/MS was 1.39 [-0.83, 3.60] ng/dl. CLIA correlated strongly with LC-MS/MS (r = 0.806; p < 0.0001). While Bland-Altman analysis suggested no systematic bias, Deming regression analysis suggested that, as measured values increased, values obtained by CLIA tended to be progressively, albeit only modestly, higher than those obtained by LC-MS/MS. CONCLUSIONS: These data support the use of rigorously-performed and carefully-validated direct T immunoassays in high-quality endocrine research in peripubertal adolescent girls.

Insulin Resistance, Hyperinsulinemia, and LH: Relative Roles in Peripubertal Obesity-Associated Hyperandrogenemia.

Context: Peripubertal obesity is associated with variable hyperandrogenemia, but precise mechanisms remain unclear. Objective: To assess insulin resistance, hyperinsulinemia, and LH roles in peripubertal obesity-associated hyperandrogenemia. Design: Cross-sectional analysis. Setting: Academic clinical research unit. Participants: Eleven obese (body mass index for age ≥95%) peripubertal girls. Intervention: Blood samples were taken during a mixed-meal tolerance test (1900 to 2100), overnight (2100 to 0700), while fasting (0700 to 0900), and during an 80 mU/m2/min hyperinsulinemic-euglycemic clamp (0900 to 1100). Main Outcome Measures: The dependent variable was morning free testosterone level; independent variables were insulin sensitivity index (ISI), estimated 24-hour insulin, and estimated 24-hour LH levels. Results: All participants demonstrated insulin resistance and hyperinsulinemia. ISI, but not estimated 24-hour insulin level, correlated positively with morning free testosterone level when correcting for estimated 24-hour LH level and Tanner stage (rs = 0.68, P = 0.046). The correlation between estimated 24-hour LH and free testosterone levels approached significance after adjusting for estimated 24-hour insulin level and Tanner stage (rs = 0.63, P = 0.067). Estimated 24-hour insulin level did not correlate with free testosterone level after adjusting for estimated 24-hour LH level and Tanner stage (rs = 0.47, P = 0.20). Conclusion: In insulin-resistant obese girls with hyperinsulinemia, free testosterone levels correlated positively with insulin sensitivity and, likely, circulating LH concentrations but not with circulating insulin levels. In the setting of relatively uniform hyperinsulinemia, variable steroidogenic-cell insulin sensitivity may correlate with metabolic insulin sensitivity and contribute to variable free testosterone concentrations.

Progesterone administration does not acutely alter LH pulse secretion in the mid-follicular phase in women.

It remains unclear how rapidly progesterone suppresses luteinizing hormone (LH) pulse frequency in women. Previous studies suggested that progesterone markedly increases LH pulse amplitude but does not slow LH pulse frequency within 10 h in estradiol-pretreated women studied during the late follicular phase. However, this experimental paradigm may be a model of preovulatory physiology, and progesterone may have different effects at other times of the cycle. We studied regularly cycling, nonobese women without hyperandrogenism to assess the acute effect of progesterone during the midfollicular phase and in the absence of estradiol pretreatment. The study involved two admissions in separate cycles (cycle days 5-9). For each admission, either oral micronized progesterone (100 mg) or placebo was administered at 0900 h in a randomized, double-blind fashion. Frequent blood sampling was performed between 0900 and 1900 h to define 10-h LH pulsatility. Treatment crossover (placebo exchanged for progesterone and vice versa) occurred in a subsequent cycle. After an interim futility analysis, the study was halted after 7 women completed study. Mean progesterone concentrations after placebo and progesterone administration were 0.5 ± 0.1 (mean ± SD) and 6.7 ± 1.6 ng/mL, respectively. Compared to placebo, progesterone was not associated with a significant difference in 10-h LH pulse frequency (0.79 ± 0.35 vs. 0.77 ± 0.28 pulses/h, P = 1.0) or amplitude (3.6 ± 2.8 vs. 4.3 ± 2.8 IU/L, P = 0.30). This study suggests that LH pulse frequency is not rapidly influenced by progesterone administration during the midfollicular phase.

Influence of Sleep Stage on LH Pulse Initiation in the Normal Late Follicular Phase and in Polycystic Ovary Syndrome.

OBJECTIVE: During the early follicular phase, sleep-related luteinizing hormone (LH) pulse initiation is positively associated with brief awakenings but negatively associated with rapid eye movement (REM) sleep. The relationship between sleep architecture and LH pulse initiation has not been assessed in other cycle stages or in women with polycystic ovary syndrome (PCOS). DESIGN AND METHODS: We performed concomitant frequent blood sampling (LH pulse analysis) and polysomnography on 8 normal women (cycle day 7-11) and 7 women with PCOS (at least cycle day 7). RESULTS: In the normal women, the 5 min preceding LH pulses contained more wake epochs and fewer REM epochs than the 5 min preceding randomly determined time points (wake: 22.3 vs. 9.1%, p = 0.0111; REM: 4.4 vs. 18.8%, p = 0.0162). However, LH pulse initiation was not related to wake or REM epochs in PCOS; instead, the 5 min preceding LH pulses contained more slow-wave sleep (SWS) than the 5 min before random time points (20.9 vs. 6.7%, p = 0.0089). Compared to the normal subjects, the women with PCOS exhibited a higher REM-associated LH pulse frequency (p = 0.0443) and a lower proportion of wake epochs 0-5 min before LH pulses (p = 0.0205). CONCLUSIONS: Sleep-related inhibition of LH pulse generation during the later follicular phase is normally weakened by brief awakenings and strengthened by REM sleep. In women with PCOS, LH pulse initiation is not appropriately discouraged by REM sleep and may be encouraged by SWS; these abnormalities may contribute to a high sleep-related LH pulse frequency in PCOS.

Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status.

Context: During normal, early puberty, luteinizing hormone (LH) pulse frequency is low while awake but increases during sleep. Mechanisms underlying such changes are unclear, but a small study in early pubertal girls suggested that differential wake-sleep sensitivity to progesterone negative feedback plays a role. Objective: To test the hypothesis that progesterone acutely reduces waking LH pulse frequency more than sleep-associated pulse frequency in late pubertal girls. Design: Randomized, placebo-controlled, double-blinded crossover study. Setting: Academic clinical research unit. Participants: Eleven normal, postmenarcheal girls, ages 12 to 15 years. Intervention: Subjects completed two 18-hour admissions in separate menstrual cycles (cycle days 6 to 11). Frequent blood sampling for LH assessment was performed at 1800 to 1200 hours; sleep was encouraged at 2300 to 0700 hours. Either oral micronized progesterone (0.8 mg/kg/dose) or placebo was given at 0700, 1500, 2300, and 0700 hours, before and during the first admission. A second admission, performed at least 2 months later, was identical to the first except that placebo was exchanged for progesterone or vice versa (treatment crossover). Main Outcome Measures: LH pulse frequency during waking and sleeping hours. Results: Progesterone reduced waking LH pulse frequency by 26% (P = 0.019), with no change observed during sleep (P = 0.314). The interaction between treatment condition (progesterone vs placebo) and sleep status (wake vs sleep) was highly significant (P = 0.007). Conclusions: In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.

Progesterone Suppression of Luteinizing Hormone Pulse Frequency in Adolescent Girls With Hyperandrogenism: Effects of Metformin.

Context: Polycystic ovary syndrome (PCOS) and adolescent hyperandrogenism (HA) are characterized by rapid luteinizing hormone (LH) pulse frequency. This partly reflects impaired gonadotropin-releasing hormone pulse generator (hypothalamic) sensitivity to progesterone (P4) negative feedback. We assessed whether metformin may improve P4 sensitivity in adolescent HA, for which it is prescribed widely. Objective: To test the hypothesis that metformin improves hypothalamic P4 sensitivity in adolescent HA. Design: Nonrandomized, interventional trial. Setting: Academic clinical research unit. Participants: Ten adolescent girls with HA. Intervention: The girls underwent LH sampling every 10 minutes for 11 hours, at study baseline and after 7 days of oral P4 and estradiol (E2). Participants then took metformin (1 g twice daily) for 9.4 to 13.7 weeks, after which participants again underwent frequent LH sampling before and after 7 days of oral P4 and E2 (while continuing metformin). Total and free testosterone (T) and fasting insulin were assessed at each admission. At admissions 1 and 3, 2-hour oral glucose tolerance tests were performed. Main Outcome Measure: Metformin-related change in hypothalamic P4 sensitivity index [percent change in LH pulse frequency (before vs after P4 and E2) divided by day 7 P4 level]. Results: Free T levels decreased by 29% with metformin (P = 0.0137). Measures of hyperinsulinemia and P4 sensitivity index did not significantly change with metformin use. Conclusion: Short-term metformin use improved biochemical hyperandrogenemia, but did not improve hypothalamic sensitivity to P4 suppression, in adolescent girls.