The Search for the Causes of Common Hyperandrogenism, 1965 to circa 2015.

From 1965-2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology; insulin resistance, hyperinsulinism, type 2 diabetes mellitus; folliculogenesis; androgen secretion; obesity; phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicates that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and pro-inflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in one-quarter of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.

Normal and Premature Adrenarche.

Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory response to adrenocorticotropin (ACTH) that are best indexed by dehydroepiandrosterone sulfate (DHEAS) rise. These changes are related to the development of the zona reticularis (ZR) and its unique gene/enzyme expression pattern of low 3ß-hydroxysteroid dehydrogenase type 2 with high cytochrome b5A, sulfotransferase 2A1, and 17ß-hydroxysteroid dehydrogenase type 5. Recently 11-ketotestosterone was identified as an important bioactive adrenarchal androgen. Birth weight, body growth, obesity, and prolactin are related to ZR development. Adrenarchal androgens normally contribute to the onset of sexual pubic hair (pubarche) and sebaceous and apocrine gland development. Premature adrenarche causes ≥90% of premature pubarche (PP). Its cause is unknown. Affected children have a significantly increased growth rate with proportionate bone age advancement that typically does not compromise growth potential. Serum DHEAS and testosterone levels increase to levels normal for early female puberty. It is associated with mildly increased risks for obesity, insulin resistance, and possibly mood disorder and polycystic ovary syndrome. Between 5% and 10% of PP is due to virilizing disorders, which are usually characterized by more rapid advancement of pubarche and compromise of adult height potential than premature adrenarche. Most cases are due to nonclassic congenital adrenal hyperplasia. Algorithms are presented for the differential diagnosis of PP. This review highlights recent advances in molecular genetic and developmental biologic understanding of ZR development and insights into adrenarche emanating from mass spectrometric steroid assays.

Letter to the Editor: "Glucocorticoid Resistance in Premature Adrenarche and PCOS: From Childhood to Adulthood".

The conclusion of Panayiotopoulos et al. that glucocorticoid resistance accounted for 57% to 67% of their premature adrenarche and polycystic ovary syndrome cases cannot be accepted from the data presented. This is because proper validation of their method for determining glucocorticoid sensitivity is not presented. Furthermore, the method seems insensitive to physiologic glucocorticoid concentrations.

Current concepts of polycystic ovary syndrome pathogenesis.

PURPOSE OF REVIEW: This review provides a model for understanding polycystic ovary syndrome (PCOS) pathophysiology and updates the evidence on which it is based. Then, it highlights complimentary molecular genetic and epigenetic advances in understanding PCOS cause. RECENT FINDINGS: Important studies into PCOS cause built on the 2014 discovery of a novel regulatory protein variant that underlies the typical PCOS steroidogenic abnormalities: DENND1A.V2 (differentially expressed in normal and neoplastic development, isoform 1A, variant 2). Over 30 DENND1A gene variants have been found, the vast majority upstream of the coding sequence and potentially regulatory. These variants are individually uncommon but collectively plausibly cause 50% of PCOS. Anti-Müllerian hormone (AMH)/AMH receptor variants with decreased function possibly cause 6.7% of PCOS. DENNND1A was recently reported to belong to a signaling network that upregulates luteinizing hormone receptor expression and insulin mitogenic signaling. Prenatal androgen administration has proven to be a potent epigenetic regulator that causes transgenerational epigenomic changes in a mouse PCOS model with similarities to those in human PCOS and PCOS daughters. SUMMARY: In addition to finding how gene variants contribute to PCOS pathogenesis, better understanding of androgen epigenetic mechanisms of action in diverse tissues can be expected to expand our understanding of PCOS pathogenesis.

Perspectives on the International Recommendations for the Diagnosis and Treatment of Polycystic Ovary Syndrome in Adolescence.

Recommendations have been provided for the diagnosis and therapy of polycystic ovary syndrome in adolescence from 3 international expert conferences 2015-2018. Despite agreement about essentials, differences among details of these recommendations have engendered confusion. This commentary provides perspective about the agreements and disagreements among these recommendations and how these recommendations relate to other guidance. It concludes with practice suggestions that align with these recommendations.

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.

Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations.

Context: Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied. Evidence Acquisition: We conducted a systematic search of PubMed for studies related to TS and puberty. Evidence Synthesis: The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement. Conclusion: Evidence supports the effectiveness of starting pubertal estrogen replacement with low-dose transdermal E2. When transdermal E2 is unavailable or the patient prefers, evidence supports use of oral micronized E2 or an intramuscular preparation. Only when these are unavailable should ethinyl E2 be prescribed. We recommend against the use of conjugated estrogens. Once progestin is added, many women prefer the ease of use of a pill containing both an estrogen and a progestin. The risks and benefits of different types of preparations, with examples, are discussed.

The Effect of the Testis on the Ovary: Structure-Function Relationships in a Neonate with a Unilateral Ovotestis (Ovotesticular Disorder of Sex Development)
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AIMS: To evaluate gonadal function in a newborn with suspected ovotesticular disorder of sex development (DSD). METHODS: Gonadal function was evaluated at baseline and after gonadotropin-releasing hormone agonist (GnRHag) stimulation testing. RESULTS: A full-term 46,XX neonate with genital ambiguity produced serum testosterone and anti-Müllerian hormone (AMH) levels appropriate for males within days, while serum estradiol remained prepubertal, both spontaneously and in response to GnRHag stimulation testing. Ovotesticular DSD was diagnosed at laparoscopy: the left gonad was an ovotestis and the right gonad an ovary arrested at the primordial follicle stage of development. Mosaicism for an isochromosome of the Y short arm in 6-18% of gonadal cells was demonstrated. After ovotestis removal at 3 weeks of age, serum AMH became low within a month, but the elevated testosterone was slow to resolve, apparently from ovarian androgenic hyperfunction coincident with ovarian estrogenic hyperfunction and an adult degree of ovarian development. Ovarian morphology and function gradually normalized as neonatal minipuberty waned. CONCLUSIONS: In a neonate with genital ambiguity due to ovotesticular DSD, testicular AMH and testosterone production respectively appear to account for the initial arrest of ovarian development and subsequent rapid hyperfunction of the contralateral ovary after ovotestis removal.
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The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.

The Diagnosis of Polycystic Ovary Syndrome in Adolescents.

Consensus has recently been reached by international pediatric subspecialty societies that otherwise unexplained persistent hyperandrogenic anovulation using age- and stage-appropriate standards are appropriate diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescents. The purpose of this review is to summarize these recommendations and discuss their basis and implications. Anovulation is indicated by abnormal uterine bleeding, which exists when menstrual cycle length is outside the normal range or bleeding is excessive: cycles outside 19 to 90 days are always abnormal, and most are 21 to 45 days even during the first postmenarcheal year. Continued menstrual abnormality in a hyperandrogenic adolescent for 1 year prognosticates at least 50% risk of persistence. Hyperandrogenism is best indicated by persistent elevation of serum testosterone above adult norms as determined in a reliable reference laboratory. Because hyperandrogenemia documentation can be problematic, moderate-severe hirsutism constitutes clinical evidence of hyperandrogenism. Moderate-severe inflammatory acne vulgaris unresponsive to topical treatment is an indication to test for hyperandrogenemia. Treatment of PCOS is symptom-directed. Cyclic estrogen-progestin oral contraceptives are ordinarily the preferred first-line medical treatment because they reliably improve both the menstrual abnormality and hyperandrogenism. First-line treatment of the comorbidities of obesity and insulin resistance is lifestyle modification with calorie restriction and increased exercise. Metformin in conjunction with behavior modification is indicated for glucose intolerance. Although persistence of hyperandrogenic anovulation for ≥2 years ensures the distinction of PCOS from physiologic anovulation, early workup is advisable to make a provisional diagnosis so that combined oral contraceptive treatment, which will mask diagnosis by suppressing hyperandrogenemia, is not unnecessarily delayed.

Commentary: Launch of a quality improvement network for evidence-based management of uncommon pediatric endocrine disorders: Turner syndrome as a prototype.

BACKGROUND: Traditional, hypothesis-oriented research approaches have thus far failed to generate sufficient evidence to achieve consensus about the management of children with many endocrine disorders, partly because of the rarity of these disorders and because of regulatory burdens unique to research in children. OBJECTIVE: The Pediatric Endocrine Society is launching a quality improvement network in spring 2015 for the management of pediatric endocrine disorders that are relatively uncommon in any single practice and/or for which there is no consensus on management. DESIGN: The first of the quality improvement programs to be implemented seeks to improve the care of 11- to 17-year-old girls with Turner syndrome who require initiation of estrogen replacement therapy by providing a standardized clinical assessment and management plan (SCAMP) for transdermal estradiol treatment to induce pubertal development. The SCAMP algorithm represents a starting point within current best practice that is meant to undergo refinement through an iterative process of analysis of deidentified data collected in the course of clinical care by a network of pediatric endocrinologists. CONCLUSION: It is anticipated that this program will not only improve care, but will also result in actionable data that will generate new research hypotheses and changes in management of pediatric endocrine disorders.

The Diagnosis of Polycystic Ovary Syndrome during Adolescence.

BACKGROUND/AIMS: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents. METHODS: The literature has been reviewed and evidence graded to address a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligo-anovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention. RESULTS AND CONCLUSION: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls. © 2015 S. Karger AG, Basel.

The Polycystic Ovary Morphology-Polycystic Ovary Syndrome Spectrum.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of chronic hyperandrogenic anovulation. Two-thirds of PCOS patients have functionally typical PCOS, with typical functional ovarian hyperandrogenism manifest as 17-hydroxyprogesterone hyper-responsiveness to gonadotropin stimulation. Most, but not all, of the remainder have atypical functional ovarian hyperandrogenism. Many asymptomatic volunteers with polycystic ovary morphology (PCOM) have similar abnormalities. OBJECTIVE: The objective of this paper is to review the relationship of biochemical ovarian function to the clinical spectrum observed in PCOS and in normal volunteers with PCOM. FINDINGS: Adolescents and adults with PCOS are similar clinically and biochemically. Ninety-five percent of functionally typical PCOS have classic PCOS, ie, hyperandrogenic anovulation with PCOM. In addition to having more severe hyperandrogenism and a greater prevalence of PCOM than other PCOS, they have a significantly greater prevalence of glucose intolerance although insulin resistance is similarly reduced. Half of normal-variant PCOM have PCOS-related steroidogenic dysfunction, which suggests a PCOS carrier state. CONCLUSIONS: There is a spectrum of ovarian androgenic dysfunction that ranges from subclinical hyperandrogenemia in some normal-variant PCOM to severe ovarian hyperandrogenism in most classic PCOS. A minority of mild PCOS cases do not fall on this spectrum of ovarian androgenic dysfunction, but rather seem to have obesity as the basis of their hyperandrogenism, or, less often, isolated adrenal androgenic dysfunction. Half of normal-variant PCOM also do not fall on the PCOS spectrum, and some of these seem to have excessive folliculogenesis as a variant that may confer mild prolongation of the reproductive lifespan. Improved understanding of PCOM in young women is needed.

Adolescent polycystic ovary syndrome due to functional ovarian hyperandrogenism persists into adulthood.

BACKGROUND: Menstrual irregularity and above-average testosterone levels in adolescence may presage polycystic ovary syndrome (PCOS) in adulthood but persist in only a minority. Prolonged anovulatory cycles in normal adolescents are associated with increased testosterone levels. Thus, questions have been raised about the accuracy of PCOS diagnosed in adolescents. OBJECTIVE: The purpose of this study was to follow-up hyperandrogenic adolescents with features of PCOS to test the hypothesis that adolescent functional ovarian hyperandrogenism (FOH) persists into adulthood. STUDY SUBJECTS: A series of adults previously reported to have adolescent PCOS, with most documented to have FOH by GnRH agonist or dexamethasone androgen-suppression test criteria, were recalled. METHODS: Recall occurred >3 years after the initial diagnosis and at the age of >18.0 years. Respondents underwent examination, baseline androgen evaluation, and an oral glucose tolerance test after discontinuing oral contraceptive therapy. RESULTS: Of the adolescent hyperandrogenic patients, 68% (15 of 22) were traceable, and 60% of those traced returned for follow-up, including half (n = 8) of the original FOH group. The baseline characteristics of respondents and nonrespondents were not significantly different. Patients with FOH were reevaluated when their mean age was 23.0 years (range, 18.4-29.4 years), gynecologic age was 10.7 years (range, 5.5-18.4 years), and body mass index was 42.3 kg/m(2) (range, 28.3-52.1 kg/m(2); P = .02 vs adolescence). Serum free testosterone was 24 pg/mL (range, 10-38 pg/mL, normal, 3-9 pg/mL; not significant vs adolescence); all were oligomenorrheic. Whereas 3 of 8 had impaired glucose tolerance as adolescents, at follow-up 6 of 8 had developed abnormal glucose tolerance (2 with type 2 diabetes mellitus). CONCLUSIONS: Adolescents with FOH, which underlies most PCOS, uniformly have persistent hyperandrogenism, and glucose tolerance tends to deteriorate. Testing ovarian androgenic function in hyperandrogenic adolescents may be of prognostic value.

Clinical review: Adolescent anovulation: maturational mechanisms and implications.

CONTEXT: Adolescents are at high risk for menstrual dysfunction. The diagnosis of anovulatory disorders that may have long-term health consequences is too often delayed. EVIDENCE ACQUISITION: A review of the literature in English was conducted, and data were summarized and integrated from the author's perspective. MAIN FINDINGS: Normal adolescent anovulation causes only minor menstrual cycle irregularity: most cycles range from 21-45 days, even in the first postmenarcheal year, 90% by the fourth year. Approximately half of symptomatic menstrual irregularity is due to neuroendocrine immaturity, and half is associated with increased androgen levels. The former is manifest as aluteal or short/deficient luteal phase cycles and usually resolves spontaneously. The latter seems related to polycystic ovary syndrome because adolescent androgen levels are associated with adult androgens and ovulatory dysfunction, but data are sparse. Obesity causes hyperandrogenemia and, via unclear mechanisms, seems to suppress LH; it may mimic polycystic ovary syndrome. The role of pubertal insulin resistance in physiological adolescent anovulation is unclear. High-sensitivity gonadotropin and steroid assays, the latter by specialty laboratories, are necessary for accurate diagnosis of pubertal disorders. Polycystic ovaries are a normal ultrasonographic finding in young women and are associated with nearly 2-fold increased anti-Müllerian hormone levels. Oral contraceptives are generally the first-line treatment for ongoing menstrual dysfunction, and the effects of treatment are similar among preparations. CONCLUSIONS: Menstrual cycle duration persistently outside 21-45 days in adolescents is unusual, and persistence ≥ 1 year suggests that disordered hypothalamic-pituitary-gonadal function be considered. Research is needed on the mechanisms and prognosis of adolescent anovulation.

Comparison of detection of normal puberty in girls by a hormonal sleep test and a gonadotropin-releasing hormone agonist test.

CONTEXT: The magnitude of sleep-related gonadotropin rise required to activate pubertal feminization is not established. OBJECTIVE: The objective of the study was to determine the normal relationship of pubertal hormone responses to sleep and to GnRH agonist (GnRHag) challenge across the female pubertal transition. DESIGN/SETTING: This was a prospective study in a General Clinical Research Center. PARTICIPANTS: Sixty-two healthy 6- to 13-year-old volunteer girls participated in the study. INTERVENTIONS: Interventions included overnight blood sampling followed by GnRHag (leuprolide acetate) injection. PRIMARY OUTCOME VARIABLES: The primary outcome variables included LH, FSH, and estradiol. RESULTS: LH levels rose steadily during sleep and after GnRHag throughout the prepubertal years. The LH response to sleep and GnRHag correlated well across groups (eg, r = 0.807, peak vs 4 h post-GnRHag value); however, this correlation was less robust than in boys (r = 0.964, P < .01). Sleep peak LH of 1.3 U/L or greater had 85% sensitivity and 2.1 U/L or greater 96% specificity for detecting puberty (thelarche). The LH 1-hour post-GnRHag value of 3.2 U/L or greater had 95% sensitivity and 5.5 U/L or greater 96% specificity for detecting puberty. Girls entered puberty at lower LH levels than boys. FSH levels rose day and night during the prepubertal years to reach 1.0 U/L or greater during puberty but discriminated puberty poorly. Estradiol of 34 pg/mL or greater at 20-24 hours after GnRHag was 95% sensitive and 60 pg/mL or greater was 95% specific for puberty. Thirty-six percent of overweight early pubertal girls had meager hormonal evidence of puberty. CONCLUSIONS: These data suggest that sleep-related pubertal hormone levels critical for puberty are normally reflected in the responses to GnRHag testing across the normal female pubertal transition. Inconsistencies between clinical and hormonal staging may arise from peripubertal cyclicity of neuroendocrine function and from excess adiposity.

Comparison of detection of normal puberty in boys by a hormonal sleep test and a gonadotropin-releasing hormone agonist test.

CONTEXT: The magnitude of sleep-related gonadotropin rise required to activate pubertal gonadal function is not established. OBJECTIVE: Our objective was to determine the normal relationship between sleep-related pubertal hormone levels and pituitary-testicular responsiveness to a GnRH agonist (GnRHag) test across the pubertal transition. DESIGN/SETTING AND PARTICIPANTS: We conducted a prospective study in a General Clinical Research Center with healthy 9- to 15-yr-old volunteer boys. INTERVENTIONS: INTERVENTIONS included overnight blood sampling followed by leuprolide acetate injection (10 µg/kg). PRIMARY OUTCOME VARIABLES: LH, FSH, and testosterone levels were evaluated. RESULTS: LH levels during sleep and post-GnRHag rose steadily during the late prepubertal years. Sleep peak LH correlated highly with the LH response to GnRHag across groups (r = 0.913). A sleep peak LH level of at least 3.7 U/liter predicted pubertal testicular activation with 100% accuracy. LH of at least 14.8 and at least 19.0 U/liter 4 h after GnRHag, respectively, predicted puberty with 100% sensitivity/94% specificity and 100% specificity/94% sensitivity. Overweight pubertal boys had transiently prolonged responses to GnRHag. FSH rose during both waking and sleeping hours during the prepubertal years, and all pubertal boys had an FSH level of at least 0.9 U/liter awake and at least 1.2 U/liter asleep. Sleep LH was more closely related than FSH to testicular size. CONCLUSIONS: These data suggest that a critical LH level during sleep (≥3.7 U/liter) heralds the onset of pubertal virilization and that this level is predictable by LH of at least 14.8-19 U/liter 4 h after GnRHag. These data also suggest that LH stimulation of testicular androgen production plays a role in stimulating testicular tubule growth once a critical level of FSH is achieved.

Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry.

CONTEXT: A genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry. OBJECTIVE: The objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry. DESIGN: This was a case-control study. SETTING: The study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States. PATIENTS: Cases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively. INTERVENTION: There were no interventions. MAIN OUTCOMES: Main outcomes were allele frequencies for seven variants in PCOS cases and controls. RESULTS: Two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria. CONCLUSIONS: We replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.