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.

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

From 1965 to 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 indicate that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and proinflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in 40 percent of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.

Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test.

BACKGROUND: Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A). METHODS: Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4-7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all. RESULTS: Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671-0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, P< 0.01). Glucose intolerance was absent in PCOS-A, but present in 30% of PCOS-T (P < 0.001). Most of the PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese. CONCLUSIONS: Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction.

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.

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: Our objective was to develop clinical practice guidelines for the evaluation and treatment of hirsutism in premenopausal women. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, two methodologists, and a medical writer. The Task Force received no corporate funding or remuneration. EVIDENCE: Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations, and "suggest" for weak recommendations. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and e-mail communications. The drafts prepared by the Task Force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: We suggest testing for elevated androgen levels in women with moderate or severe hirsutism or hirsutism of any degree when it is sudden in onset, rapidly progressive, or associated with other abnormalities such as menstrual dysfunction, obesity, or clitoromegaly. For women with patient-important hirsutism despite cosmetic measures, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral 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 women who choose hair removal therapy, we suggest laser/photoepilation.

Improving balance in regulatory oversight of research in children and adolescents: a clinical investigator's perspective.

The current regulatory environment, designed to protect children, imposes barriers to research in children that are a deterrent to high-quality clinical research in minors. This article summarizes the special procedures necessary to obtain approval for research in healthy children that poses more than minimal risk according to the code of federal regulations (45 CFR 46.407 and 21 CFR 50.54). The operational realities of the process are illustrated by the case of the most recent research protocol to be reviewed under these rules. The current process poses obstacles to future studies of complex research questions in children and adolescents that require unaffected controls, such as the relationship of adolescent anovulatory disorders to adult illness. It is concluded that current regulatory procedures, while protecting children, increase the potential for the neglect of important research needs of children and are a disincentive to pursuit of a career in clinical research for young clinicians. Suggestions are made for improving the balance between the need for research in children and adolescents and its regulation.

What every physician should know about polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine cause of hirsutism, acne, and pattern alopecia. It is a heterogeneous syndrome of hyperandrogenic anovulation that is typically due to intrinsic ovarian dysfunction, which is often aggravated by insulin-resistant hyperinsulinemia with its risks of diabetes mellitus and metabolic syndrome and their complications. Because there are many pitfalls to androgen assays, evaluation for hyperandrogenemia is suggested in women with moderate or severe hirsutism or hirsutism equivalents, menstrual irregularity, acanthosis nigricans, or intractable obesity. An endocrinologic work-up is necessary to rule out other hyperandrogenic disorders that require specific therapy (e.g., virilizing tumors, nonclassic congenital adrenal hyperplasia, hyperprolactinemia, and Cushing's syndrome). Ultrasonography helps in the differential diagnosis and may demonstrate the polycystic ovaries that have recently been vetted as an alternative to oligo-anovulation as a diagnostic criterion. Management of PCOS is determined by symptomatology. For those women not desiring pregnancy, the most common therapies are oral contraceptive pills, antiandrogens (contraindicated in the absence of adequate contraception), and insulin-lowering treatments (which have little effect on hirsutism).

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.

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.

Clinical review: Identifying children at risk for polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) appears to arise as a complex trait with contributions from both heritable and nonheritable factors. Polygenic influences appear to account for about 70% of the variance in pathogenesis. In view of this evidence for congenital contributions to the syndrome, childhood manifestations may be expected. OBJECTIVE: The objective has been to review the evidence that risk factors for PCOS can be recognized in childhood. DESIGN: This study consisted of screening of the PCOS literature for articles pertaining to potential childhood and adolescent antecedents. RESULTS: Congenital virilizing disorders; above average or low birth weight for gestational age; premature adrenarche, particularly exaggerated adrenarche; atypical sexual precocity; or intractable obesity with acanthosis nigricans, metabolic syndrome, and pseudo-Cushing syndrome or pseudo-acromegaly in early childhood have been identified as independent prepubertal risk factors for the development of PCOS. During adolescence, PCOS may masquerade as physiological adolescent anovulation. Asymptomatic adolescents with a polycystic ovary occasionally (8%) have subclinical PCOS but often (42%) have a subclinical PCOS type of ovarian dysfunction, the prognosis for which is unclear. CONCLUSION: Identifying children at risk for PCOS offers the prospect of eventually preventing some of the long-term complications associated with this syndrome once our understanding of the basis of the disorder improves.

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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Characterization of the basal promoter element of the human type 5 17beta-hydroxysteroid dehydrogenase gene.

Testosterone biosynthesis from androstenedione is carried out by androgenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity. Of the androgenic 17beta-HSD isoenzymes, only type 5 (17beta-HSD5) is expressed ubiquitously, including the human adrenal gland and ovary. To characterize this gene promoter, luciferase constructs of the human 5'-flanking region were transiently transfected into the H295R human adrenal carcinoma cell line. A series of fragment deletion constructs and electrophoretic mobility shift assays suggested that a sequence of CCTCCTCCT at -65 to -58 bp is the core sequence and demonstrated Sp1/Sp3 binding to this CCT repeat. Forskolin stimulated the promoter activity of the HSD17B5 gene through this Sp1/Sp3 binding site. Mutation of this site resulted in a significant reduction of HSD17B5 promoter basal and forskolin-induced activity. Mithramycin A, which inhibits the binding of Sp1 and Sp3 to DNA, also remarkably decreased HSD17B5 mRNA expression in the H295R cell line. These results indicate that members of the Sp family of transcription factors play an important role in regulating constitutive and stimulated expression of the HSD17B5 gene in H295R cells.

Functional significance of polycystic-size ovaries in healthy adolescents.

CONTEXT: The relevance of adult polycystic ovary criteria to adolescence is unclear. OBJECTIVE: The objective was to determine the functional significance of polycystic-size ovaries (PSO) in healthy adolescents. DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS: Healthy 11- to 18-yr-old postmenarcheal volunteers (n = 22) were recruited and divided into groups with normal size ovaries (VNSO; n = 10) or a polycystic-size ovary (VPSO; n = 12). They were secondarily compared with adolescents with polycystic ovary syndrome (PCOS; n = 8) matched for gynecological age and a PSO. All underwent GnRH agonist (GnRHag), oral glucose tolerance, and ACTH1-24 testing in our General Clinical Research Center. RESULTS: VPSO had a higher peak 17-hydroxyprogesterone (17PROG) response to GnRHag than VNSO (146 +/- 14 ng/dl, mean +/- sem, vs. 85 +/- 11; P = 0.008), as well as larger ovaries (13.3 +/- 0.7 cc vs. 8.5 +/- 0.8 cc). VPSO peak 17PROG was elevated (>137 ng/dl) in 42% (5 of 12). However, VPSO and VNSO androgen levels were similar, with the exception of one VPSO subject who had hyperandrogenemia and thus met criteria for PCOS. VPSO were similar to VNSO in LH, FSH, estradiol, and adrenal androgenic function. Although the VPSO group resembled the PCOS group in their 17PROG response to the GnRHag test, they differed in having significantly smaller ovaries and lower body mass index and in lacking evidence of peripheral androgen excess and of insulin resistance. CONCLUSION: A PSO in asymptomatic adolescents seems typically to be a normal variant. However, about half have a subclinical PCOS type of ovarian dysfunction; it is unknown whether this indicates a genetic carrier state or a risk for anovulation.

Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome.

CONTEXT: We determined the relationship of metabolic syndrome (MBS) to polycystic ovary syndrome (PCOS). OBJECTIVE: We tested the hypothesis that parental MBS is related to the PCOS phenotype in their offspring. DESIGN/SETTING: We phenotyped for MBS and PCOS in our General Clinical Research Center. PATIENTS: Girls with PCOS, 12-19 yr old (n = 36, including one pair of siblings), and their parents (35 mothers, 19 fathers) were recruited from the Pediatric Endocrinology Clinic. Healthy girls, 12-19 yr old (n = 21), were recruited as a reference population. INTERVENTIONS: We measured anthropometrics, blood pressure, fasting lipids and androgens, oral glucose tolerance, and ultrasonographically determined polycystic ovary status. MAIN OUTCOME MEASURES: MBS in parents, and PCOS features in mothers, were related to the presence of PCOS features in probands. RESULTS: Fathers had strikingly high prevalence of excess adiposity (94% were obese or overweight) and MBS (79%). Premenopausal mothers more commonly had MBS (36%) than features of PCOS (< or =22%). Polycystic ovaries in proband offspring of premenopausal mothers were associated with maternal polycystic ovaries only in a minority of cases. Proband polycystic ovary status was completely concordant to fathers' MBS status (P = 0.008), but not their own or their mothers' MBS status, in families whose premenopausal mothers lacked polycystic ovaries. Proband prevalence of MBS was 27.8%, 3-fold greater than expected for obesity status. CONCLUSION: Familial factors related to paternal MBS seem to be fundamental to the pathogenesis of PCOS.

Identification of a functional polymorphism of the human type 5 17beta-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is characterized by chronic hyperandrogenic anovulation and is associated with insulin resistance. Its pathogenesis is believed to be multifactorial, and abnormal gene regulation could be one contributing factor. Type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD5) appears to be the major testosterone-forming 17beta-HSD isoenzyme in females. OBJECTIVE: Our objective was to investigate the role of a potentially activating 17beta-HSD5 gene (HSD17B5) variant in hyperandrogenism. DESIGN AND SETTING: We conducted a case study and case-control cohort study in our General Clinical Research Center. STUDY SUBJECTS: Subjects included a case of PCOS who had hyperthecosis associated with profound type B insulin resistance and an unusual, frankly male testosterone response to a GnRH agonist test, as well as 121 PCOS patients and 128 population controls. INTERVENTIONS: Interventions were diagnostic. MAIN OUTCOME MEASURES: Main outcome measures included sequencing of HSD17B5 5'-flanking region and nine exons, genotype/phenotype studies, and in vitro functional studies. RESULTS: Our case had a previously undescribed homozygous HSD17B5 variant (G-to-A substitution) -71 bp in the promoter region. Genotyping controls showed this to be a single-nucleotide polymorphism (SNP)-71G. Luciferase activity of a SNP-71G promoter construct was significantly higher than that of the wild type, and EMSAs revealed that SNP-71G possessed significantly increased affinity to nuclear transcription factors. SNP-71G allele frequency (32.2 vs. 22.3%) and SNP-71G allele presence (53.7% vs. 38.3%) were significantly increased in PCOS (P = 0.01) [corrected] SNP-71G homozygosity tended to contribute about 20% to the plasma testosterone level. CONCLUSIONS: SNP-71G is a functional polymorphism that may contribute to testosterone excess in a subset of PCOS patients.

A workshop on pubertal hormone replacement options in the United States.

BACKGROUND: The optimal pubertal hormone replacement therapy in females and males is unclear. OBJECTIVE: To review hormone replacement options for hypogonadal teenagers and to determine the relevant attitudes and practices of pediatric endocrinologists in the United States. DESIGN/METHODS: A workshop on pubertal hormone replacement options was held during the Lawson Wilkins Pediatric Endocrine Society meeting in 2004. A questionnaire was distributed to investigate the audience's attitudes and practices in inducing puberty. RESULTS: The majority of respondents used conjugated estrogens to treat hypogonadal girls with the primary aim of treatment being attainment of maximal adult height. The majority of respondents used depot testosterone to treat hypogonadal boys with the primary aim of treatment being pubertal development and virilization. CONCLUSIONS: The use of physiological sex hormone replacement to optimize the induction of puberty in hypogonadal adolescents was recommended. The workshop revealed striking differences between US and European pediatric endocrinologists regarding their practices and attitudes regarding the induction of puberty in hypogonadal females. Detailed studies are necessary to develop more uniform guidelines.