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.

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.

Go Girls!-Dance-Based Fitness to Increase Enjoyment of Exercise in Girls at Risk for PCOS.

Weight loss can reduce the hyperandrogenemia associated with polycystic ovary syndrome (PCOS) in peripubertal girls. Yet, adolescent girls have the lowest rates of physical activity and enjoyment of exercise. We created a dance-based support group (Go Girls!) to entice physical activity and improve enjoyment. Girls ages 7-21 over the 85th BMI percentile were recruited and attended once-weekly sessions for 3-6 months. We assessed changes in Physical Activity Enjoyment Scale (PACES), anthropometrics, laboratory data, and amounts of home exercise at 0, 3, and 6 months. Sixteen girls completed either 3 or 6 months. PACES scores were surprisingly high at baseline and remained high. Systolic blood pressure percentile decreased post-intervention. Although no group differences were observed, the majority of individual girls had decreased waist circumference, triglycerides, and metabolic syndrome severity score. Forty percent had decreased free testosterone levels. More girls enjoyed physical education class, got exercise outside of school, and made other lifestyle changes. This dance-based support group was enjoyed by girls and demonstrated health benefits. Continued efforts to engage girls in physical activity are necessary to protect girls from the consequences of obesity, including PCOS and metabolic syndrome. Dance exercise remains a promising tool to encourage physical activity in girls.

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.

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.

Increased Adrenal Androgens in Overweight Peripubertal Girls.

CONTEXT: Peripubertal hyperandrogenemia-a precursor to polycystic ovary syndrome-is prominent in girls with obesity. OBJECTIVE: We examined sources of overnight testosterone (T) and progesterone (P4) and potential sources of obesity-associated hyperandrogenemia during puberty. DESIGN: Cross-sectional. SETTING: Research unit. PARTICIPANTS/INTERVENTIONS: Fifty girls ages 7 to 18 years-both normal weight (NW) and overweight (OW)-underwent dexamethasone (DEX) suppression (1 mg orally; 10 pm) and cosyntropin stimulation testing (0.25 mg intravenously; 8 am the following day), with blood sampled before and 30 and 60 minutes after cosyntropin. Thirty-nine subjects receiving DEX had frequent blood sampling overnight (every 10 minutes from 10 pm to 7 am) and were compared with 70 historical controls who did not receive DEX. OUTCOMES: Random coefficient regression modeling assessed changes in hormone concentrations after DEX and cosyntropin. RESULTS: NW early pubertal controls exhibited early morning increases in free T and P4 levels; NW and OW late pubertal controls exhibited early morning increases in P4. Such changes were not observed in subjects receiving DEX. Post-DEX morning free T levels were fourfold higher in OW vs NW late pubertal girls. Postcosyntropin changes in free T and androstenedione were both 2.3-fold higher in OW vs NW late pubertal girls. CONCLUSIONS: These data suggest that (1) overnight increases in free T and P4 concentrations in NW early pubertal girls and P4 concentrations in late pubertal girls are of adrenal origin and (2) OW late pubertal girls demonstrate elevated nonadrenal free T levels after DEX and exaggerated adrenal androgen (free T and androstenedione) responses to cosyntropin.

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

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

Hemoglobin A1c (HbA1c) changes over time among adolescent and young adult participants in the T1D exchange clinic registry.

OBJECTIVE: Hemoglobin A1c (HbA1c) levels among individuals with type 1 diabetes (T1D) influence the longitudinal risk for diabetes-related complications. Few studies have examined HbA1c trends across time in children, adolescents, and young adults with T1D. This study examines changes in glycemic control across the specific transition periods of pre-adolescence-to-adolescence and adolescence-to-young adulthood, and the demographic and clinical factors associated with these changes. RESEARCH DESIGN AND METHODS: Available HbA1c lab results for up to 10 yr were collected from medical records at 67 T1D Exchange clinics. Two retrospective cohorts were evaluated: the pre-adolescent-to-adolescent cohort consisting of 85 016 HbA1c measurements from 6574 participants collected when the participants were 8-18 yr old and the adolescent-to-young adult cohort, 2200 participants who were 16-26 yr old at the time of 17 279 HbA1c measurements. RESULTS: HbA1c in the 8-18 cohort increased over time after age 10 yr until ages 16-17; followed by a plateau. HbA1c levels in the 16-26 cohort remained steady from 16-18, and then gradually declined. For both cohorts, race/ethnicity, income, health insurance, and pump use were all significant in explaining individual variations in age-centered HbA1c (p < 0.001). For the 8-18 cohort, insulin pump use, age of onset, and health insurance were significant in predicting individual HbA1c trajectory. CONCLUSIONS: Glycemic control among patients 8-18 yr old worsens over time, through age 16. Elevated HbA1c levels observed in 18 yr-olds begin a steady improvement into early adulthood. Focused interventions to prevent deterioration in glucose control in pre-adolescence, adolescence, and early adulthood are needed.

Neuroendocrine dysfunction in polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is a common disorder characterized by ovulatory dysfunction and hyperandrogenemia (HA). Neuroendocrine abnormalities including increased gonadotropin-releasing hormone (GnRH) pulse frequency, increased luteinizing hormone (LH) pulsatility, and relatively decreased follicle stimulating hormone contribute to its pathogenesis. HA reduces inhibition of GnRH pulse frequency by progesterone, causing rapid LH pulse secretion and increasing ovarian androgen production. The origins of persistently rapid GnRH secretion are unknown but appear to evolve during puberty. Obese girls are at risk for HA and develop increased LH pulse frequency with elevated mean LH by late puberty. However, even early pubertal girls with HA have increased LH pulsatility and enhanced daytime LH pulse secretion, indicating the abnormalities may begin early in puberty. Decreasing sensitivity to progesterone may regulate normal maturation of LH secretion, potentially related to normally increasing levels of testosterone during puberty. This change in sensitivity may become exaggerated in girls with HA. Many girls with HA-especially those with hyperinsulinemia-do not exhibit normal LH pulse sensitivity to progesterone inhibition. Thus, HA may adversely affect LH pulse regulation during pubertal maturation leading to persistent HA and the development of PCOS.

Obesity and the pubertal transition in girls and boys.

Childhood obesity has become a major health concern in recent decades, especially with regard to metabolic abnormalities that impart a high risk for future cardiovascular disease. Recent data suggest that excess adiposity during childhood may influence pubertal development as well. In particular, excess adiposity during childhood may advance puberty in girls and delay puberty in boys. Obesity in peripubertal girls may also be associated with hyperandrogenemia and a high risk of adolescent polycystic ovary syndrome. How obesity may perturb various hormonal aspects of pubertal development remains unclear, but potential mechanisms are discussed herein. Insulin resistance and compensatory hyperinsulinemia may represent a common thread contributing to many of the pubertal changes reported to occur with childhood obesity. Our understanding of obesity's impact on pubertal development is in its infancy, and more research into pathophysiological mechanisms and longer-term sequelae is important.