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-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.

Blunted day-night changes in luteinizing hormone pulse frequency in girls with obesity: the potential role of hyperandrogenemia.

CONTEXT: Puberty is marked by sleep-associated changes in LH pulse frequency and amplitude. Early pubertal girls with obesity exhibit blunted day-to-night changes in LH secretion; whether this occurs in late pubertal obese girls is unknown. OBJECTIVE: The objective of the study was to test two hypotheses: 1) blunted day-to-night changes in LH secretion occur in both early and late pubertal obese girls, and 2) such alterations are specifically associated with hyperandrogenemia. DESIGN: This was a cross-sectional analysis. SETTING: The study was conducted at a clinical research center. PATIENTS OR OTHER PARTICIPANTS: Twenty-seven early pubertal, premenarcheal girls (12 of whom were obese) and 63 late pubertal (postmenarcheal) girls (27 of whom were obese) participated in the study. INTERVENTION: Blood samples were taken every 10 minutes from 7:00 pm to 7:00 am. MAIN OUTCOME MEASURE: Change in LH pulse frequency [LH interpulse interval (IPI)] from daytime hours (7:00 pm-11:00 pm, while awake) to nighttime hours (11:00 pm to 7:00 am, while generally asleep). RESULTS: Both nonobese and obese postmenarcheal girls demonstrated significant day-to-night decreases in LH pulse frequency (IPI increases of 33% and 16%, respectively), but day-to-night changes were blunted in obese girls (P = .004, obese vs nonobese). Day-to-night LH pulse frequency decreased significantly in postmenarcheal obese subjects with normal T concentrations (26% IPI increase) but not in those with hyperandrogenemia. Similar differences were evident for LH pulse amplitude. Nonobese and obese early pubertal girls exhibited nonsignificant differences in day-night LH pulse frequency (day to night IPI increase of 26% vs decrease of 1%, respectively). CONCLUSIONS: Day-to-night changes in LH pulse secretion are blunted in postmenarcheal obese adolescent girls. This phenomenon may in part reflect hyperandrogenemia.

Differential sleep-wake sensitivity of gonadotropin-releasing hormone secretion to progesterone inhibition in early pubertal girls.

CONTEXT: Early pubertal luteinizing hormone (LH), and by inference gonadotropin-releasing hormone (GnRH), pulse secretion is marked by high nocturnal but low daytime frequency; however, the underlying mechanisms remain unclear. Plasma concentrations of progesterone, the major regulator of GnRH frequency in women, increase in the early morning in early pubertal girls and may help slow daytime GnRH frequency. OBJECTIVE: To evaluate the effect of progesterone on LH pulse frequency in early to mid-pubertal girls. DESIGN: Controlled interventional study. SETTING: General clinical research center. PARTICIPANTS: Eighteen non-obese, non-hyperandrogenemic Tanner 1-3 girls. INTERVENTION: Twelve-hour (19:00-07:00 h) blood sampling with or without oral progesterone administration (25-50 mg at 16:00 and 20:00 h). MAIN OUTCOME MEASURE: LH pulse frequency. RESULTS: Girls receiving progesterone (n = 5) exhibited lower 12-hour LH pulse frequency than controls (n = 13), but this difference was not statistically significant (average interpulse intervals 196.0 ± 61.9 and 160.4 ± 67.1 min, respectively; p = 0.2793). In contrast to controls, however, girls receiving progesterone exhibited no LH pulses during waking hours (19:00-23:00 h; estimated interpulse interval 326.0 ± 52.7 vs. 212.0 ± 120.9 min; p = 0.0376), while nighttime (23:00-07:00 h) interpulse intervals were similar (174.8 ± 62.0 vs. 167.5 ± 76.9 min, respectively; p = 0.7750). CONCLUSIONS: Exogenous progesterone acutely suppressed daytime, but not nocturnal, LH pulse frequency in early to mid-pubertal girls, suggesting that GnRH pulse frequency is differentially regulated by progesterone depending on sleep status.

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.