Modulation of gonadotropin-releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls--implications for regulation of pubertal maturation.

CONTEXT: Adult women with polycystic ovary syndrome (PCOS) have decreased GnRH pulse generator sensitivity to progesterone (P)-mediated slowing. This defect is androgen mediated because it is reversed with androgen receptor blockade. Adolescent hyperandrogenism often precedes PCOS. OBJECTIVE: The aim of the study was to evaluate GnRH pulse generator sensitivity to P-mediated slowing in normal and hyperandrogenic girls. DESIGN: We conducted a controlled interventional study. SETTING: The study was conducted in a general clinical research center. PARTICIPANTS: A total of 26 normal control (NC) and 26 hyperandrogenic (HA) girls were studied. INTERVENTION: Frequent blood sampling was performed for 11 h to assess LH pulse frequency before and after 7 d of oral estradiol and P. MAIN OUTCOME MEASURE: We measured the slope of the percentage reduction in LH pulse frequency as a function of d 7 P (slope). RESULTS: Overall, Tanner 3-5 HA subjects were less sensitive to P-mediated slowing than Tanner 3-5 NC (slope, 4.7 +/- 3.4 vs. 10.3 +/- 7.7; P = 0.006). However, there was variability in the responses of HA subjects; 15 had P sensitivities within the range seen in NC, whereas nine were relatively P insensitive. The two groups had similar testosterone levels. Fasting insulin levels were higher in P-insensitive HA girls (39.6 +/- 30.6 vs. 22.2 +/- 13.9 microIU/ml; P = 0.02), and there was an inverse relationship between fasting insulin and P sensitivity in HA girls (P = 0.02). Tanner 1-2 NC had lower testosterone levels and were more P sensitive than Tanner 3-5 NC (slope, 19.3 +/- 5.8; P = 0.04). CONCLUSIONS: Hyperandrogenism is variably associated with reduced GnRH pulse generator sensitivity to P-mediated slowing during adolescence. In addition to androgen levels, insulin resistance may modulate P sensitivity.

Maturation of luteinizing hormone (gonadotropin-releasing hormone) secretion across puberty: evidence for altered regulation in obese peripubertal girls.

CONTEXT: Peripubertal obesity (body mass index-for-age >or= 95%) in girls is associated with hyperandrogenemia. LH likely contributes to this relationship, but overnight LH secretion in obese girls is poorly characterized. OBJECTIVE: The aim of the study was to evaluate LH pulse characteristics in obese girls throughout pubertal maturation. DESIGN: We conducted a cross-sectional analysis. SETTING: The study was performed in a general clinical research center. PARTICIPANTS: Eight nonobese and five obese Tanner 1-2 girls participated, as well as 32 nonobese and 12 obese Tanner 3-5 girls. INTERVENTION: Blood samples were collected every 10 min overnight (from 1900 to 0700 h). MAIN OUTCOME MEASURES: LH pulse frequency, amplitude, and mean LH were measured in three 4-h time blocks (block 1, 1900-2300 h; block 2, 2300-0300 h; and block 3, 0300-0700 h). RESULTS: Tanner stage 1-2 nonobese girls demonstrated nocturnal increases of LH frequency (P < 0.01, block 1 vs. 2) and mean LH (P < 0.05, block 1 vs. 2 and 3). Obese Tanner 1-2 girls had lower 12-h LH frequency and LH amplitude (P < 0.05 for both), with no overnight changes of LH pulse parameters. Compared to normal, LH frequency was elevated in Tanner 3-5 obese girls (P < 0.01 in all blocks), whereas LH amplitude was low (P < 0.05 in all blocks). Overnight increases of LH amplitude were observed in nonobese Tanner 3-5 girls (P < 0.0001), but not in obese Tanner 3-5 girls. CONCLUSIONS: Obesity in prepubertal and early pubertal girls is associated with reduced LH secretion and reduced nocturnal changes of LH. In later pubertal girls, obesity is linked with reduced LH amplitude, but elevated LH frequency; the latter may reflect effects of hyperandrogenemia.

Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls.

CONTEXT: Peripubertal obesity is associated with abnormal sex steroid concentrations, but the timing of onset and degree of these abnormalities remain unclear. OBJECTIVE: The objective of the study was to assess the degree of hyperandrogenemia across puberty in obese girls and assess overnight sex steroid changes in Tanner stage 1-3 girls. DESIGN: This was a cross-sectional analysis. SETTING: The study was conducted at general clinical research centers. SUBJECTS: Thirty normal-weight (body mass index for age < 85%) and 74 obese (body mass index for age >or= 95%) peripubertal girls. INTERVENTION: Blood samples (circa 0500-0700 h) were taken while fasting. Samples from the preceding evening (circa 2300 h) were obtained in 23 Tanner 1-3 girls. MAIN OUTCOME MEASURES: Hormone concentrations stratified by Tanner stage were measured. RESULTS: Compared with normal-weight girls, mean free testosterone (T) was elevated 2- to 9-fold across puberty in obese girls, whereas fasting insulin was 3-fold elevated in obese Tanner 1-3 girls (P < 0.05). Mean LH was lower in obese Tanner 1 and 2 girls (P < 0.05) but not in more mature girls. In a subgroup of normal-weight Tanner 1-3 girls (n = 17), mean progesterone (P) and T increased overnight 2.3- and 2.4-fold, respectively (P

The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism.

CONTEXT: Adolescent hyperandrogenemia is considered a forerunner of adult polycystic ovary syndrome, but its etiology remains uncertain. OBJECTIVE: Our objective was to explore the hypothesis that peripubertal obesity is associated with hyperandrogenemia. DESIGN AND SETTING: We performed a cross-sectional analysis of data obtained at General Clinical Research Centers. SUBJECTS: Subjects were 41 obese [body mass index (BMI) for age, >or=95%] and 35 normal-weight (BMI for age, <95%) peripubertal girls. INTERVENTION: We used pooled blood samples (approximately 0500-0700 h; n = 64) while fasting or single morning (fasting) samples (n = 12). MAIN OUTCOME MEASURES: We assessed adiposity and androgen concentrations. RESULTS: BMI correlated with total testosterone (T) (r(s) = 0.59), SHBG (r(s) = -0.69), and free T (r(s) = 0.69); free T was three times as great in obese girls compared with normal-weight girls (P < 0.0001 for all). BMI correlated with insulin (r(s) = 0.52); both insulin and LH correlated with free T (r(s) = 0.45 and 0.44, respectively; P < 0.001 for all). When analyzing early pubertal girls (pubertal stages 1-3; n = 36) alone, BMI correlated with total T (r(s) = 0.65), SHBG (r(s) = -0.74), and free T (r(s) = 0.75); free T was five times as great in obese early-pubertal girls (P < 0.001 for all). BMI correlated with insulin (r(s) = 0.65), and insulin correlated with free T (r(s) = 0.63, P < 0.01 for both). BMI correlated with free T while simultaneously adjusting for age, pubertal stage, insulin, LH, and dehydroepiandrosterone sulfate. CONCLUSION: Peripubertal obesity is associated with marked hyperandrogenemia, which is especially pronounced in early puberty.

Progesterone inhibition of the hypothalamic gonadotropin-releasing hormone pulse generator: evidence for varied effects in hyperandrogenemic adolescent girls.

Compared with normal women, adults with polycystic ovarian syndrome (PCOS) require higher progesterone (P) concentrations to inhibit GnRH (LH) pulse frequency, which contributes to persistently rapid GnRH pulses and elevated LH levels in PCOS. To explore the origin of this abnormality, we assessed hypothalamic sensitivity to P feedback in nine normal controls and 11 hyperandrogenemic (HA) adolescents. Subjects first underwent frequent blood sampling for 11 h to assess baseline LH pulse frequency. Thereafter, oral estradiol and micronized P were given for 7 d to achieve mean estradiol and P levels of 143 +/- 16 pg/ml (524 +/- 60 pmol/liter) and 7.8 +/- 0.7 ng/ml (24.9 +/- 2.3 nmol/liter), respectively. LH pulse frequency was then reassessed. On d 7, the slope of the percent reduction of LH pulses per 11 h as a function of the d 7 P concentration was less in the HA group compared with controls (P = 0.02) despite similar P levels. LH pulse frequency was suppressed in all NC (mean, 7.0 to 3.4 pulses/11 h), but was unchanged in six of the HA girls (mean, 8.3 to 7.5 pulses/11 h). In contrast, in the other five HA adolescents, P induced similar slowing of LH pulses to that seen in NC (mean, 10.0 to 5.0 pulses/11 h). Baseline free testosterone levels were similar in both HA groups; the only observed difference between these HA groups is that the P-suppressible subjects were all of Hispanic descent. These data suggest that hyperandrogenemia during adolescence is variably associated with decreased sensitivity to P, which may have a partially genetic basis.