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.

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.

Obese patients with polycystic ovary syndrome: evidence that metformin does not restore sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by ovarian steroids.

Women with polycystic ovary syndrome (PCOS) have reduced GnRH sensitivity to suppression by ovarian steroids, which can be ameliorated by androgen blockade. We studied nine PCOS women and nine controls to determine whether metformin could change feedback inhibition by estradiol (E(2)) and progesterone (P). LH was measured every 10 min, and FSH, E(2), P, and testosterone (T) were measured every 2 h. Frequently sampled iv glucose tolerance test was performed at the end of each admission. After the first admission, metformin (500 mg, three times a day) was started. The second admission occurred on d 8-11 of the next menstrual cycle in controls and on d 28 in PCOS patients. Patients subsequently took E(2) and P for 1 wk until the third admission. At baseline, PCOS women had higher T, free T, androstenedione, and estrone. After 4 wk of metformin, controls had a slight reduction in total T, but free T was unchanged. However, PCOS patients had reduced insulin, T, and E(2), and increased LH mean/amplitude and FSH. After ovarian steroids, controls had a greater reduction in LH pulse frequency than PCOS (61 vs. 25%). These results suggest that the beneficial effects of metformin on ovulatory function in obese PCOS women are probably not mediated by enhanced hypothalamic sensitivity.

Regulation of gonadotropin secretion: implications for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism and chronic anovulation. Although the etiology of PCOS is unknown, perturbations of gonadotropin secretion are one of the hallmarks of this disorder. In normal menstrual physiology, the monotropic rise of plasma follicle-stimulating hormone (FSH) during the luteal-follicular transition is critical for follicular development and subsequent ovulation. One of the mechanisms by which FSH is differentially synthesized involves the luteal slowing of gonadotropin-releasing hormone (GnRH) pulse frequency by ovarian steroids. In PCOS, plasma leutinizing hormone (LH) is commonly increased, FSH is typically in the lower follicular range, and LH (and by inference GnRH) pulse frequency is persistently rapid at approximately one LH pulse per hour. The etiology of the neuroendocrine abnormalities in PCOS remain unclear; however, recent studies have revealed decreased sensitivity of the GnRH pulse generator to inhibition by ovarian steroids, particularly progesterone. This abnormality is reversed by the androgen receptor antagonist flutamide, suggesting that elevated androgen levels may alter the sensitivity of the hypothalamic GnRH pulse generator to steroid inhibition and lead to enhanced LH secretion. As such, women with PCOS require higher levels of progesterone to slow the frequency of GnRH pulse secretion, resulting in inadequate FSH synthesis and persistent LH stimulation of ovarian androgens. The decreased sensitivity of the GnRH pulse generator may help to explain the genesis of PCOS during puberty. In normal early puberty, sleep-entrained increases in LH stimulate ovarian steroids, which subsequently suppress LH frequency and amplitude during the subsequent day. In hyperandrogenemic girls destined to develop PCOS, this nocturnal increase in ovarian steroids may not be adequate to suppress the GnRH pulse generator, leading to a persistently rapid LH pulse frequency, impaired FSH production, and inadequate follicular development.