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.

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.

Polycystic ovary syndrome in adolescence.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive-aged women and is characterized by hyperandrogenemia, menstrual dysfunction, and polycystic ovarian morphology. The hormonal abnormalities inherent in PCOS often begin in adolescence and include hyperinsulinemia and rapid luteinizing hormone (LH) pulse frequency, both of which mediate ovarian and adrenal overproduction of androgens. Although differences exist regarding the diagnostic criteria for PCOS, we believe that hyperandrogenemia is the final common pathway for the development of adolescent PCOS, and we propose a hypothesis to illustrate such. Recognizing and reducing androgen levels in adolescence is critical given their association with the metabolic syndrome (MBS), diabetes, and infertility in adulthood.

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