Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls—Implications for Regulation of Pubertal Maturation

• Published in: Endocrine reviews Vol. 30; no. 4; p. 411
• Main Authors: Blank, Susan K., McCartney, Christopher R., Chhabra, Sandhya, Helm, Kristin D., Eagleson, Christine A., Chang, R. Jeffrey, Marshall, John C.
• Format: Journal Article
• Language: English
• Published: Cary Oxford University Press 01.06.2009
• Subjects: 17β-Estradiol; Adolescents; Androgen receptors; Androgens; Fasting; Girls; Gonadotropin-releasing hormone; Gonadotropins; Insulin; Insulin resistance; Luteinizing hormone; Pituitary (anterior); Polycystic ovary syndrome; Progesterone; Pulse generators; Research facilities; Sensitivity analysis; Sex hormones; Testosterone
• ISSN: 0163-769X; 1945-7189
• DOI: 10.1210/edrv.30.4.9995

ContextAdult 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.ObjectiveThe aim of the study was to evaluate GnRH pulse generator sensitivity to P-mediated slowing in normal and hyperandrogenic girls.DesignWe conducted a controlled interventional study.SettingThe study was conducted in a general clinical research center.ParticipantsA total of 26 normal control (NC) and 26 hyperandrogenic (HA) girls were studied.InterventionFrequent blood sampling was performed for 11 h to assess LH pulse frequency before and after 7 d of oral estradiol and P.Main Outcome MeasureWe measured the slope of the percentage reduction in LH pulse frequency as a function of d 7 P (slope).ResultsOverall, 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 mIU/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).ConclusionsHyperandrogenism 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.