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

• Published in: The journal of clinical endocrinology and metabolism Vol. 94; no. 7; pp. 2360 - 2366
• 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: Bethesda, MD Oxford University Press 01.07.2009; Copyright by The Endocrine Society; Endocrine Society; The Endocrine Society
• Subjects: 17β-Estradiol; Adolescent; Androgen receptors; Androgens; Biological and medical sciences; Child; Drug Administration Schedule; Drug Combinations; Drug Resistance - physiology; Endocrinopathies; Estradiol - administration & dosage; Fasting; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Girls; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - blood; Gonadotropin-Releasing Hormone - metabolism; Gonadotropins; Humans; Hyperandrogenism - blood; Hyperandrogenism - drug therapy; Hyperandrogenism - metabolism; Insulin; Insulin resistance; Luteinizing hormone; Luteinizing Hormone - blood; Medical sciences; Original; Pituitary (anterior); Polycystic ovary syndrome; Progesterone; Progesterone - administration & dosage; Progesterone - therapeutic use; Puberty - blood; Puberty - drug effects; Pulsatile Flow - drug effects; Sensitivity analysis; Sexual Maturation - drug effects; Testosterone; Treatment Outcome; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Human; Obesity; Puberty; Nutrition; Nutrition disorder; Gonadotropin RH; Metabolic diseases; Ovarian hormone; Progestagen; Hypothalamic hormone; Regulation(control); Sensitivity; Modulation; Adolescent; Hyperandrogenism; Inhibitor; Inhibition; Progesterone; Hormone releasing factor; Sex steroid hormone; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2008-2606

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 μIU/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.