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

Center for Research in Reproduction and Division of Endocrinology (S.K.B., C.R.M., S.C., K.D.H., C.A.E., J.C.M.), Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908; and Division of Reproductive Endocrinology (J.R.C.), Department of Reproductive Medicine, University of California-San Diego, La Jolla, California 92093

Address all correspondence and requests for reprints to: Susan K. Blank, M.D., Division of Endocrinology, Department of Internal Medicine, Box 800391, University of Virginia Health System, Charlottesville, Virginia 22908. E-mail: sek2h{at}virginia.edu.

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.

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