Modulation of gonadotropin-releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls--implications for regulation of pubertal maturation.
BACKGROUND
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.


METHODS
We conducted a controlled interventional study.


METHODS
The study was conducted in a general clinical research center.


METHODS
A total of 26 normal control (NC) and 26 hyperandrogenic (HA) girls were studied.


METHODS
Frequent blood sampling was performed for 11 h to assess LH pulse frequency before and after 7 d of oral estradiol and P.


METHODS
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.
Center for Research in Reproduction and Division of Endocrinology, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA. sek2h@virginia.edu
Susan K
SK
Blank
Christopher R
CR
McCartney
Sandhya
S
Chhabra
Kristin D
KD
Helm
Christine A
CA
Eagleson
R Jeffrey
RJ
Chang
John C
JC
Marshall
D000293:Adolescent; D002648:Child; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004351:Drug Resistance / Q000502:physiology; D004958:Estradiol / Q000008:administration & dosage; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000097:blood* / Q000378:metabolism; D006801:Humans; D017588:Hyperandrogenism / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D011374:Progesterone / Q000008:administration & dosage / Q000627:therapeutic use*; D011627:Puberty / Q000097:blood / Q000187:drug effects*; D011673:Pulsatile Flow / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects*; D016896:Treatment Outcome
D004338:Drug Combinations; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone