MINISYMPOSIUM II. PRENATAL ORIGINS OF REPRODUCTIVE DYSFUNCTION IN THE FEMALE
Monday, August 2, 2004
9:00 AM–10:30 AM
Chair: Douglas L. Foster (University of Michigan, Ann Arbor, MI)
(MS6) EARLY PROGRAMMING OF REPRODUCTIVE DYSFUNCTION: EVIDENCE FROM HUMAN CLINICAL STUDIES.
Marshall, John1, 2, McCartney, Christopher1, 2, Prendergast, Kathleen1, 2, Chhabra, Sandhya1, 2, Chopra, Chandan1, 1 Center for Research in Reproduction, Charlottesville, VA2 Division of Endocrinology & Metabolism, Charlottesville, VA
ABSTRACT- Women with polycystic ovarian syndrome (PCOS) have irregular ovulation, elevated plasma LH and androgens, and persistently rapid LH (GnRH) pulses. Normally luteal progesterone (P) slows GnRH pulses favoring FSH synthesis and the later rise in FSH. In adults with PCOS, a higher P is required to suppress GnRH pulses – indicating insensitivity to P feedback in hyperandrogenemia. The AR blocker flutamide restores sensitivity of the GnRH pulse generator – thus androgens impair P regulation of GnRH pulse secretion. In hyperandrogenic adolescents, GnRH/LH pulses are also rapid and persist through 24 h. In normal puberty the mechanisms effecting daytime inhibition of prior nights GnRH secretion are unclear. Plasma P increases from 50-250 pg/ml from 2400-0800 h in early puberty, which may inhibit GnRH secretion the following day. Early puberty in girls is dominated by an androgen milieu, plasma testosterone (T) > estradiol by 30-50 fold. As puberty advances, T increases (75-250 pg/ml), which may impair P inhibition of GnRH the next day – reflected in the progressive daytime rise in LH and ovarian steroids through puberty. If excess androgens are present, steroid inhibition of GnRH may be impaired from early puberty – resulting in frequent pulses and elevated LH as occurs in hyperandrogenic adolescents. To test this thesis we used exogenous P to suppress LH pulses (> 3/12 h in normal controls). In contrast LH pulse frequency was not suppressed in most hyperandrogenemic girls. We propose that peripubertal exposure to excess androgens impairs steroid inhibition of GnRH pulse frequency. This leads to persistent 24-h rapid GnRH secretion, favoring LH secretion and stimulation of ovarian androgens – creating a self perpetuating syndrome. The source of elevated peripubertal androgens is unclear. In prepubertal obese (> 95%ile BMI for age) girls, total T is increased to adult female levels, and as SHBG is reduced, free T is elevated 20-30 fold above non-obese controls. In sum, androgens impair P inhibition of GnRH secretion and contribute to the elevated plasma LH in women with PCOS. Excess T during puberty may underlie the elevated LH in hyperandrogenic girls. Obese prepubertal girls with elevated plasma insulin exhibit marked hyperandrogenemia, representing a potential mechanism linking obesity and the abnormal LH secretion in PCOS.
KEY WORDS: puberty, obesity, polycystic ovarian syndrome (PCOS), hyperandrogenemia