ANDROGENS AND HYPOTHALAMIC SENSITIVITY TO PROGESTERONE FEEDBACK IN FEMALE PUBERTY - DESCRIPTION (provided by applicant): Women with polycystic ovary syndrome (PCOS) have elevated plasma LH and persistently rapid GnRH pulse frequency. They also require higher levels of progesterone (P) to suppress LH(GnRH) pulse frequency than normal controls. Treatment with the androgen receptor blocker flutamide restores hypothalamic sensitivity to P in women with PCOS, indicating that androgens mediate hypothalamic P insensitivity. In normal girls, hypothalamic sensitivity to estradiol (E2) and P diminishes as puberty advances, while testosterone (T) levels rise 5-fold. We propose that this rise in T may cause a progressive reduction in the sensitivity of the GnRH pulse generator to P feedback during normal female puberty. This process may be exaggerated in girls with hyperandrogenemia (HA), perhaps explaining the rapid LH(GnRH) pulses and accelerated maturation of the LH(GnRH) pulse pattern seen in adolescent HA. Preliminary results in adolescents suggest that while overall HA girls have reduced hypothalamic P sensitivity similar to women with PCOS, some girls maintain P sensitivity despite equivalent degrees of HA. The HA girls who maintain P sensitivity trend towards younger gynecologic age, suggesting a possible role for duration of androgen exposure, and, to date, are all Hispanic, suggesting a possible role for genetic factors. One genetic candidate for the variable effects of elevated androgens on hypothalamic P sensitivity is the androgen receptor (AR) polymorphic trinucleotide (CAG) repeat region. CAG repeat length is inversely correlated with transactivation activity of the AR, with longer CAG repeat length conferring reduced receptor activity. The distribution of CAG repeat length varies among racial and ethnic groups, with Hispanics tending to have longer CAG repeat length than Caucasians or African-Americans. Thus, Hispanics may have reduced androgen action, potentially explaining why the Hispanic girls maintained hypothalamic P sensitivity despite the presence of elevated plasma androgens. We plan to assess hypothalamic sensitivity to P feedback by measuring LH pulsatility before and after 7 d of oral E2 and P in normal and HA girls at all pubertal stages. In normal girls, we will assess the evolution of P sensitivity during puberty. In HA girls, we will assess the effect of duration of androgen exposure and androgen blockade on P sensitivity. In addition, we will determine the AR CAG repeat length in all subjects and assess whether AR CAG repeat length modulates androgen effects on hypothalamic P sensitivity. PCOS affects 6-7% of women and is a leading cause of infertility. Better understanding the causes of PCOS will hopefully lead to improved screening, prevention, and treatment of the disorder.
