Effects of Androgen Blockade on Sensitivity of the GnRH Pulse Generator to Suppression by Estradiol and Progesterone

The purpose of this study is to understand the effects of elevated male hormones in adolescent girls and how they effect the development of polycystic ovary syndrome (PCOS). If the investigators understand the effects of elevated male hormones levels in girls, the investigators may be able to better treat girls with elevated male hormone levels and perhaps even learn how to prevent the development of PCOS. Females with elevated levels of male hormones respond differently to estrace (estradiol) and progesterone than females with normal male hormone levels. The investigators will be giving you estrogen and progesterone to see how you respond after the male hormone has been blocked by a medication called flutamide.

Similar to women with PCOS, girls with hyperandrogenemia have an increased frequency of LH pulses when compared to age matched controls. An ongoing study by our group is investigating whether the progesterone insensitivity of the GnRH pulse generator in adult women with PCOS is also seen in adolescent girls with hyperandrogenemia. Analysis of the data to date suggests that the hyperandrogenic adolescent girls have decreased hypothalamic progesterone sensitivity when compared to adolescent controls, with a subgroup (consisting of approximately half of the hyperandrogenic girls) having marked progesterone insensitivity similar to that seen in adult women with PCOS. These data have recently been published.

Given that androgens mediate hypothalamic progesterone insensitivity in adult women with PCOS, we hypothesize that androgens play a similar role in adolescent girls with hyperandrogenemia and that progesterone sensitivity can be restored with the use of the androgen receptor blocker flutamide.

Better understanding the effects of hyperandrogenemia in adolescence and its role in the development of PCOS will hopefully lead to improved prevention and treatment strategies for PCOS. This may prove increasingly important if the current epidemic in childhood obesity results in a growing number of girls with elevated androgen levels.

Eligibility Criteria:
Inclusion Criteria:

* Girls ages 13 to 17
* Tanner IV or V stage of puberty
* Post-menarche
* Hyperandrogenemic (total testosterone \> 0.4 ng/mL or free testosterone \> 35 pmol/L) with or without hirsutism
* Normal aspartate aminotransferase/alanine aminotransferase (AST/ALT) (AST \< 35 U/L, ALT \< 55 U/L)
* Hemoglobin \> 12 mg/dL or Hematocrit \> 36%
* Normal screening labs (with exception of the expected hormonal abnormalities inherent in hyperandrogenemia)
* Sexually active subjects must agree to abstain or use double barrier contraception during the study
* Subjects must agree not to take any other medications during the course of the study without approval by the study investigators

Exclusion Criteria:

* Abnormal screening labs (with the exception of the expected hormonal abnormalities inherent in hyperandrogenemia)
* Elevated AST/ALT (AST \> 35 U/L, ALT \> 55 U/L)
* Hemoglobin \<12 mg/dL or hematocrit \< 36%
* Weight \< 32 kg
* History of liver disease, peanut allergy, deep venous thrombosis, breast cancer, endometrial cancer, or cervical cancer
* Pregnant or breastfeeding
* On medications known to affect the reproductive axis within 3 months of the study (including oral contraceptive pills, metformin, and spironolactone)
* On medications known or likely to inhibit or induce CYP1A2 or CYP3A4 (please see "Restrictions on use of other drugs or treatments" section below for common examples of such drugs)
* Are currently participating in another study or have been in one in the last 30 days.