Androgen Blockade and Progesterone Augmentation of Gonadotropin Secretion

• Status: Recruiting
• Trial end date: 2025-10-01
• Target enrollment: 0
• Participant gender: Female

Summary

This study is trying to find out if flutamide (a medication that blocks the effects of testosterone) may help normalize an aspect of pituitary function (specifically, gonadotropin surge generation) in PCOS. This is a randomized, placebo-controlled, double-blinded, crossover study. The investigators hypothesize that in estradiol-pretreated women with PCOS, acute progesterone augmentation of FSH release (positive feedback) will be enhanced by flutamide.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Virginia
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Treatments: Estradiol; Flutamide; Progesterone

Criteria

Inclusion Criteria:

• Post-pubertal (> 4 years post-menarche) adult woman aged 18-30 years

• PCOS, defined as clinical and/or laboratory evidence of hyperandrogenism (hirsutism and/or elevated serum [calculated] free testosterone concentration) plus ovulatory dysfunction (irregular menses, fewer than 9 per year), but without evidence for other potential causes of hyperandrogenism and/or ovulatory dysfunction

• General good health (excepting overweight, obesity, hyperandrogenism, PCOS, and adequately-treated hypothyroidism)

• Capable of and willing to provide informed consent

• Willing to strictly avoid pregnancy with use of reliable non-hormonal methods during the study period

Exclusion Criteria:

• Inability/incapacity to provide informed consent

• Males will be excluded (PCOS is unique to females)

• Age < 18 years or > 30 years (ovarian reserve may decrease beyond age 30)

• Obesity resulting from a well-defined endocrinopathy or genetic syndrome

• Positive pregnancy test or current lactation

• Evidence for non-physiologic or non-PCOS causes of hyperandrogenism and/or anovulation

• Evidence of virilization (e.g., rapidly progressive hirsutism, deepening of the voice, clitoromegaly)

• Total testosterone > 150 ng/dl, which suggests the possibility of virilizing ovarian or adrenal tumor

• DHEA-S elevation > 1.5 times the upper reference range limit. Mild elevations may be seen in PCOS, and will be accepted in these groups

• Early morning 17-hydroxyprogesterone > 200 ng/dl measured in the follicular phase, which suggests the possibility of congenital adrenal hyperplasia (if elevated during the luteal phase, the 17-hydroxyprogesterone will be repeated during the follicular phase). NOTE: If a 17-hydroxyprogesterone > 200 ng/dl is confirmed on repeat testing, an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl performed by the subject's personal physician will be required for study participation.

• Abnormal thyroid stimulating hormone (TSH): Note that subjects with stable and adequately treated primary hypothyroidism, reflected by normal TSH values, will not be excluded.

• Hyperprolactinemia > 20% higher than the upper limit of normal. Mild prolactin elevations may be seen in women with PCOS, and elevations within 20% higher than the upper limit of normal will be accepted in this group.

• History and/or physical exam findings suggestive of Cushing's syndrome, adrenal insufficiency, or acromegaly

• History and/or physical exam findings suggestive of hypogonadotropic hypogonadism (e.g., symptoms of estrogen deficiency) including functional hypothalamic amenorrhea (which may be suggested by a constellation of symptoms including restrictive eating patterns, excessive exercise, psychological stress, etc.)

• Persistent hematocrit < 37% and hemoglobin < 12 g/dl

• Severe thrombocytopenia (platelets < 50,000 cells/microliter) or leukopenia (total white blood count < 4,000 cells/microliter)

• Previous diagnosis of diabetes, fasting glucose > or = 126 mg/dl, or a hemoglobin A1c > or = 6.5%

• Given that this study involves flutamide use, any liver panel abnormality will be grounds for exclusion

• Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure, asthma requiring intermittent systemic corticosteroids, etc.)

• Decreased renal function evidenced by GFR < 60 ml/min/1.73m2

• A personal history of breast, ovarian, or endometrial cancer

• History of allergy to micronized progesterone, flutamide, or transdermal estradiol

• BMI < 18 or > 40 kg/m2

• Due to the amount of blood being drawn, volunteers with body weight < 110 pounds must be excluded