Androgen Blockade and Progesterone Augmentation of Gonadotropin Secretion (CRM010)

Ability of Androgen-receptor Blockade to Normalize Progesterone-induced Augmentation of Gonadotropin Secretion in PCOS (CRM010)

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.

Study Overview

• Status: Recruiting
• Conditions: Polycystic Ovary Syndrome; PCOS
• Intervention / Treatment: Drug: Placebo; Drug: Micronized progesterone; Drug: Flutamide; Drug: Estradiol patch

Detailed Description

Women with PCOS appear to exhibit impaired progesterone (P4) augmentation of gonadotropin release (positive feedback), and this is at least partly independent of BMI differences. To test more directly the role of hyperandrogenemia/hyperandrogenism (HA), we will assess if the androgen-receptor blocker flutamide enhances P4 augmentation of gonadotropin release in estradiol (E2)-treated women with PCOS. We will study 10 women with PCOS. This is a randomized, placebo-controlled, double-blinded, crossover study, with subjects undergoing two assessments of P4 positive feedback - once after 4 weeks' pretreatment with flutamide and once after 4-weeks' pretreatment with placebo (in random order). We will assess P4 positive feedback via frequent sampling for 16 hours. Subjects will be pretreated for 3 days (prior to CRU admission) with transdermal E2 (0.2 mg/day), starting no earlier than cycle day 7. Subjects will be admitted to the CRU the evening of day 3 of E2 treatment. Starting at 0200 h, blood will be collected for 16 hours. After 6 h of sampling (0800 h), subjects will receive a single oral dose of P4. A second CRU admission - performed at least 2 months later to permit adequate washout of flutamide (as needed) - will be identical to the first except that placebo pretreatment will be exchanged for flutamide pretreatment or vice versa. We will assess the P4-mediated augmentation of FSH release, with secondary endpoints including the P4-mediated augmentation of LH release. We hypothesize that in E2-pretreated women with PCOS, acute P4 augmentation of FSH release (positive feedback) will be enhanced by androgen-receptor blockade (flutamide).

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Melissa Gilrain, BS; Phone Number: 4342436911; Email: pcos@virginia.edu
• Study Contact Backup: Name: Christopher M McCartney, MD

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22901
      • Recruiting
      • University of Virginia
      • Contact: Melissa Gilrain, BS; Phone Number: 434-243-6911; Email: pcos@virginia.edu
      • Contact: Christopher M McCartney, MD; Phone Number: 434-243-6911; Email: cm2hq@virginia.edu
      • Principal Investigator: Christopher M McCartney, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 30 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Prior to the first or the second admission (randomly determined), participants will be pretreated for 2 weeks with placebo (twice daily).	Drug: Placebo; Placebo contains only inert ingredients and is not expected to exert any direct physiological effects.; Drug: Micronized progesterone; oral micronized progesterone suspension, 100 mg oral dose at 0800 during each study admission; Other Names: progesterone; Drug: Estradiol patch; Two 0.1 mg/day transdermal estradiol patches will be applied 3 days prior to each inpatient admission; on the morning of study admission, these two patches will be removed and immediately replaced with two new 0.1 mg/day patches.; Other Names: Vivelle
Experimental: Flutamide; Prior to the first or second admission (randomly determined), subjects will be pretreated for 4 weeks with Flutamide (250 mg twice daily)	Drug: Micronized progesterone; oral micronized progesterone suspension, 100 mg oral dose at 0800 during each study admission; Other Names: progesterone; Drug: Flutamide; Flutamide, 250 mg taken orally twice daily for four weeks before study admission.; Drug: Estradiol patch; Two 0.1 mg/day transdermal estradiol patches will be applied 3 days prior to each inpatient admission; on the morning of study admission, these two patches will be removed and immediately replaced with two new 0.1 mg/day patches.; Other Names: Vivelle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean FSH concentration with progesterone administration	Change in mean FSH concentrations (post-progesterone FSH concentrations vs. pre-progesterone FSH concentrations)	After 4 weeks of placebo administration
Change in mean FSH concentration with progesterone administration	Change in mean FSH concentrations (post-progesterone FSH concentrations vs. pre-progesterone FSH concentrations)	After 4 weeks of flutamide administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean LH concentration with progesterone administration	Change in mean LH concentrations (post-progesterone LH concentrations vs. pre-progesterone LH concentrations)	After 4 weeks of placebo administration
Change in mean LH concentration with progesterone administration	Change in mean LH concentrations (post-progesterone LH concentrations vs. pre-progesterone LH concentrations)	After 4 weeks of flutamide administration

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Christopher M McCartney, MD, Univsersity of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2022
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: October 11, 2020
• First Submitted That Met QC Criteria: October 17, 2020
• First Posted (Actual): October 22, 2020

Study Record Updates

• Last Update Posted (Actual): November 2, 2023
• Last Update Submitted That Met QC Criteria: November 1, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: PCOS; Polycystic Ovary Syndrome
• Additional Relevant MeSH Terms: Neoplasms; Endocrine System Diseases; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Polycystic Ovary Syndrome; Physiological Effects of Drugs; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Estrogens; Hormone Antagonists; Androgen Antagonists; Progestins; Estradiol; Progesterone; Flutamide
• Other Study ID Numbers: HSR200016; R01HD102060 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No