Androgen Blockade and Progesterone Augmentation of Gonadotropin Secretion

NCT ID: NCT04597099

Last Updated: 2023-11-02

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-26
• Study Completion Date: 2025-10-01

Brief 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.

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).

Conditions

PCOS; Polycystic Ovary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Flutamide

Prior to the first or second admission (randomly determined), subjects will be pretreated for 4 weeks with Flutamide (250 mg twice daily)

Group Type: EXPERIMENTAL

Micronized progesterone

Intervention Type: DRUG

oral micronized progesterone suspension, 100 mg oral dose at 0800 during each study admission

Flutamide

Intervention Type: DRUG

Flutamide, 250 mg taken orally twice daily for four weeks before study admission.

Estradiol patch

Intervention Type: DRUG

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.

Placebo

Prior to the first or the second admission (randomly determined), participants will be pretreated for 2 weeks with placebo (twice daily).

Group Type: PLACEBO_COMPARATOR

Micronized progesterone

Intervention Type: DRUG

oral micronized progesterone suspension, 100 mg oral dose at 0800 during each study admission

Placebo

Intervention Type: DRUG

Placebo contains only inert ingredients and is not expected to exert any direct physiological effects.

Estradiol patch

Intervention Type: DRUG

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.

Interventions

Micronized progesterone

oral micronized progesterone suspension, 100 mg oral dose at 0800 during each study admission

Intervention Type: DRUG

Placebo

Placebo contains only inert ingredients and is not expected to exert any direct physiological effects.

Intervention Type: DRUG

Flutamide

Flutamide, 250 mg taken orally twice daily for four weeks before study admission.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

progesterone; Vivelle

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: lead

Responsible Party

Chris McCartney

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Christopher M McCartney, MD

Role: PRINCIPAL_INVESTIGATOR

Univsersity of Virginia

Locations

University of Virginia

Charlottesville, Virginia, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Melissa Gilrain, BS

Role: CONTACT

pcos@virginia.edu

4342436911

Christopher M McCartney, MD

Role: CONTACT

Facility Contacts

Melissa Gilrain, BS

Role: primary

pcos@virginia.edu

434-243-6911

Christopher M McCartney, MD

Role: backup

cm2hq@virginia.edu

434-243-6911

Other Identifiers

R01HD102060

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HSR200016

Identifier Type: -

Identifier Source: org_study_id