Androgen Blockade and Progesterone Augmentation of Gonadotropin Secretion

NCT04597099 | Unknown Early Phase 1 DMC FDA Drug

• 2 other identifiers: HSR200016R01HD102060
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

PCOS; Polycystic Ovary Syndrome

Keywords

PCOS; Polycystic Ovary Syndrome

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Change in mean LH concentration with progesterone administration

  After 4 weeks of placebo administration

• Change in mean LH concentration with progesterone administration

  After 4 weeks of flutamide administration

Study Arms (2)

Flutamide

EXPERIMENTAL

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; Drug: Flutamide; Drug: Estradiol patch

Placebo

PLACEBO COMPARATOR

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

Drug: Micronized progesterone; Drug: Placebo; Drug: Estradiol patch

Interventions

Micronized progesterone DRUG

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

Also known as: progesterone

Flutamide; Placebo

Placebo DRUG

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

Placebo

Flutamide DRUG

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

Flutamide

Estradiol patch 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.

Also known as: Vivelle

Flutamide; Placebo

Eligibility Criteria

• Age: 18 Years - 30 Years
• Gender Eligibility Details: This is a study regarding PCOS, so only females will be eligible
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Virginia: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

University of Virginia

Charlottesville, Virginia, 22901, United States

RECRUITING

MeSH Terms

Conditions

Polycystic Ovary Syndrome

Interventions

Progesterone; Flutamide; Ortho Evra; Estradiol

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Estrenes; Estranes; Estradiol Congeners

Study Officials

• Christopher M McCartney, MD

  Univsersity of Virginia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Melissa Gilrain, BS

CONTACT

4342436911; pcos@virginia.edu

Christopher M McCartney, MD

CONTACT

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Randomized, placebo-controlled, double-blinded, crossover study

Study Record Dates

• First Submitted: October 11, 2020
• First Posted: October 22, 2020
• Study Start: October 26, 2022
• Primary Completion: October 1, 2025
• Study Completion: October 1, 2025
• Last Updated: November 2, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)