Ovarian Response to Recombinant Follicle Stimulating Hormone in Women With PCOS

Ovarian Function in Women With Polycystic Ovary Syndrome

Women with PCOS suffer from anovulation and, as a result, infertility. Efforts to clinically induce ovulation in these women using follicle stimulating hormone (FSH) administered subcutaneously seemingly requires prolonged administration compared to that of ovulatory women without PCOS. The apparent differing ovarian responsiveness to FSH between PCOS and normal women has not been carefully studied. We propose to address this issue by performing a dose-response study and examine ovarian follicle (estrogen, E2) responses to FSH administered subcutaneously in women with PCOS compared to responses observed in normal women.

Study Overview

• Status: Completed
• Conditions: Healthy; Polycystic Ovary Syndrome; Hyperandrogenism; Anovulation
• Intervention / Treatment: Drug: Recombinant Follicle Stimulating Hormone

Detailed Description

In women with polycystic ovary syndrome (PCOS) androgen excess is fundamental to the clinical and physiological alterations of this disorder. In particular, androgen overproduction induces distinctive PCO morphology and appears to influence follicle function. Studies conducted in animals and nonhuman primates have demonstrated that androgens increase follicle number and in small antral follicles enhance granulosa cell (GC) responsiveness to gonadotropin stimulation. However, androgens also have been shown to clearly inhibit GC aromatase activity, and in PCOS follicular fluid, androgen content is abnormally increased. Efforts to reconcile these differences are nonexistent. Moreover, appropriate clinical studies to examine the effects of androgen on follicle health in women are lacking. Excessive androgen exposure in women due to functional tumors or high-dose testosterone treatment in F-M transsexuals has been associated with PCO morphology. Use of androgen therapy to promote follicle growth prior to ovarian hyperstimulation in women undergoing in vitro fertilization has not provided consistent results. However, in these studies GC responses to FSH were not carefully assessed, study populations were exclusively women with previously poor ovarian responses to FSH, and women with PCOS were not included. In fact, there are essentially no clinical studies that have addressed in detail the impact of androgen on follicle function in normal or PCOS women. We hypothesize that androgen facilitates GC responses to FSH in normal women and androgen excess further amplifies follicle growth and function in women with PCOS. We propose to study the effect of increased ovarian androgen on follicle function by increasing intraovarian androgen accumulation using aromatase inhibition followed by FSH stimulation. The experiments in this project are designed to provide insight into whether androgen excess facilitates or interferes with follicle function and ovulation in women with PCOS.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California, San Diego

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 37 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Subjects determined to have PCOS based on clinical history of irregular menses and clinical or laboratory evidence of hyperandrogenism and polycystic ovaries on ultrasound OR
• Subjects determined to have a clinical history of regular periods.

Exclusion Criteria:

1. Women with hemoglobin less than 11 gm/dl at screening evaluation
2. Women with untreated thyroid abnormalities
3. Pregnant women or women who are nursing
4. Women with BMI > 37
5. Women with known sensitivity to the agents being used
6. Women with diabetes, or renal, liver, or heart disease
7. Women with any hormonal therapy or metformin for at least 2 months prior to study start.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Women with normal menses	Drug: Recombinant Follicle Stimulating Hormone; A modified dose-response study will be done using recombinant FSH (r-FSH), injected sc for 3 days at any one dose. r-FSH will be administered at weight-adjusted doses equivalent to 37.5, 75, and 150 IU based on an average weight of 70 kg, which approximates the weight of the average woman in the United States according to the Centers for Disease Control. Therefore, the actual dose of r-FSH will be 0.53 IU/kg for the 37.5 dose group. Accordingly, r-FSH will be repeated at doses of 1.1 IU/kg and 2.2 IU/kg that are equivalent to 75 and 150 IU for a 70 kg subject. Each FSH stimulation test will be assigned randomly and be separated by an interval of 8 weeks.
ACTIVE_COMPARATOR: Women with Polycystic Ovary Syndrome	Drug: Recombinant Follicle Stimulating Hormone; A modified dose-response study will be done using recombinant FSH (r-FSH), injected sc for 3 days at any one dose. r-FSH will be administered at weight-adjusted doses equivalent to 37.5, 75, and 150 IU based on an average weight of 70 kg, which approximates the weight of the average woman in the United States according to the Centers for Disease Control. Therefore, the actual dose of r-FSH will be 0.53 IU/kg for the 37.5 dose group. Accordingly, r-FSH will be repeated at doses of 1.1 IU/kg and 2.2 IU/kg that are equivalent to 75 and 150 IU for a 70 kg subject. Each FSH stimulation test will be assigned randomly and be separated by an interval of 8 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in granulosa cell function in 24 hours intervals following FSH administration	Granulosa function will be assessed using estradiol and inhibin levels	Serum levels will be assessed daily during each 3 day FSH stimulation test and for five days following the initial FSH administration
Change in follicle count in following FSH administration	Number of ovarian follicles will be assessed by pelvic ultrasound	With each dose tested, a pelvic ultrasound will be done before and 3 days after commencing FSH
Change in follicular size in following FSH administration	Size of ovarian follicles will be assessed by pelvic ultrasound	With each dose tested, a pelvic ultrasound will be done before and 3 days after commencing FSH

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: R. Jeffrey Chang, MD, University of California, San Diego

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 2, 2017
• Primary Completion (ACTUAL): June 30, 2021
• Study Completion (ACTUAL): June 30, 2021

Study Registration Dates

• First Submitted: August 8, 2017
• First Submitted That Met QC Criteria: August 14, 2017
• First Posted (ACTUAL): August 17, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 8, 2021
• Last Update Submitted That Met QC Criteria: September 6, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: polycystic ovary syndrome; hyperandrogenism; anovulation
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Congenital Abnormalities; Polycystic Ovary Syndrome; Hyperandrogenism; Syndrome; Anovulation; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Follicle Stimulating Hormone; Hormones
• Other Study ID Numbers: 170684; P50HD012303 (NIH); K12HD001259 (NIH)

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