Ovarian Response to Recombinant Follicle Stimulating Hormone in Women With PCOS

• ClinicalTrials.gov Identifier: NCT03252223
• Recruitment Status: Recruiting
• First Posted: August 17, 2017
• Last Update Posted: July 24, 2020
• Sponsor: University of California, San Diego
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Jeffrey Chang, MD, University of California, San Diego

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Polycystic Ovary Syndrome; Healthy; Anovulation; Hyperandrogenism	Drug: Recombinant Follicle Stimulating Hormone	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 42 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Ovarian Function in Women With Polycystic Ovary Syndrome
• Actual Study Start Date: October 2, 2017
• Estimated Primary Completion Date: December 31, 2020
• Estimated Study Completion Date: June 30, 2021

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 37 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Contacts

Contact: Tracy Hadnott, MD; 858-535-8930; thadnott@ucsd.edu

Locations

United States, California

University of California, San Diego; Recruiting

La Jolla, California, United States, 92037

Contact: Tracy N Hadnott, MD 858-822-1481 thadnott@ucsd.edu

Principal Investigator: R. Jeffrey Chang, MD

Sponsors and Collaborators

University of California, San Diego

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

Investigators

• Principal Investigator: R. Jeffrey Chang, MD; University of California, San Diego

More Information

• Responsible Party: Jeffrey Chang, MD, Professor, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT03252223
• Other Study ID Numbers: 170684; P50HD012303 ( U.S. NIH Grant/Contract ); K12HD001259 ( U.S. NIH Grant/Contract )
• First Posted: August 17, 2017
• Last Update Posted: July 24, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jeffrey Chang, MD, University of California, San Diego:

polycystic ovary syndrome; anovulation; hyperandrogenism

Additional relevant MeSH terms:

Polycystic Ovary Syndrome; Hyperandrogenism; Anovulation; Syndrome; Disease; Pathologic Processes; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Gonadal Disorders; Endocrine System Diseases; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Congenital Abnormalities; Hormones; Follicle Stimulating Hormone; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs