Does Treatment of Androgen Excess Using Spironolactone Improve Ovulatory Rates in Girls With Androgen Excess? (CBS009)

Adolescent girls with androgen excess have a higher rate of irregular periods and decreased ovulation rates compared to normal girls, and are considered at-risk for developing polycystic ovary syndrome (PCOS). This pilot study will look at whether giving spironolactone might improve ovulation rates in girls with androgen excess, ages 13-19. If this is true, spironolactone treatment to young girls might prevent PCOS from developing and avoid future infertility.

Study Overview

• Status: Recruiting
• Conditions: Polycystic Ovary Syndrome; Puberty Disorders; Ovulation Disorder
• Intervention / Treatment: Drug: Spironolactone

Detailed Description

This is a non-randomized, clinical pilot study testing whether 16 weeks of spironolactone improves ovulation rates in post-menarcheal girls with androgen excess. The investigators will recruit girls ages 13-19 with clinical or biochemical androgen excess (defined as hirsutism and/or elevated Tanner stage-specific free testosterone concentrations) who are 4 to 6 years post-menarche. Girls will keep a menstrual diary and collect twice weekly saliva samples for progesterone and estradiol for 16 weeks before and for 16 weeks during spironolactone (if ≤ 60 kg, 50 mg twice daily; if > 60 kg, 100 mg twice daily [1.7-3.3 mg/kg/24 hr]) use. Girls will be asked to continue to collect saliva twice weekly for progesterone and estradiol testing for an additional 16 weeks after discontinuation of spironolactone and to continue menstrual diaries off of study medication for 12 additional months to assess persistence of any spironolactone effect. Ovulation events will be counted per 100 days based on definitive rises in salivary progesterone. The primary outcome will be changes in ovulation rate during spironolactone use compared to baseline. Changes in menstrual regularity via inter-menstrual interval will also be assessed as a secondary outcome of spironolactone administration. Another secondary outcome will be changes in acne and/or hirsutism.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Melissa Gilrain, BS; Phone Number: 434-243-6911; Email: pcos@virginia.edu
• Study Contact Backup: Name: Christine Burt Solorzano, MD; Phone Number: 434-243-6911; Email: pcos@virginia.edu

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Recruiting
      • University of Virginia Center for Research in Reproduction
      • Contact: Melissa Gilrain; Phone Number: 434-243-6911; Email: pcos@virginia.edu
      • Principal Investigator: Christine Burt Solorzano, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 19 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Girls age 13 - 19 years, with clinical or biochemical HA (defined as hirsutism and/or elevated Tanner stage-specific free testosterone concentrations) that are 4-6 years post-menarche
• Screening labs within age-appropriate normal range
• Volunteers who are 18-19 y old must be willing and able to provide written informed consent.
• When the subject is a minor (i.e., age < 18 y), the subject and custodial parents must be willing and able to provide written informed assent and consent, respectively.
• Willingness to strictly avoid pregnancy (using non-hormonal methods) during the time of study.

Exclusion Criteria:

• Age < 13 or > 19 y
• Girls ≤ 3 years and ≥ 7 years post-menarche will be excluded
• Being a study of androgen excess in adolescent girls with HA, men and boys are excluded
• Inability to comprehend what will be done during the study or why it will be done
• Precocious puberty (breast development before age 7)
• Primary amenorrhea (no menses by age 16)
• BMI-for-age < 5th percentile
• Patients currently enrolled in another research protocol will be excluded, except for those enrolled in IRB-HSR 17633 DENND1A
• Obesity due to genetic syndrome (e.g. Prader-Willi syndrome)
• Cushing syndrome
• Positive pregnancy test or lactation. Subjects with a positive pregnancy test will be informed of the result by the screening physician. Under Virginia law, parental notification is not required for minors. However, the screening physician will encourage them to tell their parent(s) and counsel them about the importance of appropriate prenatal care and counseling. We will arrange follow-up for them at the Teen Health Clinic at the University of Virginia or their primary care physician's office in a timely manner.
• Diabetes mellitus
• History of congenital adrenal hyperplasia or 17-hydroxyprogesterone > 300 ng/dL in the follicular phase, which suggests the possibility of congenital adrenal hyperplasia. NOTE: If a 17-hydroxyprogesterone > 300 ng/dL is confirmed on repeat testing, and ACTH-stimulated 17-hydroxyprogesterone < 1000 ng/dL will be required for study participation.
• Total testosterone > 150 ng/dL
• Abnormal thyroid stimulating hormone (TSH) for age. Subjects with adequately treated hypothyroidism, reflected by normal TSH values, will not be excluded.
• Abnormal sodium, potassium, or bicarbonate concentrations, or elevated creatine concentration (confirmed on repeat)
• Subjects must not take exogenous steroids or any medications known to affect the reproductive axis or glucose metabolism for 3 months prior to the study (or in the 2 months prior to screening). Such medications include oral contraceptives, progestins, metformin, glucocorticoids, and antipsychotic medications
• If sexually active, subjects will be required to abstain and/or use barrier forms of contraception during the study.

Note: Abnormal laboratory studies may be confirmed by repeat testing to exclude laboratory error.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Spironolactone; 16 weeks without medication, then 16 weeks with medication, then 12 months without medication; spironolactone 50 mg tablets: 50-100 mg orally twice daily (1.7-3.3 mg/kg/24 hr)

Drug: Spironolactone; Spironolactone is an androgen-receptor commonly used (off-label) for hyperandrogenism in girls and women. It is used in this study to determine if androgen blockade can improve ovulation rates in girls with androgen excess, who often have low rates of ovulation in the years following menarche. The spironolactone dose will be as follows: If ≤ 60 kg, 50 mg twice daily; if > 60 kg, 100 mg twice daily.; Other Names: Aldactone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ovulation Rate Changes	Ovulation rate during and after spironolactone compared to before medication. Ovulation will be counted based on salivary progesterone levels. The rate of ovulation will be defined as the number of ovulatory cycles per 100 days of follow-up.	Rates of ovulation during weeks 17-32 (on medication) and weeks 33-48 (after medication) compared to weeks 1-16 (baseline, prior to medication)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Menstrual Regularity Changes	Menstrual length during and after spironolactone compared to before medication. Changes in menstrual regularity will be assessed using inter-menstrual interval (IMI)	IMI for weeks 1-16 (before medication, baseline), weeks 17-32 (on medication), and weeks 33-52 (after medication)
Acne	Changes in acne before vs. after spironolactone treatment assessed using the Global Acne Grading System	weeks 16 and 32
Hirsutism	Changes in hirsutism before vs. after spironolactone assessed using a modified Ferriman-Gallwey scoring system	weeks 16 and 32

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: Waterloo Foundation
• Investigators: Principal Investigator: Christine Burt Solorzano, MD, University of Virginia

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2019
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: August 29, 2019
• First Submitted That Met QC Criteria: August 29, 2019
• First Posted (Actual): August 30, 2019

Study Record Updates

• Last Update Posted (Actual): October 27, 2023
• Last Update Submitted That Met QC Criteria: October 25, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: PCOS; Polycystic Ovary Syndrome; ovulation; hyperandrogenemia; puberty; androgen excess
• Additional Relevant MeSH Terms: Neoplasms; Endocrine System Diseases; 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; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Polycystic Ovary Syndrome; Hyperandrogenism; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: 21768

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
• product manufactured in and exported from the U.S.: No