Does Spironolactone Normalize Sleep-wake Luteinizing Hormone Pulse Frequency in Pubertal Girls With Hyperandrogenism?

NCT04723862 | Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: HSR200015R01HD102060
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine if, in mid- to late pubertal girls with hyperandrogenism (HA), androgen-receptor blockade (spironolactone) alone normalizes sleep-wake luteinizing hormone (LH) pulse frequency (primary endpoint) and overall LH and follicle-stimulating hormone secretion (secondary endpoints).

Conditions

Hyperandrogenism; Polycystic Ovary Syndrome; Puberty

Keywords

Hyperandrogenism; Polycystic ovary syndrome; Puberty

Outcome Measures

Primary Outcomes (1)

• Change in Sleep-Associated Luteinizing Hormone (LH) Pulse Frequency Between Admission With Spironolactone Versus Placebo

  The sleep-associated (22:00 h - 07:00 h) luteinizing hormone (LH) pulse frequency data from the spironolactone and placebo admissions will be analyzed via a hierarchical linear mixed model (HLMM). Sleep-associated LH pulse frequency will be compared between the spironolactone admission and the placebo admission via a linear contrast of the HLMM least squares LH pulse frequency means.

  Baseline to 2 months

Secondary Outcomes (2)

• Change in Wake-Associated Luteinizing Hormone (LH) Pulse Frequency Between Admission With Spironolactone Versus Placebo

  Baseline to 2 months

• Change in Proportion of Luteinizing Hormone (LH) Pulses with Preceding REM Sleep With and Without Spironolactone

  Baseline to 2 months

Study Arms (2)

Spironolactone

EXPERIMENTAL

Prior to the first or second admission (randomly determined), participants will be pretreated for 2 weeks with spironolactone (50 mg twice daily).

Drug: Spironolactone

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: Placebo

Interventions

Spironolactone DRUG

Spironolactone is an androgen-receptor blocker commonly used (off-label) for hyperandrogenism. The spironolactone dose will be 50 mg taken orally twice daily (for two weeks before admission to the Clinical Research Unit).

Spironolactone

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 10 Years - 17 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Mid- to late pubertal adolescent girls as signified by either (a) post-menarcheal status (Tanner breast stages 2-5) or (b) Tanner breast stage of 4 or 5 (whether pre-menarcheal or post-menarcheal) ages 10-17 years.
• Hyperandrogenism, defined as a serum (calculated) free testosterone concentration greater than the Tanner stage-specific reference range and/or clinical hirsutism
• General good health (excepting obesity, hyperandrogenism, PCOS, and adequately-treated hypothyroidism)
• 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 (hyperandrogenism is unique to females)
• Age \< 10 or \> 17 years (this study is designed to elucidate mechanisms underlying emerging PCOS in mid- to late pubertal adolescent girls
• Post-menarcheal by \> 4 years
• Obesity resulting from a well-defined endocrinopathy, or genetic syndrome
• Positive pregnancy test or current 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 the subject to tell her parent(s). We will counsel the adolescent about the importance of appropriate prenatal care/counseling. We will offer appropriate follow-up at the Teen Health Clinic at UVA and/or encourage the adolescent to secure prompt care via their primary care physician's office.
• 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 adolescent HA and in PCOS, and will be accepted in these groups.
• Early morning 17-hydroxyprogesterone \> 300 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-hydorxyprogesterone \> 300 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.
• Any abnormal TSH concentration will trigger repeat testing. In many cases when TSH is initially abnormal, a repeat TSH will be normal. These subjects will be permitted to continue study. If TSH remains abnormal on repeat testing, the subject will be referred to her primary medical provider. In some cases, a participant's primary medical provider will elect to simply observe a mildly low (\> 0.1) or mildly elevated (\< 10) if stable. In such cases, we will accept a TSH between 0.3 and 7 (inclusive) if it has remained stable for at least 6 months-such TSH values are exceedingly unlikely to influence the central reproductive axis or to influence the risks of the study. Notably, subjects with reasonably-treated primary hypothyroidism-reflected by TSH values between 0.3 and 7-on a stable dose of thyroid hormone (i.e., same dose for at least 2 months) will not be excluded.
• Prolactin concentration \> 30 ng/mL (confirmed on repeat). Mild prolactin elevations may be seen in adolescents and women with HA/PCOS or obesity.
• 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.)

Sponsors & Collaborators

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

Study Sites (1)

Center for Research in Reproduction, University of Virginia

Charlottesville, Virginia, 22908, United States

RECRUITING

MeSH Terms

Conditions

Hyperandrogenism; Polycystic Ovary Syndrome

Interventions

Spironolactone

Condition Hierarchy (Ancestors)

46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Adrenogenital Syndrome; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Gonadal Disorders; Endocrine System Diseases; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Genital Diseases

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Christine Burt Solorzano, MD

  University of Virginia Center for Research in Reproduction

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Melissa Gilrain, BS

CONTACT

434-243-6911; mg7zb@hscmail.mcc.virginia.edu

Christine Burt Solorzano, MD

CONTACT

434-243-6911; cmb6w@hscmail.mcc.virginia.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Treatment allocation will be double-blinded. The blind will be broken in the event of any adverse effects that would also lead to study withdrawal. The blind for a given subject will be lifted after the subject completes the study and analysis is complete for that subject.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor in Pediatrics

Model Details: Randomized, placebo-controlled, crossover study

Study Record Dates

• First Submitted: November 18, 2020
• First Posted: January 26, 2021
• Study Start: November 12, 2021
• Primary Completion: October 1, 2025
• Study Completion: December 1, 2025
• Last Updated: August 5, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)