Using spironolactone to normalize hormone levels in pubertal girls with high androgen levels

Does Spironolactone Normalize Sleep-wake Luteinizing Hormone (LH) Pulse Frequency in Pubertal Girls With Hyperandrogenism? (CBS010)

This study is testing if the medication spironolactone can help normalize hormone levels in pubertal girls with high androgen levels by looking at how it affects their sleep and hormone pulses.

Quick facts

• Phase: Early Phase 1
• Study type: Interventional
• Enrollment: 32 (estimated)
• Ages: 10 Years to 17 Years
• Sex: Female
• Sponsor: University of Virginia (Academic / other)
• Locations: 1 site (Charlottesville, Virginia)
• Trial ID: NCT04723862 on ClinicalTrials.gov

What this trial studies

This study investigates whether spironolactone, an androgen-receptor blocker, can normalize sleep-wake luteinizing hormone (LH) pulse frequency in mid- to late pubertal girls diagnosed with hyperandrogenism. It is a randomized, placebo-controlled, double-blinded crossover study involving 16 participants who will receive either spironolactone or a placebo for two weeks before undergoing two clinical research unit admissions. During these admissions, blood samples will be collected every 10 minutes to assess LH secretion, and formal polysomnography will be conducted to evaluate sleep patterns. The primary goal is to determine the effect of spironolactone on LH pulse frequency compared to placebo.

Who should consider this trial

Good fit: Ideal candidates are mid- to late pubertal girls aged 10-17 with hyperandrogenism, as indicated by elevated testosterone levels or clinical hirsutism.

Not a fit: Patients who are male, younger than 10 or older than 17, or have obesity due to a well-defined endocrinopathy or genetic syndrome may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could help normalize hormone levels and improve reproductive health in pubertal girls with hyperandrogenism.

How similar studies have performed: While this approach is novel in this specific context, previous studies have shown that spironolactone can be effective in managing hyperandrogenism in women.

Eligibility criteria

Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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
* To ensure that blood withdrawal is within safe limits, weight \< 21.5 kg is an exclusion criterion.
* Since underweight can alter pulsatile LH secretion, BMI-for-age percentile \< 5 is an exclusion criterion.
* 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.)
* Persistent hemoglobin \< 11.5 g/dL for non-African American subjects; hemoglobin \< 11.0 g/dL for African American subjects (confirmed on repeat). Importantly, documentation of a hemoglobin ≥ 11.0 g/dL for African American subjects or ≥ 11.5 g/dL for non-African American subjects in the month prior to the CRU admission is required for frequent sampling protocol in the CRU.
* Severe thrombocytopenia (platelets \< 50,000 cells/microliter) or leukopenia (total white blood count \< 4,000 cells/microliter)
* Previous diagnosis of diabetes, fasting glucose ≥ 126 mg/dl, or a hemoglobin A1c ≥ 6.5%
* Persistently abnormal sodium or potassium concentration. Bicarbonate concentrations \< 20 or \> 30.
* Liver test abnormalities, with two exceptions: (1) mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome or when the subject's primary care provider provides a presumptive diagnosis of Gilbert's syndrome and has no plans for further work-up; (2) mild transaminase (ALT, AST) elevations may be seen in obese/HA/PCOS girls, so stable elevations \< 1.5 times the upper limit of normal will be accepted in this group.
* Absolute contraindications to spironolactone use include history of allergy to spironolactone, anuria, acute renal insufficiency, significant impairment of renal excretory function, hyperkalemia, primary adrenal insufficiency (Addison's disease), and concomitant use of eplerenone
* Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure, asthma requiring intermittent systemic corticosteroids, etc.)
* Decreased renal function evidenced by GFR \< 60 ml/min/1.73m2
* History of cancer diagnosis and/or treatment (with the exception of basal cell or squamous cell skin carcinoma) unless they have remained clinically disease free (based on appropriate surveillance) for five years.

Where this trial is running

Charlottesville, Virginia

• Center for Research in Reproduction, University of Virginia — Charlottesville, Virginia, United States (Recruiting)

Study contacts

• Principal investigator: Christine Burt Solorzano, MD — University of Virginia Center for Research in Reproduction
• Study coordinator: Melissa Gilrain, BS

Conditions Hyperandrogenism; Polycystic Ovary Syndrome; Puberty; Polycystic ovary syndrome