Investigating hormone treatment effects in girls with high androgen levels

Study to Evaluate if Androgen-receptor Blockade (Spironolactone) Improves Progesterone-suppression of Wake Luteinizing Hormone Pulse Frequency in Pubertal Girls With Hyperandrogenism

This study is testing if a medication called spironolactone can help girls with high androgen levels by making another hormone treatment more effective in lowering certain 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: NCT03068910 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate whether spironolactone, an androgen-receptor blocker, enhances the effectiveness of progesterone in reducing luteinizing hormone (LH) pulse frequency in mid- to late pubertal girls with hyperandrogenism. It employs a randomized, placebo-controlled, double-blinded crossover design, where participants will undergo two Clinical Research Unit admissions after receiving either spironolactone or placebo for two weeks. During these admissions, blood samples will be collected to measure hormone levels and assess LH secretion patterns. The primary outcome is the frequency of LH pulses while awake, which will help determine the impact of the treatment.

Who should consider this trial

Good fit: Ideal candidates for this study are mid- to late pubertal girls diagnosed with hyperandrogenism.

Not a fit: Patients who are male or those with obesity due to a well-defined endocrinopathy or genetic syndrome may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide a new therapeutic approach for managing hyperandrogenism in adolescent girls, potentially improving their hormonal balance and related symptoms.

How similar studies have performed: While there have been studies on hormone treatments for hyperandrogenism, this specific approach using spironolactone in a crossover design is relatively novel.

Eligibility criteria

Inclusion Criteria:

* Mid- to late pubertal adolescent girl (at least Tanner breast stage 3, but no more than 2 years postmenarcheal)
* Hyperandrogenism, defined as a serum (calculated) free testosterone concentration greater than the Tanner stage-specific reference range and/or unequivocal evidence for hirsutism
* General good health (excepting overweight, obesity, hyperandrogenism, and adequately-treated hypothyroidism)
* Capable of and willing to provide informed assent (adolescents under age 16 years) and/or consent (adolescents over age 16 years; custodial parents or guardians of all adolescent volunteers)
* 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)
* Obesity resulting from a well-defined endocrinopathy or genetic syndrome
* Positive pregnancy test or current lactation
* 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 \> 200 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-hydroxyprogesterone \> 200 ng/dl is confirmed on repeat testing, an ACTH stimulated 17-hydroxyprogesterone \< 1000 ng/dl will be required for study participation.
* Abnormal thyroid stimulating hormone (TSH): Note that subjects with stable and adequately treated primary hypothyroidism, reflected by normal TSH values, will not be excluded.
* Hyperprolactinemia \> 20% higher than the upper limit of normal. Mild prolactin elevations may be seen in adolescents and women with HA/PCOS, and elevations within 20% higher than the upper limit of normal will be accepted in this group.
* 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 hematocrit \< 36% and hemoglobin \< 12 g/dl.
* Severe thrombocytopenia (platelets \< 50,000 cells/microliter) or leukopenia (total white blood count \< 4,000 cells/microliter)
* Previous diagnosis of diabetes, fasting glucose \> or = 126 mg/dl, or a hemoglobin A1c \> or = 6.5%
* Persistent liver panel abnormalities, with two exceptions. Mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome. Also, mild transaminase elevations may be seen in obesity/HA/PCOS; therefore, elevations \< 1.5 times the upper limit of normal will be accepted in this group.
* 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
* A personal history of breast, ovarian, or endometrial cancer
* History of any other 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
* History of allergy to micronized progesterone or spironolactone
* Body mass index (BMI)-for-age percentile \< 5% (underweight)
* Due to the amount of blood being drawn, adolescent volunteers with body weight \< 25 kg will be excluded.
* Restrictions on use of other drugs or treatments: No medications known to affect the reproductive system, glucose metabolism, lipid metabolism, or blood pressure can be taken in the 2 months prior to the screening visit and in the 3 months prior to the start of the study medications. Such medications include oral contraceptive pills, progestins, metformin, systemic glucocorticoids, some antipsychotic medications, and sympathomimetics/stimulants (e.g., methylphenidate).

Where this trial is running

Charlottesville, Virginia

• University of Virginia Clinical Research Unit — Charlottesville, Virginia, United States (Recruiting)

Study contacts

• Principal investigator: Christine Burt Solorzano, M.D. — University of Virginia Center for Research in Reproduction
• Study coordinator: Melissa Gilrain, MS

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