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).
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.
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
Crossover
Spironolactone
DrugSpironolactone 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).
Placebo
DrugPlacebo contains only inert ingredients and is not expected to exert any direct physiological effects.
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.
Change in Wake-Associated Luteinizing Hormone (LH) Pulse Frequency Between Admission With Spironolactone Versus Placebo
The wake-associated (16:00 - 22:00) luteinizing hormone (LH) pulse frequency data from the spironolactone and placebo admissions will be analyzed via a hierarchical linear mixed model (HLMM). Wake-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.
Change in Proportion of Luteinizing Hormone (LH) Pulses with Preceding REM Sleep With and Without Spironolactone
We will analyze the proportion of luteinizing hormone (LH) pulses with REM sleep documented in the 5 minutes before each pulse and assess whether this is different between admissions with and without spironolactone. Our hypothesis is that, in the setting of hyperandrogenemia, androgen excess results in more LH pulses associated with REM sleep and that androgen blockade with spironolactone will decrease the number of LH pulses that have REM sleep immediately before the pulse. The determination of sleep stages before LH pulse initiation will be conducted as recently described by our group (Lu et al., Neuroendocrinology 2018 \[Epub ahead of print - doi: 10.1159/000488110\]). The differences in proportion of REM sleep-associated LH pulses between spironolactone and placebo admissions will be analyzed via a hierarchical linear mixed model (HLMM) and compared via a linear contrast of the HLMM least squares LH pulse frequency means.
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University of Virginia
Lead sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Collaborator
