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).
This is a randomized, placebo-controlled, double-blinded crossover study to test the following hypothesis: In mid- to late pubertal girls with hyperandrogenism, spironolactone (50 mg twice daily) for 2 weeks will reduce sleep-associated luteinizing hormone (LH) pulse frequency compared to placebo treatment. To test this hypothesis, 16 late pubertal girls (signified by either \[a\] post-menarcheal status \[Tanner breast stages 2-5\] or \[b\] Tanner breast stage of 4 or 5 \[whether pre-menarcheal or post-menarcheal\], but no more than 4 years post-menarcheal) with hyperandrogenism (serum \[calculated\] free testosterone concentration greater than the Tanner stage-specific reference range and/or clinical hirsutism) will undergo two clinical research unit (CRU) admissions separated by at least 4 weeks. During each admission, blood will be obtained every 10 minutes through an indwelling IV catheter from 1600 to 0700 h. This will allow full characterization of pulsatile LH secretion in addition to other hormone measurements. Formal polysomnography will be performed during CRU admissions. Subjects will be randomized to be pretreated for 2 weeks with either spironolactone (an androgen receptor blocker commonly used for hyperandrogenism) or placebo prior to the first admission; subjects will be pretreated with the other medication (placebo or spironolactone) for 2 weeks before the second admission in accordance with a cross-over design. The primary endpoint is LH pulse frequency while asleep. (LH pulse frequency while awake is an important secondary endpoint). The sleep-associated LH pulse frequency data from the spironolactone and placebo admissions will be analyzed via a hierarchical linear mixed model (HLMM). Secondary endpoints will include the relationships between sleep stages and LH pulse initiation (analyzed as per Lu et al., Neuroendocrinology 2018 \[Epub ahead of print - doi: 10.1159/000488110\]), and we will test the following hypothesis: In mid- to late pubertal girls with hyperandrogenism, spironolactone will enhance the ability of rapid eye movement (REM) sleep to inhibit LH pulse initiation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
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).
Placebo contains only inert ingredients and is not expected to exert any direct physiological effects.
Center for Research in Reproduction, University of Virginia
Charlottesville, Virginia, United States
RECRUITINGChange 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.
Time frame: Baseline to 2 months
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.
Time frame: Baseline to 2 months
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.
Time frame: Baseline to 2 months
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Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
32