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Efficacy of micronized progesterone for sleep: a systematic review and meta-analysis of randomized controlled trial data
Brendan J. Nolan, Bonnie Liang, Ada S. Cheung
Abstract
Context: Pre-clinical data has shown progesterone metabolites improve sleep parameters through positive allosteric modulation of the GABA-A receptor. We undertook a systematic review and meta-analysis of randomized controlled trials to assess micronized progesterone treatment on sleep outcomes.
Evidence Acquisition: Using PRISMA guidelines, we searched MEDLINE, Embase, PsycInfo, and the Cochrane Central Register of Controlled Trials for randomized controlled trials of micronized progesterone treatment on sleep outcomes up to March 31, 2020. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42020165981. A random-effects model was used for quantitative analysis.
Evidence Synthesis: Our search strategy retrieved 9 randomized controlled trials comprising 388 participants. One additional unpublished trial was found. Eight trials enrolled post-menopausal women. Compared with placebo, micronized progesterone improved various sleep parameters as measured by polysomnography, including total sleep time and sleep onset latency, though studies were inconsistent. Meta-analysis of 4 trials favoured micronised progesterone for sleep onset latency (effect size, 7.10; C.I. 1.30, 12.91) but not total sleep time (effect size, 20.72; C.I -0.16, 41.59) or sleep efficiency (effect size, 1.31; C.I. -2.09, 4.70). Self-reported sleep outcomes improved in most trials. Concomitant estradiol administration and improvement in vasomotor symptoms limit conclusions in some studies.
Conclusions: Micronised progesterone improves various sleep outcomes in randomized controlled trials, predominantly in studies enrolling post-menopausal women. Further research could evaluate the efficacy of micronized progesterone monotherapy using polysomnography or validated questionnaires in larger cohorts.
Introduction
Progesterone is a sex steroid with biological roles including preparation of the uterus for implantation. However, accumulating preclinical data has demonstrated additional nonreproductive effects in the central nervous system in both sexes (1). Progesterone metabolites, including allopregnanolone, are positive allosteric modulators of the γ-aminobutyric acid type A (GABA-A) receptor (2,3) and have been shown to produce similar changes to sleep architecture as benzodiazepines (4).
Micronised progesterone or progestin treatment is often prescribed with estradiol as menopausal hormone therapy for women with an intact uterus. Impaired sleep is commonly reported at the menopausal transition (5-7) and has been shown to improve with combination estrogen/progesterone therapy (8). Given pre-clinical data demonstrating modulation of the GABA-A receptor with progesterone monotherapy, we undertook a systematic review of randomized controlled trials that reported the effects of micronized progesterone treatment compared with placebo or an active comparator on sleep outcomes in adult women and men.
Progestogens and sleep physiology
Progestogens, including micronized progesterone and progestins, are commonly prescribed as menopausal hormone therapy. Oral micronized progesterone is bioidentical to human progesterone whereas the progestins are synthetic progestogen derivatives (24). MPA is a derivative of 17αhydroxyprogesterone with agonistic activity at the progesterone, androgen, and glucocorticoid receptors, whereas dydrogesterone is a retroprogesterone with almost exclusive progestogenic activity (24).
Progesterone is known to produce sedative and hypnotic effects (25). Progesterone metabolites, including allopregnanolone, are positive allosteric modulators of the γ-aminobutyric acid type A (GABA-A) receptor (2,3,26) and have been shown to produce similar changes to sleep architecture as benzodiazepines (4).
Pre-clinical studies have demonstrated that both MPA (27) and dydrogesterone (28) also increase central nervous system allopregnanolone concentrations, providing a plausible basis for improvement in sleep parameters. However, the focus of this review remains on micronized progesterone given long-term safety concerns with progestins. MPA, together with conjugated equine estrogen, was associated with an increased risk of breast cancer and coronary heart disease in the Women’s Health Initiative (WHI) trial (29). Estrogen plus micronized progesterone, compared to estrogen plus progestin therapy, is associated with a lower risk of breast cancer (30) and does not impair endothelial function (31) or other cardiovascular safety parameters (32).
Micronised progesterone dose
Doses of 100-300mg oral micronized progesterone were used in the included studies. All studies that utilized polysomnography showed improvement in sleep parameters with doses of 200-300mg. Treatment with 100mg micronized progesterone resulted in improvements in improvements in sleep quality (14,16,18) but did not differ from comparator or control groups in two studies (16,18). There is significant inter-individual variability following oral micronized progesterone (35), and the dose that results in maximal effect while minimizing potential side effects such as drowsiness has not been studied.
Clinical implications
Micronised progesterone could be considered for improvement of sleep in postmenopausal women treated with menopausal hormone therapy, with placebo-controlled trials utilizing polysomnography prescribing 300mg at night. Given its mechanism of action, drowsiness is a documented adverse effect so night-time administration is recommended and does not impair morning cognitive function (21).
Conclusions
Randomized controlled data demonstrates that micronized progesterone improves various aspects of the sleep cycle and self-reported sleep outcomes, predominantly in studies involving postmenopausal women. However, results are inconsistent between studies. Further research should utilize polysomnography or validated sleep questionnaires such as PSQI in larger cohorts.
Brendan J. Nolan, Bonnie Liang, Ada S. Cheung
Abstract
Context: Pre-clinical data has shown progesterone metabolites improve sleep parameters through positive allosteric modulation of the GABA-A receptor. We undertook a systematic review and meta-analysis of randomized controlled trials to assess micronized progesterone treatment on sleep outcomes.
Evidence Acquisition: Using PRISMA guidelines, we searched MEDLINE, Embase, PsycInfo, and the Cochrane Central Register of Controlled Trials for randomized controlled trials of micronized progesterone treatment on sleep outcomes up to March 31, 2020. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42020165981. A random-effects model was used for quantitative analysis.
Evidence Synthesis: Our search strategy retrieved 9 randomized controlled trials comprising 388 participants. One additional unpublished trial was found. Eight trials enrolled post-menopausal women. Compared with placebo, micronized progesterone improved various sleep parameters as measured by polysomnography, including total sleep time and sleep onset latency, though studies were inconsistent. Meta-analysis of 4 trials favoured micronised progesterone for sleep onset latency (effect size, 7.10; C.I. 1.30, 12.91) but not total sleep time (effect size, 20.72; C.I -0.16, 41.59) or sleep efficiency (effect size, 1.31; C.I. -2.09, 4.70). Self-reported sleep outcomes improved in most trials. Concomitant estradiol administration and improvement in vasomotor symptoms limit conclusions in some studies.
Conclusions: Micronised progesterone improves various sleep outcomes in randomized controlled trials, predominantly in studies enrolling post-menopausal women. Further research could evaluate the efficacy of micronized progesterone monotherapy using polysomnography or validated questionnaires in larger cohorts.
Introduction
Progesterone is a sex steroid with biological roles including preparation of the uterus for implantation. However, accumulating preclinical data has demonstrated additional nonreproductive effects in the central nervous system in both sexes (1). Progesterone metabolites, including allopregnanolone, are positive allosteric modulators of the γ-aminobutyric acid type A (GABA-A) receptor (2,3) and have been shown to produce similar changes to sleep architecture as benzodiazepines (4).
Micronised progesterone or progestin treatment is often prescribed with estradiol as menopausal hormone therapy for women with an intact uterus. Impaired sleep is commonly reported at the menopausal transition (5-7) and has been shown to improve with combination estrogen/progesterone therapy (8). Given pre-clinical data demonstrating modulation of the GABA-A receptor with progesterone monotherapy, we undertook a systematic review of randomized controlled trials that reported the effects of micronized progesterone treatment compared with placebo or an active comparator on sleep outcomes in adult women and men.
Progestogens and sleep physiology
Progestogens, including micronized progesterone and progestins, are commonly prescribed as menopausal hormone therapy. Oral micronized progesterone is bioidentical to human progesterone whereas the progestins are synthetic progestogen derivatives (24). MPA is a derivative of 17αhydroxyprogesterone with agonistic activity at the progesterone, androgen, and glucocorticoid receptors, whereas dydrogesterone is a retroprogesterone with almost exclusive progestogenic activity (24).
Progesterone is known to produce sedative and hypnotic effects (25). Progesterone metabolites, including allopregnanolone, are positive allosteric modulators of the γ-aminobutyric acid type A (GABA-A) receptor (2,3,26) and have been shown to produce similar changes to sleep architecture as benzodiazepines (4).
Pre-clinical studies have demonstrated that both MPA (27) and dydrogesterone (28) also increase central nervous system allopregnanolone concentrations, providing a plausible basis for improvement in sleep parameters. However, the focus of this review remains on micronized progesterone given long-term safety concerns with progestins. MPA, together with conjugated equine estrogen, was associated with an increased risk of breast cancer and coronary heart disease in the Women’s Health Initiative (WHI) trial (29). Estrogen plus micronized progesterone, compared to estrogen plus progestin therapy, is associated with a lower risk of breast cancer (30) and does not impair endothelial function (31) or other cardiovascular safety parameters (32).
Micronised progesterone dose
Doses of 100-300mg oral micronized progesterone were used in the included studies. All studies that utilized polysomnography showed improvement in sleep parameters with doses of 200-300mg. Treatment with 100mg micronized progesterone resulted in improvements in improvements in sleep quality (14,16,18) but did not differ from comparator or control groups in two studies (16,18). There is significant inter-individual variability following oral micronized progesterone (35), and the dose that results in maximal effect while minimizing potential side effects such as drowsiness has not been studied.
Clinical implications
Micronised progesterone could be considered for improvement of sleep in postmenopausal women treated with menopausal hormone therapy, with placebo-controlled trials utilizing polysomnography prescribing 300mg at night. Given its mechanism of action, drowsiness is a documented adverse effect so night-time administration is recommended and does not impair morning cognitive function (21).
Conclusions
Randomized controlled data demonstrates that micronized progesterone improves various aspects of the sleep cycle and self-reported sleep outcomes, predominantly in studies involving postmenopausal women. However, results are inconsistent between studies. Further research should utilize polysomnography or validated sleep questionnaires such as PSQI in larger cohorts.
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