Prometrium Sleep Architecture Impact: What the Clinical Evidence Shows

Does Prometrium have a sleep indication?

No. The label lists two indications: prevention of endometrial hyperplasia in postmenopausal women with a uterus who are receiving conjugated estrogens tablets, and secondary amenorrhea [3]. The labeled dose is a single daily dose at bedtime, either 200 mg for 12 days per 28-day cycle alongside daily conjugated estrogens or 400 mg for 10 days for amenorrhea [3].

The bedtime instruction is a tolerability instruction. The label states that Prometrium may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery, and that it should be taken as a single daily dose at bedtime [3]. A 1999 review of oral micronized progesterone described mild, transient drowsiness as the only specific side effect and noted that it is minimized by taking the drug at bedtime [6].

How progesterone could affect sleep

Progesterone is converted to neuroactive metabolites, including allopregnanolone (3-alpha-hydroxy-5-alpha-dihydroprogesterone). In laboratory work on isolated brain vesicles and cultured rat neurons, that metabolite and a deoxycorticosterone metabolite acted as barbiturate-like ligands at the GABA-A receptor-chloride ion channel complex at concentrations between 10^-7 and 10^-5 M: they inhibited binding of a convulsant to the complex, increased benzodiazepine binding, stimulated chloride uptake and potentiated GABA's inhibitory effect on the neurons [7]. That is test-tube and cell evidence, not a human sleep result.

One human study measured sleep EEG and plasma neurosteroids together. In a double-blind, placebo-controlled crossover of nine healthy men, progesterone taken at 9:30 PM significantly increased the amount of non-REM sleep. During non-REM sleep, EEG spectral power in the 0.4 to 4.3 Hz band fell significantly, while power above 15 Hz tended to rise. The authors said some of the changes appeared to be mediated in part by conversion of progesterone into its GABA-active metabolites [8]. The subjects were men, so the result does not directly describe postmenopausal women.

What the sleep-lab studies in women show

Sleep efficiency versus medroxyprogesterone acetate

Twenty-one postmenopausal women were randomized to conjugated estrogen (Premarin) 0.625 mg plus either medroxyprogesterone acetate 5 mg (n=11) or oral micronized progesterone (Prometrium) 200 mg (n=10), and recorded in a sleep laboratory for two consecutive nights at baseline and again after 6 months [1]. Sleep efficiency rose by 8% in the micronized progesterone group (p=0.014), and no such increase was seen in the medroxyprogesterone group. Time spent awake after sleep onset improved significantly in the micronized progesterone group but not in the medroxyprogesterone group, while subjective sleep questionnaires and menopausal symptoms improved in both groups [1]. There was no placebo arm; every woman took estrogen.

Slow-wave sleep, but only when sleep was disturbed

Eight healthy postmenopausal women aged 48 to 74, with no sleep complaints and no vasomotor symptoms, took a capsule of 300 mg progesterone or placebo at 11 PM for 3 weeks in a randomized, double-blind, placebo-controlled study, with sleep recorded on the last two nights [2]. On the first night, with no blood sampling, sleep was similar on progesterone and placebo. On the other recorded night blood was drawn every 15 minutes, and that procedure produced marked sleep disturbance on placebo. The disturbance was considerably smaller on progesterone: mean wake after sleep onset was 53% lower, slow-wave sleep duration almost 50% higher and total slow-wave activity almost 45% higher than with placebo (P ≤ 0.05) [2]. The authors concluded that progesterone had no effect on undisturbed sleep but restored normal sleep when sleep was disturbed, acting as a physiological regulator rather than a hypnotic [2].

PEPI: the largest trial of this regimen

The PEPI trial was a 3-year, multicenter, double-blind, placebo-controlled trial of 875 healthy postmenopausal women aged 45 to 64, with five arms including conjugated equine estrogen 0.625 mg plus cyclic micronized progesterone 200 mg for 12 days a month [9]. The abstracts of its reports describe heart-disease risk factors [9], endometrial histology in 596 women [10] and self-reported symptom groups [11]; none describes polysomnography. In the symptom report, all active treatments reduced vasomotor symptoms (odds ratios 0.17 to 0.28 versus placebo), only progestin-containing regimens were associated with more breast discomfort (odds ratios 1.92 to 2.27), and anxiety, cognitive and affective symptoms did not differ by treatment [11].

Large cohort data, with limits

SWAN followed 3,045 women aged 42 to 52 at baseline with seven annual assessments. The odds of difficulty falling asleep and staying asleep rose across the menopausal transition, more frequent vasomotor symptoms were associated with higher odds of each sleep difficulty, and postmenopausal women using hormones generally had lower odds of disturbed sleep than non-users [12]. That analysis looked at hormone use as a group rather than micronized progesterone specifically, and it relied on self-report rather than sleep recording [12].

Dose, timing and absorption

After an oral dose, maximum serum progesterone concentrations were reached within 3 hours. In postmenopausal women after five daily doses, mean Cmax was 17.3 ng/mL at 100 mg/day (Tmax 1.5 hours) and 38.1 ng/mL at 200 mg/day (Tmax 2.3 hours), with high between-person variability [4]. Food increased bioavailability of the 200 mg dose relative to fasting [4]; in a randomized crossover study of 15 postmenopausal women, absorption of micronized progesterone was enhanced about twofold by food, without a change in time to peak [5].

Sleepiness, dizziness and the label's warnings

The label's adverse reaction tables give rates for the labeled populations. In postmenopausal women taking cyclic Prometrium 200 mg plus conjugated estrogens 0.625 mg for 3 years (n=178) versus placebo (n=174), dizziness was reported by 15% versus 9% [4]. In estrogen-primed postmenopausal women taking 400 mg/day for secondary amenorrhea (n=25) versus placebo (n=24), dizziness was reported by 24% versus 4% [4]. In the 200 mg table the active arm also took estrogen, so it cannot separate progesterone's effects from estrogen's.

The label notes that during initial therapy a few women have experienced extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath [4].

Interactions and other label points

The label's only drug-interaction statement concerns ketoconazole: metabolism of progesterone by human liver microsomes was inhibited by ketoconazole at an IC50 below 0.1 micromolar, which the label says suggests that ketoconazole or other known inhibitors of this enzyme may increase progesterone bioavailability, with the clinical relevance of the in-vitro findings unknown [4]. The label has no separate drug-interactions section, does not name CYP3A4 inducers, and does not mention grapefruit [4].

The capsules contain peanut oil, and peanut allergy is a contraindication, as are unexplained abnormal genital bleeding, known or suspected breast cancer or a history of it, active or prior deep vein thrombosis or pulmonary embolism, active or prior arterial thromboembolic disease, and known liver dysfunction or disease [3].

Limits of the sleep evidence

The two sleep-lab studies enrolled 8 and 21 women. The 8-woman result depended on sleep being disturbed by blood sampling, the 8-woman study enrolled women without sleep complaints, and the 21-woman study had no placebo arm. Each study tested a single progesterone dose, so these data do not establish a dose-response for sleep.