Oral Micronized Progesterone Sleep Architecture Impact

What does the label say about sleep?

The Prometrium label lists exactly two uses: prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving conjugated estrogens tablets, and secondary amenorrhea [1]. Sleep is not one of them.

The bedtime instruction sits in the dosing section. The label specifies 200 mg orally as a single daily dose at bedtime for 12 days sequentially per 28-day cycle for a postmenopausal woman with a uterus who is receiving daily conjugated estrogens, and 400 mg at bedtime for 10 days for secondary amenorrhea [1]. The patient leaflet gives the reason: some women become very drowsy or dizzy [2].

The warnings are more specific. 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 it describes a few women who, during initial therapy, had extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath [1][2].

In the 3-year trial of 875 postmenopausal women summarized in the label, dizziness was reported by 15% of women taking cyclic Prometrium 200 mg with conjugated estrogens 0.625 mg (n=178) and by 9% of those on placebo (n=174) [2]. That arm also took estrogen, so the figure cannot be assigned to progesterone alone. Sedation appears in the label's postmarketing list of nervous-system reactions, for which the label says the frequency cannot be reliably estimated [1].

What do the polysomnographic studies show?

Three small sleep-laboratory studies underlie most claims that progesterone changes sleep architecture. They differ in population, dose, duration and what was measured.

8 postmenopausal women, 300 mg nightly for three weeks

Caufriez and colleagues randomized 8 healthy postmenopausal women aged 48 to 74, none with sleep complaints or vasomotor symptoms and none on hormone therapy, to 300 mg progesterone or placebo each night at 11 pm for 3 weeks, double-blind [3]. Sleep was recorded on two nights at the end of treatment, and on one of those nights blood was sampled every 15 minutes for 24 hours [3].

On the night without blood sampling, sleep was similar in both conditions. On the night with blood sampling, which markedly disturbed sleep under placebo, progesterone was associated with wake after sleep onset 53% lower, slow-wave sleep duration almost 50% higher, and total slow-wave activity almost 45% higher than placebo (P ≤ 0.05) [3]. The authors concluded that progesterone had no effect on undisturbed sleep but restored normal sleep when sleep was disturbed, acting as a physiologic regulator rather than as a hypnotic drug [3].

9 healthy men, evening progesterone

Friess and colleagues gave progesterone at 9:30 pm to 9 healthy men in a double-blind, placebo-controlled crossover, with polysomnography and simultaneous measurement of progesterone, allopregnanolone and pregnanolone [6]. Non-REM sleep increased significantly. Spectral power in the slow-wave range (0.4 to 4.3 Hz) fell significantly during non-REM sleep, while power above 15 Hz tended to rise [6]. The authors suggested the changes were mediated in part by conversion of progesterone into its GABA-active metabolites [6].

This was a study in 9 men, and its slow-wave power finding is not easy to reconcile with the higher slow-wave activity reported in postmenopausal women above: the populations, doses and measures differ.

21 postmenopausal women, two progestogens over six months

Montplaisir and colleagues randomized 21 postmenopausal women to conjugated estrogens (Premarin 0.625 mg) plus medroxyprogesterone acetate 5 mg (n=11) or plus oral micronized progesterone 200 mg (n=10), with two consecutive nights in the sleep laboratory at baseline and again after 6 months [4]. Sleep efficiency improved by 8% in the micronized progesterone group (p=0.014), and no such increase was seen with medroxyprogesterone acetate. Time awake after sleep onset also improved in the micronized progesterone group but not in the other arm, while subjective sleep and menopausal symptoms improved in both groups [4].

Both arms took estrogen, so this trial compares one progestogen with another on top of estrogen, not progesterone with nothing.

Does the route of administration change the picture?

The sleep work centers on GABA-active progesterone metabolites such as allopregnanolone and pregnanolone [6]. In one crossover study, the ratio of 5-alpha and 5-beta pregnanolone to progesterone in plasma was dramatically higher after oral than after vaginal administration while progesterone levels were similar [5]. A separate comparison of 100 mg doses in six premenopausal women found higher plasma concentrations of pregnanolone and deoxycorticosterone after oral than after vaginal dosing [7].

Both route comparisons measured hormone and metabolite levels, not sleep, so a difference in sleep outcomes between routes has not been shown by them.

Do the large menopause trials answer the sleep question?

The Kronos Early Estrogen Prevention Study randomized 727 women aged 42 to 58 who were within 3 years of their final menstrual period to oral conjugated estrogens 0.45 mg (n=230) or transdermal estradiol 50 micrograms (n=225), each with micronized progesterone 200 mg for 12 days of each month, or placebo (n=275) [8]. Insomnia decreased from baseline to 6 months in every group, placebo included. There was an intermittent reduction in insomnia in both active arms compared with placebo: oral conjugated estrogens was more effective than placebo at 36 and 48 months (P=0.002 and 0.05) and transdermal estradiol at 48 months (P=0.004) [8].

Both active arms contained estrogen and progesterone was taken only 12 days a month, so the design cannot separate the progesterone contribution, and insomnia here was a recorded symptom rather than a sleep-architecture measurement.

What about sleep-disordered breathing?

The relevant trial gave 9 women who had undergone hysterectomy and oophorectomy one week of placebo or medroxyprogesterone acetate 20 mg three times daily plus Premarin 1.25 mg twice daily, and recorded their sleep [9]. Sleep-disordered breathing episodes fell from an average of 15 ± 4 to 3 ± 1 per subject, and hypopneas became shorter [9]. The progestin was medroxyprogesterone acetate rather than oral micronized progesterone, the sample was 9 women, and treatment lasted one week, so this does not establish an effect of Prometrium on apnea.

Safety points that matter around a bedtime dose

Peanut allergy is a contraindication, not a caution, because the capsules contain peanut oil [1]. The other labeled contraindications are hypersensitivity to ingredients, abnormal genital bleeding of unknown cause, 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 such as stroke or myocardial infarction, and known liver dysfunction or disease [1].

The label also notes that progesterone may cause some degree of fluid retention and that women with cardiac or renal dysfunction warrant careful observation [1]. The label says to discontinue Prometrium immediately if pulmonary embolism, deep vein thrombosis, stroke or myocardial infarction occurs or is suspected [1].