Prometrium Mental Health and Mood Impact: What the Evidence Actually Shows

Does Prometrium lift mood or ease anxiety?

One randomized source of symptom data is the PEPI trial, a 3-year, multicenter, double-blind, placebo-controlled study of 875 healthy postmenopausal women aged 45 to 64 [7]. Women were randomized to one of five arms: placebo, conjugated equine estrogen 0.625 mg daily, that estrogen plus cyclic medroxyprogesterone acetate 10 mg for 12 days a month, the same estrogen plus continuous medroxyprogesterone acetate 2.5 mg daily, or the estrogen plus cyclic micronized progesterone 200 mg for 12 days a month [7]. Estradiol was not used in any arm, and the placebo group took placebo pills and no hormones [7].

A separate analysis of the same 875 women looked at symptoms, which were self-reported on a checklist at 1 and 3 years. Anxiety, cognitive and affective symptoms did not differ by treatment assignment [1]. All active regimens reduced vasomotor symptoms compared with placebo (odds ratios 0.17 to 0.28), and only the progestin-containing regimens were linked to more breast discomfort (odds ratios 1.92 to 2.27) [1].

PEPI's primary endpoints were heart disease risk factors, not mood [7]. Its micronized progesterone arm also took conjugated estrogens, so it was not a test of progesterone alone.

What the Prometrium label records

The label's adverse reaction table comes from a 3-year trial in which 178 postmenopausal women took cyclic Prometrium 200 mg plus conjugated estrogens 0.625 mg and 174 took placebo [2]. Depression was reported by 19% versus 12%, worry by 8% versus 4%, dizziness by 15% versus 9% and headache by 31% versus 27% [2]. The comparison group received no hormones at all [2].

A second table covers 49 estrogen-primed postmenopausal women with secondary amenorrhea given 400 mg a day (25 women) or placebo (24 women). Irritability was reported by 8% versus 4%, headache by 16% versus 8%, and dizziness by 24% versus 4% [2]. These groups were small.

An open-label dosing study of 220 premenopausal women with secondary amenorrhea, given 300 mg or 400 mg with conjugated estrogens for 10 days per cycle, listed mood swing among treatment-emergent reactions reported in 5% or more of participants [4]. With no placebo arm, that listing does not establish cause.

The allopregnanolone explanation, and the paradoxical reaction

Progesterone is metabolized primarily in the liver, largely to pregnanediols and pregnanolones [2]. Allopregnanolone and pregnanolone, both neuroactive progesterone metabolites, are positive modulators of the GABA-A receptor, the main inhibitory system in the mammalian central nervous system [8].

Effects of progesterone metabolites on GABA-A receptors are believed to underlie negative mood in some women who take progesterone [8]. Positive GABA-A modulators have a biphasic effect: low concentrations increase an anxiogenic effect, while higher concentrations decrease it and produce calming [8]. Negative mood symptoms occur when the allopregnanolone serum concentration is similar to ordinary luteal-phase levels, an inverted U-shaped relationship [8]. One review puts paradoxical negative mood at 3% to 8% of people exposed to positive GABA-A modulators as a class, with up to 25% having moderate symptoms [3]. Women with premenstrual dysphoric disorder show altered GABA-A receptor sensitivity, and PMDD itself affects 3% to 8% of women of fertile age [3].

These are mechanistic reviews, not trials of Prometrium, and only certain women appear to react this way [8].

Sleep and drowsiness

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 is dosed as a single daily dose at bedtime [4]. The patient labeling says to take it at bedtime because some women become very drowsy or dizzy [2]. During initial therapy, a few women have had extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk and shortness of breath [4].

One small randomized trial looked at sleep: 8 healthy postmenopausal women aged 48 to 74, with no sleep complaints, took 300 mg of oral progesterone or placebo each night at 11 pm for 3 weeks, with sleep recorded on the last two nights [5]. On the first of those nights, without blood sampling, sleep was similar on progesterone and placebo. On the night with blood sampling, which markedly disturbed sleep on placebo, progesterone reduced wake after sleep onset by 53%, raised slow-wave sleep duration by almost 50% and raised total slow-wave activity by almost 45% (P of 0.05 or less) [5]. The authors concluded that progesterone had no effect on undisturbed sleep and restored normal sleep when it was disturbed [5].

Eight women is a small study, and 300 mg is above the 200 mg endometrial-protection dose in the label.

KEEPS-Cog: cognition and mood over four years

KEEPS-Cog followed 693 of the 727 women enrolled in the Kronos Early Estrogen Prevention Study for up to 4 years [6]. Women were randomized to oral conjugated equine estrogen 0.45 mg plus micronized progesterone 200 mg for the first 12 days of each month (220 women), transdermal estradiol 50 micrograms plus the same micronized progesterone schedule (211 women), or placebo pills and patches (262 women). Mood was a primary outcome, measured with the Profile of Mood States [6]. Average age was 52.6 years and participants were about 1.4 years past their last menstrual period [6].

Both active arms received micronized progesterone, and neither received a synthetic progestin. KEEPS-Cog therefore cannot compare micronized progesterone with medroxyprogesterone acetate on cognition or mood [6].

What the label covers, and what stays unknown

The label's indications are prevention of endometrial hyperplasia in postmenopausal women with a uterus who are receiving conjugated estrogens tablets, and secondary amenorrhea [4]. It gives 200 mg at bedtime for 12 days per 28-day cycle with daily conjugated estrogens, or 400 mg at bedtime for 10 days for amenorrhea [4]. The label's dosing and trials use conjugated estrogens and do not describe use with estradiol [4]. Prometrium is not approved to treat depression, anxiety or insomnia; the label's bedtime instruction relates to drowsiness and dizziness [2][4].

The label lists peanut allergy as a contraindication, because the capsules contain peanut oil [4].

PEPI, the label trials and KEEPS-Cog all tested progesterone together with estrogen, so none can show whether progesterone alone caused any mood finding [1][2][6].