Oral Micronized Progesterone Side Effects: Incidence Rates Across Trials

What the label's two incidence tables measured

Prometrium is oral micronized progesterone in 100 mg and 200 mg capsules, approved in 1998 for preventing endometrial hyperplasia in postmenopausal women who are taking conjugated estrogens tablets and for secondary amenorrhea [2]. Its current label, Revision 02/2026, contains two placebo-controlled side-effect tables, and nearly every incidence figure quoted for this drug traces back to them [1].

Table 7 comes from a 3-year, multicenter, randomized, double-blind trial in 875 postmenopausal women. It lists reactions of 2% or more in 178 women taking cyclic Prometrium 200 mg for 12 days per 28-day cycle plus conjugated estrogens 0.625 mg daily, compared with 174 women taking placebo, who received no hormones [1].

Table 8 comes from a separate trial of 49 estrogen-primed postmenopausal women with secondary amenorrhea: 25 took Prometrium 400 mg per day and 24 took placebo [1].

The label notes that adverse reaction rates from trials run under widely varying conditions cannot be directly compared with one another and may not reflect rates seen in practice [2]. That applies to these two tables.

Incidence rates at 200 mg with conjugated estrogens

From Table 7, active treatment versus placebo over 3 years [1]:

• Headache: 31% vs 27%
• Breast tenderness: 27% vs 6%
• Joint pain: 20% vs 29%
• Depression: 19% vs 12%
• Dizziness: 15% vs 9%
• Abdominal bloating: 12% vs 5%
• Vaginal discharge: 10% vs 3%
• Nausea or vomiting: 8% vs 7%
• Breast pain: 6% vs 2%
• Hot flashes: 11% vs 35%; night sweats: 7% vs 17%

The comparison is a progesterone-plus-estrogen arm against a no-hormone placebo arm. Because the active group took conjugated estrogens as well, differences such as breast tenderness and bloating cannot be assigned to progesterone alone [1].

Headache was the most frequently reported reaction in the active arm (31%), but it was also common on placebo (27%). In the placebo arm, hot flashes (35%) were reported more often than headache. Hot flashes, night sweats and joint pain were all less frequent in the active arm; the lower vasomotor rates fit PEPI's finding that every active regimen reduced vasomotor symptoms [1][4].

Dizziness and drowsiness

The label's warnings section 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 [2]. The patient labeling repeats the bedtime instruction and gives the reason: some women become very drowsy or dizzy [1].

The label also describes an early-treatment reaction in which a few women have experienced extreme dizziness or drowsiness together with blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk and shortness of breath [2]. The postmarketing list adds sedation, stupor, syncope with and without hypotension, dysarthria and transient ischemic attack; those are voluntary reports from a population of uncertain size, so the label states that frequency cannot be reliably estimated and causation cannot be established [2].

The 400 mg secondary amenorrhea trial

Table 8 enrolled 25 women on progesterone and 24 on placebo, so each woman in the progesterone arm moves the percentage by about 4 points [1]. With that caveat, the full list at 5% or more reads: dizziness 24% versus 4%, abdominal cramping 20% versus 13%, headache 16% versus 8%, breast pain 16% versus 8%, musculoskeletal pain 12% versus 4%, viral infection 12% versus 0%, fatigue 8% versus 4%, irritability 8% versus 4%, diarrhea 8% versus 4%, nausea 8% versus 0%, coughing 8% versus 0%, bloating 8% versus 8% and back pain 8% versus 8% [1].

Because the 200 mg and 400 mg figures come from different trials in different populations, they cannot be read as a dose-response curve.

What PEPI adds

PEPI randomized 875 healthy postmenopausal women aged 45 to 64 to placebo, conjugated equine estrogen 0.625 mg alone, or estrogen plus one of three progestin regimens: medroxyprogesterone 10 mg for 12 days a month, medroxyprogesterone 2.5 mg daily, or micronized progesterone 200 mg for 12 days a month, for 3 years [5]. The estrogen was conjugated equine estrogen, no arm used estradiol, and the placebo arm took no hormones [5].

Symptom data from the same cohort showed that only the progestin-containing regimens were associated with more breast discomfort (odds ratios 1.92 to 2.27 versus placebo at 1 year), while anxiety, cognitive and affective symptoms did not differ by treatment assignment [4].

Contraindications and serious events

The label lists six contraindications: hypersensitivity to the ingredients, including peanut allergy because the capsules contain peanut oil; abnormal genital bleeding of unknown cause; known, suspected or past breast cancer; 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 [2].

Prometrium has no boxed warning in the current label [1]. The cardiovascular, breast cancer and probable dementia boxed-warning language was removed when FDA approved labeling changes for six menopausal hormone therapy products on 12 February 2026, and Prometrium was one of the six [3][6]. The WHI data on estrogen plus progestin remain in the warnings and clinical studies sections [1].

Table 7 also lists breast carcinoma in 2% of the combination arm versus less than 1% of placebo over 3 years [2].

Where the clotting and breast cancer numbers come from

Most of the risk figures attached to this drug class come from the WHI trial of 16,608 women aged 50 to 79, which used conjugated estrogens 0.625 mg plus medroxyprogesterone 2.5 mg [7]. The Prometrium label summarizes the WHI results at an average 5.6 years, including a relative risk of 1.24 for invasive breast cancer, 1.87 for deep vein thrombosis, 1.98 for pulmonary embolism and 1.37 for stroke [2]. The label states that the relevance of these findings to other doses, other routes or other estrogen-progestogen products is not known [2].

Evidence on micronized progesterone and breast cancer comes largely from observational work. A population-based case-control study identified 43,183 breast cancers and matched them to 431,830 controls: micronized progesterone had an odds ratio of 0.99 (0.55 to 1.79, a wide interval) and synthetic progestins 1.28 (1.22 to 1.35) [8]. An expert-panel systematic review concluded that estrogens combined with oral approved micronized progesterone do not increase breast cancer risk for up to 5 years of treatment, with limited evidence of an increase beyond that [9].

Interactions, liver disease and pregnancy

The label reports that ketoconazole inhibited progesterone metabolism in a laboratory test, but says the clinical relevance is unknown. It also reports increased progesterone bioavailability with food and changes in estrogen levels when Prometrium was taken with conjugated estrogens [1].

Known liver dysfunction or disease is a contraindication, and the effect of hepatic impairment on progesterone pharmacokinetics has not been studied [2][1].

The label states that Prometrium capsules should not be used during pregnancy [1].