Prometrium vs Compounded Micronized Progesterone: A Clinical Comparison

How does compounded micronized progesterone differ from Prometrium?

Prometrium is an FDA-approved oral micronized progesterone product. The label says its progesterone is micronized and chemically identical to progesterone of ovarian origin, synthesized from a plant-source starting material, with micronization used to increase oral bioavailability [2]. Prometrium is NDA 019781, first approved 14 May 1998, supplied as 100 mg and 200 mg capsules for oral use; generic progesterone capsules also exist [1][2]. Compounded progesterone is not FDA-approved, and FDA does not verify the safety, effectiveness or quality of compounded drugs before they are marketed [3].

FDA's stated position is that compounded drugs should only be used in patients whose medical needs cannot be met by an FDA-approved drug, and that unnecessary use may expose patients to serious risks; poor compounding practice can produce contamination or a product with too much or too little active ingredient [3]. Oversight also differs by setting: state boards of pharmacy have primary responsibility for day-to-day oversight of state-licensed pharmacies, while facilities registered with FDA as outsourcing facilities must follow current good manufacturing practice and are inspected by FDA on a risk-based schedule [3].

What evidence exists for Prometrium that compounded products do not have?

In the label's endometrial trial, 358 postmenopausal women with an intact uterus were treated for up to 36 months with Prometrium 200 mg for 12 days per 28-day cycle plus conjugated estrogens 0.625 mg (n=120), conjugated estrogens alone (n=119), or placebo (n=119). Hyperplasia by 36 months occurred in 6% (7 of 117) with the combination, 64% (74 of 115) with estrogen alone, and 3% (3 of 116) with placebo; atypical hyperplasia occurred in 1%, 12% and 0% [1].

PEPI was a 3-year, multicenter, double-blind, placebo-controlled trial of 875 healthy postmenopausal women aged 45 to 64, randomized to placebo, conjugated equine estrogen (CEE) 0.625 mg/day alone, CEE plus cyclic medroxyprogesterone acetate (MPA) 10 mg/day for 12 days a month, CEE plus continuous MPA 2.5 mg/day, or CEE plus cyclic micronized progesterone 200 mg/day for 12 days a month [5]. Mean HDL-cholesterol change was -0.03 mmol/L with placebo, +0.14 with CEE alone, +0.11 with CEE plus micronized progesterone, and +0.03 to +0.04 with the two MPA regimens [5].

The endometrial substudy, which biopsied 596 women, found simple hyperplasia in 27.7% of those on estrogen alone versus 0.8% on placebo, complex hyperplasia in 22.7% versus 0.8%, and atypical hyperplasia in 11.8% versus 0%; all three estrogen-plus-progestin regimens, including CEE plus cyclic micronized progesterone, had hyperplasia rates similar to placebo (P=.16) [6]. In the symptom analysis of the same 875 women, only the progestin-containing regimens were associated with more breast discomfort (odds ratio 1.92 to 2.27 versus placebo at 1 year), and every active treatment reduced vasomotor symptoms (OR 0.17 to 0.28) [7].

Two details matter when reading PEPI: the estrogen was conjugated equine estrogen, never estradiol, and the placebo group received placebo pills and no hormones [5].

The label trial studied Prometrium capsules. PEPI studied micronized progesterone with conjugated equine estrogen. Neither trial compared a compounded product with Prometrium.

How is Prometrium taken, and why at bedtime?

The label gives two doses. For prevention of endometrial hyperplasia, 200 mg orally as a single dose at bedtime for 12 days sequentially per 28-day cycle, in a postmenopausal woman with a uterus who is receiving daily conjugated estrogens tablets. For secondary amenorrhea, 400 mg at bedtime for 10 days [1]. The patient leaflet says to take it at bedtime because some women become very drowsy or dizzy [2]. For women who have trouble swallowing the capsules, the label says to take them with a glass of water while standing [1].

Those two indications are the only labeled ones, and the label's dosing and studies use conjugated estrogens; it does not describe use with estradiol [1].

What is known about absorption?

Prometrium's label states that after oral administration as a micronized soft-gelatin capsule, maximum serum concentrations were reached within 3 hours, and that the absolute bioavailability of micronized progesterone is not known [2]. After five daily doses in postmenopausal women, mean Cmax was 17.3 ng/mL at 100 mg (Tmax 1.5 h), 38.1 ng/mL at 200 mg (Tmax 2.3 h) and 60.6 ng/mL at 300 mg; serum concentrations were linear and dose proportional from 100 to 300 mg per day, with wide between-person variability (standard deviations often larger than the means) [2]. Food increased bioavailability relative to fasting at a 200 mg dose [2]. The label also states that pharmacokinetics have not been studied in hepatic impairment, renal impairment or obesity [2].

The clearest published comparison involving Prometrium is about route, not brand: Levine and colleagues (2000) gave 12 healthy postmenopausal women, six per group, either Crinone 8% progesterone gel 90 mg vaginally or Prometrium 100 mg orally. Mean Cmax was 10.51 ng/mL vaginally versus 2.20 ng/mL orally, mean Tmax was 7.67 hours versus 1.00 hour, and mean AUC per milligram was 1.48 versus 0.035 ng·h/mL [8]. It did not test a compounded capsule.

What about compounded creams and other routes?

Prometrium's labeling covers the oral capsules only [1]. For creams, a 2005 review by Stanczyk and colleagues raised the concern that serum progesterone levels achieved with progesterone creams are too low to have a secretory effect on the endometrium, while noting that antiproliferative effects on the endometrium have been demonstrated with creams when circulating progesterone is low; the authors argue that endometrial effects should be judged by endometrial histology rather than serum levels, and that salivary progesterone levels are very high with creams [9]. One small study, Burry et al. (1999), measured serum progesterone in six postmenopausal women using transdermal estradiol who applied progesterone cream 30 mg/day for 2 weeks and then 60 mg/day; mean serum progesterone ranged from 1.6 to 3.3 ng/mL, varied between women, and rose in all six [10].

What does the label warn about?

The label lists six contraindications: hypersensitivity to its ingredients, and the capsules contain peanut oil so they are contraindicated in patients allergic to peanuts; 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 [1].

On drowsiness, the label says Prometrium may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery. During initial therapy a few women experienced extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath [1][2]. Progesterone may cause some degree of fluid retention, and women with cardiac or renal dysfunction warrant careful observation [1].

The label says to stop Prometrium immediately if a pulmonary embolism, deep vein thrombosis, stroke or myocardial infarction occurs or is suspected, and, if feasible, to stop it at least 4 to 6 weeks before surgery associated with increased thromboembolic risk or during prolonged immobilization; it says to discontinue if a hormone-sensitive malignancy is diagnosed [2]. It states that the capsules should not be used during pregnancy [2].

Rates come from two label trials. In the 875-woman, 3-year trial of cyclic Prometrium 200 mg plus conjugated estrogens 0.625 mg (n=178) versus placebo (n=174): breast tenderness 27% versus 6%, abdominal bloating 12% versus 5%, headache 31% versus 27%, dizziness 15% versus 9%, and depression 19% versus 12% [2]. The comparator took no hormones, so those figures cannot separate progesterone from estrogen [2]. In the secondary amenorrhea trial, Prometrium 400 mg/day (n=25) versus placebo (n=24): dizziness 24% versus 4%, abdominal cramping 20% versus 13%, headache 16% versus 8%, and breast pain 16% versus 8% [2].

Does Prometrium have a boxed warning?

No. The current label, Revision 02/2026, carries no boxed warning [2]. Prometrium was one of the first six menopausal hormone therapy products whose updated labeling FDA approved on 12 February 2026, with cardiovascular, breast cancer and probable dementia language removed from the boxed warning [4][11]. The WHI estrogen-plus-progestin data remain in the label's Warnings and Clinical Studies sections, and the progestin used in WHI was medroxyprogesterone acetate 2.5 mg, not micronized progesterone [2][12]. In the WHI estrogen-plus-progestin trial summarized in the Prometrium label, 16,608 women aged 50 to 79 were followed for an average of 5.6 years. The reported relative risks were 1.24 for invasive breast cancer, 1.87 for deep vein thrombosis, 1.98 for pulmonary embolism, and 1.37 for stroke [1].

What about interactions?

The label's drug-interaction information is limited. It reports that progesterone metabolism by human liver microsomes was inhibited by ketoconazole (IC50 <0.1 micromolar) and that this suggests ketoconazole or other known inhibitors of the enzyme may increase the bioavailability of progesterone, with the clinical relevance of the in-vitro finding unknown [2]. It also reports a study in 29 postmenopausal women in which conjugated estrogens 0.625 mg with Prometrium 200 mg for 12 days raised total estrone Cmax from 3.68 to 4.93 ng/mL and total equilin Cmax from 2.27 to 3.22 ng/mL, and lowered circulating 17-beta estradiol Cmax from 0.037 to 0.030 ng/mL, with conjugated estrogen half-life unchanged [2]. The label has no separate drug-interactions section and does not name CYP3A4 inducers [2].