Progesterone is the body’s own progestogen, a steroid hormone made mainly by the ovary after ovulation and by the placenta in pregnancy. As a medicine it is chemically identical to the natural hormone. In the US it is sold as oral micronized capsules (Prometrium and generics), as vaginal gels and inserts, and as an oil-based injection.
Its main approved job is protecting the lining of the uterus in postmenopausal women who take estrogen, where it cut endometrial hyperplasia from 64% to 6% over three years in the pivotal trial. It is also approved for absent periods (secondary amenorrhea) and, in vaginal form, for luteal support during IVF. It has no approved use in men, and it lowers LH, FSH and testosterone when given to men.
This page summarizes what the FDA labels and the major clinical trials report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Natural progestogen (steroid hormone, pregn-4-ene-3,20-dione) |
| US products | Prometrium oral capsules (NDA 019781, approved 1998) and generics; Bijuva (with estradiol, 2018); Crinone vaginal gel; Endometrin vaginal insert (2007); progesterone injection USP in oil |
| Routes | Oral, vaginal, intramuscular |
| Strengths | Capsules 100 and 200 mg; vaginal gel 45 and 90 mg per dose; vaginal insert 100 mg; injection 50 mg/mL |
| Labeled oral doses | 200 mg at bedtime for 12 days per 28-day cycle (with estrogen); 400 mg at bedtime for 10 days (amenorrhea) |
| Half-life | Minutes once in the blood (5–20 min); effective ≈ 9–10 h after daily oral dosing; ≈ 20–55 h apparent from vaginal or intramuscular depots (labels) |
| Oral bioavailability | ≈ 9% relative to intramuscular; roughly doubled by food |
| US status | Prescription drug; not a controlled substance |
| WADA status | Not on the 2026 Prohibited List |
What it is
Progesterone has the formula C₂₁H₃₀O₂ and a molecular weight of 314.47 g/mol (Prometrium label). The pharmaceutical product is synthesized from a plant-derived starting material, and the label states it is chemically identical to progesterone of ovarian origin. “Micronized” means it is milled into very fine particles, which the label says increases oral bioavailability.
In the presence of estrogen, progesterone turns the growing (proliferative) lining of the uterus into a secretory lining that can accept an embryo, and it maintains early pregnancy. It also lowers the release of gonadotropins (LH and FSH) from the pituitary (Crinone label).
The word “progestin” usually refers to synthetic progestogens such as medroxyprogesterone acetate (MPA), the drug used in the Women’s Health Initiative (WHI) trial. A 2013 Endocrine Reviews analysis concluded that progesterone and the various progestins differ in structure, metabolism, receptor activity and clinical effects, so they should not be treated as one interchangeable class (Stanczyk et al., Endocr Rev 2013). This matters when reading safety data, because much of it comes from MPA.
| Product | Form | Labeled use |
|---|---|---|
| Prometrium and generics | Oral capsule in peanut oil, 100 or 200 mg | Endometrial protection with estrogen; secondary amenorrhea |
| Bijuva | Oral capsule, 100 mg progesterone plus 0.5 or 1 mg estradiol | Moderate to severe menopausal hot flashes in women with a uterus |
| Crinone 4% / 8% | Vaginal gel, 45 / 90 mg per applicator | Secondary amenorrhea (4%, then 8%); ART support (8%) |
| Endometrin | Vaginal insert, 100 mg | ART support in women under 35, up to 10 weeks of pregnancy |
| Progesterone injection USP | 50 mg/mL in sesame oil, intramuscular | Amenorrhea and abnormal uterine bleeding from hormonal imbalance |
Sources: Prometrium, Bijuva, Crinone, Endometrin and progesterone injection labels.
Pharmacokinetics
Oral capsules
Taken by mouth, progesterone is heavily broken down by the liver on first pass. In a crossover study of 15 postmenopausal women, oral micronized progesterone had a bioavailability of 8.6% relative to an intramuscular injection, and food roughly doubled absorption (Simon et al., Fertil Steril 1993). The Prometrium label reports these values in postmenopausal women after five daily doses:
| Daily dose | Peak level (Cmax) | Time to peak | AUC 0–10 h |
|---|---|---|---|
| 100 mg | 17.3 ng/mL | 1.5 h | 43.3 ng·h/mL |
| 200 mg | 38.1 ng/mL | 2.3 h | 101.2 ng·h/mL |
| 300 mg | 60.6 ng/mL | 1.7 h | 175.7 ng·h/mL |
Levels rose in proportion to dose. The label adds that in male volunteers, levels were also dose-proportional from 100 to 400 mg/day, with kinetics generally similar to those in women. Variability between people is large: the standard deviations in the label table are about as big as the means.
The Prometrium label does not state a half-life. The Bijuva label, which uses 100 mg oral progesterone, reports an effective half-life of 9 ± 3 h and 10 ± 3 h at steady state, with peaks about 2–3 h after dosing. A high-fat meal raised progesterone Cmax by 162% and AUC by 79% (Bijuva label).
Vaginal and intramuscular forms
Progesterone itself is cleared from the blood within minutes. The Crinone label gives an elimination half-life of 5–20 minutes, so the longer “half-lives” measured after vaginal or injected doses reflect slow absorption from the depot rather than slow clearance (Crinone label). Single-dose data in 20 estrogen-treated postmenopausal women:
| Measure | Vaginal gel 45 mg | IM 45 mg | Vaginal gel 90 mg | IM 90 mg |
|---|---|---|---|---|
| Cmax | 13.2 ng/mL | 39.1 ng/mL | 14.9 ng/mL | 53.8 ng/mL |
| Time to peak | 5.6 h | 8.2 h | 6.8 h | 9.2 h |
| Apparent half-life | 55.1 h | 28.1 h | 34.8 h | 19.6 h |
| Bioavailability vs IM | 27.6% | Reference | 19.8% | Reference |
For the oil injection, 10, 25 and 50 mg IM produced mean peaks of 7, 28 and 50 ng/mL, and a 10 mg dose kept levels above baseline for about 24 hours (progesterone injection label).
Distribution and metabolism
- Protein binding: 96–99%, mainly to albumin (50–54%) and transcortin, also called cortisol-binding globulin (43–48%).
- Metabolism: in the liver, mostly to pregnanediols and pregnanolones, which are conjugated and excreted in urine and bile.
- CYP3A4: ketoconazole blocked progesterone metabolism in human liver microsomes in the lab. The labels say strong CYP3A4 inhibitors may therefore raise progesterone exposure, but the clinical relevance is unknown.
Approved medical use
Protecting the uterus during estrogen therapy
Estrogen taken alone stimulates the uterine lining and raises the risk of endometrial hyperplasia, a thickening that can lead to cancer. The Prometrium dose for this use is 200 mg as a single dose at bedtime for 12 days of each 28-day cycle, in a postmenopausal woman with a uterus taking daily conjugated estrogens (Prometrium label). Bijuva combines estradiol and progesterone in one evening capsule for menopausal hot flashes.
Secondary amenorrhea and abnormal bleeding
Secondary amenorrhea means periods have stopped for months in a woman who previously menstruated. The labeled doses are:
- Prometrium 400 mg at bedtime for 10 days;
- Crinone 4% gel every other day, up to six doses, with 8% if 4% fails;
- progesterone injection 5–10 mg daily for six to eight days, with withdrawal bleeding expected 48–72 hours after the last injection.
Assisted reproduction
After egg retrieval in IVF, the body’s own progesterone production is often inadequate. Endometrin is labeled at 100 mg vaginally two or three times daily for up to 10 weeks (Endometrin label). Crinone 8% is labeled at 90 mg once daily for supplementation, or twice daily in women with partial or complete ovarian failure.
What the research shows
Endometrial protection
In the randomized, double-blind trial behind the Prometrium label, 358 postmenopausal women with a uterus were treated for up to 36 months (Prometrium label):
| Group | Any hyperplasia | Atypical hyperplasia |
|---|---|---|
| Conjugated estrogens 0.625 mg + progesterone 200 mg (12 days/cycle) | 6% | 1% |
| Conjugated estrogens 0.625 mg alone | 64% | 12% |
| Placebo | 3% | 0% |
These women were part of the PEPI trial, which randomized 875 women aged 45–64 to placebo, estrogen alone, or estrogen with one of three progestogen regimens for 3 years (PEPI Trial, JAMA 1995). Its key findings:
| Outcome | Estrogen + micronized progesterone | Estrogen + MPA | Estrogen alone | Placebo |
|---|---|---|---|---|
| HDL cholesterol change | +4.1 mg/dL | +1.2 to +1.6 mg/dL | +5.6 mg/dL | −1.2 mg/dL |
| Adenomatous or atypical hyperplasia | About 1% (all combined arms) | About 1% (all combined arms) | 34% | — |
The authors concluded that, for women with a uterus, estrogen with cyclic micronized progesterone had the most favorable effect on HDL without excess hyperplasia.
Secondary amenorrhea
In a randomized, double-blind study, 80% of women given Prometrium 300 mg/day for 10 days had withdrawal bleeding, compared with 10% on placebo (n = 20 and 21). In estrogen-primed postmenopausal women, 400 mg/day for 10 days produced complete secretory change of the uterine lining in 45%, versus 0% on placebo (Prometrium label).
Miscarriage prevention
Two large UK trials tested vaginal micronized progesterone 400 mg twice daily in early pregnancy. Neither found a statistically significant increase in live births:
| Trial | Population | n | Live births, progesterone vs placebo | Relative rate (95% CI) |
|---|---|---|---|---|
| PROMISE (Coomarasamy et al., NEJM 2015) | Unexplained recurrent miscarriage | 836 | 65.8% vs 63.3% | 1.04 (0.94–1.15) |
| PRISM (Coomarasamy et al., NEJM 2019) | Bleeding in early pregnancy | 4,153 | 75% vs 72% | 1.03 (1.00–1.07), p = 0.08 |
Adverse events did not differ significantly between groups in either trial.
Preterm birth
Results here depend on who is treated:
- OPPTIMUM. In 1,228 women at risk of preterm birth, vaginal progesterone 200 mg daily from 22–24 to 34 weeks did not significantly reduce fetal death or birth before 34 weeks (OR 0.86, 95% CI 0.61–1.22). Cognitive scores at 2 years were no different (Norman et al., Lancet 2016).
- EPPPIC meta-analysis. Pooling individual data from 31 trials (11,644 women), vaginal progesterone reduced birth before 34 weeks in high-risk singleton pregnancies, mostly women with a prior preterm birth or a short cervix (RR 0.78, 95% CI 0.68–0.90). It did not help twin pregnancies (RR 1.01, 95% CI 0.84–1.20). The authors judged the evidence for oral progesterone insufficient (EPPPIC Group, Lancet 2021).
Traumatic brain injury
Progesterone looked protective in animal models of brain injury and in two early-phase human trials. Two large phase 3 trials then found no benefit. In ProTECT III, 73.7% of patients were men:
| Trial | n | Treatment | Main result |
|---|---|---|---|
| ProTECT III (Wright et al., NEJM 2014) | 882 | IV progesterone for 96 h, started within 4 h | Stopped for futility; relative benefit 0.95 (95% CI 0.85–1.06). Phlebitis 3 times as common (RR 3.03) |
| SyNAPSe (Skolnick et al., NEJM 2014) | 1,195 | Progesterone for 120 h, started within 8 h | Favorable outcome 50.4% vs 50.5%; OR 0.96 (95% CI 0.77–1.18) |
Effects in men
There is no approved use of progesterone in men. In a study of 20 healthy men randomized to 50 mg IM progesterone or 300 µg oral desogestrel (a synthetic progestin) daily for 7 days, progesterone lowered LH, FSH and testosterone and reduced LH pulse amplitude and frequency. Its effect was at least as marked as that of a maximally effective desogestrel dose (Brady et al., Clin Endocrinol 2003). Because progesterone has negligible affinity for the androgen receptor, the authors concluded that this effect runs through the progesterone receptor.
Side effects and risks
Labels and the former boxed warning
US labels for menopausal hormone products, including Prometrium, previously carried a boxed warning about cardiovascular disease, breast cancer and probable dementia, based largely on the WHI trial of conjugated estrogens plus MPA. The Bijuva label lists that boxed warning as removed in February 2026, and the current Prometrium label (revised 02/2026) has none (Bijuva label; Prometrium label).
The WHI results still appear in the Warnings section. In the overall WHI population, estrogen plus MPA raised these risks compared with placebo:
| Event | Relative risk (95% CI) | Extra cases per 10,000 women-years |
|---|---|---|
| Deep vein thrombosis | 1.87 (1.37–2.54) | 12 |
| Pulmonary embolism | 1.98 (1.36–2.87) | 9 |
| Stroke | 1.37 (1.07–1.76) | 9 |
| Invasive breast cancer | 1.24 (1.01–1.53) | 9 |
The label notes that only CE 0.625 mg with MPA 2.5 mg was studied, so how these risks apply to other progestogens, doses or routes is not known.
Breast cancer
The evidence on progesterone specifically is observational. The Prometrium label cites a meta-analysis of 24 prospective studies that found a relative risk of 2.08 (95% CI 2.02–2.15) with 5–14 years of current estrogen-plus-progestogen use, and says those studies generally did not find significant differences between combinations or routes. In contrast, the French E3N cohort of 80,377 postmenopausal women found that the risk depended on the progestogen (Fournier et al., Breast Cancer Res Treat 2008):
| Regimen vs never-use | Relative risk (95% CI) |
|---|---|
| Estrogen + progesterone | 1.00 (0.83–1.22) |
| Estrogen + dydrogesterone | 1.16 (0.94–1.43) |
| Estrogen + other synthetic progestins | 1.69 (1.50–1.91) |
| Estrogen alone | 1.29 (1.02–1.65) |
Observational studies cannot rule out differences between women who choose different regimens. A history of breast cancer remains a contraindication.
Common side effects
In the 3-year placebo-controlled trial, these effects were reported in women taking Prometrium 200 mg cyclically with conjugated estrogens (n = 178) versus placebo (n = 174) (Prometrium label):
| Effect | Progesterone + estrogen | Placebo |
|---|---|---|
| Breast tenderness | 27% | 6% |
| Depression | 19% | 12% |
| Dizziness | 15% | 9% |
| Abdominal bloating | 12% | 5% |
| Vaginal discharge | 10% | 3% |
| Headache | 31% | 27% |
Because the active group also took estrogen, not all of these effects come from progesterone. At 400 mg/day in a smaller trial (n = 25 vs 24), dizziness occurred in 24% versus 4% on placebo.
Drowsiness and dizziness
Prometrium can cause transient dizziness and drowsiness, which is why it is labeled as a single dose at bedtime. The label describes a few women who, early in treatment, had a cluster of symptoms such as extreme drowsiness, blurred vision, slurred speech, difficulty walking, confusion and loss of consciousness. Caution is advised when driving or operating machinery.
Who should not use it
The Prometrium label lists these contraindications:
- allergy to peanuts (the capsules contain peanut oil) or to other ingredients;
- abnormal genital bleeding of unknown cause;
- known, suspected or past breast cancer;
- active or past deep vein thrombosis or pulmonary embolism;
- active or past arterial clotting disease, such as stroke or heart attack;
- known liver dysfunction or disease.
The injection label adds missed abortion and known sensitivity to the injection. The injection is in sesame oil with benzyl alcohol. Postmarketing reports for Prometrium include cholestatic hepatitis, hepatic necrosis and liver failure, although the label notes that a causal link cannot always be established from voluntary reports.
Fluid retention and other precautions
Progesterone may cause some fluid retention, so the labels advise close observation in heart or kidney disease. The injection label also advises watching patients with a history of depression, and notes reduced glucose tolerance in a small share of patients on estrogen-progestin combinations.
Legal status and use outside medicine
- US: progesterone is a prescription drug. It is not listed in the DEA’s Schedule III, which names the anabolic steroids (21 CFR 1308.13).
- Sport: progesterone does not appear on the WADA 2026 Prohibited List.
- Men: no product is labeled for men. Its main measurable effect in men is suppression of LH, FSH and testosterone (see above).
Key takeaways
- Identical to the natural hormone. Pharmaceutical progesterone is the same molecule the ovary makes. Synthetic progestins such as MPA are different drugs with different effects.
- Proven for endometrial protection. Cyclic 200 mg with estrogen cut hyperplasia from 64% to 6% over three years, and in PEPI it preserved more of estrogen’s HDL rise than MPA did.
- Short-acting by mouth. Oral bioavailability is about 9% of an injection, food roughly doubles absorption, and the effective half-life after oral doses is about 9–10 hours.
- Mixed results in pregnancy. Large trials found no clear benefit for recurrent miscarriage or early bleeding. Vaginal progesterone reduced early preterm birth in high-risk singleton pregnancies, but not in twins.
- Sedation is the signature side effect. Dizziness and drowsiness are why oral doses are taken at bedtime.
- Suppressive in men. Short-term progesterone lowered LH, FSH and testosterone in healthy men, and it has no approved male use.
Sources
- Acertis Pharmaceuticals. Prometrium (progesterone, USP) capsules, prescribing information, rev. 02/2026. DailyMed; Drugs@FDA, NDA 019781.
- Mayne Pharma. Bijuva (estradiol and progesterone) capsules, prescribing information. DailyMed.
- Allergan. Crinone (progesterone gel) 4% and 8%, prescribing information. DailyMed.
- Ferring Pharmaceuticals. Endometrin (progesterone) vaginal insert, prescribing information. DailyMed.
- Fresenius Kabi USA. Progesterone injection, USP (in sesame oil), prescribing information. DailyMed.
- Simon JA, Robinson DE, Andrews MC, et al. The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone. Fertil Steril. 1993;60(1):26–33. PubMed.
- The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273(3):199–208. PubMed.
- Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev. 2013;34(2):171–208. PubMed.
- Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107(1):103–111. PubMed.
- Coomarasamy A, Williams H, Truchanowicz E, et al. A randomized trial of progesterone in women with recurrent miscarriages. N Engl J Med. 2015;373(22):2141–2148. PubMed.
- Coomarasamy A, Devall AJ, Cheed V, et al. A randomized trial of progesterone in women with bleeding in early pregnancy. N Engl J Med. 2019;380(19):1815–1824. PubMed.
- Norman JE, Marlow N, Messow CM, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016;387(10033):2106–2116. PubMed.
- EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet. 2021;397(10280):1183–1194. PubMed.
- Wright DW, Yeatts SD, Silbergleit R, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371(26):2457–2466. PubMed.
- Skolnick BE, Maas AI, Narayan RK, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014;371(26):2467–2476. PubMed.
- Brady BM, Anderson RA, Kinniburgh D, Baird DT. Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male. Clin Endocrinol (Oxf). 2003;58(4):506–512. PubMed.
- World Anti-Doping Agency. The 2026 Prohibited List. WADA 2026 Prohibited List.
- Schedules of controlled substances: Schedule III. 21 CFR 1308.13. eCFR.