Prometrium® (bioidentical) / Provera® (synthetic)
Progesterone (micronized) / Medroxyprogesterone Acetate
Version 2025-04 · Last reviewed April 1, 2025 · Methodology
List Price
$80
With Insurance
$10-25
How It Works
Progesterone (and its synthetic analogs, progestins) acts by binding to progesterone receptors (PR-A and PR-B) in the uterus, breast, brain, and other tissues. Its primary role in HRT is to protect the uterine lining (endometrium) from the proliferative effect of estrogen — which, unopposed, increases endometrial cancer risk. Bioidentical progesterone (Prometrium) and synthetic progestins (like medroxyprogesterone acetate in Provera) bind to the same receptor but have very different profiles due to their structural differences.
Why the side effects happen
The sleepiness of Prometrium is a direct pharmacological effect of its conversion to allopregnanolone — a GABA-enhancing neurosteroid. This is why bedtime dosing is standard. Mood changes are more common with synthetic progestins due to their off-target binding to other steroid receptors. The breast cancer risk difference between bioidentical progesterone and synthetic progestins observed in French cohort data appears to relate to different proliferative effects on breast tissue — an area of ongoing research.
When Will I Feel It?
As a uterine protectant in HRT, progesterone works continuously to oppose estrogen's proliferative effect on the endometrium. Its sleep-supporting effects (with Prometrium) begin within the first few days of bedtime dosing.
Endometrial protection begins immediately. Sleep quality often improves within the first week with bedtime Prometrium dosing, attributed to allopregnanolone activity.
Irregular spotting or withdrawal bleeding may occur if using cyclic progesterone. Continuous-combined regimens (daily low-dose progesterone) are associated with less bleeding.
Amenorrhea (no periods) is common with continuous combined HRT by 3-6 months. Ongoing endometrial protection is maintained as long as progesterone is taken concurrently with estradiol.
Adherence Note
Progesterone must be taken consistently and at the prescribed dose every day (or cyclically as directed) for effective endometrial protection. Skipping doses while continuing estradiol increases endometrial cancer risk.
Medical Disclaimer
The information on this page is compiled from publicly available clinical trial data, FDA prescribing information, and peer-reviewed literature. It is provided for educational purposes only and does not constitute medical advice, diagnosis, or treatment recommendations. Individual responses to medications vary. Always consult a qualified healthcare provider before starting, stopping, or changing any medication.
Common Side Effects
While taking this medication, you may experience the following common side effects. We've included tips on how to manage them.
Drowsiness / sleepiness (Prometrium)
30-40%This is intentional when prescribed at bedtime — many providers use it to improve sleep during menopause. Take at bedtime as directed.
Dizziness
15%Most common at start of therapy; take Prometrium at bedtime to minimize impact
Breast tenderness
10%Usually mild; often improves after first 1-2 months
Bloating / water retention
8%More common with synthetic progestins (Provera) than bioidentical progesterone
Mood changes
5-10%Synthetic progestins have more pronounced mood effects in some women due to different receptor binding. Discuss with your doctor if mood changes are significant.
Headache
7%Usually resolves; discuss with doctor if persistent
Irregular spotting
5%Irregular bleeding in the first months is common; any unexpected postmenopausal bleeding should be evaluated
Vaginal discharge
3%Usually mild; report if accompanied by irritation or unusual odor
Serious Adverse Effects
- • Blood clots (DVT/PE) — risk appears lower with bioidentical progesterone than with synthetic progestins based on observational data
- • Breast cancer — current evidence suggests bioidentical progesterone has a more favorable profile than synthetic progestins, though research is ongoing
- • Allergic reaction (Prometrium contains peanut oil — contraindicated in peanut allergy)
- • Ectopic pregnancy — if used in fertility treatment
Drug Interactions
Major Interactions (Avoid)
Moderate Interactions (Caution)
Food Interactions
When to Contact Your Doctor
This medication requires ongoing medical supervision. The following situations warrant a prompt conversation with your prescribing physician — do not wait for your next scheduled appointment.
Contact soon if you notice
- Blood clots (DVT/PE) — risk appears lower with bioidentical progesterone than with synthetic progestins based on observational data
- Breast cancer — current evidence suggests bioidentical progesterone has a more favorable profile than synthetic progestins, though research is ongoing
- Allergic reaction (Prometrium contains peanut oil — contraindicated in peanut allergy)
- Ectopic pregnancy — if used in fertility treatment
- Abnormal uterine bleeding or spotting after stopping
Also discuss if you want to
- Review whether this medication is still appropriate for you
- Consider dosage adjustments based on response
- Explore lifestyle or non-drug alternatives
- Understand stopping or tapering options
- Plan monitoring labs and follow-up
In the US, call 911 or go to the nearest emergency room for severe symptoms. Poison Control: 1-800-222-1222.
Special Populations
Safety classifications for specific groups — discuss with your provider before use.
Progesterone supplementation is standard practice in IVF and to support early pregnancy in women with low progesterone. Prometrium is NOT for menopausal HRT during pregnancy.
Progesterone passes into breast milk. Not typically indicated postpartum in nursing mothers unless specifically prescribed for a separate condition.
The WHI study that caused widespread fear about HRT used medroxyprogesterone (Provera) — a synthetic progestin. The French E3N cohort study found that women using estrogen with bioidentical progesterone (Prometrium) did not have a significant increase in breast cancer risk, unlike those using synthetic progestins. This distinction is central to current menopause specialist guidance, though it is not universally agreed upon.
Any woman with an intact uterus taking systemic estradiol requires a progestogen to protect the uterine lining from endometrial hyperplasia and cancer. This is not optional — it is a safety requirement of combination HRT.
Progesterone is extensively hepatically metabolized. Liver disease may increase progesterone levels. Avoid if active liver disease.
FDA Adverse Event Reports
Patient-filed reports from the FDA FAERS database · refreshed daily
Community Reports
User-reported experiences — anonymous & anecdotal
Medical Disclaimer
The information on this page is compiled from publicly available clinical trial data, FDA prescribing information, and peer-reviewed literature. It is provided for educational purposes only and does not constitute medical advice, diagnosis, or treatment recommendations. Individual responses to medications vary. Always consult a qualified healthcare provider before starting, stopping, or changing any medication.
Metabolic & Lifestyle Alternatives
Context for Progesterone Use
In menopausal HRT, progesterone is not typically an optional add-on — it is a required component for women with an intact uterus taking systemic estradiol. The choice is between bioidentical progesterone and synthetic progestins, not whether to use it at all. For PMS or cycle irregularity, lifestyle and nutritional approaches are worth discussing with your provider.
Important context: Evidence quality varies across these approaches. Some are well-studied with randomized controlled trial data; others are based on observational or smaller studies. These interventions are not guaranteed to replace medication for all patients. Discuss with your doctor whether any of these are appropriate for your clinical situation.
Magnesium (300-400mg/day)
Research suggests magnesium deficiency may worsen PMS symptoms including mood changes and cramps
Several small trials found reduced PMS symptoms with magnesium supplementation vs. placebo
Vitamin B6 (50-100mg/day)
Involved in progesterone and serotonin synthesis; studied for PMS mood symptoms
Systematic review found modest benefit for PMS mood symptoms; doses above 100mg/day carry peripheral neuropathy risk
Vitex agnus-castus (chasteberry)
Herbal that acts on the pituitary to increase progesterone production relative to estrogen in the luteal phase
Several RCTs found improvement in PMS symptom scores; evidence quality varies
Key Studies
How It Compares
The progestogen class includes both bioidentical progesterone (Prometrium/micronized progesterone) and synthetic progestins (Provera/medroxyprogesterone, norethindrone, etc.). These are structurally and clinically different — the progestin used matters beyond simply providing endometrial protection.
Strengths
- Essential protection against estrogen-driven endometrial cancer in women with intact uterus
- Bioidentical progesterone (Prometrium) associated with improved sleep — beneficial side effect
- French E3N cohort and other data suggest more favorable breast cancer risk profile with bioidentical vs. synthetic progestins
- Generic micronized progesterone widely available at reasonable cost
- PEPI trial: better HDL preservation with micronized progesterone vs. medroxyprogesterone
Weaknesses
- Peanut allergy patients cannot use Prometrium (contains peanut oil) — requires compounded alternative
- Sedation from Prometrium limits daytime dosing for some patients
- Synthetic progestins (Provera) carry a more established association with breast cancer risk per WHI and observational data
- Compounded progesterone preparations lack FDA quality control for potency and consistency
Clinically Preferred Alternatives
Global Prescribing & Pricing
Bioidentical progesterone (Prometrium) is the dominant progestogen for HRT in France and is increasingly preferred in the UK; the US still uses a mix of synthetic progestins and bioidentical progesterone
United States
$25–60/mo
Mix of synthetic progestins and bioidentical progesterone prescribed; growing awareness of the distinction since 2010s
No national guideline mandating bioidentical over synthetic; provider preference varies widely
Usually covered with prescription
France
~$5–15/mo
French HAS guidelines explicitly prefer bioidentical progesterone (Prometrium/Utrogestan) over synthetic progestins for HRT
French data (E3N cohort) showed lower breast cancer risk with bioidentical progesterone — influenced national guidelines
Covered by Sécurité Sociale
United Kingdom
~$5–12/mo
NICE 2023 guidelines updated to acknowledge bioidentical progesterone (Utrogestan) as preferred over norethisterone for breast cancer risk
Shifting toward bioidentical progesterone in specialist menopause clinics
Covered by NHS
Germany
~$8–18/mo
Both forms available; gynecologists increasingly aware of the distinction
German Menopause Society (AHF) publications distinguish between progestogen types
Covered by GKV
Australia
~$10–22/mo
Prometrium available on PBS; growing awareness among menopause specialists
Australian Menopause Society supports individualized progestogen selection
PBS subsidized
France's national guidelines explicitly recommend bioidentical progesterone (not synthetic progestins) for HRT — a distinction that stems from the E3N-EPIC cohort study conducted in France. The US has been slower to formalize this preference, though individual providers and menopause specialists increasingly apply the same distinction.
Clinical Trials & Funding
Understanding who funds research helps contextualize results. Industry-funded trials are not automatically invalid — they undergo the same FDA review — but declared conflicts and sponsor effects are worth knowing. All linked trials can be verified on ClinicalTrials.gov.
Funding Sources
The WHI that generated the breast cancer headlines used medroxyprogesterone acetate (Provera), manufactured by Wyeth — not bioidentical progesterone. The E3N-EPIC French cohort study that found lower breast cancer risk with bioidentical progesterone was independently funded through French government institutions (INSERM, Gustave Roussy Institute). Pfizer (which acquired Wyeth) continues to manufacture Provera — the synthetic progestin at the center of the WHI controversy.
Declared Conflicts of Interest
The distinction between synthetic progestins (Provera) and bioidentical progesterone (Prometrium) was rarely communicated in mainstream coverage of the WHI findings. This distinction matters: the two molecules have different receptor binding profiles and appear to have different clinical risk profiles. Compounding pharmacies market progesterone-containing products with claims that may go beyond the available evidence.
Key Efficacy Results
E3N cohort: Women using estrogen + bioidentical progesterone had no significant increase in breast cancer risk vs. estrogen alone, while estrogen + synthetic progestins did. PEPI trial: Micronized progesterone preserved HDL cholesterol better than medroxyprogesterone.
Referenced Studies
Each study carries a Cochrane RoB-2 risk-of-bias badge — tap the badge for details.
Evidence & Transparency
Cochrane RoB-2 (Risk of Bias)
Badges reflect an editorial assessment using Cochrane's RoB-2 tool domains: randomization, intervention deviation, missing data, outcome measurement, and selective reporting. These are not certified Cochrane reviews. Learn more ↗
CMS Open Payments
Manufacturer payment disclosures are reported via the CMS Sunshine Act. Disclosure is legally required and does not imply bias or misconduct. Language uses "may," "suggests," or "appears" — never definitive clinical claims. CMS Open Payments ↗
Live Clinical Trials
Live from ClinicalTrials.gov · refreshed every 4 hours
Currently enrolling, active, and recently completed studies involving Progesterone (micronized) / Medroxyprogesterone Acetate. Data is pulled directly from the U.S. National Library of Medicine.
Recent Research
Live from PubMed · peer-reviewed literature · refreshed every 4 hours
Most recently indexed clinical trials and systematic reviews mentioning Progesterone (micronized) / Medroxyprogesterone Acetate in PubMed.
Source Documentation
Structured citations for referenced clinical trials
Each referenced trial is listed with its registry ID, funding source, and bias assessment. Use the copy button to generate a formatted citation.
| Trial | Registry ID | Cite |
|---|---|---|
| E3N-EPIC: Bioidentical Progesterone & Breast Cancer | PMID:18055563 | |
| PEPI Trial — Progesterone & Cardiovascular Risk | PMID:7807658 | |
| WHI (used Provera, not Prometrium) | NCT00000611 |
Bias ratings use Cochrane RoB-2 methodology. Editorial assessment — not a certified Cochrane review.
Our MethodologyMedical Disclaimer
The information on this page is compiled from publicly available clinical trial data, FDA prescribing information, and peer-reviewed literature. It is provided for educational purposes only and does not constitute medical advice, diagnosis, or treatment recommendations. Individual responses to medications vary. Always consult a qualified healthcare provider before starting, stopping, or changing any medication.
Stopping This Medication Safely
Progesterone does not carry the same abrupt withdrawal risks as estrogens. However, stopping the progesterone component while continuing estradiol creates endometrial cancer risk in women with an intact uterus. Stopping both together should follow the estradiol tapering plan. Discuss any changes with your provider.
What Published Research Shows About Stopping This Medication
This summarizes what published research documents — it is not personal medical advice. Any changes to your medication require discussion with your prescribing physician.
- ·Research consistently documents that stopping progesterone while continuing systemic estradiol creates endometrial cancer risk — endometrial protection is pharmacologically essential and requires medical guidance
- ·When stopping all HRT, research supports tapering estradiol as described above — progesterone can be stopped concurrently
- ·For PMS use, research shows no taper is documented as needed
Warning Symptoms — Contact Your Doctor If You Experience:
- Abnormal uterine bleeding or spotting after stopping
- Pelvic pain or pressure
- Any unexpected postmenopausal bleeding
Never change or stop a medication without consulting your prescribing physician.
Questions for Your Doctor
Questions to Ask
- 1.Are we using bioidentical progesterone (Prometrium) or a synthetic progestin — and what is the reasoning?
- 2.Is the dose and duration appropriate for endometrial protection, and how will we verify that?
- 3.I have a peanut allergy — should I use compounded progesterone instead of Prometrium?
- 4.Can I take my progesterone at bedtime to take advantage of its sleep-promoting effects?
- 5.How long will I need to continue this alongside estradiol?
Lab Tests to Request
- Progesterone level (if used for fertility or cycle support)
- Endometrial biopsy or ultrasound (if abnormal bleeding occurs)
- Liver function (progesterone is hepatically metabolized)
Medical Disclaimer
The information on this page is compiled from publicly available clinical trial data, FDA prescribing information, and peer-reviewed literature. It is provided for educational purposes only and does not constitute medical advice, diagnosis, or treatment recommendations. Individual responses to medications vary. Always consult a qualified healthcare provider before starting, stopping, or changing any medication.
Frequently Asked Questions About Prometrium® (bioidentical) / Provera® (synthetic)
- What is Prometrium® (bioidentical) / Provera® (synthetic) used for?
- Prometrium® (bioidentical) / Provera® (synthetic) (Progesterone (micronized) / Medroxyprogesterone Acetate) is a Progestogen / Sex Hormone manufactured by Various / Pfizer (Provera). FDA-approved indications include: Endometrial protection in women on estrogen therapy with intact uterus; Secondary amenorrhea; Abnormal uterine bleeding; Luteal phase support in fertility treatment; Premenstrual syndrome (off-label).
- What are the common side effects of Prometrium® (bioidentical) / Provera® (synthetic)?
- Common side effects of Prometrium® (bioidentical) / Provera® (synthetic) include: Drowsiness / sleepiness (Prometrium) (30-40%); Dizziness (15%); Breast tenderness (10%); Bloating / water retention (8%); Mood changes (5-10%).
- How much does Prometrium® (bioidentical) / Provera® (synthetic) cost?
- Prometrium® (bioidentical) / Provera® (synthetic) list price is approximately $80. With insurance it typically costs $10-25; without insurance approximately $25-60.
- Who funded the clinical trials for Prometrium® (bioidentical) / Provera® (synthetic)?
- The WHI that generated the breast cancer headlines used medroxyprogesterone acetate (Provera), manufactured by Wyeth — not bioidentical progesterone. The E3N-EPIC French cohort study that found lower breast cancer risk with bioidentical progesterone was independently funded through French government institutions (INSERM, Gustave Roussy Institute). Pfizer (which acquired Wyeth) continues to manufacture Provera — the synthetic progestin at the center of the WHI controversy.
- How strong is the clinical evidence for Prometrium® (bioidentical) / Provera® (synthetic)?
- Key studies: WHI (used Provera, not Prometrium), E3N-EPIC Cohort, PEPI Trial, Danish Nurses Study. E3N cohort: Women using estrogen + bioidentical progesterone had no significant increase in breast cancer risk vs. estrogen alone, while estrogen + synthetic progestins did. PEPI trial: Micronized progesterone preserved HDL cholesterol better than medroxyprogesterone. Potential conflicts of interest: The distinction between synthetic progestins (Provera) and bioidentical progesterone (Prometrium) was rarely communicated in mainstream coverage of the WHI findings. This distinction matters: the two .
- Are there non-drug alternatives to Prometrium® (bioidentical) / Provera® (synthetic)?
- In menopausal HRT, progesterone is not typically an optional add-on — it is a required component for women with an intact uterus taking systemic estradiol. The choice is between bioidentical progesterone and synthetic progestins, not whether to use it at all. For PMS or cycle irregularity, lifestyle See the Alternatives tab for full details.
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