What is the difference between Provera (medroxyprogesterone acetate) and progesterone?

Difference Between Provera and Progesterone

Provera (medroxyprogesterone acetate) is a synthetic progestin with different pharmacologic properties than natural progesterone, including more androgenic effects, greater impact on lipid profiles and coagulation, and potentially more side effects, whereas natural progesterone (especially micronized formulations) has a more physiologic and safer profile with fewer metabolic and cardiovascular risks. 1

Chemical Structure and Classification

• Provera (medroxyprogesterone acetate/MPA) is a synthetic derivative of progesterone that has been chemically modified at the 17-acetoxy and 6-methyl positions, making it a pregnane-type progestin 2

• Natural progesterone is the identical hormone produced by the ovaries and has not been chemically altered 1

• The structural modifications in MPA enhance oral bioavailability and prolong duration of action but also introduce non-physiologic effects 2, 3

Pharmacologic Differences

Metabolic and Cardiovascular Effects

• Synthetic progestins like Provera have unfavorable effects on lipid profiles, vasomotion, and carbohydrate metabolism compared to natural progesterone 4

• Natural micronized progesterone minimizes hormonal-related cardiovascular risks when compared to synthetic progestogens and has a neutral or beneficial effect on blood pressure 4

• Natural micronized progesterone shows one of the best safety profiles in terms of thrombotic risk compared to synthetic progestins 4

Side Effect Profile

• Synthetic progestins like Provera may produce significant side effects including fatigue, fluid retention, lipid level alterations, dysphoria, hypercoagulant states, and increased androgenicity 1

• Natural progesterones are reported to have milder adverse effects, with the specific profile depending on route of administration 1

• Micronized natural progesterone has better bioavailability and fewer side effects than both synthetic and non-micronized natural progesterone 1

Clinical Formulations and Routes

Injectable Depot Medroxyprogesterone Acetate (Depo-Provera)

• DMPA is administered as 150 mg intramuscularly or 104 mg subcutaneously every 13 weeks for contraception 4, 5

• Serum MPA concentrations plateau at approximately 1.0 ng/mL for about three months, then gradually decline, with detection possible for up to 9 months after a single injection 3

• DMPA works by suppressing ovulation, thickening cervical mucus, and causing endometrial atrophy 5, 3

• Return to fertility is delayed 9-18 months after discontinuation of DMPA 6, 7

Oral Medroxyprogesterone Acetate

• Oral MPA reaches peak plasma levels within 1-3 hours, indicating rapid gastrointestinal absorption 8

• A dose of 10 mg daily reliably inhibits ovulation, while 5 mg may not be sufficient in all women 8

Natural Progesterone Formulations

• Micronized natural progesterone is available for oral administration and is considered a safe and effective alternative for various clinical applications 1

• Natural progesterone can also be administered via intramuscular, intravenous, intravaginal, intranasal, transdermal, and rectal routes 1

Guideline Recommendations for Hormone Replacement

• The European Society for Human Reproduction and Embryology (ESHRE) includes micronized progesterone among recommended progestogens for hormone replacement therapy in women with ovarian insufficiency, based on its safer pharmacological profile 4

• For hormone replacement therapy, natural progesterone (particularly micronized progesterone at 90-mg gel or 200-mg suppository vaginally) is increasingly preferred over synthetic progestins due to cardiovascular and metabolic safety advantages 4

Specific Clinical Applications

Contraception

• DMPA (Depo-Provera) is highly effective for contraception with a typical use failure rate of 6% and perfect use failure rate of 0.2% 5

• No time limit exists for DMPA contraceptive use, and the American College of Obstetricians and Gynecologists does not recommend restricting use to 2 years despite FDA black box warnings about bone mineral density 6

Endometrial Protection and Treatment

• Depo-Provera achieved 91.8% regression of endometrial hyperplasia without atypia compared to 67.1% with oral norethisterone acetate in a randomized trial 9

• Both MPA and natural progesterone provide endometrial protection when used with estrogen in hormone replacement therapy 4

Key Clinical Pitfalls

• Do not assume Provera and natural progesterone are interchangeable—they have distinct pharmacologic profiles that affect side effects, cardiovascular risk, and patient tolerance 4, 1

• When prescribing for hormone replacement therapy, strongly consider micronized natural progesterone over MPA due to superior cardiovascular and metabolic safety profile 4

• For contraception requiring long-acting reversible methods, DMPA remains highly effective, but counsel patients about delayed return to fertility and bone density considerations 6, 5

• Do not discontinue DMPA at 2 years based solely on duration concerns, as this increases risk of unintended pregnancy without clear benefit 6