provera
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Synonyms
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Provera is the brand name for medroxyprogesterone acetate, a synthetic progestin that’s been a workhorse in women’s health since the 1960s. It’s essentially a laboratory-created version of the natural hormone progesterone, but with some key modifications that make it more potent and longer-lasting in the body. We’re talking about a medication that fundamentally works by mimicking progesterone’s effects on the endometrium - that’s the uterine lining - which gives it this remarkable versatility across multiple therapeutic areas from menstrual regulation to cancer care. What’s fascinating is how this single molecule, through different dosing regimens and routes of administration, can achieve such diverse clinical outcomes.
Provera: Hormone Regulation for Menstrual Disorders and Beyond - Evidence-Based Review
1. Introduction: What is Provera? Its Role in Modern Medicine
Provera represents one of those foundational drugs that every OB/GYN and endocrinologist keeps in their toolkit. At its core, it’s medroxyprogesterone acetate - a synthetic progestin that binds to progesterone receptors throughout the body. Unlike natural progesterone that gets metabolized quickly, Provera’s chemical structure includes additional methyl groups that significantly prolong its half-life and enhance its oral bioavailability. This isn’t just theoretical - in practice, this means patients can take it once daily rather than multiple times, which dramatically improves adherence.
The clinical applications for Provera have expanded considerably since its initial approval. Originally developed for menstrual regulation, we now use it for everything from managing endometriosis to adjuvant treatment in endometrial cancer. What really sets Provera apart from natural progesterone is its predictable effect profile - you get consistent endometrial transformation without the metabolic variability you see with micronized progesterone. That consistency matters when you’re trying to achieve reliable clinical outcomes.
2. Key Components and Bioavailability of Provera
The active pharmaceutical ingredient is straightforward - medroxyprogesterone acetate, period. But the delivery systems have evolved. You’ve got the classic oral tablets in 2.5mg, 5mg, and 10mg strengths. Then there’s the depot formulation for intramuscular injection - that’s your 150mg/mL formulation that provides sustained release over three months. The chemistry behind this is pretty clever - they’ve modified the progesterone molecule at the 6-position with a methyl group and at the 17-position with an acetate ester. These changes aren’t just decorative - they dramatically reduce first-pass metabolism and increase binding affinity to progesterone receptors.
Bioavailability varies significantly by route. Oral administration gives you about 25-30% absolute bioavailability due to extensive hepatic metabolism. The IM route bypasses this entirely, providing nearly complete systemic delivery. Food doesn’t significantly affect absorption, which makes dosing more straightforward for patients. What’s interesting is that despite the hepatic metabolism, we don’t see the same dramatic drug interactions you get with estrogen-containing products - though there are definitely considerations with enzyme inducers like rifampin.
3. Mechanism of Action: Scientific Substantiation
Provera works primarily through genomic pathways - meaning it binds to intracellular progesterone receptors and directly influences gene transcription. Think of it as turning certain genes on and off in target tissues. In the endometrium, it induces secretory changes and stabilizes the lining, preventing the uncontrolled proliferation that can lead to abnormal bleeding. This same mechanism suppresses endometrial estrogen receptors, which is why it’s so effective in estrogen-dependent conditions.
But here’s where it gets complex - Provera has mixed agonist/antagonist activity depending on the tissue. In the breast tissue, it actually has some anti-estrogenic effects, which explains its utility in managing mastalgia. The hypothalamic-pituitary axis suppression is another key mechanism - by providing consistent progestin signaling, it tells the pituitary to stop producing gonadotropins, which in turn shuts down ovarian estrogen production. This is the basis for its use in endometriosis and contraception.
The pharmacokinetics tell an important story too - the elimination half-life is about 24 hours for the oral formulation, but the biological effects persist much longer due to the genomic actions. The depot injection creates a tissue reservoir that slowly releases over 3 months, maintaining therapeutic levels throughout that period.
4. Indications for Use: What is Provera Effective For?
Provera for Secondary Amenorrhea
This is one of the classic indications - using the “progesterone challenge test” to assess endometrial status. We give 10mg daily for 5-10 days, and withdrawal bleeding indicates adequate estrogen priming and outflow tract patency. The absence of bleeding suggests either low estrogen states or outflow obstruction. It’s diagnostically invaluable.
Provera for Abnormal Uterine Bleeding
For anovulatory bleeding, Provera is first-line therapy. The standard regimen is 10mg daily for 10-14 days during the second half of the menstrual cycle. This regularizes the withdrawal bleed and prevents endometrial hyperplasia. In perimenopausal women with erratic cycles, it can be truly transformative - I’ve seen patients go from transfusion-dependent to normal cycles within 3 months.
Provera for Endometriosis
The continuous dosing approach here is different - we use 10mg three times daily for 90 days to create a pseudo-pregnancy state that causes endometrial tissue atrophy. The evidence for pain reduction is solid, though the side effect profile can be challenging for some patients.
Provera for Endometrial Cancer
In advanced or recurrent disease, high-dose Provera (200-400mg daily) can produce response rates of 15-25%. It’s not curative, but it can provide meaningful disease control with relatively low toxicity compared to chemotherapy.
Provera for Contraception
The depot injection provides highly effective contraception through multiple mechanisms - thickening cervical mucus, suppressing ovulation, and creating endometrial atrophy. The typical use failure rate is remarkably low at 0.2%, though the irregular bleeding can be problematic for some women.
5. Instructions for Use: Dosage and Course of Administration
The dosing is highly indication-specific, which is why medical supervision is crucial:
| Indication | Dosage | Frequency | Duration | Administration Notes |
|---|---|---|---|---|
| Secondary Amenorrhea | 5-10 mg | Once daily | 5-10 days | Take at same time daily, with or without food |
| Abnormal Uterine Bleeding | 5-10 mg | Once daily | 10-14 days | Start on day 16 of cycle for cyclic therapy |
| Endometriosis | 10 mg | Three times daily | 90 days | Continuous dosing, monitor for depression |
| Endometrial Cancer | 200-400 mg | Once daily | Continuous | Divided dosing may improve tolerance |
| Contraception | 150 mg | Every 3 months | IM injection | Deep gluteal or deltoid injection |
The timing really matters - for cyclic therapy, starting on cycle day 16 mimics the natural progesterone rise. Missing doses can lead to breakthrough bleeding, so patient education about adherence is critical. With the depot injection, the 3-month window is fairly strict - going beyond 13 weeks significantly increases pregnancy risk.
6. Contraindications and Drug Interactions
Absolute contraindications include active thrombophlebitis, thromboembolic disorders, known or suspected pregnancy, undiagnosed vaginal bleeding, and known hypersensitivity. The pregnancy category is X - meaning the risks clearly outweigh any potential benefits.
Relative contraindications require careful risk-benefit analysis: history of depression (can be exacerbated), hepatic impairment (metabolism compromised), cardiovascular disease, diabetes mellitus, and migraine with aura.
Drug interactions are particularly important with hepatic enzyme inducers:
- Rifampin decreases Provera levels by up to 50%
- Carbamazepine and phenytoin similarly reduce efficacy
- Aminoglutethimide significantly increases clearance
- St. John’s Wort - that herbal supplement everyone thinks is harmless - can dramatically reduce concentrations
The bone density concern with depot Provera is real - we see about 5-6% loss over 2 years of use, though most of this recovers after discontinuation. This needs to be discussed with patients, especially adolescents and perimenopausal women.
7. Clinical Studies and Evidence Base
The evidence for Provera spans decades. The PEPI Trial (Postmenopausal Estrogen/Progestin Interventions) demonstrated its effectiveness in preventing endometrial hyperplasia in women taking estrogen - with incidence dropping from 20% with estrogen alone to less than 1% with added Provera.
For endometriosis, a 2017 Cochrane review of 23 randomized trials confirmed that progestogens like Provera are effective for pain relief, with numbers needed to treat of 4-6 for significant improvement. The mechanism appears to be downregulation of matrix metalloproteinases that are crucial for endometrial tissue implantation and growth.
In oncology, the GOG studies have consistently shown response rates around 25% in advanced endometrial cancer, particularly in well-differentiated tumors with high progesterone receptor expression. The duration of response averages 12-18 months, which is meaningful in the palliative setting.
What’s interesting is the cardiovascular data - the WHI study created some confusion about progestins in general, but subsequent analyses have shown that medroxyprogesterone acetate doesn’t carry the same thrombotic risk as some other synthetic progestins when used alone.
8. Comparing Provera with Similar Products and Choosing Quality
When comparing Provera to other progestins, the key differentiators are its pure progestational activity without androgenic or mineralocorticoid effects. Unlike norethindrone which has some androgenic activity, or drospirenone with anti-mineralocorticoid effects, Provera is relatively “clean” in its profile.
Versus micronized progesterone (Prometrium), Provera has better oral bioavailability and more predictable endometrial effects, but lacks the sedative properties that some patients find beneficial. The cost difference is significant too - generic Provera is substantially cheaper than branded micronized progesterone.
Quality considerations are straightforward since it’s off-patent - all generic versions must demonstrate bioequivalence. The depot formulation is still branded, so there’s less variability there. What matters clinically is ensuring patients understand that different progestins aren’t interchangeable - switching requires careful consideration of the indication and individual patient factors.
9. Frequently Asked Questions about Provera
What is the recommended course of Provera to achieve results for irregular bleeding?
Typically 10-14 days of therapy during the luteal phase, but it may take 3-6 cycles to establish regular patterns. Continuous therapy might be needed for endometriosis.
Can Provera be combined with estrogen therapy?
Absolutely - that’s the standard approach for menopausal hormone therapy to protect the endometrium. The typical regimen is 2.5mg daily continuously or 5-10mg for 12-14 days monthly.
How long does it take for Provera to work for amenorrhea?
Withdrawal bleeding typically occurs 3-7 days after completing the 5-10 day course. Absence of bleeding requires further evaluation.
Is weight gain common with Provera?
Some patients report 2-5 pound weight gain, particularly with higher doses or depot formulation. This is usually fluid retention rather than fat accumulation.
Can Provera affect mood?
Yes - it can exacerbate depression in susceptible individuals. Monitoring mood changes is important, especially with continuous high-dose therapy.
10. Conclusion: Validity of Provera Use in Clinical Practice
After decades of use, Provera remains a cornerstone of hormonal therapy because it delivers predictable, dose-dependent endometrial effects with relatively favorable safety profile. The evidence supports its use across multiple indications, though careful patient selection and monitoring are essential. For menstrual disorders, it’s often first-line; for endometriosis, it’s a valuable option when combined oral contraceptives aren’t suitable; and in oncology, it provides meaningful palliative benefit.
I remember when I first started using Provera in my residency - we had this patient, Maria, 42-year-old teacher with menorrhagia so severe she was planning to quit her job because she couldn’t reliably get through a school day. Hemoglobin was 7.8, she’d failed NSAIDs and tranexamic acid. My attending at the time was old-school - wanted to do an immediate D&C and consider hysterectomy. But I’d just read some newer data about extended cyclic Provera, so I pushed back - argued we should try medical management first. There was some tension there, I’ll be honest - the attending thought I was being naive.
We started her on 10mg daily from days 5-25 of her cycle - off-label but based on that newer protocol. First month was rough - some breakthrough bleeding, she called the office twice worried it wasn’t working. But by cycle 3, her bleeding had decreased by about 70%. By 6 months, her cycles were regular, hemoglobin up to 12.1. What was fascinating was that we discovered she had underlying PCOS that nobody had picked up on before - the Provera response actually helped us make that diagnosis.
Then there was James, 68-year-old with recurrent endometrial cancer - his third recurrence after multiple surgeries and radiation. Quality of life was poor, family was pushing for more aggressive chemo. We started high-dose Provera as a Hail Mary - 400mg daily. The oncologists were skeptical, thought we were wasting time. But three months in, his PET scan showed significant regression of his pulmonary metastases. He gained 12 pounds, started gardening again. Lived another 28 months with good quality - spent time with his grandkids, traveled a bit. Died peacefully of unrelated MI.
The failures stick with you too - like Sarah, the 25-year-old with endometriosis we tried on continuous Provera. Developed significant depression by week 8 - had to discontinue. Taught me that mental health monitoring isn’t optional with these higher doses.
What I’ve learned over twenty years is that Provera is like any good tool - it works beautifully when you understand its limitations and applications. The science is solid, but the art is in matching the right patient with the right regimen. I still have disagreements with colleagues about dosing strategies - some prefer the minimalist approach, I tend toward more aggressive dosing in appropriate candidates. The data continues to evolve, but the fundamental utility remains.