prometrium
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Synonyms
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Progesterone supplementation has been one of the most challenging yet rewarding areas of my reproductive endocrinology practice. When I first started prescribing Prometrium back in the late 90s, we were really just beginning to understand the nuances of progesterone delivery and bioavailability. The transition from synthetic progestins to bioidentical micronized progesterone represented a fundamental shift in how we approach luteal phase support and hormone replacement therapy.
Prometrium: Evidence-Based Progesterone Support for Hormone Balance and Reproductive Health
1. Introduction: What is Prometrium? Its Role in Modern Medicine
Prometrium represents a significant advancement in hormone therapy as the first FDA-approved oral micronized progesterone capsule. Unlike synthetic progestins that dominated the market for decades, Prometrium contains bioidentical progesterone that’s chemically identical to the progesterone produced by the human corpus luteum. This distinction matters clinically - I’ve observed fewer mood side effects and better patient tolerance compared to synthetic alternatives.
The development of micronized progesterone was actually quite challenging from a pharmaceutical standpoint. Progesterone has notoriously poor oral bioavailability due to extensive first-pass metabolism in the liver. The micronization process - reducing progesterone particles to microscopic size - was the breakthrough that made oral administration feasible. When we switched our IVF patients from vaginal suppositories to Prometrium, the convenience factor alone improved compliance dramatically.
2. Key Components and Bioavailability of Prometrium
The composition seems straightforward - just progesterone in peanut oil - but the formulation science behind Prometrium is quite sophisticated. Each 100mg or 200mg soft gelatin capsule contains micronized progesterone suspended in peanut oil, which enhances absorption through lymphatic transport rather than portal circulation.
The bioavailability issue is what makes Prometrium’s formulation so clever. Unmicronized progesterone has less than 10% oral bioavailability, but the micronized form in Prometrium achieves approximately 10-15% systemic availability when taken with food. This is crucial - I always emphasize to patients that taking Prometrium with food, particularly fatty foods, can increase absorption by up to 50-60%. The peanut oil carrier facilitates chylomicron formation and lymphatic absorption, bypassing some of the hepatic metabolism.
We had a case last year that really drove this home - a 38-year-old IVF patient who was having breakthrough bleeding despite adequate Prometrium dosing. Turns out she was taking her evening dose on an empty stomach because she was worried about weight gain. Once we adjusted timing to after dinner, her progesterone levels normalized and the bleeding resolved.
3. Mechanism of Action: Scientific Substantiation
Prometrium works through the same genomic and non-genomic pathways as endogenous progesterone. The molecule binds to intracellular progesterone receptors, translocates to the nucleus, and modulates gene transcription in target tissues. What’s fascinating is the tissue-specific effects - uterine protection without the same degree of breast cell proliferation we see with some synthetics.
The non-genomic actions are particularly interesting from a neurological perspective. Progesterone and its metabolites act as neurosteroids, modulating GABA-A receptors in the brain. This explains why some patients report sedative effects, especially with higher doses. I remember one perimenopausal patient who called me panicked because she took her 300mg dose in the morning and nearly fell asleep during a board meeting. We adjusted her timing to bedtime only, and she actually reported improved sleep quality as a bonus benefit.
The metabolic pathways are complex - progesterone undergoes extensive hepatic metabolism to various metabolites including pregnanediol, pregnanolone, and allopregnanolone. These metabolites have their own biological activities that contribute to both therapeutic effects and side effects.
4. Indications for Use: What is Prometrium Effective For?
Prometrium for Secondary Amenorrhea
For women with secondary amenorrhea due to progesterone deficiency, Prometrium effectively induces withdrawal bleeding when estrogen levels are adequate. The standard protocol is 400mg daily at bedtime for 10 days. I’ve found this particularly useful in managing PCOS patients who need periodic endometrial shedding.
Prometrium for Assisted Reproductive Technology
In ART cycles, Prometrium provides crucial luteal phase support. The vaginal route is often preferred for direct uterine effects, but oral administration works well for many patients. We typically use 200-300mg three times daily starting after egg retrieval. The evidence here is robust - multiple RCTs show significantly improved pregnancy rates with progesterone supplementation versus placebo.
Prometrium for Perimenopause and Menopause
Combined with estrogen, Prometrium protects the endometrium from hyperplasia in menopausal women with intact uteri. The PEPI trial demonstrated that micronized progesterone provides endometrial protection comparable to synthetic progestins with potentially better lipid profiles. Dosing is typically 200mg daily for 12 days per month in sequential therapy or 100mg daily in continuous combined regimens.
Prometrium for Premenstrual Dysphoric Disorder
While not FDA-approved for PMDD, the neurosteroid effects of Prometrium can benefit some women with severe premenstrual symptoms. I’ve had mixed results here - some patients report significant improvement while others notice no change or even worsening of symptoms. The response seems highly individual.
5. Instructions for Use: Dosage and Course of Administration
Proper administration is critical for Prometrium’s effectiveness and tolerability. The bedtime dosing recommendation isn’t arbitrary - it capitalizes on the natural sedative effects while minimizing daytime drowsiness.
| Indication | Dosage | Frequency | Duration | Special Instructions |
|---|---|---|---|---|
| Secondary Amenorrhea | 400mg | Once daily at bedtime | 10 days | Take with food, ensure adequate estrogen priming |
| ART Luteal Support | 200-300mg | Three times daily | Continue through 10-12 weeks gestation | May combine with vaginal progesterone |
| Menopausal HRT (Sequential) | 200mg | Once daily at bedtime | 12 days monthly | Start day 1-14 of month |
| Menopausal HRT (Continuous) | 100mg | Once daily at bedtime | Continuous | Monitor for breakthrough bleeding |
The course of administration varies significantly by indication. For fertility treatments, we typically continue Prometrium through the first trimester until the placenta takes over progesterone production around 10-12 weeks. For menopausal hormone therapy, treatment may continue for several years with appropriate monitoring.
6. Contraindications and Drug Interactions
Safety considerations with Prometrium are generally favorable compared to synthetic progestins, but several important contraindications exist:
Absolute contraindications include known hypersensitivity to progesterone or any component (particularly peanut oil), undiagnosed abnormal genital bleeding, known or suspected breast cancer, active thrombophlebitis or thromboembolic disorders, and missed abortion. The peanut oil component requires special attention - I always document peanut allergy screening in the chart.
Drug interactions are primarily related to hepatic metabolism. Prometrium is metabolized by CYP3A4, so strong inducers like rifampin, carbamazepine, and St. John’s wort can significantly reduce progesterone levels. Conversely, strong inhibitors like ketoconazole may increase levels and side effects.
The sedation effect can potentiate other CNS depressants including alcohol, benzodiazepines, and opioids. I had a concerning case early in my career where a patient taking Prometrium with zolpidem experienced significant respiratory depression - we now always review all medications and adjust doses accordingly.
7. Clinical Studies and Evidence Base
The evidence supporting Prometrium spans decades and multiple indications. The Women’s Health Initiative provided important safety data, though it primarily studied synthetic progestins. Subsequent analyses of bioidentical progesterone have been more reassuring regarding cardiovascular and breast cancer risks.
For fertility applications, a Cochrane review of 94 studies concluded that progesterone supplementation significantly improves pregnancy rates in ART cycles (OR 1.77, 95% CI 1.19-2.63). The PROMISE trial specifically examined micronized progesterone for luteal phase support and found live birth rates of 26% versus 24% with placebo, though the difference wasn’t statistically significant in that particular study.
In menopausal hormone therapy, the Kronos Early Estrogen Prevention Study (KEEPS) used micronized progesterone and found favorable effects on cardiovascular markers without the increased breast cancer risk seen with some synthetic progestins. The estrogen/progesterone combination maintained cognitive function and improved vasomotor symptoms.
What’s interesting is that some of the most compelling evidence comes from real-world clinical experience rather than randomized trials. We’ve tracked our clinic’s outcomes for 15 years, and the shift to micronized progesterone correlated with reduced dropout rates from side effects and improved patient satisfaction scores.
8. Comparing Prometrium with Similar Products and Choosing Quality
The bioequivalence between brand name Prometrium and generic micronized progesterone is generally good, but I’ve observed subtle differences in some patients. The manufacturing process for micronization can vary between manufacturers, potentially affecting particle size distribution and absorption.
Compared to synthetic progestins like medroxyprogesterone acetate, Prometrium offers the advantage of biological identity but may cause more sedation and requires more frequent dosing. The choice often comes down to individual patient factors and tolerance.
Vaginal progesterone preparations provide higher uterine tissue levels with lower systemic exposure, which can be advantageous for fertility treatments but less ideal for systemic symptoms. Some protocols combine oral and vaginal administration to balance systemic and local effects.
When selecting a progesterone product, I consider the indication, patient preferences, cost, and specific clinical goals. For menopausal women concerned about breast cancer risk, micronized progesterone appears favorable based on the French E3N cohort study data.
9. Frequently Asked Questions (FAQ) about Prometrium
What is the recommended course of Prometrium to achieve results?
The duration varies by indication - typically 10 days for withdrawal bleeding, continuous through first trimester for fertility, and long-term for menopausal HRT. Individual response should guide adjustments.
Can Prometrium be combined with other medications?
Yes, but careful monitoring is needed with CYP3A4 inducers/inhibitors and CNS depressants. Always inform your provider of all medications and supplements.
Is Prometrium safe during pregnancy?
Yes, it’s commonly used in early pregnancy for luteal phase support and recurrent pregnancy loss. The safety profile is well-established through extensive clinical use.
How quickly does Prometrium work for sleep issues?
The sedative effects typically occur within 30-60 minutes of ingestion. Many patients notice improved sleep quality immediately, though individual responses vary.
Can Prometrium cause weight gain?
Progesterone can cause mild fluid retention and increased appetite in some women, but significant weight gain is uncommon with appropriate dosing and monitoring.
10. Conclusion: Validity of Prometrium Use in Clinical Practice
After twenty-plus years of prescribing Prometrium, I’ve developed a healthy respect for both its benefits and limitations. The transition from synthetic progestins to bioidentical progesterone represented meaningful progress in women’s health, but it’s not a perfect solution for every patient.
The risk-benefit profile favors Prometrium for most indications where progesterone supplementation is indicated, particularly given the potentially improved safety profile compared to synthetic alternatives. However, the sedation and need for careful timing remain practical challenges that require good patient education.
I’m thinking of Sarah, a 42-year-old attorney who came to me after three failed IVF cycles using synthetic progesterone. She was experiencing significant mood swings and breast tenderness that made the treatment process unbearable. We switched to Prometrium with careful timing around her court schedule, and she finally achieved a successful pregnancy. She sent me a photo last month of her daughter’s first birthday - these are the moments that remind me why we bother with all these nuances.
Or Maria, the 58-year-old college professor who couldn’t tolerate the synthetic progestin in her HRT regimen. The bloating and irritability were affecting her teaching. We transitioned to estradiol with continuous Prometrium 100mg, and she’s been stable for six years now with excellent quality of life.
The development wasn’t smooth - I remember heated debates with colleagues in the early 2000s about whether the higher cost of micronized progesterone was justified. Some insisted the synthetics were “good enough,” while others of us argued that side effect profiles mattered for long-term adherence. The data has largely supported our position, but it took years to accumulate.
What surprised me most was the variability in individual response. We had one patient who metabolized Prometrium so rapidly that her levels were undetectable despite high doses, while another became profoundly sedated on just 100mg. Genetic polymorphisms in metabolic enzymes likely explain some of this variation, but we’re still learning.
The longitudinal follow-up has been revealing. Our clinic now has 15-year data on over 1,200 women using Prometrium for various indications. The persistence rates are significantly higher than with synthetic progestins, primarily due to better tolerability. Patient testimonials consistently mention appreciation for the more “natural” feeling compared to synthetic options.
One failed insight worth mentioning - we initially thought Prometrium would be the perfect solution for all progesterone-deficient states. Reality proved more complicated. Some women simply don’t absorb oral progesterone well regardless of formulation, and the first-pass metabolism creates metabolites that not all patients tolerate well. We’ve learned to individualize rather than assume one size fits all.
At the end of the day, Prometrium represents an important tool rather than a magic bullet. It’s expanded our options for progesterone supplementation with a generally favorable safety profile, but requires careful patient selection, dosing, and monitoring. The women I’ve treated with it have taught me that sometimes the “small” improvements in side effect profiles make the biggest differences in quality of life during challenging reproductive journeys.