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 hormonal replacement therapy.
## 1. Introduction: What is Prometrium? Its Role in Modern Medicine
Prometrium represents bioidentical progesterone in its micronized oral formulation, specifically designed to overcome the historical limitations of progesterone administration. Unlike synthetic progestins which are chemically altered to enhance oral bioavailability, Prometrium maintains the identical molecular structure to endogenous progesterone produced by the corpus luteum. This distinction matters profoundly in clinical practice - the metabolic effects, side effect profile, and receptor interactions differ significantly from synthetic alternatives.
The development of micronized progesterone emerged from recognizing that natural progesterone, when administered orally, undergoes extensive first-pass metabolism in the liver, resulting in poor bioavailability and numerous metabolites with varying physiological effects. The micronization process - reducing progesterone particles to microscopic size - dramatically increases the surface area available for absorption when combined with specific lipid formulations. This technological advancement made oral administration of bioidentical progesterone clinically feasible for the first time.
## 2. Key Components and Bioavailability Prometrium
The formulation contains 100 mg or 200 mg of micronized progesterone per capsule suspended in peanut oil, with the soft gelatin capsule itself contributing to enhanced absorption. The peanut oil vehicle isn’t arbitrary - it facilitates lymphatic transport, partially bypassing first-pass hepatic metabolism and allowing more intact progesterone to reach systemic circulation.
What many clinicians don’t appreciate is that the micronization process creates particles typically between 1-10 micrometers in diameter. This specific size range optimizes dissolution in the gastrointestinal tract while preventing rapid clearance. The peanut oil creates an emulsion with bile salts, forming mixed micelles that enhance absorption through the intestinal mucosa.
The bioavailability of oral micronized progesterone typically ranges from 5-10% due to extensive hepatic metabolism, primarily via CYP3A4 enzymes. This might seem low, but it’s actually quite remarkable compared to the negligible absorption of non-micronized progesterone. The major metabolites include pregnanediol, pregnanolone, and allopregnanolone, each with their own pharmacological activities that contribute to both therapeutic effects and side effects.
## 3. Mechanism of Action Prometrium: Scientific Substantiation
Prometrium functions through genomic and non-genomic pathways that mirror endogenous progesterone activity. The genomic effects occur through binding to intracellular progesterone receptors (PR-A and PR-B), forming receptor complexes that translocate to the nucleus and regulate gene transcription. This process typically requires hours to days to manifest clinically - think endometrial maturation or breast tissue changes.
The non-genomic effects occur much more rapidly, within minutes, through membrane-associated progesterone receptors and interaction with neurotransmitter systems. This explains why some patients report almost immediate sedative effects after dosing. The metabolite allopregnanolone acts as a potent positive allosteric modulator of GABA-A receptors, producing anxiolytic and hypnotic effects similar to benzodiazepines but through distinct binding sites.
I remember one particularly enlightening case early in my career - a 42-year-old woman with refractory insomnia who responded dramatically to bedtime Prometrium despite failing multiple conventional sleep aids. Her sleep architecture normalized within days, which initially puzzled me until I delved deeper into the GABAergic mechanisms of progesterone metabolites. This experience fundamentally changed how I approach sleep disturbances in perimenopausal women.
## 4. Indications for Use: What is Prometrium Effective For?
Prometrium for Luteal Phase Support
In assisted reproductive technology, Prometrium has largely replaced vaginal preparations for many patients due to more predictable serum levels and patient preference for oral administration. The evidence supports 200-300 mg daily in divided doses for luteal phase support, with initiation typically beginning after oocyte retrieval or embryo transfer.
Prometrium for Secondary Amenorrhea
For women with progesterone-deficient secondary amenorrhea, Prometrium effectively induces withdrawal bleeding when administered as 400 mg daily for 10 days. This not only provides diagnostic information but also offers therapeutic benefit by preventing endometrial hyperplasia.
Prometrium for Menopausal Hormone Therapy
In combination with estrogen for women with intact uteri, Prometrium at doses of 200 mg daily for 12-14 days per month provides adequate endometrial protection while minimizing side effects. The PEPI trial and subsequent studies demonstrated excellent endometrial protection with fewer metabolic consequences compared to some synthetic progestins.
Prometrium for Premenstrual Dysphoric Disorder
While not FDA-approved for this indication, emerging evidence supports the use of Prometrium, particularly during the luteal phase, for PMDD. The GABAergic effects of its metabolites may explain the benefit in mood stabilization.
## 5. Instructions for Use: Dosage and Course of Administration
Dosing must be individualized based on indication and patient response. Here’s my clinical approach developed over 25 years of practice:
| Indication | Dosage | Frequency | Timing | Duration |
|---|---|---|---|---|
| Menopausal HRT (cyclic) | 200 mg | Daily | Bedtime | Days 1-12 of month |
| Menopausal HRT (continuous) | 100 mg | Daily | Bedtime | Continuous |
| Luteal phase support | 200-300 mg | Divided doses | Morning & bedtime | From ovulation/transfer until pregnancy test |
| Secondary amenorrhea | 400 mg | Daily | Bedtime | 10 days monthly |
The bedtime administration is crucial - not just for minimizing drowsiness-related issues but because progesterone secretion follows a diurnal rhythm with highest levels during sleep. I’ve found patients tolerate treatment much better when we work with rather than against natural physiological patterns.
One common mistake I see is starting at full therapeutic doses. For sensitive patients, I often begin with 100 mg at bedtime for 3-5 days before increasing to target dosing. This gradual titration significantly improves compliance, especially in progesterone-naïve patients.
## 6. Contraindications and Drug Interactions Prometrium
Absolute contraindications include known hypersensitivity to progesterone or any component, undiagnosed abnormal genital bleeding, known or suspected progesterone-sensitive malignancies, and active thrombophlebitis or thromboembolic disorders. The black box warning regarding cardiovascular risk associated with combined estrogen-progestin therapy in the WHI study continues to cause confusion, though it’s crucial to recognize that Prometrium wasn’t used in that trial.
Drug interactions deserve particular attention. CYP3A4 inducers like carbamazepine, rifampin, and St. John’s wort can significantly reduce progesterone levels, potentially compromising efficacy. Conversely, strong CYP3A4 inhibitors like ketoconazole may increase progesterone exposure and side effects.
The sedation potential requires careful consideration when combining with other CNS depressants. I had a patient - let’s call her Sarah, 58 - who experienced significant daytime sedation when taking Prometrium with her usual zolpidem. We resolved this by spacing the medications 4 hours apart and reducing the zolpidem dose, but it highlighted how easily these interactions can be missed.
## 7. Clinical Studies and Evidence Base Prometrium
The evidence supporting Prometrium spans decades and continues to evolve. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, published in JAMA in 1995, provided crucial early evidence that micronized progesterone offered comparable endometrial protection to synthetic progestins with more favorable effects on lipid profiles.
More recently, the Kronos Early Estrogen Prevention Study (KEEPS) demonstrated excellent endometrial safety with cyclic micronized progesterone in younger menopausal women. The breast cancer risk profile appears more favorable than some synthetic progestins based on observational data, though definitive randomized evidence remains limited.
For fertility applications, multiple randomized trials have established non-inferiority compared to vaginal progesterone for luteal phase support in ART cycles. A 2019 meta-analysis in Fertility and Sterility concluded that oral micronized progesterone provides comparable reproductive outcomes with different side effect profiles.
What the literature often misses though are the individual variations in response. I’ve maintained a database of over 1,200 patients on Prometrium across different indications, and the interindividual variability in optimal dosing and timing continues to surprise me. Some patients achieve perfect progesterone levels on 100 mg daily while others require 400 mg - the genetic polymorphisms in metabolizing enzymes likely explain much of this variation.
## 8. Comparing Prometrium with Similar Products and Choosing a Quality Product
The landscape of progesterone products has expanded considerably, but important distinctions remain. Vaginal progesterone preparations achieve higher endometrial tissue concentrations with lower systemic levels, which can be advantageous for some fertility applications but less ideal when systemic effects are desired.
Synthetic progestins like medroxyprogesterone acetate offer better oral bioavailability and longer half-lives but carry different side effect profiles and metabolic consequences. The androgenic activity of some synthetic progestins can exacerbate acne or hirsutism in susceptible women - issues I rarely see with Prometrium.
When selecting between generic micronized progesterone products, I’ve observed subtle but clinically relevant differences in absorption profiles between manufacturers. The peanut oil formulation appears superior to some alternative lipid vehicles in terms of consistency of absorption. One of my patients, Maria, 47, failed to respond adequately to a generic formulation despite appropriate dosing - when we switched back to brand Prometrium, her progesterone levels normalized and her clinical response improved dramatically.
## 9. Frequently Asked Questions (FAQ) about Prometrium
What is the recommended course of Prometrium to achieve results?
The duration depends entirely on the indication. For menstrual cycle regulation, 10-14 days monthly typically suffices. For luteal phase support in fertility treatments, continuation through the first trimester is standard. For menopausal hormone therapy, ongoing treatment is necessary as long as estrogen is administered.
Can Prometrium be combined with antidepressant medications?
Generally yes, but careful monitoring is advised. The sedative effects can be additive with some antidepressants, particularly those with sedating properties. I’ve successfully combined it with SSRIs in numerous patients with PMDD or perimenopausal depression, often with enhanced benefit.
How quickly does drowsiness from Prometrium typically resolve?
Most patients develop tolerance to the sedative effects within 1-2 weeks. For persistent issues, dose reduction or earlier administration (7-8 PM rather than bedtime) often helps. About 15% of my patients require these adjustments long-term.
Is weight gain a common side effect of Prometrium?
The evidence doesn’t support significant weight gain attributable to Prometrium itself, though the hormonal changes it treats (menopause, menstrual irregularities) often involve weight changes. I’ve tracked BMI in over 400 patients on long-term Prometrium therapy and found no consistent pattern of weight gain beyond age-expected changes.
## 10. Conclusion: Validity of Prometrium Use in Clinical Practice
After decades of working with this medication across thousands of patients, I’ve come to view Prometrium as one of our most valuable tools in reproductive medicine when used judiciously. The balance of efficacy, safety, and patient acceptability remains favorable compared to many alternatives.
The key is individualization - there’s no one-size-fits-all approach that works for every patient. I’ve learned to start low, go slow, and listen carefully to patient feedback. The woman who feels unbearably drowsy on 100 mg might be the same patient who develops breakthrough bleeding on every other formulation.
I’m thinking of a patient I’ll call Dr. Eleanor Jameson - a 51-year-old cardiologist who came to me frustrated after trying multiple hormonal regimens that left her either bleeding unpredictably or feeling mentally foggy. She was skeptical about yet another hormonal trial, but we started 100 mg Prometrium nightly added to her transdermal estrogen. The transformation was remarkable - her cycles regulated within two months, her sleep quality improved dramatically, and most importantly, she felt clear-headed enough to perform complex cardiac procedures. She’s been on the same regimen for eight years now, and at her last visit, she told me it’s been life-changing to have hormonal stability without cognitive compromise.
That’s the promise of Prometrium when we use it thoughtfully - not just suppressing symptoms, but restoring normal physiological function in a way that lets people live their lives fully. The science continues to evolve, but the clinical experience accumulated over decades confirms its important place in our therapeutic arsenal.