Progesterone Natural USP

• Hormonal balance support
• Potential bone density preservation
• Possible cardiovascular protection

• Sleep quality improvement
• Mood stabilization
• Potential neuroprotective effects
• Endometrial protection when used with estrogen

Absorption: Natural progesterone has poor oral bioavailability (approximately 10-15%) due to extensive first-pass metabolism in the liver. Micronization (reducing particle size) improves absorption, increasing bioavailability to about 80% compared to non-micronized forms. Transdermal and vaginal applications bypass first-pass metabolism, offering more direct delivery to target tissues with different absorption profiles.

Distribution: Progesterone is highly lipophilic and approximately 96-99% bound to plasma proteins, primarily to albumin and corticosteroid-binding globulin. It readily crosses the blood-brain barrier and placenta. The volume of distribution is large due to its lipophilic nature and tissue distribution.

Metabolism: Primarily metabolized in the liver through reduction, hydroxylation, and conjugation pathways. Major metabolites include pregnanediol, pregnanetriol, and various hydroxylated derivatives. The 5α-reduction pathway produces neurologically active metabolites like allopregnanolone. Significant interindividual variability exists in metabolism rates and pathways.

Elimination: Metabolites are primarily excreted in urine (50-60%) and feces (10-15%). The elimination half-life of natural progesterone is approximately 5-20 minutes for the parent compound, but metabolites have longer half-lives (up to several hours). Micronized oral progesterone has a terminal half-life of about 16-18 hours due to its formulation and release characteristics.

Reproductive System: Converts proliferative endometrium to secretory phase, preparing for potential implantation. Inhibits estrogen-induced proliferation, reducing hyperplasia risk., Reduces contractility of uterine smooth muscle by decreasing excitability, calcium influx, and oxytocin sensitivity., Alters cervical mucus to become thicker and less permeable to sperm, contributing to contraceptive effects during luteal phase., Provides negative feedback to hypothalamic-pituitary axis, modulating gonadotropin release and follicular development.

Breast Tissue: Promotes alveolar-lobular development and differentiation. Counterbalances estrogen’s proliferative effects, potentially reducing breast cancer risk.

Central Nervous System: Exerts anxiolytic, sedative, and neuroprotective effects through GABA-A receptor modulation and other mechanisms. Influences mood, cognition, and sleep architecture.

Cardiovascular System: Modulates vascular tone, potentially improving endothelial function and reducing inflammation. May have beneficial effects on lipid metabolism and atherosclerosis development.

Bone: Influences bone metabolism, potentially supporting bone mineral density through effects on osteoblasts and osteoclasts, though effects are less pronounced than estrogen’s.

Natural progesterone dosing varies based on the specific condition being treated, administration route, individual response, and whether it’s used alone or in combination with estrogen. Dosages should be individualized under healthcare provider supervision, with the general principle of using the lowest effective dose for the shortest duration necessary to achieve therapeutic goals.

Circadian Factors: Oral progesterone is often recommended at bedtime due to its sedative effects, which can improve sleep while minimizing daytime drowsiness. This timing also aligns with natural circadian patterns of higher progesterone levels in the evening.

Cyclical Patterns: For perimenopausal women, progesterone is often prescribed cyclically (typically days 14-28 of the menstrual cycle) to mimic natural hormonal rhythms and reduce the risk of endometrial hyperplasia while allowing for regular withdrawal bleeding.

Continuous Vs Sequential: Postmenopausal hormone therapy may use either continuous progesterone (daily administration, potentially leading to amenorrhea) or sequential regimens (12-14 days per month, typically resulting in predictable withdrawal bleeding).

Women With Cardiovascular Risk: Lower doses and non-oral routes may be preferred to minimize potential metabolic effects. Bioidentical progesterone may have more favorable cardiovascular effects compared to synthetic progestins.

Women With History Of Breast Cancer: Generally contraindicated, though some evidence suggests natural progesterone may have a more favorable risk profile than synthetic progestins. Any use should involve careful risk-benefit assessment and oncology consultation.

Women With Mood Disorders: May require careful monitoring as progesterone and its metabolites can affect mood. Some women experience mood improvement, while others may have adverse mood effects.

Women With Migraines: Stable hormone levels are preferred; continuous rather than cyclical regimens may reduce hormone-withdrawal headaches. Transdermal routes may be preferred for more stable hormone levels.

Clinical Assessment: Regular evaluation of symptom response, side effects, bleeding patterns, and overall well-being.

Endometrial Monitoring: For women using estrogen therapy, endometrial thickness assessment by transvaginal ultrasound may be recommended periodically. Any abnormal bleeding warrants evaluation.

Hormone Level Testing: Routine blood testing of progesterone levels is generally not recommended for monitoring therapy, as levels fluctuate and correlation with tissue effects is inconsistent. May be considered in specific situations to confirm absorption or compliance.

Cardiovascular Risk Factors: Regular monitoring of blood pressure, lipid profiles, and other cardiovascular risk factors is recommended for women on long-term hormone therapy.

The bioavailability of natural progesterone varies significantly depending on the route of administration, formulation, and individual factors. Understanding these differences is crucial for optimal therapeutic outcomes, as the amount of hormone that reaches target tissues directly impacts efficacy and side effect profiles.

Standard Bioavailability: Non-micronized oral progesterone has extremely poor bioavailability (approximately 10-15%) due to extensive first-pass metabolism in the gastrointestinal tract and liver.

Micronization Effects: Micronization (reducing particle size to <10 μm) significantly improves absorption, increasing relative bioavailability to approximately 80% compared to non-micronized forms. However, absolute bioavailability remains around 10-15% compared to intravenous administration.

Oil Suspension Benefits: Dissolving micronized progesterone in oil (as in commercial products like Prometrium) further enhances absorption by improving dissolution and lymphatic uptake.

Food Effects: Taking oral progesterone with food, particularly a fat-containing meal, can increase bioavailability by 2-3 fold compared to fasting conditions. This is due to increased bile secretion, prolonged gastric emptying time, and enhanced lymphatic transport.

Pharmacokinetic Profile: After oral administration of 100 mg micronized progesterone, peak serum concentrations typically occur at 1-3 hours, with levels returning to baseline within 12-24 hours. Significant interindividual variability exists.

Bioavailability Factors: Transdermal progesterone creams and gels bypass first-pass metabolism, but absorption is limited by the stratum corneum barrier and progesterone’s molecular properties.

Absorption Rates: Absorption rates vary widely (5-20%) depending on formulation, skin condition, application site, and individual factors. Penetration enhancers and specialized delivery systems can improve absorption.

Serum Vs Tissue Levels: Transdermal application often results in relatively low serum progesterone levels (typically 0.5-3.0 ng/mL) but may achieve higher concentrations in local tissues. This discrepancy has led to debate about efficacy for systemic effects like endometrial protection.

Application Site Importance: Areas with thinner skin and better blood supply (inner arms, neck, chest, inner thighs) generally provide better absorption than areas with thicker skin (abdomen, back).

Pharmacokinetic Profile: Transdermal progesterone typically produces more stable but lower serum levels compared to oral administration, with less pronounced peaks and troughs.

Bioavailability Characteristics: Vaginal administration provides a ‘first uterine pass effect’ where progesterone is preferentially delivered to the uterus via direct vaginal-to-uterine transport, resulting in higher endometrial concentrations despite moderate systemic levels.

Absorption Efficiency: Absorption efficiency varies by formulation (suppositories, gels, tablets, rings) but generally ranges from 30-80%, significantly higher than oral routes.

Endometrial Concentrations: Endometrial tissue concentrations can be 10-100 times higher than those achieved with equivalent doses of oral progesterone, making this route particularly effective for endometrial protection and fertility applications.

Pharmacokinetic Profile: After vaginal administration, serum levels rise more gradually than with oral dosing, reaching peak concentrations in 3-8 hours and maintaining more stable levels over 24 hours.

Absorption Mechanism: Sublingual and buccal routes allow progesterone to be absorbed directly into the bloodstream through the highly vascularized oral mucosa, bypassing first-pass metabolism.

Bioavailability Comparison: Bioavailability is typically higher than oral administration (approximately 30-40%) but lower than vaginal or injectable routes.

Pharmacokinetic Profile: Faster onset of action compared to oral routes, with peak levels typically occurring within 30-60 minutes. Duration of effect is generally shorter than other routes.

Bioavailability: Injectable progesterone in oil has nearly 100% bioavailability, as it bypasses first-pass metabolism and delivers the hormone directly into circulation.

Pharmacokinetic Profile: Intramuscular injection of progesterone in oil provides sustained release over 24-48 hours, with peak levels occurring within 2-8 hours after administration.

Clinical Applications: Primarily used in fertility treatments and for prevention of preterm birth due to reliable absorption and high bioavailability.

Route Selection Guidance: Route selection should consider the specific therapeutic goal, desired systemic vs. local effects, convenience, and individual patient factors.

Monitoring Considerations: Due to variable bioavailability, clinical response monitoring is often more valuable than serum level testing for assessing adequacy of therapy.

Dose Adjustment Principles: Dose adjustments should account for bioavailability differences between routes; equivalent effects may require significantly different doses by different routes.

Natural/USP progesterone generally has a favorable safety profile when used appropriately under medical supervision. It typically causes fewer side effects and metabolic disturbances than synthetic progestins. However, as with any hormone therapy, there are potential risks and contraindications that must be considered. The safety profile varies based on administration route, dosage, duration of use, and individual risk factors.

Common:

Uncommon:

Rare But Serious:

Absolute:

Relative:

Oral:

• Higher rates of sedation and dizziness due to first-pass metabolism producing neurosteroid metabolites. Potential for more systemic effects.
• Well-studied, predictable effects, FDA-approved options available.
• Bedtime dosing can minimize sedative side effects and potentially improve sleep.

Transdermal:

• Variable absorption, potential for skin irritation, limited data on endometrial protection efficacy.
• Bypasses first-pass metabolism, potentially fewer systemic side effects, easy application.
• Rotate application sites, use on areas with thin skin for better absorption.

Vaginal:

• Local irritation, discharge, potential for infection with improper use.
• Direct delivery to target tissue, higher endometrial concentrations, fewer systemic effects.
• Proper hygiene, following application instructions carefully.

Sublingual:

• Taste issues, limited research on efficacy and safety.
• Bypasses first-pass metabolism, potentially faster onset of action.
• Allow to dissolve completely without swallowing.

Injectable:

• Pain at injection site, risk of infection, higher systemic exposure.
• High bioavailability, reliable absorption.
• Proper sterile technique, administration by healthcare professionals.

Pregnancy:

• Category B (US FDA historical classification)
• Used in specific situations for prevention of preterm birth and luteal phase support in assisted reproduction. Should only be used when benefit outweighs risk.
• Extensive data from use in pregnancy support safety for specific indications. Natural progesterone is preferred over synthetic progestins when progesterone supplementation is indicated during pregnancy.

Breastfeeding:

• Generally considered compatible
• Minimal amounts enter breast milk. Consider timing administration to minimize infant exposure if concerned.
• Limited data suggest no adverse effects on breastfed infants. Progesterone may affect milk production in some women.

Pediatric:

• Not indicated
• Not recommended outside of specialized pediatric endocrinology settings for specific conditions.
• Limited data on safety and efficacy in pediatric populations.

Geriatric:

• Use with caution
• Consider lower starting doses and careful monitoring. Benefits may not outweigh risks for long-term use in elderly women.
• Limited specific data in elderly populations. Increased risk of certain adverse effects due to age-related changes in metabolism and comorbidities.

Hepatic Impairment:

• Use with caution in mild to moderate impairment; avoid in severe impairment
• Consider non-oral routes to bypass first-pass metabolism. Dose reduction may be necessary.
• Hepatic metabolism is a major clearance pathway for progesterone. Impaired liver function may lead to increased hormone exposure and side effects.

Renal Impairment:

• No specific dose adjustment required
• Standard precautions apply; monitor for fluid retention.
• Renal excretion is not a major elimination pathway for progesterone, but metabolites are excreted in urine.

Cardiovascular Effects:

• Natural progesterone appears to have neutral or potentially beneficial effects on cardiovascular risk factors compared to synthetic progestins.
• Studies suggest natural progesterone has minimal impact on lipid profiles, blood pressure, and inflammatory markers. May have vasodilatory effects and improve endothelial function.

Breast Cancer Risk:

• Controversial area with mixed evidence. Some data suggest natural progesterone may have a more favorable profile than synthetic progestins when combined with estrogen.
• The French E3N cohort study suggested lower breast cancer risk with natural progesterone compared to synthetic progestins when combined with estrogen, but other studies show mixed results. More research is needed.

Endometrial Effects:

• Effective for endometrial protection when used at appropriate doses with estrogen therapy.
• Well-established efficacy for preventing estrogen-induced endometrial hyperplasia when used at adequate doses (oral 100-200 mg daily or equivalent).

Cognitive Effects:

• Limited data suggest potential neuroprotective effects, but clinical significance remains uncertain.
• Preclinical studies show neuroprotective properties. Limited clinical data on cognitive outcomes with long-term use.

Bone Health:

• Neutral to potentially beneficial effects when combined with estrogen.
• Does not appear to attenuate estrogen’s beneficial effects on bone mineral density. Some data suggest progesterone itself may have modest positive effects on bone.

Baseline Assessments:

• Complete medical history and physical examination
• Breast examination and mammography according to age-appropriate guidelines
• Pelvic examination and Pap smear as indicated
• Blood pressure measurement
• Assessment of cardiovascular risk factors
• Liver function tests if oral administration planned

Follow Up Monitoring:

• Clinical evaluation at 3-6 months initially, then annually
• Blood pressure monitoring
• Breast examination annually and mammography according to guidelines
• Endometrial assessment if abnormal bleeding occurs
• Periodic assessment of risks and benefits for continued therapy

Warning Signs Requiring Attention:

• Abnormal vaginal bleeding
• Breast lumps or nipple discharge
• Severe headaches or migraines
• Visual disturbances
• Severe leg pain or swelling
• Chest pain or shortness of breath
• Yellowing of skin or eyes
• Severe mood changes or depression

Ema Approved Products: Array, Array

Country Specific Variations: Pioneered the use of natural progesterone in hormone therapy; wider range of approved products and indications than many other countries., Stricter regulation of compounded bioidentical hormones than the US; emphasis on standardized approved products., NICE guidelines specifically mention micronized progesterone as an option for menopausal hormone therapy with potentially fewer side effects than synthetic progestins.

Compounding Regulations: More restrictive than US regulations. Compounding is generally limited to specific patient needs that cannot be met by commercial products. Standardized formulations are preferred over customized hormone combinations.

Health Canada Approved Products: Array, Array

Compounded Formulations: Regulated provincially rather than federally. Standards vary by province, but generally require prescription and preparation by licensed pharmacists.

Natural Health Products: Some progesterone creams are classified as Natural Health Products (NHPs) and regulated under the Natural Health Products Regulations, requiring a Natural Product Number (NPN) and adherence to quality standards.

Tga Approved Products: Array, Array

Compounding Regulations: Regulated under the Therapeutic Goods Act. Compounded hormones must be prepared by licensed pharmacists based on prescription for individual patients. TGA has issued warnings about claims regarding compounded bioidentical hormones.

Pmda Approved Products: Limited approved natural progesterone products compared to synthetic progestins. Available products are prescription-only and primarily indicated for reproductive health applications.

Regulatory Approach: Conservative approach to hormone therapy with preference for lower doses and shorter durations of treatment.

Who Essential Medicines: Progesterone is included in the WHO Model List of Essential Medicines for specific reproductive health indications, including prevention of preterm birth.

International Guidelines: The International Menopause Society acknowledges that natural progesterone may have a more favorable side effect profile than some synthetic progestins, particularly regarding cardiovascular and breast effects., The International Federation of Gynecology and Obstetrics includes progesterone in guidelines for specific reproductive health applications, including luteal phase support and preterm birth prevention.

Prescription Coverage: Generally covered by insurance for FDA-approved indications, though coverage varies by plan. Typical copays range from $10-75 for generics and $30-150 for brand-name products., Often not covered by insurance, requiring full out-of-pocket payment. Some plans may provide partial coverage with prior authorization., Many plans restrict coverage to specific formulations, require prior authorization, or limit quantity based on diagnosis.

Health Savings Accounts: Progesterone prescribed for medical conditions (rather than general wellness) is typically eligible for payment through Health Savings Accounts (HSAs) and Flexible Spending Accounts (FSAs), including compounded formulations with prescription.

Medicare Coverage: Most Medicare Part D plans cover FDA-approved progesterone products for approved indications, though often with significant copays or coinsurance., Coverage varies widely among Medicare Advantage plans, with some offering better coverage for hormone therapy than traditional Medicare.

Patient Perspective: Value varies significantly based on symptom severity, side effect experiences with alternatives, and individual financial circumstances. Many women report willingness to pay premium prices for natural progesterone if they experience fewer side effects compared to synthetic alternatives.

Payer Perspective: Insurance companies and healthcare systems typically focus on direct acquisition costs and established outcomes, often favoring lower-cost synthetic progestins despite potential long-term benefits of natural progesterone.

Societal Perspective: From a broader societal perspective, natural progesterone may offer good value despite higher upfront costs if it reduces long-term complications, improves quality of life, and enhances productivity.

Molecular Characteristics: Progesterone (pregn-4-ene-3,20-dione) is a steroid hormone with a ketone group at C-3 and C-20 positions. These functional groups, particularly the C-3 ketone in conjugation with the C-4,5 double bond, are susceptible to oxidation and other degradation reactions. The molecule is relatively stable in solid form but more vulnerable to degradation in solution.

Degradation Pathways:

Degradation Products: Common degradation products include various oxidized derivatives (hydroxy-progesterones, progesterone epoxides), isomers, and fragmentation products. Some degradation products may retain partial hormonal activity or exhibit different biological effects than the parent compound.

Pharmaceutical Formulations: FDA-approved products like Prometrium typically have a shelf life of 2-3 years when stored properly in original packaging. The oil-based formulation and sealed capsules help protect progesterone from degradation., Generally 2-3 years in unopened packaging. Once opened, vaginal gels in applicators typically maintain stability for 1-3 months depending on the specific product., Oil-based injectable progesterone typically has a shelf life of 1-2 years when stored properly. Multi-dose vials should be used within 28 days after first puncture unless otherwise specified by the manufacturer.

Compounded Preparations: Typically assigned beyond-use dates of 6 months or less, depending on the specific formulation and testing performed by the compounding pharmacy., Usually assigned beyond-use dates of 30-180 days, depending on the base formulation, preservative system, and storage conditions., Typically 30-90 days when refrigerated, with shorter dating at room temperature. Specific stability depends on the base used (e.g., fatty acid, polyethylene glycol).

Over The Counter Products: Commercial progesterone creams typically claim shelf lives of 1-2 years unopened. Once opened, stability is generally reduced to 6-12 months, though this varies by formulation.

Temperature: Most progesterone formulations should be stored at controlled room temperature (20-25°C or 68-77°F), with excursions permitted to 15-30°C (59-86°F)., Oral Capsules: Store at room temperature away from moisture and heat. Refrigeration is not necessary and may cause the oil base to thicken, though this doesn’t affect potency., Vaginal Gels: Generally stored at room temperature. Some products may require refrigeration – check specific product labeling., Creams And Gels: Room temperature storage is typically adequate. Avoid excessive heat which can cause separation of the emulsion., Suppositories: Many require refrigeration to maintain proper consistency and prevent melting. Check specific product instructions.

Light Exposure: Protect from light, particularly direct sunlight and UV light, which can accelerate degradation. Amber containers, opaque packaging, or secondary packaging (cartons) provide protection from light.

Moisture: Keep containers tightly closed to protect from humidity, which can accelerate degradation, particularly for solid dosage forms. Desiccants are sometimes included in packaging to absorb moisture.

Oxygen Exposure: Minimize exposure to air/oxygen, which can accelerate oxidative degradation. Keep containers tightly closed when not in use. Some formulations include antioxidants to mitigate oxidation.

Accelerated Stability: Storage under elevated temperature and humidity conditions (typically 40°C/75% RH) to predict long-term stability in a shorter timeframe. Used extensively in pharmaceutical development.

Real Time Stability: Storage under recommended conditions with periodic testing throughout the intended shelf life. Provides the most reliable data but requires longer testing periods.

Photostability: Exposure to defined light conditions to assess vulnerability to photodegradation, following standardized protocols like ICH Q1B.

Analytical Methods: HPLC, UPLC, or GC methods to quantify progesterone content and detect degradation products., UV, IR, or NMR spectroscopy to identify structural changes or degradation., To identify and characterize degradation products with high specificity.

Synthesis Methods

Natural Sources

Commercial Forms

Quality Considerations

Sourcing Recommendations

Sustainability Considerations

Natural/USP progesterone has substantial scientific evidence supporting its use for several indications, particularly endometrial protection during estrogen therapy, management of certain menopause symptoms, and reproductive health applications. The evidence is strongest for FDA-approved indications and formulations. Research comparing natural progesterone to synthetic progestins generally shows a more favorable safety profile for natural progesterone, particularly regarding metabolic and cardiovascular effects.

However , evidence for some applications (such as mood disorders, neuroprotection, and cardiovascular benefits) remains preliminary or mixed.

Endocrine Society: Acknowledges that bioidentical hormones may have different physiological effects than synthetic hormones but emphasizes the importance of FDA-approved formulations and appropriate monitoring.

North American Menopause Society: Recognizes that natural progesterone has a different side effect profile than synthetic progestins and may be preferred by some women. Recommends FDA-approved formulations over compounded products.

American College Of Obstetricians And Gynecologists: Supports the use of FDA-approved bioidentical hormone preparations but cautions against claims of superior safety or efficacy for compounded bioidentical hormones.

Long-term comparative safety studies between natural progesterone and synthetic progestins for breast cancer and cardiovascular outcomes, Optimal dosing and administration routes for specific indications, Personalized approaches based on genetic factors, metabolism, and individual risk profiles, Clearer understanding of progesterone’s effects on brain function, mood, and cognition, Better characterization of tissue-specific effects and receptor-mediated actions