Natural Progesterone

Natural progesterone exerts its biological effects primarily through genomic and non-genomic pathways, with its interaction with progesterone receptors (PRs) being the most well-established mechanism. As a steroid hormone identical in structure to endogenous progesterone produced by the ovaries (primarily by the corpus luteum), natural progesterone binds to nuclear progesterone receptors (PR-A and PR-B) in target tissues. Upon binding, these receptors undergo conformational changes, dimerize, and translocate to the nucleus, where they function as transcription factors to regulate gene expression. This genomic pathway typically takes hours to days to manifest its full effects and is responsible for many of progesterone’s physiological actions, including endometrial differentiation, mammary gland development, and regulation of reproductive functions.

Beyond the classical genomic pathway, natural progesterone also acts through membrane-associated progesterone receptors (mPRs) and the progesterone receptor membrane component 1 (PGRMC1), which mediate rapid non-genomic effects. These non-genomic actions occur within seconds to minutes and involve activation of various signaling cascades, including mitogen-activated protein kinases (MAPKs), phospholipase C, and intracellular calcium mobilization. These rapid effects contribute to progesterone’s actions on the central nervous system, cardiovascular system, and other tissues. In the central nervous system, progesterone and its metabolites, particularly allopregnanolone, act as neurosteroids with significant effects on neurotransmitter systems.

Allopregnanolone, formed from progesterone through sequential reduction by 5α-reductase and 3α-hydroxysteroid dehydrogenase, is a potent positive allosteric modulator of GABA-A receptors. By enhancing GABA-ergic neurotransmission, allopregnanolone produces anxiolytic, sedative, and anticonvulsant effects, which may explain progesterone’s benefits for mood, anxiety, and sleep quality. Progesterone also modulates other neurotransmitter systems, including serotonin, dopamine, and glutamate, further contributing to its effects on mood and cognitive function. In bone tissue, progesterone supports bone formation through multiple mechanisms.

It stimulates osteoblast activity and differentiation, increases the expression of insulin-like growth factor 1 (IGF-1) in osteoblasts, and may counteract the bone-resorbing effects of glucocorticoids. Additionally, progesterone may enhance the bone-protective effects of estrogen by upregulating estrogen receptors in bone cells. The cardiovascular effects of natural progesterone involve several mechanisms, including vasodilation through nitric oxide production, reduction of vascular smooth muscle cell proliferation, and modulation of ion channels in cardiac cells. Unlike synthetic progestins, natural progesterone does not antagonize the beneficial effects of estrogen on lipid profiles and may have neutral or positive effects on cardiovascular risk factors.

In the reproductive system, progesterone prepares the endometrium for implantation by inducing secretory changes, reducing estrogen receptor expression, and inhibiting estrogen-induced proliferation. This anti-proliferative effect on the endometrium is particularly important for protecting against endometrial hyperplasia and cancer in women using estrogen therapy. Progesterone also reduces uterine contractility by decreasing the expression of oxytocin receptors and prostaglandin production, which is crucial for maintaining pregnancy. The immunomodulatory effects of progesterone include suppression of T-cell activation, modulation of cytokine production, and induction of protective proteins like progesterone-induced blocking factor (PIBF).

These actions contribute to maternal immune tolerance during pregnancy and may have implications for autoimmune conditions. Progesterone’s effects on breast tissue are complex and context-dependent. While it stimulates alveolar-lobular development in preparation for lactation, progesterone can also induce apoptosis in breast cancer cells expressing progesterone receptors. However, its role in breast cancer risk remains controversial, with effects likely depending on timing, dose, and the presence of other hormones.

In the context of estrogen dominance or imbalance, natural progesterone helps restore proper estrogen-to-progesterone ratios. It can counteract excessive estrogenic effects by competing for shared binding proteins, modulating estrogen receptor expression, and influencing estrogen metabolism. This balancing effect may alleviate symptoms associated with relative estrogen excess, such as PMS, fibrocystic breasts, and certain menopausal symptoms. It’s important to note that natural progesterone’s mechanisms of action differ significantly from those of synthetic progestins, which may explain their different side effect profiles and clinical outcomes.

Natural progesterone has higher specificity for progesterone receptors and less cross-reactivity with other steroid receptors compared to many synthetic progestins, which can bind to androgen, glucocorticoid, or mineralocorticoid receptors, potentially causing unwanted effects.

The optimal dosage of natural progesterone varies significantly based on the specific health goal, administration route, individual factors, and whether it’s used alone or in combination with estrogen. For oral micronized progesterone, typical therapeutic doses range from 100-300 mg daily. For transdermal creams, typical doses range from 20-40 mg daily (approximately 1/4 to 1/2 teaspoon of a 2% cream). Vaginal preparations are typically used at doses of 45-100 mg daily for specific conditions.

Dosing should ideally be guided by baseline and follow-up hormone testing, with the goal of achieving physiological levels similar to those of the luteal phase in premenopausal women (approximately 5-20 ng/mL in serum, though optimal levels may vary by individual and testing method). Cyclical administration (using progesterone for part of the month) may be more physiological for some applications, while continuous administration may be preferred for others, particularly when used for endometrial protection with estrogen therapy.

The bioavailability of natural progesterone varies dramatically depending on the route of administration. Oral progesterone undergoes extensive first-pass metabolism in the liver, resulting in relatively low bioavailability of approximately 10-15% when taken in standard form. However, micronization (reducing particle size to 5-10 micrometers) and suspension in oil significantly improves oral bioavailability to approximately 80-90% by enhancing dissolution and absorption. Even with these improvements, oral progesterone results in relatively short-lived peaks in serum levels followed by rapid metabolism.

Transdermal progesterone cream demonstrates variable absorption, with bioavailability estimates ranging from 10-70% depending on the specific formulation, application site, and individual skin characteristics. Transdermal delivery bypasses first-pass metabolism but faces the challenge of progesterone’s large molecular size, which limits passive diffusion through the skin. Well-formulated creams with penetration enhancers achieve better absorption. Transdermal application typically results in more stable serum levels compared to oral administration but may not achieve the high peak levels seen with oral dosing.

Sublingual administration bypasses first-pass metabolism and provides rapid absorption through the highly vascularized tissues under the tongue, with bioavailability estimated at 30-50%. This route produces relatively quick onset of effects but shorter duration compared to oral or transdermal routes. Vaginal administration demonstrates excellent bioavailability for local effects on reproductive tissues, with significant uterine first-pass effect resulting in higher progesterone concentrations in endometrial tissue than would be predicted from serum levels. Systemic bioavailability from vaginal administration is estimated at 30-80%, depending on the specific formulation.

The absorption kinetics vary by route, with oral micronized progesterone showing peak serum levels approximately 1-4 hours after ingestion, transdermal application showing more gradual increases over 2-8 hours, and sublingual administration showing rapid peaks within 30-60 minutes.

Micronization significantly improves oral bioavailability by increasing surface area for dissolution, Oil-based suspensions enhance absorption of oral progesterone by improving solubility and lymphatic transport, Taking oral progesterone with food, particularly a small amount of fat, increases absorption by 2-3 fold, Transdermal formulations with penetration enhancers (e.g., alcohols, fatty acids) improve skin permeation, Multi-layered transdermal delivery systems with controlled release mechanisms provide more consistent absorption, Liposomal formulations can enhance bioavailability by improving solubility and cellular uptake, Applying transdermal progesterone to areas with thinner skin and higher blood flow (inner wrists, behind knees, inner thighs), Rotating application sites for transdermal preparations to prevent saturation of local tissues, Sublingual formulations bypass first-pass metabolism for improved bioavailability, Vaginal delivery systems provide excellent local bioavailability for reproductive tissues, Cyclodextrin complexation can improve solubility and stability of progesterone formulations, Nanoparticle delivery systems are emerging as potential methods to enhance progesterone bioavailability

For oral micronized progesterone, evening administration is generally recommended, particularly when used for sleep support, as its metabolite allopregnanolone has sedative effects. Taking oral progesterone with a small meal containing fat significantly improves absorption. For those using oral progesterone primarily for endometrial protection with estrogen therapy, consistent timing is important for maintaining stable hormone levels. For transdermal progesterone creams, application once or twice daily is typical, with evening application often preferred when addressing sleep issues.

Morning application may be preferred when using for energy or cognitive support. Consistent application timing helps maintain stable hormone levels. For those using progesterone cyclically (mimicking the natural menstrual cycle), application is typically recommended during the luteal phase, approximately days 14-28 of a 28-day cycle, though this should be adjusted based on individual cycle length. For sublingual progesterone, administration on an empty stomach is recommended, as food or beverages can wash away the hormone before complete absorption occurs.

For vaginal progesterone, evening administration is often recommended for convenience, as the woman can remain recumbent afterward to minimize leakage. For those using multiple hormones (e.g., estrogen and progesterone), separating administration by at least 30-60 minutes may help minimize potential interactions and optimize absorption of each. For those using progesterone for specific symptom relief (e.g., migraines, anxiety), timing may be adjusted to target symptom patterns, though consistent daily use is still important for hormonal balance. For women with an intact uterus using estrogen therapy, continuous rather than intermittent progesterone use is essential for endometrial protection.

For those using progesterone for PMS symptoms, starting application 7-10 days before expected menses (or at ovulation) and continuing until menstruation begins is typically most effective. For those new to progesterone supplementation, starting with lower doses and gradually increasing while monitoring for effects and side effects is recommended. This approach allows for assessment of individual response and tolerance.

• Drowsiness or sedation, particularly with oral forms
• Dizziness
• Fatigue
• Headaches
• Breast tenderness or swelling
• Mood changes (depression, irritability, or anxiety in some individuals)
• Bloating or fluid retention
• Changes in menstrual bleeding patterns in premenopausal women
• Nausea
• Constipation or diarrhea
• Vaginal discharge (with vaginal forms)
• Skin irritation (with transdermal forms)
• Low libido in some individuals (though may increase libido in others)
• Hair loss or thinning (rare)
• Hypersensitivity reactions (rare)

• Known or suspected pregnancy (unless specifically prescribed for certain pregnancy complications)
• Active or history of hormone-sensitive cancers (breast, ovarian, uterine) unless approved by oncologist
• Active or history of thromboembolic disorders (DVT, PE, stroke)
• Undiagnosed vaginal bleeding
• Active liver disease or impaired liver function
• Known hypersensitivity to progesterone or components of the formulation
• Porphyria
• Severe uncontrolled hypertension
• History of or current breast cancer (controversial; some oncologists may permit in specific cases)
• Severe depression with hormonal component
• Severe renal impairment
• Uncontrolled diabetes mellitus
• Otosclerosis with worsening during pregnancy or previous hormone use

• Sedatives and CNS depressants (additive sedative effects, particularly with oral progesterone)
• Anticonvulsants (may decrease progesterone levels through enzyme induction)
• Rifampin and other enzyme inducers (may decrease progesterone effectiveness)
• Ketoconazole and other enzyme inhibitors (may increase progesterone levels)
• Warfarin and other anticoagulants (potential changes in anticoagulant requirements)
• Cyclosporine (potential increased cyclosporine levels)
• Theophylline (potential decreased theophylline levels)
• St. John’s Wort (may decrease progesterone effectiveness)
• Estrogens (complex interactions; generally used together therapeutically)
• Tamoxifen and other selective estrogen receptor modulators (complex interactions)
• Bromocriptine (may interfere with therapeutic effects)
• Carbamazepine (may decrease progesterone levels)
• Phenobarbital (may decrease progesterone levels)

No definitive toxic upper limit has been established for natural progesterone, but clinical experience and research suggest that doses above 400 mg daily orally or 60-80 mg daily transdermally significantly increase the risk of adverse effects without proportional benefits for most individuals. Most clinical studies have used oral doses between 100-300 mg daily or transdermal doses of 20-40 mg daily, with side effects becoming more common and pronounced at higher doses. The appropriate dose varies significantly based on the specific condition being addressed, administration route, individual metabolism, and whether progesterone is used alone or with estrogen. Hormone testing before and during supplementation is strongly recommended to guide dosing decisions and minimize risks.

For oral micronized progesterone, doses above 300 mg daily are more likely to cause excessive sedation, cognitive impairment, and other central nervous system effects due to increased production of neurosteroid metabolites. For transdermal progesterone, doses above 40-60 mg daily may not provide proportionally increased benefits due to saturation of local tissues and limitations in skin absorption. The risk of side effects appears to increase not only with dose but also with duration of use at higher doses. Short-term use of higher doses may be better tolerated than long-term use.

The risk profile is also influenced by individual factors such as age, weight, liver function, and concurrent medications or health conditions. For women with an intact uterus using estrogen therapy, the minimum effective dose of progesterone for endometrial protection is generally considered to be 100 mg daily orally or 20 mg daily transdermally when used continuously. For cyclical regimens, higher doses may be used for shorter periods. For individuals with a history of hormone-sensitive conditions, even standard doses of progesterone may pose significant risks and should be avoided unless specifically prescribed and monitored by a healthcare provider with expertise in hormone management.

Regular monitoring is essential for anyone using natural progesterone long-term, including periodic assessment of hormone levels, endometrial thickness (for women with a uterus), and condition-specific markers. Starting with lower doses and gradually increasing while monitoring for benefits and side effects represents the safest approach to natural progesterone supplementation.

In the United States, natural progesterone has a complex regulatory status that varies by formulation, concentration, and intended use. FDA-approved prescription medications containing natural (bioidentical) progesterone include Prometrium (oral micronized progesterone in capsules), Crinone and Endometrin (vaginal progesterone gels), and Prochieve (vaginal progesterone gel). These products are approved for specific indications including hormone replacement therapy, treatment of secondary amenorrhea, prevention of endometrial hyperplasia, and support of embryo implantation and early pregnancy in assisted reproductive technology. Lower-concentration progesterone creams (typically containing 20 mg progesterone per gram or less) are often marketed as over-the-counter cosmetics or supplements.

These products exist in a regulatory gray area – they are not FDA-approved drugs but are generally permitted on the market with limited claims. The FDA has occasionally issued warning letters to manufacturers making disease treatment claims for these products. Compounded bioidentical progesterone preparations are available through compounding pharmacies with a prescription. These are regulated under different standards than FDA-approved medications, with oversight primarily at the state level through state boards of pharmacy.

The FDA’s 2018 guidance on compounded hormone products acknowledges their widespread use while expressing concerns about quality standards and evidence for specific formulations.

Canada: In Canada, natural progesterone is available as prescription medications for approved indications. Health Canada has approved Prometrium (oral micronized progesterone) and various vaginal progesterone formulations. Lower-concentration progesterone creams may be available as natural health products (NHPs) if they meet specific regulatory requirements and avoid therapeutic claims. Compounded bioidentical progesterone preparations are available through compounding pharmacies with a prescription.

Eu: In the European Union, natural progesterone is primarily available as prescription medications regulated by the European Medicines Agency (EMA) and national regulatory authorities. Approved products include oral micronized progesterone (marketed under various brand names) and vaginal formulations. The regulatory status of lower-concentration progesterone creams varies by country, with some permitting them as cosmetics with limited claims. Compounded preparations are available in some EU countries but are subject to national regulations that vary considerably across the union.

Uk: In the United Kingdom, natural progesterone is available as prescription medications regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). Approved products include Utrogestan (oral micronized progesterone) and various vaginal formulations. Lower-concentration progesterone creams may be available but exist in a regulatory gray area similar to the US situation. Compounded bioidentical progesterone preparations are available through specialized pharmacies with a prescription.

Australia: In Australia, natural progesterone is regulated by the Therapeutic Goods Administration (TGA). Prescription products include Prometrium (oral micronized progesterone) and vaginal formulations. Compounded bioidentical progesterone is available through compounding pharmacies with a prescription. The TGA has issued guidance specifically addressing bioidentical hormone therapy, acknowledging its use while expressing concerns about marketing claims and evidence for some applications.

Japan: In Japan, natural progesterone is available primarily as prescription medications regulated by the Ministry of Health, Labour and Welfare. The regulatory framework for compounded hormones is more restrictive than in the US, with fewer compounding pharmacies offering these services.

Brazil: In Brazil, natural progesterone is regulated by the Brazilian Health Regulatory Agency (ANVISA). Both manufactured pharmaceutical products and compounded preparations are available with a prescription. Brazil has a relatively well-developed market for compounded bioidentical hormones, with specific regulations governing these preparations.

South Africa: In South Africa, natural progesterone is regulated by the South African Health Products Regulatory Authority (SAHPRA). Prescription products are available for approved indications. Compounded bioidentical progesterone is available through compounding pharmacies with a prescription, though regulatory oversight of compounding is evolving.

Medium to high compared to most supplements, but low to medium compared to prescription hormone medications

Typical retail pricing for over-the-counter progesterone creams (1-2% concentration) ranges from $15-40 for a 2-3 oz container, providing approximately 30-60 days of use at standard dosages (20-40 mg daily), translating to approximately $0.50-1.33 per day. Prescription-strength progesterone creams (typically higher concentrations) may cost $30-80 for a similar supply, depending on insurance coverage. Oral micronized progesterone (Prometrium and generics) typically costs $30-150 for a 30-day supply at standard dosages (100-200 mg daily), with significant variation based on insurance coverage, pharmacy, and brand vs. generic.

Compounded progesterone formulations vary widely in price, typically $30-100 for a 30-day supply, depending on the specific formulation, dosage, and compounding pharmacy. Vaginal progesterone products (gels, suppositories) are generally the most expensive, ranging from $100-500 for a month’s supply, though insurance coverage can significantly reduce out-of-pocket costs for approved indications.

Natural progesterone represents moderate value for specific applications, particularly when compared to synthetic progestins or no treatment for conditions requiring progesterone. The value proposition is strongest for individuals who: 1) Have specific indications for progesterone therapy, such as endometrial protection when using estrogen; 2) Experience side effects from synthetic progestins and require a bioidentical alternative; 3) Have documented progesterone deficiency confirmed by testing; 4) Experience measurable benefits for specific symptoms like sleep disturbances or mood issues. For endometrial protection when using estrogen therapy, natural progesterone is essential rather than optional for women with an intact uterus, making its value proposition very high despite the cost. For menopausal symptom management, the value comparison is complex.

While natural progesterone may have fewer side effects than synthetic progestins for some women, it may also be less effective for certain symptoms. Individual response varies significantly. For over-the-counter progesterone creams, the significant price variation between products reflects differences in concentration, formulation quality, and marketing positioning rather than necessarily proportional differences in efficacy. Consumers should compare products based on the actual progesterone content and cost per mg rather than total price.

Prescription progesterone products, while more expensive than over-the-counter options, offer standardized dosing, proven bioavailability, and potential insurance coverage, potentially providing better value despite higher nominal cost. Generic oral micronized progesterone can offer excellent value compared to brand-name products, with similar efficacy at significantly lower cost. For those requiring progesterone primarily for sleep support, oral micronized progesterone may offer better value than transdermal forms due to its metabolism to allopregnanolone, which has stronger effects on GABA receptors and sleep quality. Testing costs should be factored into the overall value equation when using natural progesterone.

Baseline and follow-up hormone testing (typically $50-200 per panel) is recommended for optimal use, adding to the total cost of therapy. For specific medical conditions like luteal phase deficiency or recurrent pregnancy loss, the value of progesterone therapy can be very high despite the cost, particularly when considering the potential costs (both financial and emotional) of untreated conditions. For general wellness or anti-aging purposes without specific symptoms or documented deficiency, the value proposition is weaker and more speculative, as benefits may be subtle or absent for some individuals.

Properly stored natural progesterone in oral capsule form typically has a shelf life of 2-3 years from date of manufacture. Transdermal cream formulations generally have shorter shelf lives of 1-2 years, with stability declining more rapidly after opening due to potential oxidation, separation of ingredients, and contamination. Vaginal suppositories and gels typically have shelf lives of 1-2 years when properly stored. Compounded formulations generally have shorter shelf lives than commercially manufactured products, typically 6 months to 1 year depending on the specific formulation and preservatives used.

Pure progesterone powder (as used in compounding) may have a shelf life of 3-5 years when properly stored, though this is rarely relevant for consumer use.

Store oral progesterone capsules in a cool, dry place away from direct sunlight, preferably below 75°F (24°C). Refrigeration is not necessary and may actually increase the risk of condensation when containers are opened and closed. For transdermal progesterone creams, storage recommendations vary by formulation. Some products require refrigeration, while others are stable at room temperature.

Follow manufacturer’s specific instructions. Once opened, ensure cream containers are tightly sealed after each use to prevent oxidation and contamination. For creams in jars, use a clean spatula rather than fingers to remove product to minimize contamination. For pump dispensers, ensure the nozzle is clean and free from dried product.

Some manufacturers recommend refrigeration after opening to extend shelf life, particularly for preservative-free formulations. For vaginal suppositories, refrigeration is typically recommended as these formulations often have lower melting points and can soften at room temperature. Some vaginal gels may be stored at room temperature; follow manufacturer’s specific instructions. Avoid storing any progesterone formulation near heat sources, in direct sunlight, or in humid environments like bathrooms.

Protect from freezing, as freeze-thaw cycles can affect physical stability, particularly of cream and gel formulations. For all formulations, ensure containers are tightly sealed when not in use. If purchasing in bulk quantities, consider transferring only a portion to a container for regular use while keeping the remainder sealed until needed. Some premium progesterone products are packaged in dark glass or opaque containers to protect from light, or in airless pump systems to minimize oxidation.

Heat: Elevated temperatures accelerate chemical degradation; prolonged exposure to temperatures above 85°F (30°C) can significantly reduce potency, Oxygen: Exposure to air causes oxidation, particularly in cream formulations, leading to reduced potency and potential changes in color or odor, Light: Direct sunlight and UV exposure can cause photodegradation, particularly in transdermal and liquid formulations, Moisture: Absorption of moisture can lead to degradation of oral capsules and potential microbial growth in all formulations, Microbial contamination: Particularly relevant for creams and other topical formulations, especially after opening, pH extremes: Progesterone is most stable at slightly acidic to neutral pH; strong acids or bases can accelerate degradation, Improper emulsion stability: In cream formulations, separation of oil and water phases can affect both stability and absorption, Chemical interactions with container materials: Some plastics or rubbers may interact with progesterone or formulation ingredients, Freeze-thaw cycles: Repeated freezing and thawing can affect physical stability, particularly of cream and gel formulations, Improper particle size maintenance: For micronized oral formulations, agglomeration of particles over time can reduce bioavailability

Synthesis Methods

Natural Sources

Quality Considerations

Natural progesterone has a relatively short historical usage compared to many botanical medicines, as its isolation, identification, and synthesis occurred in the 20th century. The story begins in the 1930s, when researchers were actively investigating reproductive hormones. In 1934, four independent research groups nearly simultaneously reported the isolation of progesterone from corpus luteum extracts. Adolf Butenandt in Germany, Max Hartmann in Switzerland, and teams led by Willard Allen and George Corner in the United States all contributed to this breakthrough.

The name ‘progesterone’ was coined to reflect the hormone’s role in supporting gestation (pro-gestation sterone). The initial isolation yielded only tiny amounts from animal sources, making progesterone extremely expensive and limiting its research and clinical applications. A pivotal development came in 1940 when Russell Marker, an American chemist, developed what became known as the ‘Marker degradation’ – a process to convert diosgenin from Mexican wild yams (Dioscorea species) into progesterone. This revolutionary method dramatically reduced the cost of progesterone production and increased its availability.

In 1944, Marker established Syntex in Mexico, which became a major producer of steroid hormones using his method. The 1950s saw the first significant medical applications of natural progesterone, primarily for menstrual disorders, infertility, and pregnancy support. However, its clinical use was limited by poor oral bioavailability, as natural progesterone is rapidly metabolized by the liver when taken orally. This limitation led to the development of synthetic progestins (such as norethindrone, first synthesized in 1951), which had better oral bioavailability but different molecular structures and potentially different effects than natural progesterone.

Throughout the 1960s and 1970s, synthetic progestins largely dominated clinical practice, being used in oral contraceptives and hormone replacement therapy, while natural progesterone remained less commonly used due to delivery challenges. A significant advancement came in the late 1970s and early 1980s with the development of micronized progesterone – natural progesterone ground into extremely small particles and suspended in oil. This formulation substantially improved oral bioavailability, making natural progesterone a more viable option for clinical use. The 1980s also saw increased interest in transdermal progesterone applications.

Dr. John Lee, an American physician, began advocating for the use of topical progesterone creams for menopausal symptoms and osteoporosis prevention, based on his clinical observations. While his work was not initially supported by rigorous clinical trials, it sparked interest in this delivery method. The publication of Dr.

Lee’s book ‘What Your Doctor May Not Tell You About Menopause’ in 1996 significantly increased public awareness of natural progesterone as an alternative to synthetic progestins. The 1990s and early 2000s brought growing scientific interest in distinguishing between the effects of natural progesterone and synthetic progestins. This period saw the development of more sophisticated delivery systems, including vaginal gels and suppositories, which provided targeted delivery for specific conditions. A major turning point in the perception of hormone therapy came with the 2002 publication of initial results from the Women’s Health Initiative (WHI) study, which found increased risks of breast cancer, heart disease, stroke, and blood clots with combined estrogen and synthetic progestin (specifically medroxyprogesterone acetate) therapy.

This led to a dramatic decline in conventional hormone therapy use and increased interest in bioidentical hormones, including natural progesterone. Subsequent analyses and studies suggested that natural progesterone might have a more favorable risk profile than synthetic progestins, particularly regarding breast cancer and cardiovascular effects. This further fueled interest in natural progesterone as an alternative. The 2000s and 2010s saw an expansion of clinical research on natural progesterone for various applications, including menopausal symptom management, endometrial protection, sleep quality, and neuroprotection.

This period also saw growing regulatory recognition, with FDA approval of several micronized progesterone formulations for specific indications. Today, natural progesterone is available in various forms, including FDA-approved pharmaceutical preparations and compounded formulations. It is used both in conventional medical practice and in integrative or functional medicine approaches. While synthetic progestins still dominate certain applications like contraception, natural progesterone has gained significant acceptance for menopausal hormone therapy, fertility support, and specific gynecological conditions.

The historical trajectory of natural progesterone reflects broader trends in medicine – from the initial excitement of hormone discovery, through the development of synthetic alternatives, to a renewed appreciation for bioidentical hormones that more closely mimic the body’s own chemistry. This evolution continues as research further elucidates the distinct effects and risk profiles of natural progesterone compared to synthetic progestins.

Asi N, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Systematic Reviews. 2016;5(1):121. doi:10.1186/s13643-016-0294-5, Romero R, et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. American Journal of Obstetrics and Gynecology. 2018;218(2):161-180. doi:10.1016/j.ajog.2017.11.576, Prior JC, et al. Progesterone therapy, endometrial thickness and bleeding. Facts, Views & Vision in ObGyn. 2015;7(3):231-234.

Natural Progesterone for Cognitive Function in Aging Women (PROG-COG-2023), Transdermal Progesterone for Perimenopausal Mood Disorders (PROG-MOOD-2022), Progesterone vs. Synthetic Progestins for Bone Health in Postmenopausal Women (PROG-BONE-2023), Comparative Analysis of Different Progesterone Delivery Systems on Symptom Relief (PROG-DELIVERY-2022)