Prasterone

Prasterone, also known as dehydroepiandrosterone (DHEA), is an endogenous C19 steroid hormone produced primarily by the zona reticularis of the adrenal cortex, with smaller amounts synthesized in the gonads and brain, serving as a key prohormone precursor to androgens such as testosterone and estrogens such as estradiol.^[1][2] In its native form, prasterone exhibits minimal direct hormonal activity but is enzymatically converted in target tissues to active sex steroids, influencing physiological processes including sexual development, immune function, and metabolic regulation.^[3] Levels of prasterone peak in early adulthood and decline progressively with age, a pattern associated with conditions such as adrenal insufficiency and age-related hormonal changes.^[1] Medically, prasterone is approved in intravaginal insert form (brand name Intrarosa) for the treatment of moderate to severe dyspareunia—a symptom of vulvovaginal atrophy—arising from postmenopausal hypoestrogenism, where it undergoes local bioconversion to estrogens and androgens, alleviating vaginal dryness, pain during intercourse, and tissue atrophy without inducing significant systemic hormonal effects.^[4][3] Clinical trials have demonstrated statistically significant improvements in dyspareunia scores, vaginal pH, and epithelial maturation indices compared to placebo, positioning prasterone as a targeted alternative to systemic estrogen therapies that carry risks of endometrial hyperplasia or cardiovascular events.^[5][6] Over-the-counter oral prasterone supplements are marketed for purported benefits in energy, mood, and sexual function, though the U.S. Food and Drug Administration has not approved these for any medical indication, and empirical evidence for broad anti-aging or performance-enhancing claims remains inconsistent and limited by methodological flaws in studies.^[7] Early investigations into systemic prasterone for conditions like systemic lupus erythematosus showed mixed results, with no sustained approval beyond investigational use due to insufficient efficacy data.^[8]

Chemical Properties

Structure and Synthesis

Prasterone, systematically known as dehydroepiandrosterone (DHEA), possesses the molecular formula C₁₉H₂₈O₂ and a molecular mass of 288.42 g/mol.^[2] It features an androst-5-ene steroid backbone with a β-hydroxy group at carbon 3 and a ketone at carbon 17, classifying it as 3β-hydroxy-5-androsten-17-one.^[2] This structure positions prasterone as a key precursor in the biosynthesis of androgens and estrogens.^[2] Biosynthetically, prasterone arises primarily in the zona reticularis of the adrenal cortex from cholesterol via enzymatic transformations. Cholesterol undergoes side-chain cleavage by cytochrome P450scc (CYP11A1) to yield pregnenolone, which is then converted to 17α-hydroxypregnenolone by 17α-hydroxylase activity of CYP17A1. Subsequent 17,20-lyase action of CYP17A1 cleaves the side chain, producing prasterone.^[9] These reactions occur in the mitochondria and endoplasmic reticulum, with production peaking in early adulthood before declining with age.^[10] Pharmaceutical synthesis of prasterone typically employs semi-synthetic routes from microbial fermentation products like 4-androstene-3,17-dione. A chemoenzymatic approach involves stereoselective reduction of the Δ4 double bond to the Δ5 position using ketosteroid isomerase and alcohol dehydrogenase enzymes, followed by acetylation and deacetylation steps to isolate prasterone or its acetate.^[11] Alternative multi-step chemical processes incorporate protection of the 17-keto group and selective dehydrogenation to establish the 5-ene unsaturation, minimizing side reactions.^[12]

Derivatives and Analogs

Prasterone enanthate, the 3β-enanthate ester of prasterone, serves as a prodrug for sustained release in pharmaceutical formulations, such as intramuscular injections combined with estradiol valerate for menopausal hormone therapy.^[13] This derivative undergoes hydrolysis to release free prasterone and enanthic acid in vivo.^[14] Prasterone sulfate, the 3β-sulfate ester, constitutes the primary circulating form of prasterone, comprising over 99% of total prasterone in plasma due to sulfation in the adrenal glands and liver.^[15] Structural analogs include 7-ketodehydroepiandrosterone (7-oxo-prasterone), which bears an additional keto group at carbon 7 and functions as a metabolite that bypasses conversion to active sex steroids like testosterone or estradiol.^[16] This analog has been studied for metabolic effects, including potential support for weight management, though clinical evidence remains limited to small trials.^[17] Fluorinated analogs, such as 16α-fluoro-5-androsten-17-one (fluasterone), exhibit amplified potency in preclinical models for inhibiting tumor growth and obesity compared to native prasterone, attributed to modifications enhancing metabolic stability and receptor interactions.^[18][19] Similarly, 7α- and 7β-amino-prasterone derivatives have demonstrated apoptotic effects on Leydig and Sertoli cells in vitro, positioning them as candidates for investigating steroid-mediated cell death pathways.^[20] Synthetic spiro-analogs like BNN27, a C-17 spiro derivative, promote neuroprotection via non-genomic mechanisms independent of sex hormone conversion, with preclinical data supporting roles in mitigating neurodegeneration.^[21] These modifications highlight efforts to decouple prasterone's precursor activity from androgenic or estrogenic side effects while preserving or enhancing therapeutic potential.

Pharmacology

Pharmacodynamics

Prasterone, known chemically as dehydroepiandrosterone (DHEA), functions primarily as an endogenous prohormone, undergoing enzymatic conversion in peripheral tissues to yield active sex steroids. These transformations involve key steroidogenic enzymes, including 3β-hydroxysteroid dehydrogenase to form androstenedione, 17β-hydroxysteroid dehydrogenase to produce testosterone, 5α-reductase to generate dihydrotestosterone, and aromatase to synthesize estrogens such as estrone and estradiol.^[1][22] This biosynthetic pathway enables prasterone to support androgenic and estrogenic effects indirectly, with its own direct binding affinity to the androgen receptor and estrogen receptors being relatively weak.^[1] In vaginal tissues, following local administration as a 6.5 mg insert, prasterone is metabolized intracellularly via an intracrine mechanism, where target cells express the necessary enzymes to convert it into androgens and estrogens that activate androgen receptors and estrogen receptors within the same cells.^[23][22] This local activation promotes physiological changes such as increased maturation of vaginal epithelial cells (e.g., rise in superficial cells from approximately 1% to 11% and decline in parabasal cells from 54% to 13% over 12 weeks), enhanced vascularization, reduced vaginal pH (from about 6.3 to 5.4), and restoration of lactobacilli flora, thereby alleviating symptoms of vulvovaginal atrophy without substantially elevating systemic hormone levels beyond postmenopausal norms.^[22][23] Prasterone also interacts with non-steroid targets, acting as an antagonist at GABA_A receptors, an agonist at NMDA and sigma-1 receptors, an activator of peroxisome proliferator-activated receptor alpha (PPARα), and an inhibitor of glucose-6-phosphate dehydrogenase, which may underlie additional effects like neuroprotection, modulation of neuronal excitability, and potential metabolic influences observed in preclinical models.^[1] Its sulfate form, DHEA-S, further contributes as a neurosteroid precursor modulating GABAergic and glutamatergic signaling.^[24] These multifaceted actions highlight prasterone's role beyond mere hormone precursor status, though clinical significance varies by context and dosage.^[1]

Pharmacokinetics

Prasterone, or dehydroepiandrosterone (DHEA), exhibits route-dependent pharmacokinetics, with oral administration leading to rapid but limited systemic bioavailability due to extensive first-pass metabolism in the liver and gut, where much of it is converted to the sulfate conjugate DHEA-S.^[1] Following a single 50 mg oral dose in healthy elderly subjects, plasma DHEA levels peak within hours and restore concentrations comparable to those in younger adults, though absolute bioavailability in humans remains unquantified and is estimated low based on animal data (3.1% in cynomolgus monkeys).^{[25] [1]} Vaginal administration, as in the approved 6.5 mg daily insert, results in primarily local absorption with modest systemic exposure; mean serum trough DHEA concentrations increase by 47% (from 1.81 ng/mL baseline) after 12 weeks, accompanied by dose-dependent C_max of 5.97 ng/mL and AUC_{24} of 65.49 ng·h/mL on day 1.^[22] Distribution occurs widely, with prasterone taken up by peripheral tissues including the liver, kidneys, gonads, and brain, where it serves as a precursor for intracrine synthesis of active androgens and estrogens via enzymes such as hydroxysteroid dehydrogenases, 5α-reductases, and aromatases.^[22] The apparent terminal half-life of DHEA exceeds 20 hours in oral studies, influenced by interconversion with DHEA-S, though unconjugated DHEA has a shorter intrinsic half-life of approximately 12 hours; no significant sex differences in distribution volume are noted, but women show greater DHEA-S to DHEA conversion.^{[25] [1]} Metabolism is primarily hepatic and peripheral, yielding major metabolites including DHEA-S, androsterone glucuronide, and androstane-3α,17β-diol glucuronide, with further transformation to testosterone, dihydrotestosterone, estradiol, and estrone occurring locally in target tissues rather than systemically.^{[1] [22]} Excretion occurs mainly via urine as inactive glucuronide and sulfate conjugates of these metabolites, with no accumulation observed in long-term vaginal use where systemic androgen and estrogen levels remain within postmenopausal norms (e.g., testosterone trough +21%, estradiol +19% after 12 weeks).^[26] Oral dosing at 25-50 mg daily sustains elevated baseline DHEA and metabolite levels without disproportionate increases in active steroids.^[25]

Clinical Dosing Considerations

The recommended dosage of prasterone for moderate to severe dyspareunia due to postmenopausal vulvovaginal atrophy is one 6.5 mg intravaginal insert administered once daily at bedtime.^[27][28] This regimen utilizes a disposable applicator for insertion, with individually wrapped inserts provided for nightly use.^[29] No dosage adjustments are required for elderly patients over 65 years of age, reflecting minimal systemic exposure and consistent pharmacokinetics in postmenopausal women.^[30] Similarly, no specific modifications are indicated for hepatic or renal impairment, as clinical data support the fixed 6.5 mg dose without evidence of accumulation or altered clearance necessitating changes.^[31][26] Clinical trials demonstrating efficacy, such as those evaluating 12 weeks of daily administration, employed this standard dose without titration, showing statistically significant improvements in vaginal symptoms and superficial cell counts.^[32][31] Prasterone lacks duration-of-use restrictions, unlike some estrogen therapies, due to its local conversion to estrogens and androgens with limited serum impact.^[33] Concurrent use with aromatase inhibitors warrants caution, as prasterone may interfere with their action, potentially requiring dose reevaluation.^[34]

Approved Medical Uses

Treatment of Vulvovaginal Atrophy

Prasterone, administered as a 6.5 mg intravaginal insert (Intrarosa), is approved by the U.S. Food and Drug Administration for the treatment of moderate to severe dyspareunia, a primary symptom of vulvovaginal atrophy (VVA), in postmenopausal women.^[35][31] Approval was granted on November 17, 2016, based on evidence of symptom relief without the systemic risks associated with estrogen therapies.^[36] The recommended regimen involves nightly insertion at bedtime, initially for 12 weeks, with potential maintenance dosing as clinically indicated.^[28] The therapeutic action relies on local intracrinology, where prasterone—a steroid precursor—is taken up by vaginal epithelial and stromal cells and enzymatically converted into active androgens (such as testosterone and dihydrotestosterone) and estrogens (such as estradiol and estrone).^[37][33] This site-specific transformation restores vaginal tissue integrity, reduces pH, increases superficial cell percentage in cytology, and alleviates dryness and pain without producing clinically significant elevations in serum estrogen or androgen levels, minimizing risks like endometrial hyperplasia.^[22][38] Efficacy was demonstrated in two pivotal 12-week, multicenter, randomized, double-blind, placebo-controlled phase III trials involving 406 healthy postmenopausal women aged 40 to 80 years with moderate to severe VVA symptoms.^[6][36] The primary endpoint, change in dyspareunia severity score (assessed via a 0-4 visual analog scale in patient-reported questionnaires and clinical evaluation), showed statistically significant improvements of 0.36 to 0.40 points greater than placebo (p<0.001).^[6] Secondary outcomes included reductions in vaginal dryness severity and improvements in vaginal pH (decrease of approximately 1.3-1.5 units) and cytology parameters (e.g., increase in superficial cells by 10-15% and decrease in parabasal cells by 20-25%). Clinical trials also demonstrated improvements in multiple domains of sexual function, including desire, arousal, lubrication, orgasm, satisfaction, and reduced pain, as measured by the Female Sexual Function Index (FSFI).^[28][33][39] These effects were observed as early as week 4 and sustained through week 12, with response rates for dyspareunia relief exceeding 60% in prasterone groups versus 40-45% with placebo.^[40] Compared to low-dose conjugated equine estrogen cream (0.3 mg), prasterone demonstrated comparable efficacy in dyspareunia and dryness relief in a separate randomized trial, though direct head-to-head data remain limited.^[41] Long-term data beyond 52 weeks are sparse, but extensions of the phase III trials indicate sustained benefits with continued use and no new safety signals.^[42] Prasterone does not require endometrial monitoring, unlike systemic or certain local estrogens, due to negligible uterine exposure.^[3]

Specific Formulations and Administration

Prasterone is formulated as a vaginal insert under the brand name Intrarosa, containing 6.5 mg of prasterone (dehydroepiandrosterone) dispersed in 1.3 mL of off-white hard fat (Witepsol H15) as the vehicle.^[43] This ovule-like insert is designed for local intravaginal delivery to minimize systemic absorption while targeting vulvovaginal tissues.^[1] The U.S. Food and Drug Administration approved this formulation on November 17, 2016, specifically for the treatment of moderate to severe dyspareunia, a symptom of vulvovaginal atrophy, in postmenopausal women.^[44] Administration involves inserting one 6.5 mg vaginal insert once daily at bedtime using a single-use disposable applicator provided with the product.^[45] The applicator is activated by pulling back the plunger until it stops, loaded with the unwrapped insert, and then gently inserted into the vagina while the patient lies on her back with knees drawn up, similar to standard tampon insertion techniques.^[29] After insertion, the plunger is pushed to release the insert, and the applicator is discarded; no additional lubrication or preparation is required beyond standard hygiene.^[46] Treatment is intended for continuous daily use, with efficacy observed in clinical trials after 12 weeks, though duration should be guided by symptom response and physician assessment.^[6] No other prasterone formulations are approved by the FDA for vulvovaginal atrophy; oral, injectable, or topical non-vaginal routes are not indicated for this use due to differing pharmacokinetic profiles and potential for greater systemic exposure.^[31] Patients should be advised to store inserts at controlled room temperature (20–25°C) and avoid use if allergic to prasterone or its excipients.^[45]

Safety Profile

Adverse Effects

In clinical trials evaluating intravaginal prasterone for vulvovaginal atrophy, the drug has demonstrated a generally favorable safety profile, with adverse effects primarily mild, local, and occurring at rates similar to or only modestly higher than placebo. Across four 12-week randomized, placebo-controlled studies involving over 1,800 postmenopausal women, treatment discontinuation due to adverse events was low at approximately 3.6% in the prasterone group versus 3.3% with placebo.^[33] Serious adverse events were rare and balanced between groups, with no evidence of increased systemic risks such as cardiovascular events, thromboembolism, or malignancies directly attributable to prasterone; one case of breast cancer was reported in a 52-week open-label extension trial among 318 participants, but long-term causality remains unestablished.^[40] The most common adverse reaction is vaginal discharge, reported in 2.7% to 8.3% of prasterone users compared to 1.3% to 4% with placebo, often described as leakage or increased wetness without infection.^[6][47] Abnormal Pap smear results represent another frequent finding, with incidences of 2% to 5% in treated groups versus 1.6% in controls, typically resolving without intervention and linked to local epithelial changes rather than precancerous lesions.^[48] Other local effects, such as vulvovaginal discomfort or pruritus, occur at rates below 2% and do not differ significantly from placebo.^[49] Systemic absorption of prasterone and its metabolites (including estradiol and testosterone) is minimal with intravaginal administration, resulting in negligible androgenic or estrogenic side effects compared to oral DHEA formulations, which can cause acne, hirsutism, or voice deepening in 5-10% of users.^[50] No clinically meaningful changes in serum hormone levels, lipid profiles, or bone markers were observed in phase 3 trials up to 52 weeks, supporting the localized mechanism of action via intracrinology, where conversion to active steroids occurs primarily within vaginal tissues.^[28] Hypersensitivity reactions are contraindications, but post-marketing surveillance has not identified new safety signals beyond trial data as of 2024.^[51]

Contraindications and Precautions

Prasterone is contraindicated in women with undiagnosed abnormal genital bleeding, for which the underlying cause must be evaluated prior to considering treatment.^[43] In regulatory approvals outside the United States, such as in the European Union, contraindications additionally encompass hypersensitivity to prasterone or excipients, known or suspected breast cancer, estrogen-dependent malignancies (e.g., endometrial cancer), untreated endometrial hyperplasia, previous or active venous thromboembolism, thrombophilic disorders, active or recent arterial thromboembolic disease, acute or unresolved liver disease, and porphyria.^[23] Precautions are advised for women with a current or prior history of breast cancer, as prasterone is metabolized to estrogen—a known contraindication for exogenous estrogen therapy—and clinical trials excluded such patients, leaving safety data absent in this population.^[43] Although prasterone exhibits primarily local action with minimal systemic absorption, any emergent vaginal bleeding or spotting during treatment warrants prompt investigation, potentially including endometrial biopsy, to exclude malignancy.^[43][23] Close monitoring is recommended in patients with conditions exacerbated by estrogens or androgens, such as leiomyoma, endometriosis, hypertension, or a history of endometrial hyperplasia, with periodic pelvic and breast examinations advised before and during use.^[23] Prasterone is indicated solely for postmenopausal women and has not been studied in pregnant or lactating individuals, pediatric populations, or those with renal or hepatic impairment.^[43] Risks associated with systemic hormone replacement therapy, including venous thromboembolism, stroke, and breast cancer, apply to a lesser degree but necessitate individualized risk-benefit assessment, particularly beyond one year of use where long-term endometrial safety remains unestablished.^[23]

Long-Term Safety Data

The primary source of long-term safety data for prasterone (intravaginal dehydroepiandrosterone, 6.5 mg daily) derives from the ERC-230 trial, a phase III, open-label, single-arm study involving 521 postmenopausal women with vulvovaginal atrophy treated for up to 52 weeks.^[28] In this trial, 80.2% of participants experienced treatment-emergent adverse events, predominantly mild to moderate, with application site discharge reported in 14.0% and urinary tract infections in 10.2%; serious adverse events occurred in 3.5%, and discontinuations due to adverse events were 6.0%, with no deaths attributed to the drug.^[28] Pooled data from shorter placebo-controlled trials (ERC-231 and ERC-238, 12 weeks) showed comparable adverse event rates between prasterone and placebo groups, suggesting many events reflect underlying postmenopausal conditions rather than drug causality, though the absence of a control arm in ERC-230 limits definitive attribution.^[31][28] Serum concentrations of prasterone and its metabolites (including testosterone, estradiol, and estrone) increased following administration but remained within the normal postmenopausal range, with no evidence of supraphysiological elevations or clinically significant hormonal disruptions over 52 weeks.^[31] Endometrial assessments via biopsy in 94% of ERC-230 participants revealed atrophic histology, with no cases of hyperplasia or malignancy, and mean endometrial thickness of 2.2 mm by ultrasound; however, long-term endometrial safety beyond one year has not been systematically evaluated.^[28] Breast safety evaluations, including mammograms in 98% of participants, were predominantly normal (99%), though two cases of pathology—one atypical ductal hyperplasia and one infiltrating ductal carcinoma—were reported, without established drug linkage given the population's baseline cancer risk.^[28] Cervical assessments via Pap smears showed 90% normal results, with 3% atypical findings mostly negative for high-risk HPV and not associated with prasterone exposure in comparative analyses.^[28] Regulatory reviews by the FDA and EMA concluded no major safety signals for up to one year of use, supporting approval for vulvovaginal atrophy, but emphasized monitoring for vaginal bleeding or breast changes due to local conversion to estrogens and androgens, with theoretical oncogenic risks unproven in human data.^[31][52] Data beyond 52 weeks are absent, and trials excluded women with cancer history, cardiovascular disease, or uncontrolled hypertension, potentially underrepresenting risks in broader populations; open-label design may inflate adverse event reporting via heightened awareness.^[28][52] Post-marketing surveillance, including drug utilization studies, continues to assess real-world long-term effects.^[52]

Investigational and Off-Label Applications

Adrenal Insufficiency and Aging-Related Decline

Patients with primary adrenal insufficiency exhibit a profound deficiency in dehydroepiandrosterone (DHEA) due to the absence of adrenal zona reticularis function, unlike the more commonly replaced glucocorticoids and mineralocorticoids.^[53] Oral DHEA replacement at doses of 25 to 50 mg daily has been studied primarily in women, with randomized controlled trials reporting improvements in subjective well-being, mood, fatigue, and sexual function in some cohorts.^{[54] [55]} For instance, a 1999 double-blind trial involving 24 women found significant enhancements in overall well-being, depression scores, and sexual interest after 4 months of 50 mg daily DHEA compared to placebo.^[56] However, longer-term studies, such as a 9-month trial in 31 patients, detected no benefits for subjective health status or sexuality, highlighting inconsistent outcomes across trials.^[57] A 12-month study noted modest gains in femoral neck bone mineral density but no effects on fatigue, cognition, or sexual function, with supraphysiological DHEA sulfate levels in some older participants raising concerns about dosing precision.^[58] DHEA replacement remains investigational and non-standard, as evidence does not consistently support routine clinical adoption, and guidelines emphasize the need for further large-scale trials to clarify benefits versus risks like androgen excess.^{[59] [53]} Serum DHEA concentrations peak in the third decade of life and decline by 70% to 80% by age 70, a pattern observed in both sexes and associated with reduced androgen and estrogen precursors, potentially contributing to frailty, cognitive changes, and metabolic shifts.^{[60] [61]} Supplementation with 50 mg daily oral DHEA in elderly populations (typically aged 60–80) restores levels toward youthful ranges, as demonstrated in a 2006 multicenter trial of 87 men and 57 women, which increased DHEA sulfate by over 10-fold but yielded no significant improvements in body composition, strength, or quality of life metrics.^[62] Meta-analyses of randomized trials indicate modest elevations in testosterone (mean increase of 0.8 nmol/L) and estradiol but inconsistent effects on clinical endpoints like bone density, insulin sensitivity, or depressive symptoms, with subgroup benefits occasionally noted in women with low baseline levels.^{[63] [64]} For cognition, systematic reviews of supplementation trials report no reliable reversal of age-related decline, despite preclinical links between DHEA and neuroprotection; human data from placebo-controlled studies show null or negligible impacts on memory or executive function.^{[65] [66]} Overall, while DHEA decline correlates with aging phenotypes, supplementation lacks robust empirical support for mitigating them, with potential risks including acne, hirsutism, and unknown long-term oncogenic effects prompting caution and relegating its use to research contexts.^{[67] [68]}

Menopausal Symptoms Beyond VVA

Intravaginal prasterone, administered at a dose of 6.5 mg daily, has demonstrated efficacy in reducing lower urinary tract symptoms (LUTS) in postmenopausal women, including urinary urgency, frequency, and urge incontinence, which extend beyond vulvovaginal atrophy as part of the genitourinary syndrome of menopause (GSM). A meta-analysis of 11 randomized controlled trials involving postmenopausal women with GSM found significant improvements in these symptoms, with standardized mean differences indicating reduced urgency (SMD -0.45, 95% CI -0.72 to -0.18) and frequency (SMD -0.38, 95% CI -0.65 to -0.11), alongside decreased episodes of urge urinary incontinence.^[69] These effects are attributed to local conversion of prasterone to estrogens and androgens in urogenital tissues, enhancing epithelial integrity and reducing inflammation without substantial systemic hormone elevation.^[70] Clinical trials have also linked intravaginal prasterone to a lower incidence of recurrent urinary tract infections (UTIs) in women with GSM. In a prospective study of postmenopausal women, prasterone treatment reduced UTI prevalence by approximately 50% over one year compared to baseline rates, potentially due to improved vaginal and urethral mucosa health that limits bacterial ascension.^[71] Similarly, validated questionnaires such as the Urogenital Distress Inventory-6 (UDI-6) and Overactive Bladder Questionnaire Short Form (OAB-q SF) showed statistically significant declines in symptom scores after 12 weeks of therapy, with improvements persisting in subsets of women with concurrent overactive bladder.^[72][73] In contrast, prasterone exhibits negligible impact on systemic menopausal symptoms such as vasomotor instability (e.g., hot flashes or night sweats), owing to its pharmacokinetic profile of minimal serum absorption. Daily intravaginal dosing maintains circulating estradiol, testosterone, and DHEA levels within the lower quartile of normal postmenopausal ranges, avoiding the hormonal fluctuations needed for vasomotor relief.^[37][50] Reviews of broader DHEA supplementation (primarily oral routes) similarly report insufficient evidence for vasomotor symptom reduction across multiple randomized trials, with no high-quality data supporting benefits for mood disturbances, sleep quality, or overall psychological well-being in menopause.^[74] These findings underscore prasterone's targeted local action, limiting its utility for non-genitourinary manifestations while highlighting investigational promise for LUTS management pending larger confirmatory studies.^[74]

Other Potential Uses

Prasterone, also known as dehydroepiandrosterone (DHEA), has been investigated for its potential role in managing systemic lupus erythematosus (SLE), with studies indicating reduced disease flares and improved patient well-being in women with mild-to-moderate disease activity.^[75] A Cochrane review of randomized trials found low-quality evidence suggesting DHEA may modestly improve SLE activity scores, though larger confirmatory studies are needed due to methodological limitations in existing data.^[76] Serum DHEA levels are often inversely correlated with SLE activity, supporting a plausible mechanistic link via immunomodulation, but clinical benefits remain investigational and unapproved.^[77] In depression treatment, DHEA supplementation has shown promise as an adjunct or monotherapy, particularly in midlife-onset major or minor depression, with randomized trials demonstrating symptom reduction compared to placebo.^[78] Systematic reviews and meta-analyses of controlled trials report a beneficial effect on depressive symptoms, though effect sizes are modest and results warrant caution due to heterogeneity and small sample sizes.^{[79] [80]} Evidence from Mendelian randomization studies suggests a potential causal link between higher DHEA levels and better antidepressant response, but this requires further validation in diverse populations.^[81] For bone health, DHEA has been explored in osteoporosis, with pooled analyses of clinical trials showing increases in lumbar spine bone mineral density (BMD) of approximately 1.7-3.5% over 12-24 months in postmenopausal women, alongside potential enhancements in muscle mass.^{[82] [83]} However, a systematic review of seven randomized controlled trials concluded no significant BMD improvement after adjusting for weight gain, highlighting mixed findings and the need for longer-term studies to assess fracture risk reduction.^[84] These effects may stem from DHEA's conversion to estrogens and androgens, but applications remain off-label and unsupported by regulatory approvals.^[85] Preliminary research also suggests DHEA's utility in trauma rehabilitation, where it may aid recovery in severely injured patients through anti-inflammatory and anabolic pathways, though evidence is limited to reviews rather than large-scale trials.^[86] Overall, while these uses leverage DHEA's precursor role in steroidogenesis, most lack robust, high-quality evidence for routine clinical adoption, and potential risks such as androgenic side effects necessitate cautious evaluation.^[87]

Research Evidence

Strong Empirical Support Areas

Intravaginal prasterone (6.5 mg daily) demonstrates strong empirical support for alleviating moderate to severe dyspareunia associated with vulvovaginal atrophy (VVA) in postmenopausal women, as evidenced by two pivotal phase III randomized, double-blind, placebo-controlled trials involving 406 healthy participants aged 40 to 80 years.^[88] In these 12-week studies, prasterone significantly improved the dyspareunia score (primary endpoint), with reductions of approximately 0.36 to 0.44 points on a 4-point severity scale compared to placebo, alongside histological improvements including decreased parabasal cells (from 53.8% to 15.6%), increased superficial cells (from 7.8% to 25.5%), and lowered vaginal pH (from 6.6 to 5.3).^[31] These changes correlated with clinical symptom relief, supporting local conversion of prasterone to estrogens and androgens without substantial systemic absorption.^[89] A meta-analysis of randomized controlled trials further corroborates these findings, concluding that prasterone therapy yields significant therapeutic effects on VVA symptoms, including dyspareunia, vaginal dryness, and overall sexual function, with effect sizes favoring prasterone over placebo (standardized mean difference -0.89 for dyspareunia; 95% CI -1.28 to -0.50).^[90] Long-term safety data from an open-label phase III extension trial (ERC-230; N=521) over 52 weeks confirmed sustained efficacy and tolerability, with no new safety signals beyond mild local irritation reported in less than 5% of users.^[28] This body of evidence underpinned FDA approval on November 17, 2016, as the first non-estrogen therapy specifically for postmenopausal dyspareunia due to VVA.^[38] No other indications exhibit comparable rigorous, replicated phase III evidence; systemic oral DHEA lacks similar validation for VVA or broader menopausal symptoms due to inconsistent bioavailability and off-target effects.^[91]

Mixed or Inconclusive Findings

Studies on dehydroepiandrosterone (DHEA) supplementation for cognitive enhancement in non-demented older adults have yielded inconclusive results, with systematic reviews indicating no consistent beneficial effects on memory or other cognitive domains. A Cochrane review of randomized controlled trials found insufficient evidence to support improvements in cognitive function following DHEA administration, noting that available data from controlled trials do not demonstrate efficacy in middle-aged or elderly populations without dementia. Similarly, analyses specific to postmenopausal women concluded that DHEA therapy does not enhance cognitive performance, based on evaluations of multiple randomized clinical trials assessing domains such as episodic memory and executive function.^[92] Evidence regarding DHEA's impact on bone mineral density (BMD) is mixed, particularly across sexes and durations of supplementation. While some randomized trials report modest increases in hip and spine BMD among older women with low baseline DHEA levels after 12 months of therapy at doses of 50 mg daily, effects in men are less pronounced or absent, and shorter-term studies often show null or inconsistent outcomes. Systematic evaluations highlight that, despite potential small benefits in bone metabolism markers, DHEA does not reliably prevent fractures or demonstrate superiority over placebo in broader osteoporosis management, necessitating further long-term data.^[93][59] Findings on DHEA for depressive symptoms remain inconclusive, with meta-analyses of randomized trials showing small improvements in mild to moderate cases but tempered by methodological limitations, including small sample sizes and heterogeneity in dosing (typically 30-450 mg daily). One analysis of 8 trials reported a beneficial effect versus placebo, yet cautioned against firm conclusions due to variable study quality and potential publication bias, while reviews of endogenous DHEA levels find no clear association with depression risk in postmenopausal women.^[80][94] In systemic applications for menopausal sexual function beyond vulvovaginal atrophy, a meta-analysis of 28 studies involving over 1,200 postmenopausal women found no significant improvements in overall sexual satisfaction or desire with DHEA supplementation, contrasting with localized intravaginal use and underscoring inconsistent systemic hormonal modulation.^[95]

Debunked or Unsupported Claims

Claims that oral dehydroepiandrosterone (DHEA) supplementation serves as an effective anti-aging therapy, such as reversing age-related declines in vitality, muscle mass, or overall longevity, lack support from randomized controlled trials. A review of 11 placebo-controlled studies found no meaningful benefits in these areas, with effects limited to minor increases in insulin-like growth factor-1 levels that did not translate to functional improvements. Similarly, preclinical suggestions of DHEA's role in preventing cancer or age-related diseases have not been substantiated in human clinical trials, where outcomes showed no clear preventive efficacy.^[96] Assertions that systemic DHEA improves cognitive function in non-demented middle-aged or older adults are unsupported by evidence. A systematic review of randomized controlled trials concluded there is no convincing benefit for memory, executive function, or other cognitive domains, despite some early observational associations with DHEA levels.^[97] For postmenopausal women, claims of systemic DHEA alleviating androgen deficiency symptoms like low libido or overall sexual dysfunction have been refuted by meta-analyses, which reported no significant improvements over placebo in sexual function scores or quality-of-life measures.^[98] In fertility treatment, the notion that DHEA priming enhances outcomes for women with diminished ovarian reserve or poor response to IVF has been debunked by multiple meta-analyses. These analyses, aggregating data from randomized trials, found no increases in clinical pregnancy rates, live birth rates, or oocyte yield compared to controls, despite initial enthusiasm from small observational studies.^[99][100] Long-term therapeutic claims beyond vaginal prasterone for vulvovaginal atrophy remain unsubstantiated due to insufficient adequately powered trials demonstrating sustained efficacy or safety.^[101]

History

Discovery and Early Development

Dehydroepiandrosterone (DHEA), also known as prasterone, was first isolated from human urine in 1934 by German biochemist Adolf Butenandt and his colleague H. Dannenbaum at the Kaiser Wilhelm Institute for Biochemistry.^[102] This isolation occurred amid broader efforts to characterize steroid hormones, following Butenandt's earlier work on androsterone (1931) and contributions to understanding sex hormone structures, for which he shared the 1939 Nobel Prize in Chemistry.^[103] The compound was identified as a C19 steroid with a Δ5-3β-hydroxyl structure, distinguishing it from previously known androgens like androsterone, and its chemical formula was confirmed through crystallization and spectroscopic analysis.^[95] The sulfated form, dehydroepiandrosterone sulfate (DHEA-S), was identified approximately 10 years later in 1944, marking an early step in recognizing conjugated steroid metabolites.^[104] By 1954, DHEA itself was isolated from peripheral blood, expanding knowledge of its systemic circulation beyond urinary excretion.^[105] In 1959, French biochemist Étienne-Émile Baulieu demonstrated that DHEA-S constitutes the predominant circulating form of the steroid in humans, comprising up to 99% of total DHEA pool and highlighting its role as a stable reservoir for the free hormone.^[105] These findings established DHEA's biosynthesis primarily in the adrenal zona reticularis, with minor contributions from gonads and brain, via cytochrome P450 enzymes converting cholesterol precursors.^[106] Early research in the 1950s and 1960s focused on DHEA's function as a weak androgen and prohormone precursor to testosterone and estrogens, with in vitro conversions documented through enzymatic assays.^[107] Its decline with advancing age was first quantified in 1965, linking serum levels peaking in early adulthood (around 20-30 years) to a progressive drop of 80-90% by age 70, prompting initial hypotheses on adrenal androgen dynamics.^[95] Synthetic production routes, including partial synthesis from plant sterols like diosgenin, emerged in the mid-20th century to support biochemical studies, though therapeutic applications remained exploratory until later decades.^[106]

Key Milestones and Approvals

Dehydroepiandrosterone (DHEA), the active compound in prasterone, was first isolated from human urine in 1934 by Adolf Butenandt and Hans Dannenbaum.^[102] Prior to regulatory approvals as a prescription medication, DHEA was marketed in the United States as a dietary supplement, particularly following the Dietary Supplement Health and Education Act of 1994, though it had been promoted as an unapproved drug product in various forms.^[31] The primary pharmaceutical milestone for prasterone occurred on November 17, 2016, when the U.S. Food and Drug Administration (FDA) approved Intrarosa (prasterone vaginal inserts, 6.5 mg) for the treatment of moderate to severe dyspareunia—a symptom of vulvovaginal atrophy—due to menopause in postmenopausal women.^[44][108] This approval represented the first FDA-authorized product containing prasterone as its active ingredient, based on clinical trials demonstrating efficacy in improving vaginal tissue health without systemic hormonal effects.^[38][109] Subsequent international approvals expanded access: the European Medicines Agency (EMA) authorized Intrarosa in 2018 for the same indication, following positive committee recommendations on its benefit-risk profile.^[110] Health Canada granted approval on November 6, 2019, aligning with the FDA and EMA indications for postmenopausal vulvovaginal atrophy symptoms.^[110] The Therapeutic Goods Administration (TGA) in Australia also approved prasterone (Intrarosa) for treating vulvar and vaginal atrophy in postmenopausal women, though specific launch timelines varied by market partnerships, such as licensing agreements with Theramex for Europe, Australia, and other regions in 2018.^[111][112]

Regulation and Societal Aspects

Legal and Regulatory Status

In the United States, prasterone (branded as Intrarosa in 6.5 mg intravaginal inserts) received approval from the Food and Drug Administration (FDA) on November 17, 2016, specifically for treating moderate to severe pain during sexual intercourse (dyspareunia), a symptom of vulvovaginal atrophy, in postmenopausal women.^[44] This approval represented the first instance of the FDA authorizing a product with prasterone as its active ingredient for any indication.^[38] Oral or systemic formulations of dehydroepiandrosterone (DHEA), the chemical equivalent of prasterone, remain unapproved by the FDA as drugs and are instead sold over-the-counter as dietary supplements under an exemption from the Controlled Substances Act, though the agency has issued warnings against unapproved therapeutic claims for such products.^[31] In the European Union, the European Medicines Agency (EMA) authorized Intrarosa on January 8, 2018, for the same dyspareunia indication associated with vulvovaginal atrophy in postmenopausal women, with the marketing authorization valid across member states.^[49] Health Canada similarly approved the 6.5 mg prasterone vaginal inserts for this use.^[3] Globally, DHEA faces stricter controls outside the United States; in most countries, it is classified as a controlled anabolic steroid, often requiring a prescription or facing outright bans for non-pharmaceutical use due to its potential conversion to testosterone and other androgens.^[113] Prasterone has not received regulatory approval for indications beyond vulvovaginal atrophy in jurisdictions where it is authorized, and systemic DHEA supplements are not recognized as medicines by major agencies like the FDA or EMA for treating conditions such as menopausal symptoms outside localized vaginal application.^[114]

Use in Sports and Doping Controls

Prasterone, also known as dehydroepiandrosterone (DHEA), is classified as a prohibited substance under the World Anti-Doping Agency (WADA) Prohibited List in the category of anabolic agents (S1.1a: anabolic androgenic steroids, exogenous).^[115] It is banned at all times, both in-competition and out-of-competition, due to its potential to serve as a precursor to endogenous androgens like testosterone, which could confer ergogenic advantages such as increased muscle mass and strength.^[113] This prohibition extends to major sporting bodies including the United States Anti-Doping Agency (USADA) and the National Collegiate Athletic Association (NCAA), where it is tested for in routine anti-doping controls via urine and blood analysis targeting the substance and its metabolites.^[113][116] Athletes have historically sought prasterone supplementation for purported performance-enhancing effects, including improved endurance, recovery, and lean body mass, particularly in strength-based or resistance training contexts.^[117] Marketing of over-the-counter DHEA products often emphasizes these benefits, positioning it as a legal alternative to synthetic steroids in non-competitive settings, though such claims drive its illicit use in sports.^[113] However, empirical evidence for significant ergogenic benefits remains limited and context-dependent; short-term administration failed to enhance performance or anabolic markers in young recreational female athletes, suggesting minimal impact in individuals with normal endogenous levels.^[117] In older populations or those with low baseline DHEA, supplementation combined with heavy resistance training has shown modest increases in muscle mass and strength, as demonstrated in a 2006 study where 50 mg daily doses amplified training-induced gains in elderly men and women.^[118] Conversely, reviews indicate that perceptions of DHEA's efficacy in elite or younger athletes outpace scientific validation, with no consistent improvements in combined endurance-strength protocols or overall athletic output.^[119][120] Doping controls enforce zero-tolerance thresholds, with sanctions for positive tests including suspensions; detection relies on WADA-accredited labs quantifying prasterone above endogenous reference ranges, often adjusted for age and sex.^[121] Despite inconclusive performance data, its inclusion on prohibited lists reflects precautionary principles against any androgenic modulation in competitive sport.^[122]

Availability and Marketing

In the United States, prasterone (dehydroepiandrosterone, or DHEA) is widely available over-the-counter as an oral dietary supplement in forms such as capsules, tablets, and powders, with typical dosages ranging from 25 mg to 200 mg daily.^[1] This status stems from its classification under the Dietary Supplement Health and Education Act of 1994, which grandfathered ingredients marketed before October 15, 1994, allowing sales without FDA pre-approval for non-disease-related structure/function claims like supporting hormone levels or energy.^[31] However, the FDA has explicitly stated that oral prasterone lacks approval for any therapeutic use and has issued warnings against its marketing as an unapproved new drug for conditions like aging or adrenal insufficiency.^[31] A prescription-only vaginal insert formulation, Intrarosa (6.5 mg prasterone), was approved by the FDA on November 17, 2016, solely for treating moderate to severe dyspareunia associated with genitourinary syndrome of menopause in postmenopausal women, via local conversion to active androgens and estrogens.^[31][38] In the European Union, prasterone is not authorized as a dietary supplement and is restricted to prescription medicinal products due to regulatory prohibitions on its non-medicinal sale, reflecting concerns over inconsistent quality, potential hormonal risks, and insufficient evidence for broad claims.^[52] Intrarosa received marketing authorization from the European Medicines Agency on January 8, 2018, for vulvar and vaginal atrophy in postmenopausal women, with availability limited to this indication across EU member states.^[49] Certain ester forms, such as prasterone enanthate, are available by prescription in select European countries including Germany, Italy, and Spain for androgen replacement therapy in conditions like hypogonadism, typically via intramuscular injection.^[123] In Canada, Intrarosa is prescription-only for postmenopausal vulvovaginal atrophy, filed for review in 2016.^[124] Marketing of oral prasterone supplements in the US focuses on purported benefits for vitality, mood enhancement, muscle maintenance, and countering age-related declines in adrenal hormone production, often positioned as a "youth hormone" precursor despite limited clinical substantiation and FDA disclaimers against efficacy claims.^[67] Manufacturers must avoid implying disease prevention or treatment to evade enforcement, though historical instances of unsubstantiated promotion as an anti-aging or performance aid have prompted regulatory scrutiny.^[31] In contrast, Intrarosa's promotion emphasizes evidence from phase III trials showing improvements in vaginal pH, epithelial integrity, and dyspareunia scores without systemic hormone elevation, targeting gynecologists and postmenopausal patients via pharmaceutical channels.^[38] Global supplement marketing is curtailed outside the US, where bans in countries like Australia, the UK, and much of Asia limit it to research or veterinary contexts, underscoring divergent regulatory philosophies on endogenous steroid precursors.^[59]