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%).[28][33] 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.[39] 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.[40] 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.[41] 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.[42] 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.[43] Administration involves inserting one 6.5 mg vaginal insert once daily at bedtime using a single-use disposable applicator provided with the product.[44] 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.[45] 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.[44]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.[39] 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][46] 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.[47] Other local effects, such as vulvovaginal discomfort or pruritus, occur at rates below 2% and do not differ significantly from placebo.[48] 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.[49] 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.[50]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.[42] 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.[42] 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.[42][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.[42] 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]| Safety Parameter | ERC-230 Findings (52 Weeks) | Notes |
|---|---|---|
| Application Site Discharge | 14.0% | Attributed to insert melting; most common drug-related event.[28] |
| Urinary Tract Infection | 10.2% | Similar to shorter trials; likely age-related.[28] |
| Serious Adverse Events | 3.5% (18/521) | None deemed causally related; includes hypertension and infections.[28] |
| Endometrial Biopsies | 94% atrophic (430/457) | No hyperplasia; limited to treated population excluding prior cancer history.[31][28] |
| Breast Pathology | 0.4% significant findings | Rare; baseline postmenopausal risk not controlled.[28] |