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Prasterone
Clinical data
Trade namesIntrarosa, others
Other namesEL-10; GL-701; KYH-3102; Androst-5-en-3β-ol-17-one; 3β-Hydroxyandrost-5-en-17-one; 5,6-Didehydroepiandrosterone;[1] Dehydroisoepiandrosterone[2]
AHFS/Drugs.comMonograph
MedlinePlusa617012
License data
Pregnancy
category
Routes of
administration		By mouth, vaginal (rectal), intramuscular (as prasterone enanthate), injection (as prasterone sodium sulfate)
Drug classAndrogen; Anabolic steroid; Estrogen; Neurosteroid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50%[9]
MetabolismLiver[9]
Metabolites• Androsterone[9]
• Etiocholanolone[9]
• DHEA sulfate[9]
• Androstenedione[9]
• Androstenediol[9]
• Testosterone[9]
• Dihydrotestosterone
• Androstanediol[9]
• Estrone
• Estradiol
Elimination half-lifeDHEA: 25 minutes[10]
DHEA-S: 11 hours[10]
ExcretionUrine
Identifiers
  • (3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H28O2
Molar mass288.431 g·mol−1
3D model (JSmol)
Melting point148.5 °C (299.3 °F)
  • O=C3[C@]2(CC[C@@H]1[C@@]4(C(=C/C[C@H]1[C@@H]2CC3)\C[C@@H](O)CC4)C)C
  • InChI=1S/C19H28O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h3,13-16,20H,4-11H2,1-2H3/t13-,14-,15-,16-,18-,19-/m0/s1 checkY
  • Key:FMGSKLZLMKYGDP-USOAJAOKSA-N checkY
  (verify)

Prasterone, also known as dehydroepiandrosterone (DHEA) and sold under the brand name Intrarosa among others, is a medication as well as over-the-counter dietary supplement which is used to correct DHEA deficiency due to adrenal insufficiency or old age, as a component of menopausal hormone therapy, to treat painful sexual intercourse due to vaginal atrophy, and to prepare the cervix for childbirth, among other uses.[9][11] It is taken by mouth, by application to the skin, in through the vagina, or by injection into muscle.[11]

Side effects of prasterone in women include symptoms of masculinization like oily skin, acne, increased hair growth, voice changes, and increased sexual desire, headaches, insomnia, and others.[9][11] The compound is a naturally occurring prohormone of androgens and estrogens and hence is an agonist of the androgen and estrogen receptors, the respective biological targets of androgens like testosterone and estrogens like estradiol.[9][12] Prasterone also has a variety of activities of its own, including neurosteroid and other activities.[12]

DHEA, the active ingredient of prasterone, was discovered in 1934.[9][11] An association between DHEA levels and aging was first reported in 1965.[9][11] The compound started being used as a medication in the late 1970s and as a supplement in the early 1980s.[9][11] The marketing of prasterone over-the-counter as a supplement is allowed in the United States but is banned in many other countries.[9]

Medical uses

[edit]

Deficiency

[edit]

DHEA and DHEA sulfate (DHEA-S) are produced by the adrenal glands. In people with adrenal insufficiency such as in Addison's disease, there may be deficiency of DHEA and DHEA-S. In addition, levels of these steroids decrease throughout life and are 70 to 80% lower in the elderly relative to levels in young adults. Prasterone can be used to increase DHEA and DHEA-S levels in adrenal insufficiency and older age. Although there is deficiency of these steroids in such individuals, clinical benefits of supplementation, if any, are uncertain, and there is insufficient evidence at present to support the use of prasterone for such purposes.[13][14]

Menopause

[edit]
See also: Prasterone enanthate and Estradiol valerate/prasterone enanthate

Prasterone is sometimes used as an androgen in menopausal hormone therapy.[15][16][17] In addition to prasterone itself, a long-lasting ester prodrug of prasterone, prasterone enanthate, is used in combination with estradiol valerate for the treatment of menopausal symptoms under the brand name Gynodian Depot.[18][19][20][21][22][23] The current evidence of any benefit of DHEA supplementation to menopausal and postmenopausal women is inconclusive.[24][25][26] Whereas prasterone (DHEA) supplementation in postmenopausal women can lead to an increase in E1, E2, testosterone, DHEA, and DHEAS serum levels, and a reduction in SHBG; still, the current evidence regarding the benefits of DHEA supplementation in postmenopausal women is inconclusive—while some studies suggest potential benefits, such as improved well-being, sexual function, and possibly decreased menopausal symptoms, these findings are not universally agreed upon.[27] Moreover, the long-term safety data for DHEA supplementation is lacking, which is a significant concern. This is particularly relevant given that DHEA supplementation can lead to increased estrogenic availability, which could potentially have implications for conditions sensitive to hormonal levels.[27]


Androgen replacement therapy formulations and dosages used in women
Route Medication Major brand names Form Dosage
Oral Testosterone undecanoate Andriol, Jatenzo Capsule 40–80 mg 1x/1–2 days
Methyltestosterone Metandren, Estratest Tablet 0.5–10 mg/day
Fluoxymesterone Halotestin Tablet 1–2.5 mg 1x/1–2 days
Normethandronea Ginecoside Tablet 5 mg/day
Tibolone Livial Tablet 1.25–2.5 mg/day
Prasterone (DHEA)b – Tablet 10–100 mg/day
Sublingual Methyltestosterone Metandren Tablet 0.25 mg/day
Transdermal Testosterone Intrinsa Patch 150–300 μg/day
AndroGel Gel, cream 1–10 mg/day
Vaginal Prasterone (DHEA) Intrarosa Insert 6.5 mg/day
Injection Testosterone propionatea Testoviron Oil solution 25 mg 1x/1–2 weeks
Testosterone enanthate Delatestryl, Primodian Depot Oil solution 25–100 mg 1x/4–6 weeks
Testosterone cypionate Depo-Testosterone, Depo-Testadiol Oil solution 25–100 mg 1x/4–6 weeks
Testosterone isobutyratea Femandren M, Folivirin Aqueous suspension 25–50 mg 1x/4–6 weeks
Mixed testosterone esters Climacterona Oil solution 150 mg 1x/4–8 weeks
Omnadren, Sustanon Oil solution 50–100 mg 1x/4–6 weeks
Nandrolone decanoate Deca-Durabolin Oil solution 25–50 mg 1x/6–12 weeks
Prasterone enanthatea Gynodian Depot Oil solution 200 mg 1x/4–6 weeks
Implant Testosterone Testopel Pellet 50–100 mg 1x/3–6 months
Notes: Premenopausal women produce about 230 ± 70 μg testosterone per day (6.4 ± 2.0 mg testosterone per 4 weeks), with a range of 130 to 330 μg per day (3.6–9.2 mg per 4 weeks). Footnotes: a = Mostly discontinued or unavailable. b = Over-the-counter. Sources: See template.

Vaginal atrophy

[edit]

Prasterone, under the brand name Intrarosa, is approved in the United States in a vaginal insert formulation for the treatment of atrophic vaginitis.[28][29] The mechanism of action of prasterone for this indication is unknown, though it may involve local metabolism of prasterone into androgens and estrogens.[29]

Sexual desire

[edit]

Prasterone has been used orally at a dosage of 10 mg/day to increase sexual desire in women.[30]

Childbirth

[edit]
See also: Prasterone sulfate

As the sodium salt of prasterone sulfate (brand names Astenile, Mylis, Teloin),[31][32] an ester prodrug of prasterone, prasterone is used in Japan as an injection for the treatment of insufficient cervical ripening and cervical dilation during childbirth.[2][33][34][35][36][37][38]

Available forms

[edit]
See also: Prasterone enanthate, Prasterone sulfate, Estradiol valerate/prasterone enanthate, and Testosterone propionate/testosterone cypionate/prasterone

Prasterone was previously marketed as a pharmaceutical medication under the brand name Diandrone in the form of a 10 mg oral tablet in the United Kingdom.[30]

Side effects

[edit]

Prasterone is produced naturally in the human body, but the long-term effects of its use are largely unknown.[39][40] In the short term, several studies have noted few adverse effects. In a study by Chang et al., prasterone was administered at a dose of 200 mg/day for 24 weeks with slight androgenic effects noted.[41] Another study utilized a dose up to 400 mg/day for 8 weeks with few adverse events reported.[42] A longer-term study followed patients dosed with 50 mg of prasterone for 12 months with the number and severity of side effects reported to be small.[43] Another study delivered a dose of 50 mg of prasterone for 10 months with no serious adverse events reported.[44]

As a hormone precursor, there have been reports of side effects possibly caused by the hormone metabolites of prasterone.[40]

It is not known whether prasterone is safe for long-term use. Some researchers believe prasterone supplements might actually raise the risk of breast cancer, prostate cancer, heart disease, diabetes,[40] and stroke. Prasterone may stimulate tumor growth in types of cancer that are sensitive to hormones, such as some types of breast, uterine, and prostate cancer.[40] Prasterone may increase prostate swelling in men with benign prostatic hyperplasia (BPH), an enlarged prostate gland.[39]

Prasterone is a steroid hormone. High doses may cause aggressiveness, irritability, trouble sleeping, and the growth of body or facial hair on women.[39] It also may stop menstruation and lower the levels of HDL cholesterol, which could raise the risk of heart disease.[39] Other reported side effects include acne, heart rhythm problems, liver problems, hair loss (from the scalp), and oily skin. It may also alter the body's regulation of blood sugar.[39]

Prasterone may promote tamoxifen resistance in breast cancer.[39] It may also increase the risk of uterine and prostate cancers due to metabolism into estrogens and androgens, respectively.[45] Patients on hormone replacement therapy may have more estrogen-related side effects when taking prasterone. This supplement may also interfere with other medicines, and potential interactions between it and drugs and herbs are possible.[39]

Prasterone is possibly unsafe for individuals experiencing pregnancy, breastfeeding, hormone sensitive conditions, liver problems, diabetes, depression or mood disorders, polycystic ovarian syndrome (PCOS), or cholesterol problems.[46]

Prasterone has been reported to possess few or no side effects even at very high dosages (e.g., 50 times the recommended over-the-counter supplement dosage).[45] However, it may cause masculinization and other androgenic side effects in women and gynecomastia and other estrogenic side effects in men.[45]

Pharmacokinetics

[edit]
See also: Dehydroepiandrosterone § Biological activity, and Dehydroepiandrosterone § Biochemistry

Oral uptake of prasterone is excellent. Its volume of distribution is 17.0-38.5L (whereas it is 8.5-9.3L for its active metabolite DHEA-S). Prasterone (DHEA) has a biological half-life of 15-38 min (whereas it is 7-22h for DHEA-S). 51-73% of DHEA-S and its metabolites are excreted via the renal route.[47]

Testosterone levels following a single oral dose of 300 mg crystalline (non-micronized) or micronized prasterone (DHEA) in premenopausal women.[48]
Estradiol and DHEA levels after a single intramuscular injection of Gynodian Depot (4 mg estradiol valerate, 200 mg prasterone enanthate) in women.[49][50][51]

Prasterone is metabolized into androgens and estrogens in the body,[12][52] including androstenedione, testosterone, estrone, estradiol, and estriol.[47] The transformation of prasterone into androgens and estrogens is tissue-specific, for instance occurring in the liver, fat, vagina, prostate gland, skin, and hair follicles (as well as other tissues).[12][53]

Metabolism

[edit]

Prasterone is also reversibly transformed into its active metabolite[47] prasterone sulfate (DHEA-S) by steroid sulfotransferase (specifically SULT1E1 and SULT2A1), which in turn can be converted back into prasterone by steroid sulfatase.[12][54] Interconversion takes place in both adrenal and peripheral tissues.[47]

It is transformed into androstenedione by 3β-hydroxysteroid dehydrogenase (3β-HSD), and into androstenediol by 17β-hydroxysteroid dehydrogenase (17β-HSD).[12][52] Then, androstenedione and androstenediol can be converted into testosterone by 17β-HSD and 3β-HSD, respectively.[12][52] Subsequently, testosterone can be metabolized into dihydrotestosterone by 5α-reductase.[12][52]

In addition, androstenedione and testosterone can be converted into estrone and estradiol by aromatase, respectively.[12][52]

Dose-response of hormone levels

[edit]

At a high dosage of 1,600 mg/day orally for 4 weeks, treatment of postmenopausal women with prasterone has been found to increase serum levels of DHEA by 15-fold, testosterone by 9-fold, DHEA-S, androstenedione, and DHT all by 20-fold, and estrone and estradiol both by 2-fold.[55][56]

Although prasterone can reliably increase testosterone levels in women, this isn't similarly the case in men.[45] A high dosage of 1,600 mg/day prasterone in men for 4 weeks was found to increase DHEA and androstenedione levels but did not significantly affect testosterone levels.[45]

Dosing

[edit]

In clinical studies of prasterone supplementation, dosages have ranged from 20 to 1,600 mg per day.[57]

In people with adrenal insufficiency, oral dosages of 20 to 50 mg/day prasterone have been found to restore DHEA and DHEA-S levels to physiological levels seen in young healthy adults.[57] Conversely, oral dosages of 100 to 200 mg/day prasterone have been found to result in supraphysiological levels of DHEA and DHEA-S.[57]

Micronization of prasterone has been found to significantly increase levels of DHEA-S achieved with oral administration, but to produce no significant change in levels of DHEA or testosterone levels achieved.[48]

Chemistry

[edit]
See also: List of androgens/anabolic steroids

Prasterone, also known as androst-5-en-3β-ol-17-one, is a naturally occurring androstane steroid and a 17-ketosteroid. It is closely related structurally to androstenediol (androst-5-ene-3β,17β-diol), androstenedione (androst-4-ene-3,17-dione), and testosterone (androst-4-en-17β-ol-3-one). Prasterone is the δ5 (5(6)-dehydrogenated) analogue of epiandrosterone (5α-androstan-3β-ol-17-one), and is also known as 5-dehydroepiandrosterone (5-DHEA) or δ5-epiandrosterone. A positional isomer of prasterone which may have similar biological activity is 4-dehydroepiandrosterone (4-DHEA).[58]

Derivatives

[edit]
See also: List of androgen esters § Esters of other natural AAS

Prasterone is used medically as the C3β esters prasterone enanthate and prasterone sulfate.[2] The C19 demethyl analogue of prasterone is 19-nordehydroepiandrosterone (19-nor-DHEA), which is a prohormone of nandrolone (19-nortestosterone).[59][60] The 5α-reduced and δ1 (1(2)-dehydrogenated) analogue of prasterone is 1-dehydroepiandrosterone (1-DHEA or 1-androsterone), which is a prohormone of 1-testosterone (δ1-DHT or dihydroboldenone).[61] Fluasterone (3β-dehydroxy-16α-fluoro-DHEA) is a derivative of prasterone with minimal or no hormonal activity but other biological activities preserved.[55]

History

[edit]

DHEA was discovered, via isolation from male urine, by Adolf Butenandt and Hans Dannenbaum in 1934, and the compound was isolated from human blood plasma by Migeon and Plager in 1954.[9][11] DHEA sulfate, the 3β-sulfate ester of DHEA, was isolated from urine in 1944, and was found by Baulieu to be the most abundant steroid hormone in human plasma in 1954.[9][11] From its discovery in 1934 until 1959, DHEA was referred to by a number of different names in the literature, including dehydroandrosterone, transdehydroandrosterone, dehydroisoandrosterone, and androstenolone.[11] The name dehydroepiandrosterone, also known as DHEA, was first proposed by Fieser in 1949, and subsequently became the most commonly used name of the hormone.[11] For decades after its discovery, DHEA was considered to be an inactive compound that served mainly as an intermediate in the production of androgens and estrogens from cholesterol.[11] In 1965, an association between DHEA sulfate levels and aging was reported by De Nee and Vermeulen.[9][11] Following this, DHEA became of interest to the scientific community, and numerous studies assessing the relationship between DHEA and DHEA sulfate levels and aging were conducted.[9][11]

Prasterone, the proposed INNTooltip International Nonproprietary Name and recommended INN of DHEA and the term used when referring to the compound as a medication, were published in 1970 and 1978, respectively.[62][63] The combination of 4 mg estradiol valerate and 200 mg prasterone enanthate in an oil solution was introduced for use in menopausal hormone therapy by intramuscular injection under the brand name Gynodian Depot in Europe by 1978.[64][65][66][67] In the early 1980s, prasterone became available and was widely sold over-the-counter as a non-prescription supplement in the United States, primarily as a weight loss aid.[9][11][68] It was described as a "miracle drug", with supposed anti-aging, anti-obesity, and anti-cancer benefits.[9] This continued until 1985, when the marketing of prasterone was banned by the Food and Drug Administration (FDA) due to a lack of evidence for health benefits and due to the long-term safety and risks of the compound being unknown at the time.[9][11][68] Subsequently, prasterone once again became available over-the-counter as a dietary supplement in the United States following the passage of the Dietary Supplement Health and Education Act of 1994.[9] Conversely, it has remained banned as a supplement in Canada, the United Kingdom, Australia, and New Zealand.[9][69]

In 2001, Genelabs submitted a New Drug Application of prasterone for the treatment of systemic lupus erythematosus (SLE) to the FDA.[9][70] It had the tentative brand names Anastar, Aslera, and Prestara.[9][71][70] However, this application was not approved, and while development of prasterone for SLE in both the United States and Europe continued until up to 2010, the medication was ultimately never approved for the treatment of this condition.[9] In 2016, the FDA approved prasterone in an intravaginal gel formulation for the treatment of painful sexual intercourse due to vulvovaginal atrophy in the United States under the brand name Intrarosa.[72][73] This was the first prasterone-containing medication to be approved by the FDA in this country.[72]

Society and culture

[edit]

Generic names

[edit]

Prasterone is the generic name of DHEA in English and Italian and its International Nonproprietary Name, United States Adopted Name and Italian Common Name,[2][74][75][76] while its generic name is prasteronum in Latin, prastérone in French and its French popular name, and prasteron in German.[75]

Marketing

[edit]

In the United States, prasterone or prasterone sulfate have been advertised, under the names DHEA and DHEA-S, with claims that they may be beneficial for a wide variety of ailments. Prasterone and prasterone sulfate are readily available in the United States, where they are sold as over-the-counter dietary supplements.[77]

In 1996, reporter Harry Wessel of the Orlando (Florida) Sentinel wrote about DHEA that "Thousands of people have gotten caught up in the hoopla and are buying the stuff in health food stores, pharmacies and mail-order catalogs" but that "such enthusiasm is viewed as premature by many in the medical field." He noted that "National publications such as Time, Newsweek and USA Today have run articles recently about the hormone, while several major publishers have come out with books touting it."[78] His column was widely syndicated and reprinted in other U.S. newspapers.

The product was being "widely marketed to and used by bodybuilders," Dr. Paul Donahue wrote in 2012 for King Features syndicate.[79]

Regulation

[edit]

By country

[edit]
Australia
[edit]

In Australia, a prescription is required to buy prasterone, where it is also comparatively expensive compared to off-the-shelf purchases in US supplement shops. Australian customs classify prasterone as an "anabolic steroid[s] or precursor[s]" and, as such, it is only possible to carry prasterone into the country through customs if one possesses an import permit which may be obtained if one has a valid prescription for the hormone.[80]

Canada
[edit]

In Canada, prasterone is a Controlled Drug listed under Section 23 of Schedule IV of the Controlled Drugs and Substances Act[81] and as such is available by prescription only.

United Kingdom
[edit]

Prasterone is listed as an anabolic steroid and is thus a class C controlled drug.

United States
[edit]

Prasterone is legal to sell in the United States as a dietary supplement. It is currently grandfathered in as an "Old Dietary Ingredient" being on sale prior to 1994. Prasterone is specifically exempted from the Anabolic Steroid Control Act of 1990 and 2004.[82]

Sports and athletics

[edit]

Prasterone is banned from use in athletic competition.[9][11][68] It is a prohibited substance under the World Anti-Doping Code of the World Anti-Doping Agency,[83] which manages drug testing for Olympics and other sports.

  • Yulia Efimova, who holds the world record pace for both the 50-meter and 200-meter breaststroke, and won the bronze medal in the 200-meter breaststroke in the 2012 London Olympic Games, tested positive for prasterone in an out-of-competition doping test.[84]
  • Rashard Lewis, then with the Orlando Magic, tested positive for prasterone and was suspended 10 games before the start of the 2009–10 season.[85]
  • In 2016 MMA fighter Fabio Maldonado revealed he was taking prasterone during his time with the UFC.[86]
  • In January 2011, NBA player O. J. Mayo was given a 10-game suspension after testing positive for prasterone. Mayo termed his use of prasterone as "an honest mistake," saying the prasterone was in an over-the-counter supplement and that he was unaware the supplement was banned by the NBA.[87] Mayo was the seventh player to test positive for performance-enhancing drugs since the league began testing in 1999.
  • Olympic 400-meter champion Lashawn Merritt tested positive for prasterone in 2010 and was banned from the sport for 21 months.[88]
  • Tennis player Venus Williams had permission from the International Tennis Federation to use DHEA along with hydrocortisone as a treatment for "adrenal insufficiency," but it was revoked in 2016 by the World Anti-Doping Agency, which believed DHEA use would enhance Williams' athletic performance.[89]

Research

[edit]

Anabolic uses

[edit]

A meta-analysis of intervention studies shows that prasterone supplementation in elderly men can induce a small but significant positive effect on body composition that is strictly dependent on prasterone conversion into its bioactive metabolites such as androgens or estrogens.[90] Evidence is inconclusive in regards to the effect of prasterone on strength in the elderly.[91] In middle-aged men, no significant effect of prasterone supplementation on lean body mass, strength, or testosterone levels was found in a randomized placebo-controlled trial.[92]

Cancer

[edit]

There is no evidence prasterone is of benefit in treating or preventing cancer.[39]

Cardiovascular disease

[edit]

A review in 2003 found the then-extant evidence sufficient to suggest that low serum levels of DHEA-S may be associated with coronary heart disease in men, but insufficient to determine whether prasterone supplementation would have any cardiovascular benefit.[93]

Prasterone may enhance G6PD mRNA expression, confounding its inhibitory effects.[94]

Lupus

[edit]

There is some evidence of short-term benefit in those with systemic lupus erythematosus but little evidence of long-term benefit or safety.[95] Prasterone was under development for the treatment of systemic lupus erythematosus in the United States and Europe in the 1990s and 2000s and reached phase III clinical trials and preregistration for this indication, respectively, but ultimately development was not continued past 2010.[9][71][70]

Memory

[edit]

Prasterone supplementation has not been found to be useful for memory function in normal middle aged or older adults.[96] It has been studied as a treatment for Alzheimer's disease, but there is no evidence that it is effective or ineffective. More research is needed to determine its benefits.[97]

Mood

[edit]

A few small, short term clinical studies have found that prasterone improves mood but its long-term efficacy and safety, and how it compares to antidepressants, was unknown as of 2015.[98][99]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Prasterone

View on Grokipedia
from Grokipedia
Prasterone, also known as dehydroepiandrosterone (DHEA), is an endogenous C19 produced primarily by the zona reticularis of the , with smaller amounts synthesized in the gonads and , serving as a key precursor to androgens such as testosterone and estrogens such as . 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. Levels of prasterone peak in early adulthood and decline progressively with age, a pattern associated with conditions such as and age-related hormonal changes. Medically, prasterone is approved in intravaginal insert form (brand name Intrarosa) for the treatment of moderate to severe —a symptom of vulvovaginal —arising from postmenopausal , where it undergoes local to estrogens and androgens, alleviating vaginal dryness, during intercourse, and tissue without inducing significant systemic hormonal effects. Clinical trials have demonstrated statistically significant improvements in scores, vaginal , and epithelial maturation indices compared to , positioning prasterone as a targeted alternative to systemic therapies that carry risks of or cardiovascular events. Over-the-counter oral prasterone supplements are marketed for purported benefits in energy, mood, and , though the U.S. 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. Early investigations into systemic prasterone for conditions like systemic showed mixed results, with no sustained approval beyond investigational use due to insufficient efficacy data.

Chemical Properties

Structure and Synthesis

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

Derivatives and Analogs

Prasterone enanthate, the 3β-enanthate of prasterone, serves as a for sustained release in pharmaceutical formulations, such as intramuscular injections combined with for menopausal . This derivative undergoes hydrolysis to release free prasterone and . Prasterone sulfate, the 3β- , constitutes the primary circulating form of prasterone, comprising over 99% of total prasterone in plasma due to sulfation in the adrenal glands and liver. Structural analogs include 7-ketodehydroepiandrosterone (7-oxo-prasterone), which bears an additional keto group at carbon 7 and functions as a that bypasses conversion to active sex steroids like testosterone or . This analog has been studied for metabolic effects, including potential support for , though clinical evidence remains limited to small trials. Fluorinated analogs, such as 16α-fluoro-5-androsten-17-one (fluasterone), exhibit amplified potency in preclinical models for inhibiting tumor growth and compared to native prasterone, attributed to modifications enhancing metabolic stability and receptor interactions. Similarly, 7α- and 7β-amino-prasterone derivatives have demonstrated apoptotic effects on Leydig and Sertoli cells , positioning them as candidates for investigating steroid-mediated pathways. Synthetic spiro-analogs like BNN27, a C-17 spiro , promote via non-genomic mechanisms independent of conversion, with preclinical data supporting roles in mitigating neurodegeneration. 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 , undergoing enzymatic conversion in peripheral tissues to yield active . These transformations involve key steroidogenic enzymes, including to form , 17β-hydroxysteroid dehydrogenase to produce testosterone, to generate , and to synthesize estrogens such as estrone and . This biosynthetic pathway enables prasterone to support androgenic and estrogenic effects indirectly, with its own direct binding affinity to the and receptors being relatively weak. In vaginal tissues, following local administration as a 6.5 mg insert, prasterone is metabolized intracellularly via an mechanism, where target cells express the necessary enzymes to convert it into and that activate androgen receptors and estrogen receptors within the same cells. 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 (from about 6.3 to 5.4), and restoration of lactobacilli , thereby alleviating symptoms of vulvovaginal without substantially elevating systemic levels beyond postmenopausal norms. Prasterone also interacts with non-steroid targets, acting as an at GABA_A receptors, an at NMDA and sigma-1 receptors, an activator of alpha (PPARα), and an inhibitor of , which may underlie additional effects like , modulation of neuronal excitability, and potential metabolic influences observed in preclinical models. Its sulfate form, DHEA-S, further contributes as a precursor modulating and signaling. These multifaceted actions highlight prasterone's role beyond mere hormone precursor status, though clinical significance varies by context and dosage.

Pharmacokinetics

Prasterone, or dehydroepiandrosterone (DHEA), exhibits route-dependent pharmacokinetics, with leading to rapid but limited systemic due to extensive first-pass in the liver and gut, where much of it is converted to the sulfate conjugate DHEA-S. 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 in humans remains unquantified and is estimated low based on animal data (3.1% in cynomolgus monkeys). 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. Distribution occurs widely, with prasterone taken up by peripheral tissues including the liver, kidneys, gonads, and , where it serves as a precursor for synthesis of active androgens and estrogens via enzymes such as hydroxysteroid dehydrogenases, 5α-reductases, and aromatases. The apparent terminal of DHEA exceeds 20 hours in oral studies, influenced by interconversion with DHEA-S, though unconjugated DHEA has a shorter intrinsic of approximately 12 hours; no significant sex differences in distribution volume are noted, but women show greater DHEA-S to DHEA conversion. Metabolism is primarily hepatic and peripheral, yielding major metabolites including DHEA-S, , and , with further transformation to testosterone, , , and estrone occurring locally in target tissues rather than systemically. Excretion occurs mainly via urine as inactive and conjugates of these metabolites, with no accumulation observed in long-term vaginal use where systemic and levels remain within postmenopausal norms (e.g., testosterone trough +21%, +19% after 12 weeks). Oral dosing at 25-50 mg daily sustains elevated baseline DHEA and metabolite levels without disproportionate increases in active steroids.

Clinical Dosing Considerations

The recommended dosage of prasterone for moderate to severe due to postmenopausal vulvovaginal is one 6.5 mg intravaginal insert administered once daily at bedtime. This regimen utilizes a disposable applicator for insertion, with individually wrapped inserts provided for nightly use. No dosage adjustments are required for elderly patients over 65 years of age, reflecting minimal systemic exposure and consistent pharmacokinetics in postmenopausal women. 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. 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. Prasterone lacks duration-of-use restrictions, unlike some estrogen therapies, due to its local conversion to estrogens and androgens with limited serum impact. Concurrent use with aromatase inhibitors warrants caution, as prasterone may interfere with their action, potentially requiring dose reevaluation.

Approved Medical Uses

Treatment of Vulvovaginal Atrophy

Prasterone, administered as a 6.5 mg intravaginal insert (Intrarosa), is approved by the for the treatment of moderate to severe , a primary symptom of vulvovaginal atrophy (VVA), in postmenopausal women. Approval was granted on November 17, 2016, based on evidence of symptom relief without the systemic risks associated with therapies. The recommended regimen involves nightly insertion at bedtime, initially for 12 weeks, with potential maintenance dosing as clinically indicated. The therapeutic action relies on local intracrinology, where prasterone—a precursor—is taken up by vaginal epithelial and stromal cells and enzymatically converted into active (such as testosterone and ) and (such as and estrone). This site-specific transformation restores vaginal tissue integrity, reduces , increases superficial cell percentage in cytology, and alleviates dryness and pain without producing clinically significant elevations in serum or levels, minimizing risks like . Efficacy was demonstrated in two pivotal 12-week, multicenter, randomized, double-blind, -controlled phase III trials involving 406 healthy postmenopausal women aged 40 to 80 years with moderate to severe VVA symptoms. The primary endpoint, change in 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 (p<0.001). Secondary outcomes included reductions in vaginal dryness severity and improvements in vaginal (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). These effects were observed as early as week 4 and sustained through week 12, with response rates for relief exceeding 60% in prasterone groups versus 40-45% with . Compared to low-dose conjugated equine cream (0.3 mg), prasterone demonstrated comparable efficacy in and dryness relief in a separate randomized , though direct head-to-head data remain limited. 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. Prasterone does not require endometrial monitoring, unlike systemic or certain local estrogens, due to negligible uterine exposure.

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. This ovule-like insert is designed for local intravaginal delivery to minimize systemic absorption while targeting vulvovaginal tissues. The U.S. approved this formulation on November 17, 2016, specifically for the treatment of moderate to severe , a symptom of vulvovaginal atrophy, in postmenopausal women. Administration involves inserting one 6.5 mg vaginal insert once daily at using a single-use disposable applicator provided with the product. The applicator is activated by pulling back the until it stops, loaded with the unwrapped insert, and then gently inserted into the while the patient lies on her back with knees drawn up, similar to standard insertion techniques. After insertion, the is pushed to release the insert, and the applicator is discarded; no additional lubrication or preparation is required beyond standard hygiene. 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. 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. Patients should be advised to store inserts at controlled (20–25°C) and avoid use if allergic to prasterone or its excipients.

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 . Across four 12-week randomized, -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 . Serious adverse events were rare and balanced between groups, with no evidence of increased systemic risks such as cardiovascular events, , or malignancies directly attributable to prasterone; one case of was reported in a 52-week open-label extension trial among 318 participants, but long-term causality remains unestablished. The most common adverse reaction is , reported in 2.7% to 8.3% of prasterone users compared to 1.3% to 4% with , often described as leakage or increased wetness without . 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. Other local effects, such as vulvovaginal discomfort or pruritus, occur at rates below 2% and do not differ significantly from . Systemic absorption of prasterone and its metabolites (including and testosterone) is minimal with , resulting in negligible androgenic or estrogenic side effects compared to oral DHEA formulations, which can cause , , or voice deepening in 5-10% of users. No clinically meaningful changes in serum levels, profiles, or markers were observed in phase 3 trials up to 52 weeks, supporting the localized via intracrinology, where conversion to active steroids occurs primarily within vaginal tissues. reactions are contraindications, but post-marketing surveillance has not identified new safety signals beyond trial data as of 2024.

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. 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. Precautions are advised for women with a current or prior history of , as prasterone is metabolized to —a known for exogenous estrogen therapy—and clinical trials excluded such patients, leaving safety data absent in this population. Although prasterone exhibits primarily local action with minimal systemic absorption, any emergent or spotting during treatment warrants prompt investigation, potentially including endometrial , to exclude . Close monitoring is recommended in patients with conditions exacerbated by estrogens or androgens, such as , , , or a history of , with periodic pelvic and breast examinations advised before and during use. 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. Risks associated with systemic , including , , and , apply to a lesser degree but necessitate individualized risk-benefit assessment, particularly beyond one year of use where long-term endometrial safety remains unestablished.

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 treated for up to 52 weeks. In this trial, 80.2% of participants experienced treatment-emergent s, predominantly mild to moderate, with application site discharge reported in 14.0% and urinary tract infections in 10.2%; serious s occurred in 3.5%, and discontinuations due to s were 6.0%, with no deaths attributed to the . Pooled data from shorter placebo-controlled trials (ERC-231 and ERC-238, 12 weeks) showed comparable rates between prasterone and groups, suggesting many events reflect underlying postmenopausal conditions rather than , though the absence of a in ERC-230 limits definitive attribution. Serum concentrations of prasterone and its metabolites (including testosterone, , 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. Endometrial assessments via in 94% of ERC-230 participants revealed atrophic , with no cases of or , and mean endometrial thickness of 2.2 mm by ; however, long-term endometrial safety beyond one year has not been systematically evaluated. Breast safety evaluations, including mammograms in 98% of participants, were predominantly normal (99%), though two cases of pathology—one and one infiltrating ductal —were reported, without established drug linkage given the population's baseline cancer risk. 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.
Safety ParameterERC-230 Findings (52 Weeks)Notes
Application Site Discharge14.0%Attributed to insert melting; most common drug-related event.
10.2%Similar to shorter trials; likely age-related.
Serious Adverse Events3.5% (18/521)None deemed causally related; includes and infections.
Endometrial Biopsies94% atrophic (430/457)No ; limited to treated population excluding prior cancer history.
Pathology0.4% significant findingsRare; baseline postmenopausal risk not controlled.
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 or breast changes due to local conversion to estrogens and androgens, with theoretical oncogenic risks unproven in human data. Data beyond 52 weeks are absent, and trials excluded women with cancer history, , or uncontrolled , potentially underrepresenting risks in broader populations; open-label design may inflate adverse event reporting via heightened awareness. Post-marketing surveillance, including drug utilization studies, continues to assess real-world long-term effects.

Investigational and Off-Label Applications

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. 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. 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. 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. 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. 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. 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 and precursors, potentially contributing to frailty, cognitive changes, and metabolic shifts. Supplementation with 50 mg daily oral DHEA in elderly populations (typically aged 60–80) restores levels toward youthful ranges, as demonstrated in a multicenter of 87 men and 57 women, which increased DHEA by over 10-fold but yielded no significant improvements in , strength, or metrics. Meta-analyses of randomized trials indicate modest elevations in testosterone (mean increase of 0.8 nmol/L) and but inconsistent effects on clinical endpoints like , insulin sensitivity, or depressive symptoms, with subgroup benefits occasionally noted in women with low baseline levels. For cognition, systematic reviews of supplementation trials report no reliable reversal of age-related decline, despite preclinical links between DHEA and ; human data from placebo-controlled studies show null or negligible impacts on or executive function. Overall, while DHEA decline correlates with aging phenotypes, supplementation lacks robust empirical support for mitigating them, with potential risks including , , and unknown long-term oncogenic effects prompting caution and relegating its use to contexts.

Menopausal Symptoms Beyond VVA

Intravaginal prasterone, administered at a dose of 6.5 mg daily, has demonstrated efficacy in reducing (LUTS) in postmenopausal women, including urinary urgency, frequency, and urge incontinence, which extend beyond vulvovaginal atrophy as part of the genitourinary syndrome of menopause (). A of 11 randomized controlled trials involving postmenopausal women with 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 . 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. Clinical trials have also linked intravaginal prasterone to a lower incidence of recurrent urinary tract infections (UTIs) in women with . In a prospective study of postmenopausal women, prasterone treatment reduced UTI by approximately 50% over one year compared to baseline rates, potentially due to improved vaginal and urethral mucosa health that limits bacterial ascension. Similarly, validated questionnaires such as the Urogenital Distress Inventory-6 (UDI-6) and Questionnaire Short Form (OAB-q SF) showed statistically significant declines in symptom scores after 12 weeks of , with improvements persisting in subsets of women with concurrent . In contrast, prasterone exhibits negligible impact on systemic menopausal symptoms such as instability (e.g., hot flashes or ), owing to its pharmacokinetic profile of minimal serum absorption. Daily intravaginal dosing maintains circulating , testosterone, and DHEA levels within the lower of normal postmenopausal ranges, avoiding the hormonal fluctuations needed for vasomotor relief. 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, , or overall psychological in . 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.

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. 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. Serum DHEA levels are often inversely correlated with SLE activity, supporting a plausible mechanistic link via , but clinical benefits remain investigational and unapproved. 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 . 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. Evidence from studies suggests a potential causal link between higher DHEA levels and better response, but this requires further validation in diverse populations. For bone health, DHEA has been explored in , with pooled analyses of clinical trials showing increases in lumbar spine density (BMD) of approximately 1.7-3.5% over 12-24 months in postmenopausal women, alongside potential enhancements in muscle mass. However, a of seven randomized controlled trials concluded no significant BMD improvement after adjusting for , highlighting mixed findings and the need for longer-term studies to assess risk reduction. These effects may stem from DHEA's conversion to estrogens and androgens, but applications remain off-label and unsupported by regulatory approvals. Preliminary research also suggests DHEA's utility in trauma rehabilitation, where it may aid recovery in severely injured patients through and anabolic pathways, though evidence is limited to reviews rather than large-scale trials. 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.

Research Evidence

Strong Empirical Support Areas

Intravaginal prasterone (6.5 mg daily) demonstrates strong empirical support for alleviating moderate to severe associated with vulvovaginal atrophy (VVA) in postmenopausal women, as evidenced by two pivotal phase III randomized, double-blind, -controlled trials involving 406 healthy participants aged 40 to 80 years. 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 , 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 (from 6.6 to 5.3). These changes correlated with clinical symptom relief, supporting local conversion of prasterone to estrogens and androgens without substantial systemic absorption. A of randomized controlled trials further corroborates these findings, concluding that prasterone therapy yields significant therapeutic effects on VVA symptoms, including , vaginal dryness, and overall sexual function, with effect sizes favoring prasterone over (standardized mean difference -0.89 for ; 95% CI -1.28 to -0.50). Long-term safety data from an open-label phase III extension (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. This body of evidence underpinned FDA approval on November 17, 2016, as the first non-estrogen therapy specifically for postmenopausal due to VVA. No other indications exhibit comparable rigorous, replicated phase III ; systemic oral DHEA lacks similar validation for VVA or broader menopausal symptoms due to inconsistent and off-target effects.

Mixed or Inconclusive Findings

Studies on dehydroepiandrosterone (DHEA) supplementation for cognitive enhancement in non-demented older adults have yielded inconclusive results, with systematic s indicating no consistent beneficial effects on or other cognitive domains. A Cochrane of randomized controlled trials found insufficient 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 . 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 and executive function. 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 and spine BMD among older women with low baseline DHEA levels after 12 months of 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 in broader management, necessitating further long-term data. 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 , yet cautioned against firm conclusions due to variable study quality and potential , while reviews of endogenous DHEA levels find no clear association with depression risk in postmenopausal women. In systemic applications for menopausal beyond vulvovaginal , a 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.

Debunked or Unsupported Claims

Claims that oral dehydroepiandrosterone (DHEA) supplementation serves as an effective anti-aging therapy, such as reversing age-related declines in , muscle , or overall , 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 clinical trials, where outcomes showed no clear preventive efficacy. Assertions that systemic DHEA improves cognitive function in non-demented middle-aged or older adults are unsupported by evidence. A 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. For postmenopausal women, claims of systemic DHEA alleviating symptoms like low or overall have been refuted by meta-analyses, which reported no significant improvements over in scores or quality-of-life measures. In fertility treatment, the notion that DHEA priming enhances outcomes for women with diminished or poor response to IVF has been debunked by multiple meta-analyses. These analyses, aggregating data from randomized trials, found no increases in clinical rates, live birth rates, or yield compared to controls, despite initial enthusiasm from small observational studies. Long-term therapeutic claims beyond vaginal prasterone for vulvovaginal remain unsubstantiated due to insufficient adequately powered trials demonstrating sustained efficacy or safety.

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. 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. 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. The sulfated form, dehydroepiandrosterone sulfate (DHEA-S), was identified approximately 10 years later in 1944, marking an early step in recognizing conjugated metabolites. By 1954, DHEA itself was isolated from peripheral , expanding knowledge of its systemic circulation beyond urinary excretion. In 1959, French biochemist Étienne-Émile Baulieu demonstrated that DHEA-S constitutes the predominant circulating form of the in humans, comprising up to 99% of total DHEA pool and highlighting its role as a stable reservoir for the free hormone. These findings established DHEA's biosynthesis primarily in the adrenal zona reticularis, with minor contributions from gonads and brain, via enzymes converting precursors. Early research in the and focused on DHEA's function as a weak and precursor to testosterone and estrogens, with in vitro conversions documented through enzymatic assays. 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 dynamics. Synthetic production routes, including partial synthesis from sterols like diosgenin, emerged in the mid-20th century to support biochemical studies, though therapeutic applications remained exploratory until later decades.

Key Milestones and Approvals

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

Regulation and Societal Aspects

In the , prasterone (branded as Intrarosa in 6.5 mg intravaginal inserts) received approval from the (FDA) on November 17, 2016, specifically for treating moderate to severe pain during sexual intercourse (), a symptom of vulvovaginal , in postmenopausal women. This approval represented the first instance of the FDA authorizing a product with prasterone as its active ingredient for any indication. 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 , though the agency has issued warnings against unapproved therapeutic claims for such products. In the , the (EMA) authorized Intrarosa on January 8, 2018, for the same indication associated with vulvovaginal atrophy in postmenopausal women, with the marketing authorization valid across member states. similarly approved the 6.5 mg prasterone vaginal inserts for this use. Globally, DHEA faces stricter controls outside the ; in most countries, it is classified as a controlled , often requiring a prescription or facing outright bans for non-pharmaceutical use due to its potential conversion to testosterone and other androgens. 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.

Use in Sports and Doping Controls

Prasterone, also known as dehydroepiandrosterone (DHEA), is classified as a prohibited substance under the (WADA) Prohibited List in the category of anabolic agents (S1.1a: anabolic androgenic steroids, exogenous). 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. This prohibition extends to major sporting bodies including the (USADA) and the (NCAA), where it is tested for in routine anti-doping controls via urine and blood analysis targeting the substance and its metabolites. Athletes have historically sought prasterone supplementation for purported performance-enhancing effects, including improved endurance, recovery, and , particularly in strength-based or resistance contexts. 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. However, for significant ergogenic benefits remains limited and context-dependent; short-term administration failed to enhance or anabolic markers in young recreational athletes, suggesting minimal impact in individuals with normal endogenous levels. 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 study where 50 mg daily doses amplified training-induced gains in elderly men and women. Conversely, reviews indicate that perceptions of DHEA's in or younger athletes outpace scientific validation, with no consistent improvements in combined endurance-strength protocols or overall athletic output. 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. Despite inconclusive performance data, its inclusion on prohibited lists reflects precautionary principles against any androgenic modulation in competitive sport.

Availability and Marketing

In the United States, prasterone (dehydroepiandrosterone, or DHEA) is widely available over-the-counter as an oral in forms such as capsules, tablets, and powders, with typical dosages ranging from 25 mg to 200 mg daily. 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 levels or . 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 . 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 associated with genitourinary syndrome of in postmenopausal women, via local conversion to active androgens and estrogens. In the , prasterone is not authorized as a 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. Intrarosa received marketing authorization from the on January 8, 2018, for vulvar and vaginal in postmenopausal women, with availability limited to this indication across EU member states. Certain ester forms, such as prasterone enanthate, are available by prescription in select European countries including , , and for in conditions like , typically via . In , Intrarosa is prescription-only for postmenopausal vulvovaginal , filed for review in 2016. Marketing of oral prasterone supplements in the focuses on purported benefits for , mood enhancement, muscle maintenance, and countering age-related declines in adrenal production, often positioned as a "youth hormone" precursor despite limited clinical substantiation and FDA disclaimers against claims. Manufacturers must avoid implying prevention or treatment to evade enforcement, though historical instances of unsubstantiated promotion as an anti-aging or performance aid have prompted regulatory scrutiny. In contrast, Intrarosa's promotion emphasizes evidence from phase III trials showing improvements in vaginal pH, epithelial integrity, and dyspareunia scores without systemic elevation, targeting gynecologists and postmenopausal patients via pharmaceutical channels. Global supplement marketing is curtailed outside the , where bans in countries like , the , and much of limit it to or veterinary contexts, underscoring divergent regulatory philosophies on endogenous precursors.

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