Vaginal DHEA (Prasterone)
Vaginal DHEA (prasterone / Intrarosa) is an FDA-approved intravaginal steroid for moderate-to-severe dyspareunia due to menopause. Its defining pharmacologic feature — intracrine conversion to androgens and estrogens within vaginal tissue — distinguishes it from vaginal estrogen by providing local androgenic and estrogenic effects; systemic exposure is low but not zero.[1][2][3] A placebo-controlled analysis reported improvement across all six FSFI domains, including desire and arousal; this does not establish superior sexual-function benefit over vaginal estrogen.[4]
For related agents, see Vaginal and topical estrogen, Ospemifene, and Preoperative hormonal priming. For the clinical framework, see GSM.
Mechanism — the science of intracrinology
Prasterone (synthetic DHEA) exploits intracrinology — inactive precursor hormones are converted into active sex steroids within target cells, act locally, and are then inactivated before release into circulation.[2]
Enzymatic cascade within vaginal tissue:[5][2]
- DHEA → androstenedione (3β-HSD1/HSD2)
- Androstenedione → testosterone (17β-HSD3/HSD5)
- Testosterone → DHT (5α-reductase isoforms)
- Androstenedione → estrone → estradiol (aromatase + 17β-HSD)
- Active steroids → glucuronide/sulfate conjugates (UGT + SULT) → released as inactive metabolites
Cellai 2021 confirmed the human vagina as an androgen-target organ — DHEA supplementation of human vaginal smooth-muscle cells increased androstenedione, testosterone, and DHT secretion and activated AR-dependent gene expression.[5]
Clinical consequence: after menopause, ovarian estrogen production ceases, and DHEA (the remaining endogenous androgen-estrogen precursor) declines progressively from age ~30. Delivering DHEA directly to the vagina restores both the estrogenic effects (epithelial maturation, lubrication, pH normalization) and the androgenic effects (muscularis support, improved blood flow, enhanced sexual function) of a premenopausal hormonal milieu ; the mechanistic distinction does not establish superior clinical outcomes over vaginal estrogen.[2][6]
FDA-approved indication and dosing
| Element | Details |
|---|---|
| Brand | Intrarosa[3] |
| US indication | Moderate-to-severe dyspareunia — a symptom of vulvar and vaginal atrophy due to menopause |
| EU indication | Treatment of VVA in postmenopausal women with moderate-to-severe symptoms (broader than US) |
| Dose | One vaginal insert (6.5 mg prasterone) once daily at bedtime via the provided applicator |
| Loading / taper | None |
| Progestogen | Not required for endometrial protection[7] |
| Absolute contraindication | Undiagnosed abnormal genital bleeding |
| Label warning | Estrogen is a metabolite of prasterone; exogenous estrogen is contraindicated in women with known/suspected breast cancer; Intrarosa has not been studied in breast cancer survivors |
| Pediatric | Safety not established |
| Hepatic / renal impairment | PK not studied; ~19% of clinical-trial participants were ≥65 y |
Pivotal clinical trials
Approval rested on two Phase III placebo-controlled RCTs (ERC-231, ERC-238) plus the 52-week open-label safety trial ERC-230.[3][8]
Coprimary endpoints — all four met in both trials[1]
| Endpoint | Effect over placebo | p |
|---|---|---|
| Parabasal cells (%) | ↓ 27.7% | <0.0001 |
| Superficial cells (%) | ↑ 8.44% | <0.0001 |
| Vaginal pH | ↓ 0.66 units | <0.0001 |
| Dyspareunia severity | ↓ 0.36 units over placebo (−1.42 from baseline) | 0.0002 |
| Vaginal dryness (key secondary) | ↓ 0.27 units over placebo (−1.44 from baseline) | 0.004 |
On gynecologic evaluation, vaginal secretions, epithelial integrity, surface thickness, and color all improved 86–121% over the placebo effect (p < 0.0001).[1]
2026 meta-analysis — Lemos
Systematic review and meta-analysis of 6 RCTs (5 unique; n = 1,611):[9]
- Vaginal dryness: MD −0.23 (95% CI −0.35 to −0.11) vs placebo
- Dyspareunia: MD −0.40 (95% CI −0.66 to −0.15) vs placebo
- No major safety concerns; AEs mild and infrequent
- Low-to-moderate heterogeneity
Sexual function — placebo-controlled FSFI findings
These are placebo-controlled findings, not a head-to-head comparison with vaginal estrogen. Labrie 2015 Phase III FSFI analysis (n = 482) — all six FSFI domains improved significantly over placebo at 12 weeks:[4]
| FSFI domain | Improvement vs placebo | p |
|---|---|---|
| Desire | +49.0% | 0.0105 |
| Arousal | +56.8% | 0.0022 |
| Lubrication | +36.1% | 0.0005 |
| Orgasm | +33.0% | 0.047 |
| Satisfaction | +48.3% | 0.0012 |
| Pain | +39.2% | 0.001 |
| Total FSFI | +41.3% | 0.0006 |
An earlier dose-finding Phase III (Labrie 2009, n = 216) showed dose-dependent improvements in arousal/sensation (+68%, p = 0.006), arousal/lubrication (+39%, p = 0.0014), orgasm (+75%, p = 0.047), and dryness during intercourse (−57%, p = 0.0001) with the 1.0% DHEA dose.[6]
Local androgenic activity is a proposed explanation for the desire and arousal findings. The trials do not isolate that mechanism or establish superiority to vaginal estrogen.[4][6]
Systemic exposure and its limits
Integrated LC-MS/MS serum steroid analysis (n = 723 DHEA + n = 266 placebo) after 12 weeks of 6.5 mg daily:[10][11]
| Steroid | 12-wk level on DHEA | Normal postmenopausal value | Interpretation |
|---|---|---|---|
| Estradiol (E2) | 3.26–3.36 pg/mL | 4.17 pg/mL | 19–22% BELOW normal postmenopausal |
| Estrone sulfate (E1-S) | 209–219 pg/mL | 220 pg/mL | Superimposable |
| Testosterone | Slightly ↑ | Within postmenopausal range | Lowest half of the range |
| DHEA-S | ↑ (dose-dependent) | Within postmenopausal range | — |
| ADT-G (androgen metabolite) | Within range | Normal postmenopausal | No excess androgenic activity |
Comparison with an average postmenopausal reference value does not show absence of absorption or absence of oncologic risk. The current label reports mean trough increases from baseline of 47% for prasterone, 21% for testosterone and 19% for estradiol after 12 weeks; these relative increases do not by themselves establish clinical harm or safety.[3][10][11]
In cancer survivors — NCCTG N10C1 (Alliance)
Barton 2018 (n = 345 blood samples in women with breast or gynecologic cancer history) — 3.25 mg vs 6.5 mg DHEA vs plain moisturizer:[12]
- DHEA-S and testosterone rose dose-dependently but stayed in the lowest half or quartile of the postmenopausal range
- Estradiol increased with 6.5 mg but not with 3.25 mg (p = 0.05)
- Estrogen concentrations did not change in the aromatase-inhibitor subgroup during this study; this short-term biochemical finding does not establish long-term breast-cancer safety
- Biomarkers of bone formation unchanged in all arms
- Vaginal maturation improved: 100% (3.25 mg), 86% (6.5 mg), 64% (moisturizer)
These exploratory biochemical findings may inform an oncology discussion, but they do not override the label warning or establish recurrence safety in AI users.
Comparison with vaginal estrogen
Archer 2017 indirect cross-trial comparison of prasterone 6.5 mg vs CEE 0.3 mg vs estradiol 10 µg:[13]
| Outcome | Prasterone 6.5 mg | CEE 0.3 mg | Estradiol 10 µg |
|---|---|---|---|
| Dyspareunia — total Δ from baseline | 1.27–1.63 | 1.4 | 1.23 |
| Dyspareunia — Δ over placebo | 0.35–1.21 | 0.7–1.0 | 0.33 |
| Dryness — total Δ from baseline | 1.44–1.58 | 1.1 | 1.23 |
| Dryness — Δ over placebo | 0.30–0.43 | 0.40 | 0.33 |
Authors: prasterone "appears to be at least as efficacious as 0.3 mg CEE or 10 µg estradiol" for VVA symptoms.[13] A 2023 JAMA review estimated symptom-improvement ranges of 60–80% (vaginal estrogen) vs 40–80% (prasterone) vs 30–50% (oral ospemifene).[14]
Features to discuss when choosing between treatments
- All six FSFI domains improve including desire and arousal[4]
- Androgenic effects on muscularis and lamina propria (deeper tissue layers)[6]
- Serum E2 below normal postmenopausal values[10]
- Comparative safety in AI users is unproven; unchanged short-term E2 in one study does not establish recurrence safety[12]
Disadvantages vs vaginal estrogen
- Daily dosing (vs 2×/wk inserts or 90-day ring)
- Vaginal discharge from melting vehicle (~6–14%)[1][3]
- More expensive; no generic
- No UTI-prevention evidence — vaginal estrogen is the AUA-endorsed rUTI agent (RR 0.42)[15]
- No head-to-head RCT vs vaginal estrogen[15]
See Vaginal and topical estrogen for the rUTI data.
Adverse effects and safety
Short-term (pooled 4 RCTs, n = 665 DHEA + n = 464 placebo)[3]
Only AE with ≥2% incidence and greater than placebo: vaginal discharge 5.71% (DHEA) vs 3.66% (placebo) — melting of the suppository vehicle at body temperature, not pathologic.
Long-term (52-wk open-label ERC-230, n = 521)[8][3]
- Vaginal discharge: 14.2% (74/521)
- Abnormal Pap: 2.1% (11/521) — 10 ASCUS, 1 LSIL
- No endometrial hyperplasia or carcinoma
- No clinically significant serum-steroid changes beyond normal postmenopausal ranges
- No drug-related serious AEs
Androgenic side effects
Cochrane review of DHEA (all routes) found an association with androgenic AEs, mainly acne (OR 3.77; 95% CI 1.36–10.4; p = 0.01), but this was primarily driven by oral/systemic DHEA — not the intravaginal 6.5 mg formulation.[16]
Endometrial safety
No progestogen required; no hyperplasia in 52-wk data. The cited 52-week safety study was open-label — long-term safety beyond this window is not established. Patients must be counseled to report any vaginal bleeding promptly.[14]
Use in breast cancer survivors
The most nuanced clinical question. The FDA label carries a warning; guideline positions are cautious but allow use.
| Source | Position |
|---|---|
| FDA label | Estrogen is a metabolite; use of exogenous estrogen is contraindicated in women with known/suspected breast cancer; Intrarosa has not been studied in this population[3] |
| ACOG 2021 clinical consensus | DHEA or vaginal testosterone may be considered when vaginal estrogen is not an option; this is not a requirement to try estrogen first[17] |
| NCCN Survivorship 2026 | Listed among "other topical hormones" for vaginal dryness; "limited data regarding the use of androgen therapy in survivors of hormonally mediated cancers"; "more information needed … particularly for breast cancer survivors on AIs"[18] |
| NCCN Breast Cancer Risk Reduction 2026 | "Consider avoiding bioidentical hormones or DHEA" in women on risk-reducing agents[19] |
VIBRA pilot — Mension 2022
10 breast cancer survivors on AIs, 6 months of vaginal prasterone:[20]
- Mean serum E2 3.4 → 4.3 pg/mL (p = 0.91 — not significant)
- Dyspareunia VAS 8.5 → 0.4 (p = 0.018)
- VHI 9.75 → 15.8 (p = 0.028)
- FSFI 11.2 → 20.6 (p = 0.028)
- Vaginal pH 8.1 → 6.5 (p = 0.033)
Pharmacologic rationale in AI users
Aromatase inhibition offers a mechanistic rationale for lower estrogen conversion, but it does not prove that conversion is absent in every patient or that DHEA is oncologically safe. NCCTG and the 10-patient VIBRA pilot provide short-term biochemical and symptom observations, not breast-cancer recurrence endpoints.[12][20]
Clinical implication
After nonhormonal options, vaginal DHEA may be discussed when vaginal estrogen is not an option. Explain the FDA warning, limited long-term cancer data and lack of proven comparative safety in AI users; involve oncology in the decision.[3][17]
Practical prescribing
| Parameter | Recommendation |
|---|---|
| Ideal candidate | Postmenopausal woman with moderate-to-severe dyspareunia who prefers a daily vaginal option; prasterone is a hormone precursor that forms estrogen and androgen metabolites[1] |
| Dose | 6.5 mg vaginal insert nightly at bedtime[3] |
| Onset | Significant improvement by 6 weeks; full effect by 12 weeks[1] |
| Duration | Indefinite — GSM is chronic; symptoms recur on discontinuation[3] |
| Progestogen | Not required[3] |
| Monitoring | No routine serum monitoring; evaluate any postmenopausal bleeding[14] |
| Patient counseling | ~6–14% vaginal discharge from melting vehicle — not a sign of infection; panty liner if bothersome[1][3] |
| Breast cancer survivors | May be discussed when vaginal estrogen is not an option; oncology involvement and explicit cancer-safety uncertainty[17][20] |
| Cost | Brand-name only (~$200–300/month without insurance); no generic |
| Storage | Store at 5–30 °C; room temperature or refrigeration are permitted[3] |
Comparative summary — DHEA vs vaginal estrogen vs ospemifene
| Feature | Vaginal DHEA (prasterone) | Vaginal estrogen | Ospemifene (oral SERM) |
|---|---|---|---|
| FDA indication | Dyspareunia (US); VVA (EU) | GSM symptoms | Dyspareunia + vaginal dryness |
| Mechanism | Intracrine → androgens + estrogens | Direct estrogenic | Oral SERM (vaginal agonist) |
| Dosing frequency | Daily | 2×/wk or 90-day ring | Daily oral |
| FSFI all 6 domains | Yes (including desire and arousal)[4] | Primarily pain / lubrication | Dyspareunia |
| UTI prevention | Not studied | Strong evidence (RR 0.42)[15] | Not studied |
| Systemic exposure | Low, but estrogen/testosterone metabolites can increase | Usually low with local low-dose products; formulation-dependent | Systemic SERM; not an estradiol preparation |
| Progestogen needed | No | No (low dose) | No |
| Breast cancer survivors | Label warning; limited data; oncology discussion | Consider local low-dose therapy after nonhormonal options through shared decision-making | US label advises against use with known/suspected or prior breast cancer |
| Main AE | Vaginal discharge 6–14% | Discharge / irritation | Hot flashes ~10% |
| Generic? | No | Yes (most) | No |
| Symptom improvement | 40–80%[14] | 60–80% | 30–50% |
Evidence Summary
| Domain | Evidence level | Key source |
|---|---|---|
| Dyspareunia efficacy | Level 1 (Phase III RCTs + meta-analysis) | Labrie 2018 pivotal[1]; Lemos 2026 meta[9] |
| All-FSFI-domain sexual function | Level 1 (Phase III FSFI analysis) | Labrie 2015[4]; Labrie 2009[6] |
| Systemic absorption / safety | Level 1 (pharmacology studies) | Ke 2015[10]; Martel 2016[11] |
| Long-term safety | Level 2 (52-wk open-label) | ERC-230[8] |
| Breast cancer survivors — pharmacology | Level 2 | NCCTG Barton 2018[12]; VIBRA 2022[20] |
| Indirect comparison vs vaginal estrogen | Level 3 | Archer 2017[13] |
| UTI prevention | Not studied | — |
Clinical Positioning
- Vaginal DHEA 6.5 mg nightly is FDA-approved for moderate-to-severe dyspareunia due to menopause and is supported by two Phase III placebo-controlled RCTs meeting all four coprimary endpoints.[1][3]
- FSFI improvement is supported by placebo-controlled data; superiority over vaginal estrogen or a specific androgen-mediated clinical mechanism has not been established.[4]
- Systemic exposure is low, not absent. Reference-range hormone levels do not establish safety in hormone-sensitive cancer.[10][11]
- No progestogen is required and no endometrial hyperplasia was seen at 52 weeks; long-term (>1 y) endometrial data are absent — evaluate any postmenopausal bleeding.[3][8][14]
- Prasterone is not an established UTI-prevention treatment. Vaginal estrogen remains the AUA-endorsed agent for rUTI prevention (RR 0.42). Do not substitute DHEA for UTI-driven indications.[15]
- In breast cancer survivors, DHEA may be discussed when vaginal estrogen is not an option; ACOG does not require an estrogen trial first. Small AI-user studies cannot establish recurrence safety.[17][20]
- Counsel about vaginal discharge from melting vehicle — 6% short-term, 14% long-term; not infectious; panty liner usually sufficient.[1][3]
- Cost and daily dosing are the practical downsides — no generic, ~$200–300/month; nightly application compared to 2×/wk or 90-day estrogen-ring alternatives.
- Onset is gradual — 6-week partial benefit, 12-week full effect — match expectations accordingly.[1]
- Storage is 5–30 °C, at room temperature or refrigerated; the current US label does not impose the former seven-day room-temperature rule.[3]
See Also
References
1. Labrie F, Archer DF, Koltun W, et al. "Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause." Menopause. 2018;25(11):1339–1353. doi:10.1097/GME.0000000000001238
2. Labrie F, Bélanger A, Pelletier G, et al. "Science of intracrinology in postmenopausal women." Menopause. 2017;24(6):702–712. doi:10.1097/GME.0000000000000808
3. INTRAROSA (prasterone) prescribing information. Revised January 2026; DailyMed updated July 17, 2026.
4. Labrie F, Derogatis L, Archer DF, et al. "Effect of intravaginal prasterone on sexual dysfunction in postmenopausal women with vulvovaginal atrophy." J Sex Med. 2015;12(12):2401–2412. doi:10.1111/jsm.13045
5. Cellai I, Di Stasi V, Comeglio P, et al. "Insight on the intracrinology of menopause: androgen production within the human vagina." Endocrinology. 2021;162(2):bqaa219. doi:10.1210/endocr/bqaa219
6. Labrie F, Archer D, Bouchard C, et al. "Effect of intravaginal dehydroepiandrosterone (prasterone) on libido and sexual dysfunction in postmenopausal women." Menopause. 2009;16(5):923–931. doi:10.1097/gme.0b013e31819e85c6
7. Labrie F, Luu-The V, Labrie C, et al. "Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone." Endocr Rev. 2003;24(2):152–182. doi:10.1210/er.2001-0031
8. Heo YA. "Prasterone: a review in vulvovaginal atrophy." Drugs Aging. 2019;36(8):781–788. doi:10.1007/s40266-019-00693-6
9. Lemos MJ, Queiroz LF, Diniz AF, et al. "Intravaginal dehydroepiandrosterone for the treatment of vulvovaginal atrophy: a systematic review and meta-analysis." Menopause. 2026. doi:10.1097/GME.0000000000002736
10. Ke Y, Labrie F, Gonthier R, et al. "Serum levels of sex steroids and metabolites following 12 weeks of intravaginal 0.50% DHEA administration." J Steroid Biochem Mol Biol. 2015;154:186–196. doi:10.1016/j.jsbmb.2015.08.016
11. Martel C, Labrie F, Archer DF, et al. "Serum steroid concentrations remain within normal postmenopausal values in women receiving daily 6.5 mg intravaginal prasterone for 12 weeks." J Steroid Biochem Mol Biol. 2016;159:142–153. doi:10.1016/j.jsbmb.2016.03.016
12. Barton DL, Shuster LT, Dockter T, et al. "Systemic and local effects of vaginal dehydroepiandrosterone (DHEA): NCCTG N10C1 (Alliance)." Support Care Cancer. 2018;26(4):1335–1343. doi:10.1007/s00520-017-3960-9
13. Archer DF, Labrie F, Montesino M, Martel C. "Comparison of intravaginal 6.5 mg (0.50%) prasterone, 0.3 mg conjugated estrogens and 10 µg estradiol on symptoms of vulvovaginal atrophy." J Steroid Biochem Mol Biol. 2017;174:1–8. doi:10.1016/j.jsbmb.2017.03.014
14. Crandall CJ, Mehta JM, Manson JE. "Management of menopausal symptoms: a review." JAMA. 2023;329(5):405–420. doi:10.1001/jama.2022.24140
15. Danan ER, Sowerby C, Ullman KE, et al. "Hormonal treatments and vaginal moisturizers for genitourinary syndrome of menopause: a systematic review." Ann Intern Med. 2024;177(10):1400–1414. doi:10.7326/ANNALS-24-00610
16. Scheffers CS, Armstrong S, Cantineau AE, Farquhar C, Jordan V. "Dehydroepiandrosterone for women in the peri- or postmenopausal phase." Cochrane Database Syst Rev. 2015;1:CD011066. doi:10.1002/14651858.CD011066.pub2
17. American College of Obstetricians and Gynecologists. "Treatment of urogenital symptoms in individuals with a history of estrogen-dependent breast cancer: clinical consensus." Obstet Gynecol. 2021;138(6):950–960. doi:10.1097/AOG.0000000000004601
18. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: survivorship. Updated 2026-04-08.
19. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer risk reduction. Updated 2025-08-29.
20. Mension E, Alonso I, Cebrecos I, et al. "Safety of prasterone in breast cancer survivors treated with aromatase inhibitors: the VIBRA pilot study." Climacteric. 2022;25(5):476–482. doi:10.1080/13697137.2022.2050208