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Vaginal estrogen, prasterone and ospemifene

Pooled trials found vaginal estrogen eased dryness and painful sex against placebo, and cut recurrent urinary infections by more than half, though one large trial found no difference from placebo. Prasterone and ospemifene eased painful sex. Small amounts of estradiol reach the blood. Large cohorts found no rise in breast cancer, endometrial cancer or stroke.

Add to Bio HackChecked 2026-11-13
Status
Prescription drugs in the US. Vaginal estradiol inserts and the estradiol ring are FDA-approved for vaginal atrophy symptoms or painful sex due to menopause [1][2][3]. In November 2025 FDA asked makers of vaginal estrogen products to remove the boxed warning about cardiovascular disease, breast cancer, dementia and endometrial cancer, and to condense safety information to what applies to vaginal use [4]. The Estring label revised in 2026 carries no boxed warning, while the Imvexxy label listed in October 2026 still printed one [1][2]. Prasterone (Intrarosa), a vaginal insert, is approved for moderate to severe painful sex due to menopause [5]. Ospemifene (Osphena), a pill, is approved for moderate to severe painful sex and vaginal dryness due to menopause and carries a boxed warning for endometrial cancer and cardiovascular disorders [6].
Also called
vaginal estrogen, local estrogen, low-dose vaginal estrogen, vaginal estradiol, estradiol vaginal insert, estradiol vaginal tablet, Vagifem, Yuvafem, Imvexxy, estradiol vaginal ring, Estring, estradiol vaginal cream, Estrace cream, conjugated estrogens vaginal cream, Premarin vaginal cream, prasterone, vaginal DHEA, Intrarosa, ospemifene, Osphena, treatment for genitourinary syndrome of menopause, GSM, vaginal atrophy, vulvovaginal atrophy, atrophic vaginitis
Taken for
vaginal dryness, painful sex after menopause, genitourinary syndrome of menopause, vaginal atrophy, vaginal itching and irritation, recurrent urinary tract infections, urinary urgency and frequency, overactive bladder, urinary incontinence, sexual function after menopause

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help5

Reported risks7

What people take it for, and what was found

Shown to help5

StrongStudied in women

Vaginal dryness and painful sex: vaginal estrogen

Shown to ease vaginal dryness and painful sex against placebo in pooled trials, though one 302-woman trial found no difference from placebo, which also eased symptoms.

Compared with placebo [7][8][9]; no treatment [8]; placebo tablet and placebo gel [10]; other forms of vaginal estrogen [7][9]

The numbers and sources
Effect
In a Cochrane review of 30 trials, more women reported improvement on an estradiol ring than placebo (OR 12.67, 95% CI 3.23 to 49.66, 1 trial, 67 women) and on estrogen cream than placebo (OR 4.10, 95% CI 1.88 to 8.93, 2 trials, 198 women). For estradiol tablets against placebo, a fixed-effect model found OR 12.47 (95% CI 9.81 to 15.84, 2 trials, 1,638 women), but a random-effects model did not (OR 5.80, 95% CI 0.88 to 38.29). Ring, cream and tablets did not differ from each other [7]. A 2024 review of 22 trials found vaginal estrogen may improve dryness, painful sex, the most bothersome symptom and treatment satisfaction against placebo or no treatment [8]. A 2014 review found improvement in dryness and painful sex against placebo, with similar results across products [9]. In a 12-week trial, the most bothersome symptom fell by 1.4 points on a 0 to 3 scale with a 10 µg estradiol tablet, 1.3 on placebo and 1.2 on a moisturizer, with no significant difference. Sexual function scores rose 5.4 and 4.5 points [10].
Population
30 trials with 6,235 postmenopausal women, lasting at least 12 weeks [7]. 22 trials of vaginal estrogen within 46 trials of postmenopausal women with at least one genitourinary symptom [8]. 44 studies [9]. 302 postmenopausal women, mean age 61, 60% of whom named pain with penetration as their worst symptom [10].
Sources
[7], [8], [9], [10]
Caveats
The Cochrane review rated the evidence low to moderate quality, with wide intervals [7]. The 2024 review rated certainty low, and most trials lasted 12 weeks or less [8]. In the 302-woman trial, placebo lowered symptom severity by 1.3 points [10].
StrongStudied in women

Recurrent urinary tract infections

Shown to cut recurrent urinary infections by about 58% against placebo in postmenopausal women, while estrogen taken by mouth did not lower them.

Compared with placebo [11][12]; oral antibiotics [12]

The numbers and sources
Effect
Pooling 5 trials (1,936 women), vaginal estrogen lowered recurrent urinary infections against placebo (RR 0.42, 95% CI 0.30 to 0.59), while 3 trials of oral estrogen (2,766 women) found no difference (RR 1.11, 95% CI 0.92 to 1.35). Vaginal pH fell by 1.81 (95% CI 0.52 to 3.10) [11]. A Cochrane review found vaginal estrogen lowered the number of women with infections in two small placebo-controlled trials (RR 0.25, 95% CI 0.13 to 0.50, and RR 0.64, 95% CI 0.47 to 0.86). Against antibiotics, a vaginal cream did better in one trial and antibiotics did better than vaginal pessaries in another [12]. A 2014 review also found fewer urinary infections on vaginal estrogen [9].
Population
8 trials with 4,702 postmenopausal women [11]. 9 trials with 3,345 postmenopausal women with recurrent infections [12]. 44 studies [9].
Sources
[11], [12], [9]
Caveats
The Cochrane review rests on two small trials with different products and durations [12]. The antibiotic comparisons could not be pooled [12].
ModerateStudied in women

Urinary incontinence, urgency and overactive bladder

Shown to ease incontinence and cut voids by 1 to 2 a day against placebo in postmenopausal women, while estrogen by mouth made incontinence worse.

Compared with placebo or no treatment [13][9]; pelvic floor muscle training [13]; overactive bladder drugs alone [14]

The numbers and sources
Effect
In a Cochrane review, local estrogen improved incontinence (RR 0.74, 95% CI 0.64 to 0.86), with about 1 to 2 fewer voids in 24 hours and less frequency and urgency. Oral estrogen made incontinence worse than placebo (RR 1.32, 95% CI 1.17 to 1.48). In one small trial, more women improved with pelvic floor muscle training than with local estrogen (RR 2.30, 95% CI 1.50 to 3.52) [13]. A 2014 review found vaginal estrogen improved urgency, frequency, stress incontinence and urge incontinence against placebo [9]. Adding vaginal estrogen to overactive bladder drugs lowered urinary frequency (SMD -0.36, 95% CI -0.63 to -0.08) but not overall symptom scores (SMD -0.38, 95% CI -0.81 to 0.05) or quality of life [14].
Population
34 trials with about 19,676 incontinent women, 1,464 of them in local estrogen trials [13]. 44 studies [9]. 6 studies with 544 women [14].
Sources
[13], [9], [14]
Caveats
Local estrogen trials were small, outcomes were reported inconsistently, and there was no information on effects after stopping [13].
StrongStudied in women

Painful sex and dryness: prasterone (vaginal DHEA)

Shown to ease painful sex by about 0.4 points more than placebo in postmenopausal women, while placebo alone eased it by 0.9 to 1.1 points.

Compared with placebo [5][15][8][16]

The numbers and sources
Effect
In the two pivotal 12-week trials, severity of painful sex fell from about 2.6 by 1.27 and 1.42 points on prasterone 6.5 mg, against 0.87 and 1.06 on placebo, differences of 0.40 and 0.35. Superficial vaginal cells rose and vaginal pH fell more than on placebo [5]. Pooling 5 trials (1,611 women), prasterone lowered painful sex by 0.40 more than placebo (95% CI 0.15 to 0.66) and dryness by 0.23 more (95% CI 0.11 to 0.35) [15]. Two systematic reviews found prasterone improved dryness and painful sex against placebo [8][16].
Population
255 and 558 postmenopausal women aged 40 to 80 with moderate to severe painful sex [5]. 5 trials [15]. 16 nonestrogen hormone trials [8]. 136 studies of nonestrogen therapies [16].
Sources
[5], [15], [8], [16]
Caveats
Placebo eased painful sex by 0.87 to 1.06 points [5]. The 2024 review rated certainty low [8]. Data comparing prasterone with other nonestrogen options were insufficient [16].
StrongStudied in women

Painful sex and dryness: ospemifene

Shown to ease painful sex and vaginal dryness against placebo in postmenopausal women, by 0.3 to 0.5 points more, though one of three trials found no dryness benefit.

Compared with placebo [6][17][8][16]

The numbers and sources
Effect
At week 12, painful sex fell from 2.7 by 1.4 and 1.5 points on ospemifene 60 mg, against 0.9 and 1.2 on placebo. Dryness fell by 1.3 against 0.9 in two trials, and a third trial found no significant dryness benefit [6]. A meta-analysis of 6 trials found lower vaginal pH (SMD -0.96, 95% CI -1.12 to -0.81), fewer parabasal and more superficial cells, and less painful sex than placebo [17]. Two systematic reviews found ospemifene improved dryness and painful sex [8][16].
Population
826, 919 and 631 postmenopausal women aged 40 to 81 in three 12-week trials [6]. 6 trials [17]. Reviews of nonestrogen therapies [8][16].
Sources
[6], [17], [8], [16]
Caveats
Placebo eased painful sex by 0.9 to 1.2 points [6]. The 2024 review rated certainty low [8].

Mixed results1

LimitedStudied in women

Vaginal estrogen compared with moisturizers

Mixed results: a review found vaginal estrogen eased symptoms more than moisturizers in women with two or more symptoms, while one trial found neither differed from placebo.

Compared with nonhormonal vaginal moisturizers and lubricants [9][10]; placebo [10]

The numbers and sources
Effect
In a 2014 systematic review, women with two or more symptoms of vaginal atrophy improved more with vaginal estrogen than with nonhormonal moisturizers, while women with one or minor complaints improved about equally with either [9]. In a 12-week trial, the most bothersome symptom fell by 1.4 points with an estradiol tablet and 1.2 with a moisturizer, and neither differed significantly from placebo [10]. A 2024 review found moisturizers may improve dryness against placebo [8].
Population
44 studies [9]. 302 postmenopausal women [10]. 4 moisturizer trials within 46 [8].
Sources
[9], [10], [8]
Caveats
Few trials compared the two directly.

Doses studied

Vaginal estradiol inserts were studied at 10 µg (Vagifem) and 4 or 10 µg (Imvexxy), each once daily for 2 weeks and then twice a week [3][2]. The estradiol ring holds 2 mg and releases about 7.5 µg a day over 90 days [1]. The trial comparing a tablet with a moisturizer used the 10 µg tablet [10]. Reviews of blood levels grouped doses as low (7.5 µg ring, 10 µg tablet), intermediate (25 µg estradiol or 0.3 mg conjugated estrogens) and high (50 to 2,000 µg estradiol or 0.625 to 2.5 mg conjugated estrogens) [18]. Prasterone trials used a 6.5 mg insert once nightly [5]. Ospemifene trials used 60 mg by mouth once daily with food [6].

Risks

Reported risks7

ModerateStudied in womenVery common

Boxed warning: ospemifene, endometrial cancer and stroke

The label carries a boxed warning for endometrial cancer and cardiovascular disorders. In trials, the uterine lining thickened to 5 mm or more in 10.1% against 2.1% on placebo.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Up to 52 weeks, endometrial thickening of 5 mm or more occurred at 101.4 per 1,000 women on ospemifene 60 mg and 20.9 per 1,000 on placebo, with no endometrial cancers and one simple hyperplasia. Thromboembolic and hemorrhagic stroke occurred at 1.13 and 3.39 per 1,000 woman-years on ospemifene and 3.15 and 0 on placebo, and deep vein thrombosis at 2.26 and 3.15 [6]. A meta-analysis found thicker lining at 12 weeks (SMD 0.40, 95% CI 0.17 to 0.63) and 52 weeks (SMD 0.62, 95% CI 0.23 to 1.01), and no difference in clots, heart disease, vaginal bleeding, or breast or endometrial cancer [26].
Population
2,209 women in ten trials, 1,459 on 60 mg in 12-week trials and 847 with up to 52 weeks [6]. 6 trials [26].
Sources
[6], [26]
Caveats
Endometrial cancer and hyperplasia were reported after approval [6]. Stroke and clot counts were small, a few cases in each group [6].
ModerateStudied in womenCommon

Local and other side effects of vaginal estrogen

Shown to raise vaginal yeast infection and itching against placebo with a 10 µg insert over a year, each in about 8% against 2% to 3% on placebo.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Over 12 months, rates on Vagifem 10 µg against placebo were vulvovaginal yeast infection 8% and 3%, vulvovaginal itching 8% and 2%, back pain 7% and 2%, and diarrhea 5% and 0% [3]. Reviews list breast tenderness, vaginal bleeding or spotting, discharge, irritation, burning and itching [12], and found no significant rise in vaginal discomfort against placebo (RR 3.06, 95% CI 0.79 to 11.90) [11]. Overall side effects did not differ from placebo in the Cochrane review [7]. Toxic shock syndrome has been reported with vaginal rings [1].
Population
205 women on Vagifem and 103 on placebo [3]. Trials in reviews [12][11][7]. Ring users [1].
Sources
[3], [12], [11], [7], [1]
Caveats
Toxic shock reports have no denominator [1].
ModerateStudied in womenCommon

Side effects of prasterone

Shown to raise vaginal discharge, 5.7% against 3.7% on placebo. In a year-long study without placebo, 14.2% had discharge and 2.1% an abnormal Pap smear.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In four 12-week placebo-controlled trials, vaginal discharge occurred in 38 of 665 women on prasterone (5.71%) and 17 of 464 on placebo (3.66%). In a 52-week study without a comparison group, 14.2% had discharge and 2.1% an abnormal Pap smear, 10 of them atypical cells of undetermined significance and 1 a low-grade lesion. Estrogen is a breakdown product of prasterone, and it has not been studied in women with a history of breast cancer [5].
Population
1,129 women in four trials and 521 in a 52-week study [5].
Sources
[5]
Caveats
The 52-week study had no placebo group [5].
ModerateStudied in womenCommon

Hot flashes and other side effects of ospemifene

Shown to raise hot flashes, 6.5% against 2.6% on placebo at 12 weeks, along with vaginal discharge, muscle spasms and sweating.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In 12-week trials, rates on ospemifene 60 mg against placebo were hot flush 6.5% and 2.6%, vaginal discharge 3.8% and 0.4%, muscle spasms 1.8% and 0.6%, and excess sweating 1.1% and 0.2%. In trials up to 52 weeks, hot flush occurred in 12.2% and 4.2% [6]. A meta-analysis found more hot flushes (OR 2.36, 95% CI 1.26 to 4.42) and urinary infections (OR 1.97, 95% CI 1.23 to 3.14) at 12 weeks, but not at 52 weeks [26].
Population
1,459 women on ospemifene and 1,136 on placebo in 12-week trials [6]. 6 trials [26].
Sources
[6], [26]
Caveats
Discontinuation and serious side effects did not differ from placebo in the meta-analysis [26].
ModerateStudied in womenHow often is not known

Boxed warning, being removed from vaginal estrogen

FDA states it asked makers in 2025 to drop the oral-trial boxed warning from vaginal estrogen labels. The Estring label says those risks' relevance to it is unknown.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The class boxed warning listed endometrial cancer, cardiovascular disorders, probable dementia and breast cancer, based on the Women's Health Initiative trials of daily oral conjugated estrogens [2][3]. In November 2025 FDA asked makers of all menopausal hormone products to remove the cardiovascular, breast cancer and dementia language from the boxed warning, and for vaginal products to remove the endometrial cancer language as well [4]. The 2026 Estring label carries no boxed warning and says systemic absorption occurs at lower exposure than with systemic estrogens, so the relevance of their risks to the ring is not known [1]. The Imvexxy label listed in October 2026 still printed the older boxed warning [2].
Population
Regulatory labeling [4][1][2][3].
Sources
[4], [1], [2], [3]
Caveats
Labels are being updated product by product [4][2].
ModerateStudied in womenHow often is not known

Estrogen reaching the blood

Shown to raise blood estradiol slightly, in step with dose. Low doses kept levels within the postmenopausal range, while high-dose creams reached premenopausal levels.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Untreated postmenopausal women had mean estradiol of 3.1 to 4.9 pg/mL by mass spectrometry. Measured the same way, levels were 3.6 to 3.9 pg/mL with a 4 µg insert, 4.6 to 7.4 pg/mL with a 10 µg softgel, 6.6 to 14.8 pg/mL with a 10 µg tablet and 16.7 to 22.7 pg/mL with a 25 µg tablet [19]. The 7.5 µg ring and 10 µg tablet raised estradiol but not above 20 pg/mL, intermediate doses approached or passed 20 pg/mL, and high doses gave premenopausal levels [18]. With the ring, mean steady-state estradiol was 7.0 to 8.1 pg/mL over 48 weeks [1]. Prasterone raised trough prasterone by 47%, testosterone by 21% and estradiol by 19% over 12 weeks [5]. A 2014 review found estradiol stayed within postmenopausal norms for all products except high-dose conjugated estrogens cream [9].
Population
Pharmacokinetic studies of low-dose vaginal estrogens [19][18]. 222 women using the ring [1]. Women in the prasterone trials [5]. 44 studies [9].
Sources
[19], [18], [1], [5], [9]
Caveats
Readings depended on the assay, with lower values by mass spectrometry than by immunoassay [19]. Absorption may vary with how high in the vagina the dose is placed [19].
ModerateHow often is not known

Interactions: ospemifene

The label says not to combine ospemifene with estrogens, fluconazole or rifampin. Fluconazole raised ospemifene exposure 2.7-fold and rifampin lowered it by 58%.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Ospemifene is broken down mainly by CYP3A4 and CYP2C9. Fluconazole raised its exposure 2.7-fold, ketoconazole 1.4-fold, and rifampin lowered it by 58%. The label says not to use it with estrogens or estrogen agonist/antagonists, whose combined safety was not studied. It is over 99% protein-bound and may change exposure to other highly protein-bound drugs [6].
Population
Drug interaction studies reported in the label [6].
Sources
[6]
Caveats
The effect on warfarin's clotting measures was not studied [6].

Checked, no increase found3

ModerateStudied in women

Uterine lining

Not shown to raise endometrial hyperplasia or cancer with low-dose vaginal estrogen, at 0.4% and 0.03% across 20 trials. Higher-dose creams thickened the lining more than the ring.

The numbers and sources
How common
Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect
Across 20 randomized trials (2,983 women), endometrial hyperplasia occurred in 0.4% and endometrial cancer in 0.03% of women on vaginal estrogen. In a large US cohort, endometrial cancer occurred at 1.3 per 1,000 women-years in users and 1.0 in nonusers [20]. In the Women's Health Initiative Observational Study, endometrial cancer risk in women with a uterus did not differ between users and nonusers [21]. A Cochrane review found more endometrial thickening with estrogen cream than with the ring (OR 0.36 for the ring, 95% CI 0.14 to 0.94), possibly from higher cream doses [7]. A 2014 review found hyperplasia and cancer extremely rare [9].
Population
20 trials, 8 interventional and 10 observational studies [20]. 45,663 women aged 50 to 79 not using systemic estrogen, followed a median 7.2 years [21]. 273 women in two trials [7]. 44 studies [9].
Sources
[20], [21], [7], [9]
Caveats
Trials were short. A Danish registry study was the exception to the pattern [20].
ModerateStudied in women

Breast cancer, heart disease and stroke

Not linked to higher rates of breast cancer, endometrial cancer, stroke, heart disease or blood clots in two large cohorts of postmenopausal women followed 7 to 18 years.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Among women with a uterus in the Women's Health Initiative Observational Study, risks of stroke, invasive breast cancer, colorectal cancer, endometrial cancer and blood clots did not differ between vaginal estrogen users and nonusers, and risks of coronary heart disease, fracture, death and the combined index were lower (HR 0.68, 95% CI 0.55 to 0.86). In women after hysterectomy, no outcome differed (HR 0.94, 95% CI 0.70 to 1.26) [21]. In the Nurses' Health Study, over 18 years, risks of cardiovascular disease, cancer and hip fracture did not differ between users and nonusers [22].
Population
45,663 postmenopausal women not using systemic estrogen [21]. Postmenopausal women in the Nurses' Health Study not using systemic hormones [22].
Sources
[21], [22]
Caveats
Observational studies. Women who chose vaginal estrogen may differ in health from those who did not, and lower rates in users may reflect that.
ModerateStudied in women

Breast cancer survivors

Not linked to more recurrence or death in breast cancer survivors in cohort studies, except higher recurrence in one Danish cohort among women taking aromatase inhibitors.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Pooling 8 observational studies, vaginal estrogen was not linked to more breast cancer recurrence (OR 0.48, 95% CI 0.23 to 0.98, 6 studies, 24,060 women) or breast cancer death (OR 0.60, 95% CI 0.18 to 1.95) [23]. In Scotland and Wales, breast cancer death was not higher in users than in women not using hormone therapy (HR 0.77, 95% CI 0.63 to 0.94) [24]. In Denmark, recurrence did not differ overall (RR 1.08, 95% CI 0.89 to 1.32) but was higher in women on aromatase inhibitors (RR 1.39, 95% CI 1.04 to 1.85), without higher mortality [25].
Population
8 observational studies [23]. 49,237 women aged 40 to 79 with breast cancer, 5% of whom used vaginal estrogen [24]. 8,461 postmenopausal women with early estrogen receptor-positive breast cancer, 1,957 of whom used vaginal estrogen [25].
Sources
[23], [24], [25]
Caveats
All observational, with no randomized trial. Women who chose vaginal estrogen may have had lower-risk cancers. The Danish result is a subgroup finding [25].

Possible, not studied in people1

UntestedHow often is not known

Pregnancy: ospemifene

Not studied in people. Ospemifene caused embryo deaths and birth difficulties in rats below human exposure, and the label contraindicates it in pregnancy.

No study in people. This rests on animal studies.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In rats, ospemifene caused embryo and fetal deaths, labor difficulties and more pup deaths at doses below clinical exposure, and in rabbits embryo and fetal deaths at 10 times clinical exposure [6].
Population
Rats and rabbits [6].
Sources
[6]
Caveats
Animal findings. The drug is approved for women after menopause [6].

Claims tested and not found

  1. That a low-dose vaginal estradiol tablet eases the worst vulvovaginal symptom more than placebo in every trial. In a 12-week trial of 302 women, symptom severity fell 1.4 points on the tablet and 1.3 on placebo [10].
  2. That estrogen taken by mouth prevents recurrent urinary infections. Oral estrogen did not differ from placebo (RR 1.11, 95% CI 0.92 to 1.35) [11], and a Cochrane review agreed (RR 1.08, 95% CI 0.88 to 1.33) [12].
  3. That adding vaginal estrogen to overactive bladder drugs improves overall bladder symptom scores. Pooled symptom scores and quality of life did not differ from the drugs alone [14].

Related

Menopausal hormone therapyDHEACranberryFezolinetant and elinzanetant

Sources

  1. Estring (estradiol vaginal ring), prescribing information. DailyMed, US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=110b9865-5a07-4d45-b560-e89947f12600
  2. Imvexxy (estradiol vaginal inserts), prescribing information. DailyMed, US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6ce645c0-a550-4ae9-8dbd-3853ee8b7d26
  3. Vagifem (estradiol vaginal inserts), prescribing information. DailyMed, US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e5ad3cf6-dd96-4e64-af21-c1eee38d0b88
  4. US Food and Drug Administration. FDA Requests Labeling Changes Related to Safety Information to Clarify the Benefit/Risk Considerations for Menopausal Hormone Therapies. 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-labeling-changes-related-safety-information-clarify-benefitrisk-considerations
  5. Intrarosa (prasterone) vaginal inserts, prescribing information. DailyMed, US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ada639d4-bac0-2ad0-e053-2a95a90afce7
  6. Osphena (ospemifene) tablets, prescribing information. DailyMed, US National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9accbcc9-78ee-4f84-9b7e-704f2ab1c413
  7. Lethaby A, Ayeleke RO, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database of Systematic Reviews. 2016. https://doi.org/10.1002/14651858.CD001500.pub3
  8. Danan ER, Sowerby C, Ullman KE, et al. Hormonal Treatments and Vaginal Moisturizers for Genitourinary Syndrome of Menopause: A Systematic Review. Annals of Internal Medicine. 2024. https://doi.org/10.7326/annals-24-00610
  9. Rahn DD, Carberry C, Sanses TV, et al. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstetrics & Gynecology. 2014. https://doi.org/10.1097/aog.0000000000000526
  10. Mitchell CM, Reed SD, Diem S, et al. Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms: A Randomized Clinical Trial. JAMA Internal Medicine. 2018. https://doi.org/10.1001/jamainternmed.2018.0116
  11. Chen YY, Su TH, Lau HH. Estrogen for the prevention of recurrent urinary tract infections in postmenopausal women: a meta-analysis of randomized controlled trials. International Urogynecology Journal. 2021. https://doi.org/10.1007/s00192-020-04397-z
  12. Perrotta C, Aznar M, Mejia R, et al. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database of Systematic Reviews. 2008. https://doi.org/10.1002/14651858.CD005131.pub2
  13. Cody JD, Jacobs ML, Richardson K, et al. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane Database of Systematic Reviews. 2012. https://doi.org/10.1002/14651858.CD001405.pub3
  14. Naseem S, Kershaw V, Khunda A, et al. Does the Addition of Vaginal Oestrogen to Anticholinergic Medication Improve Overactive Bladder Symptoms? A Systematic Review and Meta-Analysis. International Urogynecology Journal. 2026. https://doi.org/10.1007/s00192-026-06629-0
  15. Lemos MJ, Queiroz LF, Diniz AF, et al. Intravaginal dehydroepiandrosterone for the treatment of vulvovaginal atrophy: a systematic review and meta-analysis. Menopause. 2026. https://doi.org/10.1097/gme.0000000000002736
  16. Casiano Evans EA, Hobson DTG, Aschkenazi SO, et al. Nonestrogen Therapies for Treatment of Genitourinary Syndrome of Menopause: A Systematic Review. Obstetrics & Gynecology. 2023. https://doi.org/10.1097/aog.0000000000005288
  17. Di Donato V, Schiavi MC, Iacobelli V, et al. Ospemifene for the treatment of vulvar and vaginal atrophy: A meta-analysis of randomized trials. Part I: Evaluation of efficacy. Maturitas. 2019. https://doi.org/10.1016/j.maturitas.2018.11.016
  18. Santen RJ. Vaginal administration of estradiol: effects of dose, preparation and timing on plasma estradiol levels. Climacteric. 2015. https://doi.org/10.3109/13697137.2014.947254
  19. Santen RJ, Mirkin S, Bernick B, Constantine GD. Systemic estradiol levels with low-dose vaginal estrogens. Menopause. 2020. https://doi.org/10.1097/gme.0000000000001463
  20. Constantine GD, Graham S, Lapane K, et al. Endometrial safety of low-dose vaginal estrogens in menopausal women: a systematic evidence review. Menopause. 2019. https://doi.org/10.1097/gme.0000000000001315
  21. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study. Menopause. 2018. https://doi.org/10.1097/gme.0000000000000956
  22. Bhupathiraju SN, Grodstein F, Stampfer MJ, et al. Vaginal estrogen use and chronic disease risk in the Nurses' Health Study. Menopause. 2019. https://doi.org/10.1097/gme.0000000000001284
  23. Beste ME, Kaunitz AM, McKinney JA, Sanchez-Ramos L. Vaginal estrogen use in breast cancer survivors: a systematic review and meta-analysis of recurrence and mortality risks. American Journal of Obstetrics and Gynecology. 2025. https://doi.org/10.1016/j.ajog.2024.10.054
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