In 2025, the U.S. Food and Drug Administration (FDA) requested labeling changes for menopausal hormone therapies (MHTs) following a comprehensive review of literature published since the Women's Health Initiative (WHI) trials, updated drug utilization data, expert panel input, and public comments. The FDA noted that the original WHI studies enrolled predominantly older postmenopausal women (average age 63 years; dementia studies enrolled women 65–79 years), whereas MHT is typically initiated in younger women (approximately 45–55 years) for menopausal symptoms, prompting a reassessment of the applicability of the original boxed warnings. The FDA requested removal of boxed warning language regarding cardiovascular disease, breast cancer, and probable dementia for all MHTs, including local vaginal estrogen products, and requested that labeling for local vaginal estrogen products be condensed to emphasize safety information most relevant to the local vaginal formulation. Updated prescribing information has been approved for selected MHT products (Prometrium, Divigel, Cenestin, Enjuvia, Estring, and Bijuva). Premarin Vaginal Cream is not currently included among the products listed by the FDA as having updated prescribing information. [1]

Several professional guidelines address the safety of local low-dose vaginal estrogen, including vaginal estrogen cream. The 2025 American Urological Association (AUA), Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU), and American Urogynecologic Society (AUGS) guideline recommends local low-dose vaginal estrogen as an effective treatment for genitourinary syndrome of menopause (GSM) and states that there is no evidence linking local low-dose vaginal estrogen to the development of breast cancer. The guideline cites evidence demonstrating no increased risk of breast cancer, stroke, endometrial cancer, colorectal cancer, or venous thromboembolism among users of local vaginal estrogen and notes that a 2019 systematic review found no increased risk of endometrial hyperplasia or endometrial cancer with low-dose vaginal estrogen without progestogen. The 2021 American College of Obstetricians and Gynecologists (ACOG) Clinical Consensus similarly states that, after failure of nonhormonal therapy, low-dose vaginal estrogen, including comparable low-dose vaginal estrogen creams, may be used following shared decision-making, including in selected individuals with a history of breast cancer, and notes that no evidence indicates harm from these local treatments; available studies generally demonstrated transient or no increases in serum estradiol and did not identify increased breast cancer recurrence. The 2022 North American Menopause Society (NAMS) Position Statement states that, unlike unopposed systemic estrogen therapy, low-dose vaginal estrogen does not appear to increase endometrial cancer risk and therefore routine progestogen is not recommended for women using low-dose vaginal estrogen for GSM. The position statement also notes that vaginal estrogen has not been associated with an increased risk of breast cancer. Finally, a ACOG Committee Opinion states that topical vaginal estrogen creams and tablets have low systemic absorption and no detectable effect on coagulation proteins or the incidence of venous thromboembolism, whereas orally administered estrogen is associated with an increased risk of venous thromboembolism. Overall, these recommendations primarily apply to low-dose vaginal estrogen products and generally do not distinguish among individual formulations. [2], [3], [4], [5]

A 2020 systematic review evaluated the comparative safety of U.S. Food and Drug Administration (FDA)-approved vaginal estrogen preparations by reviewing 75 clinical trials in postmenopausal women, including studies of vaginal conjugated equine estrogen (CEE) cream. None of the included trials were designed or powered to evaluate breast cancer, endometrial cancer, cardiovascular events, venous thromboembolism, or all-cause mortality as primary outcomes, and the available data were insufficient to exclude an increased risk of endometrial cancer with long-term vaginal estrogen use. Compared with vaginal inserts, tablets, and rings, vaginal estrogen creams, including CEE cream, were associated with greater systemic hormone absorption and higher short-term increases in circulating estradiol and estrone; however, these hormonal changes did not clearly result in endometrial proliferation. Although some studies reported more frequent endometrial thickening or proliferative endometrium with higher-dose CEE cream regimens than with vaginal tablets or rings, these regimens exceeded doses commonly used in clinical practice, statistical comparisons were often lacking, and placebo-controlled trials did not demonstrate significant increases in endometrial thickness or hyperplasia through 52 weeks. Overall, the review concluded that evidence supporting the endometrial safety of vaginal estrogen is limited to studies of up to 52 weeks and that additional long-term studies are needed. [6]

A 2019 systematic review evaluated the endometrial safety of low-dose, unopposed vaginal estrogens by reviewing 20 randomized controlled trials, 8 interventional studies, and 10 observational studies. Overall, the available evidence did not support an increased risk of endometrial hyperplasia or endometrial cancer with low-dose vaginal estrogens, with rates of endometrial cancer and hyperplasia of 0.03% and 0.4%, respectively, across 20 randomized trials involving 2,983 women. Among studies of vaginal CEE cream, reports of endometrial hyperplasia were primarily observed with higher-dose 1.25 mg CEE regimens, particularly cyclic 21-day-on/7-day-off dosing, whereas a 12-month randomized trial of 0.3 mg CEE cream reported no cases of endometrial hyperplasia or endometrial cancer. Observational data, including a WHI study, did not identify an association between vaginal estrogen use and endometrial cancer, although one Danish registry study reported an association that the authors noted may have limited applicability to U.S. practice. Overall, the authors concluded that longer-term data are needed to further confirm the endometrial safety profile of vaginal estrogens. [7]

Boxed Warning: Estrogen-Alone Therapy [8]
Endometrial Cancer
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

Cardiovascular Disorders and Probable Dementia
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia.
The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) (0.625 mg)-alone, relative to placebo.

The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Warnings and Precautions [8]
Risks from Systemic Absorption
Systemic absorption occurs with the use of PREMARIN vaginal cream. The warnings, precautions, and adverse reactions associated with oral PREMARIN treatment should be taken into account.

A search of the published medical literature revealed 2 studies investigating the researchable question:

Does use of Premarin cream increase risk of cancer or blood clots like other oral estrogen products?

C - Multiple studies with limitations or conflicting results  Read more→