Vaginal Estradiol and Autoimmune Disease: What Clinicians and Patients Need to Know

What is known about vaginal estradiol in autoimmune disease?

No study of vaginal estradiol in autoimmune disease turned up. The available information is the product label, which treats estrogens as one drug class, plus laboratory work on estrogen and immune cells.

A review of sex differences reports that most autoimmune diseases are more prevalent in women and that estrogens are potent stimulators of autoimmunity, discussing lupus, rheumatoid arthritis and multiple sclerosis as examples [2]. In mouse B cells, estrogen protected primary B cells from B-cell-receptor-mediated apoptosis, and the authors suggested that estrogen skews the naive immune system toward autoreactivity [3]. Those are mouse-cell results, not outcomes in women using a vaginal cream.

What the cream label says

Estradiol Vaginal Cream, 0.01% is indicated for moderate to severe symptoms of vulvar and vaginal atrophy due to menopause [1]. The label states that systemic absorption may occur and that the warnings, precautions and adverse reactions associated with oral estrogen treatment should be taken into account [1]. It carries a boxed warning covering endometrial cancer, cardiovascular disorders, breast cancer and probable dementia [1].

That warning is based on the Women's Health Initiative, which used daily oral conjugated equine estrogens 0.625 mg with or without medroxyprogesterone 2.5 mg; the label says that in the absence of comparable data those risks should be assumed similar for other doses of conjugated estrogens and other dosage forms of estrogens [6][7][1].

The cardiovascular warnings name risk factors for venous thromboembolism that should be managed, giving personal or family history of VTE, obesity and systemic lupus erythematosus as examples [1]. Contraindications include undiagnosed abnormal genital bleeding, breast cancer or a history of it, estrogen-dependent neoplasia, active or prior DVT or pulmonary embolism, active or prior arterial thromboembolic disease, known liver dysfunction or disease, known protein C, protein S or antithrombin deficiency or other known thrombophilic disorders, and known or suspected pregnancy [1]. Antiphospholipid syndrome is not named in that list. Vaginal inserts and rings are separate products; the cream label does not establish their warnings.

Sjögren syndrome, rheumatoid arthritis and multiple sclerosis

In a study of 24 women with primary Sjögren syndrome and 24 healthy women matched for age and hormonal status, the mean Female Sexual Function Index was 19.1 (SD 7.33), significantly different from controls (p=0.004), with larger differences in dyspareunia (p<0.005) and lubrication (p=0.006); vaginal pH was 6.0 (SD 0.77) in premenopausal patients [4]. The study measured sexual function and vaginal pH, not estrogen treatment.

A review of menopause in multiple sclerosis notes the overlap between menopausal and MS symptoms, including sexual dysfunction, mood disorders and bladder function, and lists as open questions what effect the menopausal transition may have on MS course and what modulatory role hormone replacement therapies might play [5]. Rheumatoid arthritis appears in the sex-difference review alongside lupus and MS [2].