Table 2.

Pharmacologic therapies approved for the treatment of vulvovaginal atrophy (VVA)

Product	Indication	Route of administration	Side effects	Metabolism interactions	Contraindications
Systemic estrogens Examples include but are not limited to: Alora® [32]; Climara® [33]; estradiol (generic Estrace®) [34]; Femring® [35]; Premarin® [36]; Vivelle-Dot® [37]	Alora®, Climara®, Vivelle-Dot®: moderate-to-severe VMS and/or VVAa related to menopause; hypoestrogenism due to hypogonadism, castration, or primary ovarian failure; prevention of postmenopausal osteoporosisb Femring®: moderate-to-severe VMS and/or VVA due to menopause Premarin®, estradiol: moderate-to-severe VMS and/or VVAa related to menopause; hypoestrogenism due to hypogonadism, castration, or primary ovarian failure; breast cancerc in appropriately selected women and men with metastatic disease; advanced androgen-dependent carcinoma of the prostatec; prevention of postmenopausal osteoporosisb	Oral (Premarin®, estradiol) Transdermal (Alora®, Climara®, Vivelle-Dot®) Vaginal (Femring®)	Less serious, but common side effects: headache, breast pain, irregular vaginal bleeding or spotting, stomach/abdominal cramps/bloating, nausea and vomiting, hair loss, fluid retention, vaginal yeast infection. Serious, but less common side effects: heart attack, stroke, blood clots, dementia, breast cancer, uterine cancer, ovarian cancer, hypertension, high blood sugar, gallbladder disease, liver problems, fibroid enlargement, severe allergic reactions	Inducers and inhibitors of CYP3A4 may affect drug metabolism	Undiagnosed abnormal genital bleeding; known, suspected, or history of breast cancer; known or suspected estrogen-dependent neoplasia; active DVT, PE, arterial thromboembolic disease (e.g., stroke and MI), or history of these conditions; known anaphylactic reaction or angioedema with product; known liver impairment or disease; known protein C, protein S, or anti-thrombin deficiency, or other known thrombophilic disorders; known or suspected pregnancy
Vaginal low-dose estrogen Examples include but are not limited to: Estrace® cream [38]; Estring® [39]; Imvexxy® [40]; Premarin® vaginal cream [41]; Vagifem® [42]	Estrace®, Estring®: moderate-to-severe symptoms of VVA due to menopause Imvexxy®: moderate-to-severe dyspareunia, a symptom of VVA, due to menopause Premarin® vaginal cream: atrophic vaginitis and kraurosis vulvae; moderate-to-severe dyspareunia, a symptom of VVA, due to menopause Vagifem®: atrophic vaginitis due to menopause	Vaginal	Less serious, but common side effects: headache, breast pain, irregular vaginal bleeding or spotting, stomach or abdominal cramps, bloating, nausea and vomiting, fluid retention, vaginal yeast infection, vaginal irritation, hair loss. Serious, but less common side effects: heart attack, stroke, blood clots, dementia, breast cancer, uterine cancer, ovarian cancer, hypertension, gallbladder disease, liver problems, enlargement of fibroids, changes in thyroid hormone levels, high blood sugar, severe allergic reaction, hypocalcemia, worsening of angioedema, changes in certain laboratory test results, fluid retention, changes in vision, high triglyceride levels	Inducers and inhibitors of CYP3A4	Undiagnosed abnormal genital bleeding; known, suspected, or history of breast cancer; known or suspected estrogen-dependent neoplasia; active DVT, PE; or history of these conditions; active arterial thromboembolic disease (e.g., stroke and MI), or history of these conditions; known anaphylactic reaction or angioedema to product; known liver dysfunction or disease; known protein C, protein S, or anti-thrombin III deficiency; or other known thrombophilic disorders; known or suspected pregnancy
Systemic selective estrogen receptor modulator (i.e., Ospemifene/Osphena®) [43]	Moderate-to-severe dyspareunia and/or vaginal dryness, both symptoms of VVA, due to menopause	Oral	Serious, but less common side effects: stroke, blood clots, uterine cancer. Less serious, but common side effects: hot flashes, vaginal discharge, muscle spasms, increased sweating	Concomitant use of estrogens or estrogen agonists/antagonists, fluconazole, ketoconazole, rifampin, or drugs known to inhibit CYP3A4 and CYP2C9 isoenzymes, or drug products that are highly protein-bound may affect drug metabolism	Undiagnosed abnormal genital bleeding; known or suspected estrogen-dependent neoplasia; active DVT, PE, or arterial thromboembolic disease (e.g., stroke, MI) or a history of these conditions; hypersensitivity (e.g., angioedema, urticaria, rash, pruritus) to Osphena® or any ingredients; women who are or may become pregnant
DHEA (i.e., prasterone/Intrarosa®) [44]	Moderate-to-severe dyspareunia, a symptom of VVA, due to menopause	Vaginal insert	Most common side effects: vaginal discharge, changes on Pap smear	None listed	Undiagnosed abnormal genital bleeding. Prasterone has not been tested in women with a history of breast cancer

CYP cytochrome P450, DHEA dehydroepiandrosterone, DVT deep vein thrombosis, MI myocardial infarction, PE pulmonary embolism, VMS vasomotor symptoms, VVA vulvoginal atrophy

^aWhen prescribing solely for the treatment of moderate-to-severe VVA, topical vaginal products should be considered

^bWhen prescribing solely for the treatment of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered

^cPalliation only