Vaginal Estradiol: Metabolism and Energy Expenditure

What the cream is approved for

Estradiol Vaginal Cream, 0.01% is approved for moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. Its label says to choose the lowest dose and regimen that control symptoms, to limit use to the shortest duration consistent with treatment goals, and to reassess periodically [1].

How the body handles estradiol

Estradiol is converted reversibly to estrone, and both can be converted to estriol, the major urinary metabolite; these changes take place mainly in the liver. Estrogens also undergo enterohepatic recirculation, and in postmenopausal women estrone sulfate serves as a circulating reservoir for the formation of more active estrogens [1].

The Climara (estradiol patch) label says that estrogens are metabolized partly by CYP3A4, so inducers or inhibitors of CYP3A4 may affect estrogen metabolism. It says inducers such as St. John's wort, phenobarbital, carbamazepine and rifampin may reduce estrogen concentrations and therapeutic effects, while inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase estrogen concentrations and adverse reactions [6].

What menopause itself does

In a 4-year study of 156 midlife women, total body fat and visceral fat rose only in those who became postmenopausal, and fat oxidation fell 32% in that group [2]. Sleeping energy expenditure fell 7.9% in women who became postmenopausal versus 5.3% in those who did not, measured by whole-room calorimeter in a subset of 34 women [2].

What estrogen biology and systemic therapy show

Estrogen actions in hypothalamic nuclei control food intake, energy expenditure and white adipose tissue distribution; actions in skeletal muscle, liver and adipose tissue are involved in insulin sensitivity, and actions in pancreatic beta cells help regulate insulin secretion [4]. In young mice, short-term ovariectomy reduced skeletal muscle mitochondrial respiratory function and insulin sensitivity, and estradiol therapy restored them [5].

In KEEPS, 727 women were randomly assigned to oral conjugated equine estrogens 0.45 mg/day or transdermal estradiol 50 mcg/day (each with oral progesterone for 12 days per month), or to placebo, for 48 months; insulin resistance decreased with transdermal estradiol [3]. The trial did not test a vaginal product [3].

What the label says to watch for

The cream label's boxed warning covers endometrial cancer, cardiovascular disorders, breast cancer and probable dementia [1]. Contraindications include undiagnosed abnormal genital bleeding, breast cancer or a history of it, active DVT or PE or a history of them, active arterial thromboembolic disease or a history of it, liver disease, and known thrombophilic disorders [1]. Weight increase or decrease and glucose intolerance appear among reactions reported with estrogen and/or progestin therapy [1].

The practical answer

The cream treats vulvar and vaginal atrophy symptoms locally [1]. Systemic estradiol products have different labeled uses, including vasomotor symptoms and prevention of postmenopausal osteoporosis, and the Climara label says to consider topical vaginal products first when prescribing solely for vaginal symptoms [6]. Weight loss and higher energy expenditure are not labeled uses of the cream [1].