Alzheimer’s Disease Alzheimer’s disease is the most common form of dementia. Women are at greater risk for developing the disease than men, and the number of affected individuals in the United States is estimated to be more than 5 million with an annual cost of 183 billion dollars. Although several small studies suggest that hormone therapy may decrease the risk of Alzheimer’s disease, a randomized controlled study in women with mild to moderate Alzheimer’s disease showed that 1 year of estrogen therapy neither slowed disease progression nor improved cognition (61). The WHI Memory Study (WHIMS) was a randomized placebo-controlled study of women aged 65 years or older enrolled in WHI, which assessed the effect of hormone therapy on cognitive function. In contrast to observational studies, women in WHIMS randomized to hormone therapy experienced a significant twofold increased risk of dementia, most commonly Alzheimer’s disease (62). Hormone therapy use was associated with an adverse effect on cognition, as women randomized to hormone therapy scored significantly lower on the Modified Mini-Mental State Examination compared with placebo-treated women (63). Given the increased incidence of stroke identified in hormone therapy users in the WHI trial, it is possible that small, undetected cerebrovascular events were more likely to occur in the hormone therapy group, increasing the risk of dementia.
For a healthy woman with bothersome hot ﬂashes, hormone therapy remains a very reasonable option, especially if she is within 10 years of menopause or less than age 60. Hormone therapy should be used at the lowest effective dose for the shortest duration consistent with treatment goals (64–66). The need for continued hormone therapy use should be assessed at least annually.
The use of unopposed estrogen is associated with an increased risk of endometrial hyperplasia and cancer. Therefore, combination estrogen-progestin therapy is recommended for all women with a uterus. Treatment may be provided in a sequential manner, with estrogen daily and progestin for 12 to 14 days of each month, or in a continuous-combined fashion with estrogen and a lower dose of progestin daily. Sequential regimens result in regular, predictable vaginal bleeding. The majority of women using continuous-combined regimens will experience amenorrhea by the end of 1 year of therapy, but the bleeding that does occur is irregular and unpredictable. Low-dose combination hormone therapy products (e.g., Prempro 0.45/1.5 and 0.3/1.5 mg per day) generally result in a lower incidence of breakthrough bleeding and breast tenderness (67).
Women using low doses of oral or transdermal estrogens may elect intermittent progestin use (e.g., 14 days every 3 to 4 months) (68), although these are not approved regimens. A progestincontaining intrauterine device approved for contraception in premenopausal women provides endometrial protection in estrogen-treated menopausal women, although it is not approved for this indication (69). Increased endometrial surveillance is advised with these alternative regimens.
Transdermal administration of estradiol with a patch, spray, or gel may be preferred by some women. Avoiding the “first pass hepatic effect” of oral estrogens on lipids, binding globulins and clotting factors may have benefits for women on thyroid replacement or those with low libido (70). In contrast to oral administration, transdermal estradiol does not appear to increase the risk of venous thromboembolic events or gallbladder disease, though it remains contraindicated in women at high risk for venous thromboembolic disease or those with active liver or gallbladder disease.