November 2015

They are common complaints as women go through menopause: “I’m depressed, anxious;” “I can’t remember a thing…how will I function at work?” While women’s hope that hormone therapy can help is high, the evidence is mixed. And just what if hormone therapy does help…do we really know about its safety in women at the younger end of the menopause spectrum?

As they go through the various phases of menopause, about 1 in 5 women will suffer depression.^[1],[2],[3] The strongest predictor of who will experience depression with whether a woman has had a previous experience with depression. ^[4] Women who have not had clinical depression may be less affected by menopausal changes, but they too may experience mood swings of a lesser degree. Many women also complain about fuzzy thinking and a decreased verbal recall.^[5],[6],[7] Studies have been mixed on whether hormone therapy helps with mood or cognition during menopausal phases. Most of the studies, moreover, have been observational, so a number of method limitations reduce the studies’ reliability.

The Kronos Early Estrogen Prevention Study is a randomized, double-blinded, placebo-controlled clinical trial^[8] looking at, among other things, how oral and transdermal menopausal hormone therapy affects cognitive decline and mood. The study enrolled 693 women within 3 years of the onset of menopause who were wondering whether to use hormone therapy. All women were heart-healthy with intact uteri. Upon enrollment, researchers found that about 10% had some degree of depressive symptoms, ranging from mild to moderately severe, although none were diagnosed with clinical depression. The researchers randomized the study subjects into three groups: receiving oral conjugated estrogen (CEE) daily with micronized progesterone 12 days a month; applying a transdermal estradiol (E2) patch with micronized progesterone 12 days a month; or using a placebo. Each woman underwent detail in-clinic cognitive evaluations such as verbal learning and memory and the all-important executive function as well as measurements of affect and mood.

Over 48 months of treatment, women using the oral regimen had improvements in depression and anxiety symptoms when compared to the control group. The window for improvement occurred during the later stage of perimenopause through the early postmenopausal period. This window corresponds to the phases of menopause in which women are two to four times more likely to experience depression, according to the SWAN study.¹

The transdermal E2 appeared to have no effect on mood. And neither transdermal nor oral menopausal hormone therapy appeared to effect cognitive performance. This supports the findings stated in the 2012 position statement issued by the North American Menopause Society.^[9] In its statement, NAMS concluded that the negative effect of menopausal transition on cognition is transient, with negligible long-term effect.

The KEEPS study reported few adverse events among the subjects, who took the hormone therapy in the early, not the later, stages of menopause. Three women taking oral CEE, 2 using transdermal E2, and 1 taking placebo developed breast cancer. One women on oral therapy had a transient ischemic attack, 1 on transdermal reported a stroke that turned out not to be, and 1 women in each the transdermal and the placebo groups experienced venous thrombotic disease. No women developed a cognitive disorder during the study period.

As evidence has led to more limited indications for use of menopausal hormone therapy, the KEEPS trial suggests that in the transition to and early stages of menopause, clinicians may consider that oral hormone therapy may help with the concomitant mood swings. That said, the NAMS statement still stands: “Although HT might have a positive effect on mood and behavior, HT is not an antidepressant and should not be considered as such.”⁹

—Deborah Kowal, MA, PA, Executive editor of Contraceptive Technology