Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.

Objective: The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address gaps in understanding the effects of timely menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women's Health Initiative. Method: The KEEPS was a randomized, double-blinded, placebo-controlled trial to test the hypothesis that initiation of HT (oral conjugated equine estrogens [o-CEE] or transdermal 17β-estradiol [t-E₂]) in healthy, recently postmenopausal women (n = 727) would slow the progression of atherosclerosis as measured by changes in carotid artery intima-media thickness (CIMT). Results: After 4 years, neither HT affected the rate of increase in CIMT. There was a trend for reduced accumulation of coronary artery calcium with o-CEE. There were no severe adverse effects, including venous thrombosis. Several ancillary studies demonstrated a positive effect on mood with o-CEE, and reduced hot flashes, improved sleep, and maintenance of bone mineral density with both treatments. Sexual function improved with t-E₂. There were no significant effects of either treatment on cognition, breast pain, or skin wrinkling. Variants of genes associated with estrogen metabolism influenced the age of menopause and variability in effects of the HT on CIMT. Platelet activation associated with the development of white matter hyperintensities in the brain. Conclusions: KEEPS and its ancillary studies have supported the value and safety of the use of HT in recently postmenopausal women and provide a perspective for future research to optimize HT and health of postmenopausal women. The KEEPS continuation study continues to pursue these issues.

Hypoestrogenemia is the endocrine hallmark of menopause and is characterized by 5- to 10-fold reduction in circulating levels of estradiol (E₂).¹ Over time, low E₂ levels result in vaginal dryness and dyspareunia, often accompanied by symptoms of vulvovaginal atrophy.² These symptoms significantly contribute to the increased incidence of sexual disorders in menopausal women.^3-5 Estradiol is also a modulator of serotonergic function, affecting regions of the brain known to regulate mood and desire, which may have direct or indirect effects on sexual function.^1,6 Quiz Ref ID At least 23% of naturally menopausal women are distressed by their low sexual desire,⁷ whereas midlife women with higher levels of enjoyment from sexual activity experience a higher sense of purpose in life.⁸ The US Food and Drug Administration has recently identified female sexual dysfunction (FSD) as a serious condition with unmet needs as part of its program on patient-oriented drug development.⁹

Reports have correlated the use of estrogen for the treatment of menopausal symptoms with beneficial effects on the cardiovascular system. Molecular, biochemical, preclinical, and clinical studies have furnished a wealth of evidence in support of this outcome of estrogen action. The prospective randomized Women’s Health Initiative (WHI) and the Early Versus Late Intervention Trial (ELITE) showed that starting menopausal hormone treatment (MHT) within 5 to 10 years of menopause is fundamental to the success of estrogen’s cardioprotection in post-menopausal women without adverse effects. Age stratification of the WHI data has shown that starting hormone treatment within the first decade after menopause is both safe and effective, and the long-term WHI follow-up studies are supportive of cardioprotection. This is especially true in estrogen-treated women who underwent surgical menopause. A critique of the WHI and other relevant studies is presented, supporting that the timely use of estrogens protects against age- and hormone-related cardiovascular complications. Salutary long-term hormone treatment for menopausal symptoms and prevention of complications has been widely reported, but there are no prospective trials defining the correct length to continue MHT. At present, women undergoing premature menopause receive estrogen treatment (ET) until evidence of hormone-related complications intervenes. Normal women started on MHT who receive treatment for decades without hormone-related complications have been reported, and the WHI follow-up studies are promising of long-term post-treatment cardioprotection. A prevention-based holistic approach is proposed for timely and continuing MHT/ET administration as part of the general management of the menopausal woman. But this should be undertaken only with scheduled, annual patient visits including evaluations of cardiovascular status. Because of the continued occurrence of reproductive cancers well into older ages, these visits should include genital and breast cancer screening.

Objective: This study determined whether two different formulations of hormone therapy (HT): oral conjugated equine estrogens (o-CEE; 0.45 mg/d, n = 209), transdermal 17β-estradiol (t-E2; 50 μg/d, n = 201) plus cyclic progesterone (Prometrium, 200 mg) or placebo (PBO, n = 243) affected sleep domains in participants of the Kronos Early Estrogen Prevention Study. Methods: Participants completed the Pittsburgh Sleep Quality Index at baseline and during the intervention at 6, 18, 36, and 48 months. Global sleep quality and individual sleep domain scores were compared between treatments using analysis of covariance, and correlated with vasomotor symptom (VMS) scores using Spearman correlation coefficients. Results: Global Pittsburgh Sleep Quality Index scores (mean 6.3; 24% with score >8) were similar across groups at baseline and were reduced (improved sleep quality) by both HT (average change −1.27 [o-CEE] and −1.32 [t-E2]) when compared with PBO (−0.60; P = 0.001 [o-CEE vs PBO] and P = 0.002 [t-E2 vs PBO]). Domain scores for sleep satisfaction and latency improved with both HT. The domain score for sleep disturbances improved more with t-E2 than o-CEE or PBO. Global sleep scores significantly correlated with VMS severity (r _s = 0.170, P < 0.001 for hot flashes; r _s = 0.177, P < 0.001 for night sweats). Change in scores for all domains except sleep latency and sleep efficiency correlated with change in severity of VMS. Conclusions: Poor sleep quality is common in recently menopausal women. Sleep quality improved with both HT formulations. The relationship of VMS with domains of sleep suggests that assessing severity of symptoms and domains of sleep may help direct therapy to improve sleep for postmenopausal women.