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This article reviews the role of endogenous estrogen in neural and cognitive processing, followed by an examination of longitudinal cognitive data captured in various stages of the menopausal transition. The remaining text reviews the contradictory results from major hormone therapy trials to date, evidence for the "timing hypothesis," and closes with recommendations for future research and for practicing clinicians., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Evidence supports that the physical disablement process starts earlier than previously thought, in midlife when women still have many years to live. Physical activity participation and interventions have been successful in preventing disability in older adults and may be promising for maintaining function at younger ages. Changing the conversation to more relevant topics in midlife, like positive changes in body composition, sleep, and improved mood, may move the dial on participation, as midlife women do not meet guidelines for physical activity. Exploring the role of reproductive aging beyond chronologic aging may provide gender-specific insights on both disablement and participation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sexual function is an important component of quality of life for women. Midlife poses several challenges to optimal sexual function and intimacy for women. In addition to anatomic factors related to estrogen deficiency, such as genitourinary syndrome of menopause, vulvovaginal atrophy, and pelvic organ prolaps, psychosocial factors, including prior sexual trauma, play an important role in sexual function in women. Several treatments have emerged for female sexual dysfunction; long-term studies and head-to-head comparisons are lacking., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The menopause transition (MT) is a critical period of women's lives marked by several physiologic changes and menopause-related symptoms that have implications for health. Risk for cardiovascular disease, the leading cause of death in women, increases after menopause, suggesting a contribution of the MT to its development. This article focuses on the relationship between 2 main features of the MT and women's cardiovascular health: (1) dynamic alterations of sex hormones, particularly endogenous estradiol and follicle-stimulating hormone, and (2) vasomotor symptoms, the cardinal symptom of the menopause. Limitations and future directions are discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The menopause transition is a critical period for bone health, with rapid losses in bone mass and strength occurring in a 3-year window bracketing the date of the final menstrual period. Declines in bone mass are accompanied by deleterious changes in bone macrostructure and microarchitecture, which may be captured by changes in composite strength indices and indices of trabecular thickness and connectivity. The onset of the rapid bone loss phase is preceded by changes in sex steroid hormones and increases in markers of bone resorption, measurements of which may be clinically useful in predicting the onset of the rapid loss phase and in identifying the women who will lose the most bone strength over the menopause transition., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sleep and metabolism are essential components of health. Metabolic health depends largely on individual's lifestyle. Disturbances in sleep health, such as changes in sleep patterns that are associated with menopause/reproductive aging and chronologic aging, may have metabolic health consequences. Sleep restriction and age-related changes in sleep and circadian rhythms may influence changes in appetite and reproductive hormones, energy expenditure, and body adiposity. In this article, the authors describe how menopause-related sleep disturbance may affect eating behavior patterns, immunometabolism, immunometabolic dysfunction, and associations between sleep and metabolic outcomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Both chronologic aging and menopause affect the physical, physiologic, and microbiological characteristics of the genitourinary tract. The genitourinary syndrome of menopause, characterized by vulvovaginal and lower urinary tract signs and symptoms, is prevalent and has a significant negative impact on women's lives. In this article, the authors detail the genitourinary tract changes associated with menopause and/or aging. They also review the 2014 North American Menopause Society's definition of the genitourinary syndrome of menopause and present the epidemiology and impact of genitourinary aging in midlife and older women, namely, vulvovaginal, urinary, and sexual symptoms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Key cycle changes occur as women transition from reproductive life to menopause, and they can be roughly linked to menopausal staging. It is important to understand the types of studies that inform the current knowledge. Patterns of symptoms within menstrual cycles (sleep, headache) generally favor worsening in association with the perimenstrual phase of the cycle, and patterns of chronic symptoms, such as hot flashes and adverse mood, appear to be worse when hormones are more variable., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The use of androgens in the treatment of gynecic disorders has had few adherents because of the belief generally held that androgen administration to the female patient is antiphysiologic and antipharmacologic. Testosterone in physiologic doses complements estrogens and is synergestic rather than contraphysiologic. Physiologic doses of testosterone may be used to advantage in the management of the menopause, sexual dysfunction, lichen planus vel atrophicus, fibrocystic disease of the breast, and sexual infantilism resulting from hypopituitarism as well as in several other disorders.

All the existing data show that combination estrogen/progestogen therapy is mandatory if any replacement therapy is to be given to the woman over age 40. Sufficient evidence has indicated that estrogen alone is inadequate; progestogen must be given to prevent endometrial hyperplasia, lower the risk of breast cancer, and prevent bone loss. In the premenopausal woman, such therapy should also provide contraception. Because of the lack of minimal dose products fulfilling such criteria, many physicians will allow women to continue with their contraceptive if they do not smoke and have no other contraindications. It will remain to be seen if a product close to ideal can be found to fulfill the contraceptive and therapeutic needs of women traversing the most physiologically hazardous period of their lives.

Menopausal symptoms are a consequence of the decline in sex hormone production, and hormone replacement therapy aims not only to relieve these symptoms but also to prevent the development of diseases of old age such as osteoporosis. The general opinion taken from a wide variety of publications is that the serum lipid concentrations change during hormone replacement therapy with estrogen, progesterone, and testosterone, or when oral contraceptives are administered. The intolerance of many women to oral contraceptives and the many side effects developed from the birth control pill lead us to suggest that pure crystalline estrogen pellets for subcutaneous implantation are an excellent method of contraception, adding beneficial influence upon lipid metabolism by increasing HDL concentration. The use of progestogens (nortestosterone or hydroxysteroid derivatives) in order to induce withdrawal periods and to avoid endometrial hyperplasia is recommended. But it is important to note that the nortestosterone derivatives (norgestrel and norethindrone acetate) differ markedly from the nonadrogenic 17-alpha hydroxyprogesterone derivative in that the former lowers HDL levels noticeably more than the latter.

The classes of estrogens and progestogens currently in use and their routes of administration have been considered. The decision to prescribe any given estrogen or progestogen and by a particular route has a significant impact on cardiovascular risk factors. Among the estrogens, native estradiol and estrone are favored over equine and synthetic estrogens. Given this choice, oral and systemic routes of administration are not sufficiently different clinically to endorse one method over the other, except for the unusual hypertensive woman or the patient with a history of thromboembolic phenomena. Among the progestogens, oral micronized progesterone offers much promise for use in postmenopausal women. However, the oral use of lower doses of other progestogens seems appropriate at the present time. With the availability of oral micronized progesterone and in time a transdermal system, the need for alternate routes of administration for other progestogens seems unnecessary.

Thus, the effects that a specific estrogen has on the liver is the summation of several mechanisms, including the first pass mechanism and the enhanced delivery of circulating estrogens to this organ. For example, the major estrogen in conjugated estrogen is estrone sulfate. Based on the present data, very little circulating estrone sulfate is available to the brain or uterus (Fig. 25). Since most of the hypothalamus is behind the blood-brain barrier, it is unlikely estrone sulfate exerts a direct action on gonadotropin-releasing hormone (GnRH) neurons to reduce its secretion and, subsequently, gonadotropin levels. Estrone sulfate also does not interact with the estrogen receptor. It is possible the small amount of estrone sulfate that crosses the blood-brain barrier is converted to unconjugated estrogens locally and these could have function. More likely, the major mechanism by which estrone sulfate suppresses GnRH release is through conversion to unconjugated estrogens, principally estrone, in the liver. The large extraction of estrone sulfate by the liver allows accessibility of the hepatocyte for this conversion. Based on this concept, conjugated estrogen must enter the liver to be converted to its active forms. The route of administration then should have little impact on changing the relative potency of this preparation on hepatic and nonhepatic markers of estrogen action. For ethinyl estradiol, the preparation is orally active because it is rapidly and almost completely absorbed from the stomach and undergoes limited hepatic metabolism before entry into the general circulation (Fig. 26). This limited hepatic metabolism reduces the impact of the first pass mechanism on ethinyl estradiol. Thus, the enhanced hepatic action of ethinyl estradiol is principally related to the greater entry of this estrogen into the liver than other organs (Fig. 27). Consequently, the route of administration should have little impact on the exaggerated hepatic actions of this estrogen. Orally administered estradiol undergoes substantial hepatic metabolism to less active forms, principally estrogen conjugates. The amount of estradiol leaving the liver following oral administration is substantially less than that which enters it through the portal vein. The systemic administration of estradiol avoids this initial hepatic metabolism. Furthermore, only 25 per cent of nonorally administered estrogen will go to the liver at each pass, and nonhepatic tissues would be exposed to a greater extent than after oral administration. Thus, peripheral administration of estradiol reduces the exaggerated hepatic responses in comparison to nonhepatic actions.(ABSTRACT TRUNCATED AT 400 WORDS)