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PubMed2005

The menopausal transition.

Reproductive aging in women is related to the depletion of a fixed number of germ cells within the ovary. Prenatally, almost 50% of the maximal follicle pool is lost. Thereafter, atresia slows until women reach their early 40s, when total remaining follicle numbers reach a critical threshold. Atresia then becomes rapid once again, and women progress through the menopausal transition until they are left with essentially zero oocytes by a median age of 51.4 years. Fewer follicles result in a loss of inhibin B production and less physiologic "restraint" of follicle-stimulating hormone (FSH) secretion. Based on the responsiveness of the follicles present in any given month, a wide spectrum of hormonal patterns may occur. Women may alternate between inadequate folliculogenesis and more normal cycling. In the Study of Women's Health Across the Nation (SWAN), daily urine sampling was performed to assess hormonal dynamics. Older age and larger body size predicted aluteal cycles, and hormone excretion was lower in larger women. When annual hormones are examined, most of the decrease in estradiol and increase in FSH associated with menopause is found to occur during the late menopausal transition. There also is evidence that the central nervous system does not respond normally to estrogen and fails to produce preovulatory luteinizing hormone surges in women in the early transition. Clinically, it is important to appreciate that the entire reproductive system, not just the ovary, is undergoing change across the transition. Reproductive hormonal fluctuations may underlie some of the common symptomatology of the perimenopause.

Central Nervous System↗

PubMed2005

Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women's lives.

This article examines published evidence from longitudinal studies of the menopausal transition that address the following questions: (1) Which symptoms do women report during the perimenopause, and how prevalent are these symptoms as women traverse the menopausal transition? (2) How severe are symptoms and for how long do they persist? (3) To what do women attribute their symptoms, and do their attributions match findings from epidemiologic studies of community-based populations? (4) How significant are these symptoms in women's lives? Data from published longitudinal studies were examined for evidence bearing on each of these questions. Only vasomotor symptoms, vaginal dryness, and sleep disturbance symptoms varied in prevalence significantly across menopausal transition stages and postmenopause in >1 population studied. A minority of women report severe symptoms. Given the limited follow-up data available, it is unclear how long symptoms persist after menopause. Women attribute their symptoms to a variety of biologic and psychosocial factors, and their attributions correspond well to those correlates identified in epidemiologic studies of community-based populations. The significance of symptoms for women's lives remains uncertain. The impact of symptoms during the perimenopause on well-being, role performance, adaptation to demands of daily living, and quality of life warrants additional study. The appraisal of the consequences of perimenopausal symptoms by women from different ethnic groups will be enhanced significantly as a result of the Study of Women's Health Across the Nation (SWAN) and other studies in progress.

Female↗

PubMed2005

Does the menopausal transition affect health-related quality of life?

We address whether the menopausal transition affects health-related quality of life (HRQOL). To do this, we review how HRQOL is defined and measured, present HRQOL findings from the large, population-based studies of menopause, and identify key gaps in knowledge. HRQOL is defined as the value assigned to duration of life as modified by impairments, functional states, perceptions, and social opportunities that are influenced by disease, injury, treatment, or policy. The specific domains of HRQOL include resilience or the capacity to respond to stress, health perceptions, physical functioning, and symptoms. The majority of menopause studies have operationalized HRQOL as frequency and severity of symptoms. Taken together, the findings from 12 cross-sectional reports and 3 longitudinal studies suggest that the perimenopause is associated with higher levels of somatic symptoms. It is unclear whether the perimenopause is related to other domains of HRQOL. Only 1 longitudinal study reported an association between reduced physical functioning and perimenopause. Studies typically compare premenopausal women with women of other menopausal transition status separately, thereby not addressing the question of further change in HRQOL after the cessation of menses. There is a clear need for understanding the effects of the menopause beyond the domain of symptoms and to consider whether some domains of HRQOL may improve.

Female↗

PubMed2005

Mood, depression, and reproductive hormones in the menopausal transition.

This article focuses on a review of evidence related to the following 3 questions: (1) Does depression appear during the menopausal transition? (2) What factors influence the risk for depression during the menopausal transition? (3) Do age-related alterations in ovarian hormone secretion contribute to the development of depression in some middle-aged women? A brief background is provided on the importance of depressive disorders. Methodologic issues that have compromised previous studies investigating the possible relation between the menopausal transition and depression are discussed. Evidence is presented that suggests a relation between the perimenopause (the interval between the early menopausal transition and 1 year after the last menses), but not the postmenopause, and the onset of depressive illness. Finally, studies are reviewed that suggest an association between alterations in ovarian function and depression, including several randomized placebo-controlled trials examining the antidepressant efficacy of estradiol in depressed perimenopausal and postmenopausal women.

Affect↗

PubMed2005

Sexuality.

This article reviews changes in sexual function in middle-aged women and discusses how these changes relate to aging, hormone alterations, and psychosocial and physical factors. A Medline search of population-based studies that measured sexual function, menopausal status and/or hormone levels was conducted. Longitudinal findings are from the Melbourne Women's Midlife Health Project, a population-based sample of 438 Australian-born white women, aged 45 to 55 years, who were menstruating at baseline. Annual assessments included hormone levels and the Short Personal Experiences Questionnaire. Few of the population-based studies of the menopausal transition measured sexual function or hormones. Aging and the length of the woman's relationship with her partner are associated with decline in sexual function. An additional decrement in sexual function occurs in midlife associated with menopause. Findings from the Melbourne Women's Midlife Health Project using structural equation modeling, found the most important factors influencing a woman's sexual function are prior level of sexual function; losing or gaining a sexual partner; feelings toward a partner; and estradiol level. When psychosocial and lifestyle status were added to the model, mood was the only additional variable affecting sexual function. There is a decline in all aspects of female sexual function with age. A further incremental decline in most aspects of sexual function occurs as women pass through the menopausal transition and is related to decreasing estradiol levels. Other factors such as prior sexual function and partner issues have larger effects on women's sexual function than do hormonal factors.

Aging↗

PubMed2005

Vasomotor symptom relief versus unwanted effects: role of estrogen dosage.

Recent clinical trials show that low-dose estrogen reduces the number of moderate to severe vasomotor episodes by 65%. This reduction is about midway between the 35% to 40% reduction observed with placebo and the 75% to 80% reduction observed with standard dosage. Compared with standard dosages whose effects are substantial by 4 weeks, relief with lower dosages is not maximal until 8 to 12 weeks. Women using lower dosages of estrogen experience 50% lower rates of irregular bleeding or breast tenderness compared with individuals taking standard dosages. Despite several lower dosage hormone therapy (HT) formulations being approved by the US Food and Drug Administration (FDA) and brought to market, their uptake by healthcare providers has been slow. Most women who have continued HT after reports of the Women's Health Initiative (WHI) were published take estrogen at the standard dosage; only a minority of these individuals report receiving guidance about switching to a lower dosage. The purpose of this review is to summarize the clinical trial data showing, on one hand, effects of various dosages of estrogen on vasomotor symptoms and, on the other hand, the effects of these same doses on troublesome adverse events, particularly vaginal bleeding or breast tenderness. It is time to reconsider the current estrogen dosage recommendation on the basis of symptom benefit versus symptom nuisance. Furthermore, healthcare providers need to learn how and when to prescribe lower dosages of HT to optimize patient acceptance and continuation.

Estrogen Replacement Therapy↗

PubMed2005

Estrogen with and without progestin: benefits and risks of short-term use.

Estrogen therapy has been well established as an effective treatment for relief of vasomotor symptoms. In light of recent evidence from large randomized trials showing serious risks associated with use of estrogen treatment, current recommendations for hormone therapy emphasize using the lowest effective dose for the shortest possible time. The purpose of this review is to examine what has been learned from the Women's Health Initiative (WHI) Hormone Trials and other studies about the short-term risks and benefits of estrogen use. A second purpose is to examine whether short-term risks differ for women most likely to use hormone treatment, including individuals with vasomotor symptoms; women in their 50s; and women, with and without intact ovaries, who have had a hysterectomy. During the first 1 to 2 years of use of conjugated equine estrogens alone (E-alone) or combined with medroxyprogesterone acetate (E + P), women experience an elevated risk of coronary heart disease, stroke, and deep vein thrombosis or pulmonary embolism. The magnitude of risk is greater for E + P than for E-alone. Fracture risk is not reduced with 1 to 2 years of use, but a fracture benefit is seen within 5 years of use. Increased risk of breast cancer does not appear until after 4 to 5 years of E + P use and was not increased with E-alone use after < or =7 years of treatment. This pattern of risks and benefits is generally similar for women with vasomotor symptoms, women in their 50s, and women, with and without > or =1 intact ovary, who have had a hysterectomy.

Estrogen Replacement Therapy↗

PubMed2005

Therapeutic effects of progestins, androgens, and tibolone for menopausal symptoms.

Therapeutic strategies using progestins, androgens, and synthetic steroids such as tibolone are based on the understanding that estrogen, progesterone, and androgen receptors are localized to reproductive target tissues, brain, and bone. Unfortunately, these sex steroid receptors are widely distributed and localized to other tissues, often resulting in unintended effects. Progestins at high doses have been shown to be effective at reducing hot flashes by approximately 80% to 90%. Side effects include weight gain, mastalgia, fluid retention, vaginal discharge, and dry mouth. Dehydroepiandrosterone (DHEA), an adrenal-derived androgen, can be considered a prohormone that is peripherally converted to more potent androgens and estrogens. In studies with small numbers of subjects, DHEA has been reported to reduce vasomotor symptoms, increase sexual arousal, and improve cognitive performance. With regard to use of other androgens, there are no current testosterone preparations approved by the US Food and Drug Administration (FDA) for use in menopausal women. In phase 3 trials, a testosterone transdermal matrix patch has been shown to be effective in treatment of hypoactive sexual desire disorder in menopausal women on estrogen therapy. Tibolone, a synthetic steroid with estrogenic, androgenic, and progestational properties has been shown to be effective in the treatment of vasomotor symptoms and in preserving bone density, and it may provide positive effects on sexual function. The beneficial effects of these compounds in the menopausal woman for treatment of vasomotor symptoms, general well-being, cognitive deficits, bone loss, mood disorders, and sexual function are discussed. The overall clinical trial evidence for benefits and side effects also is presented.

Androgens↗

PubMed2005

Diagnosis and management of mood disorders during the menopausal transition.

Recent census data indicate that, in the United States, an increasing number of women--almost 1.5 million each year--are reaching menopause. The menopausal transition is marked by intense hormonal fluctuations, and may be accompanied by vasomotor complaints, sleep disturbances, changes in sexual function, and increased risk for osteoporosis and cardiovascular disease. In addition, there is evidence of increased risk for developing depression, even among women who never experienced depressive symptoms before. Thus depression during the perimenopause may have a substantial impact on personal, family, and professional spheres of life. A challenge to clinicians and health professionals lies in the identification of the most tolerable treatments to manage depression and improve quality of life in an aging population. Any treatment strategy should take into account not only the spectrum of side effects that may complicate treatment but also other menopause-related factors (e.g., vasomotor symptoms, psychosocial stressors) that may modulate risk for the development of mood disturbance. This article reviews the current literature on the prevalence and risk factors associated with depression during the menopausal transition. The benefits and risks of using hormonal and nonhormonal strategies for the management of depression and other menopause-related somatic symptoms are critically reviewed.

Antidepressive Agents↗

PubMed2005

Centrally active nonhormonal hot flash therapies.

Given the problems associated with hormonal therapy, and the prominent problem of hot flashes in menopausal women, there is a need for nonhormonal agents to alleviate hot flashes. Several compounds that appear to act on the central nervous system have been investigated. Potential mechanisms for their effects on hot flashes have been described. Bellergal (no longer available on the US market, where it was known as Bellergal-S), a combination preparation sedative that consists of low-dose phenobarbital, ergotamine tartrate, and levorotatory alkaloids of belladonna, is an old agent that was popular approximately 20 years ago; however, there is limited suggestion of efficacy for this agent. Clonidine, an older antihypertensive drug, is another centrally active agent that has been studied. Randomized trials have demonstrated that it clearly works for reducing hot flashes, but the magnitude of efficacy is somewhat limited. Toxicity from this agent limits its utility in the clinic. Methyldopa is another centrally active agent that has been studied but to a more limited degree. It appears to have minimal efficacy and too much toxicity to make it clinically useful. Anecdotal observations from a number of sources suggested that newer antidepressants can alleviate hot flashes. This led to pilot trials of venlafaxine and paroxetine, with results suggesting benefit from both drugs. Subsequently, randomized, placebo-controlled, double-blind clinical trials of venlafaxine, paroxetine, and fluoxetine were conducted. All 3 of these clinical trials demonstrated statistically significant reductions in hot flashes with these newer antidepressants compared with placebo. Pilot trials of citalopram and mirtazapine, 2 other newer antidepressants, have also suggested efficacy. Toxicity evaluations have suggested that these agents are, again, well tolerated by the majority of patients. A recent trial, however, was unable to demonstrate any benefit for fluoxetine or citalopram over a placebo. Anecdotal observations also suggested that gabapentin was helpful for alleviating hot flashes. This led to pilot trials that again suggested efficacy. Subsequently, 2 large placebo-controlled, randomized, double-blind clinical trials were conducted. Both of these demonstrated statistically significant efficacy for gabapentin compared with a placebo. This drug is relatively well tolerated by most patients. Thus, centrally active nonhormonal agents clearly do decrease hot flashes in women. The most efficacious and clinically appropriate agents for use are newer antidepressants and gabapentin. Continued evaluation of the efficacy and toxicity of these agents is ongoing.

Amines↗

PubMed2005

Hot flashes: behavioral treatments, mechanisms, and relation to sleep.

Hot flashes are the most common symptom of the climacteric and occur in about 75% of perimenopausal and postmenopausal women in Western societies. Although hot flashes accompany the withdrawal of estrogen at menopause, the decline in estrogen levels is not sufficient to explain their occurrence. Elevated sympathetic activation acting through central alpha(2)-adrenergic receptors contributes to the initiation of hot flashes, possibly by narrowing the thermoneutral zone in symptomatic women. Hot flashes are then triggered by small elevations in core body temperature acting within this narrowed zone. A relaxation-based method, paced respiration, has been shown in 3 controlled investigations to significantly reduce objectively measured hot flash occurrence by about 50% with no adverse effects. In 6 studies of physical exercise, however, investigators did not find positive effects on hot flashes, possibly because exercise raises core body temperature, thereby triggering hot flashes. Although many epidemiologic studies have found increased reports of sleep disturbance during the menopausal transition, recent laboratory investigations have not found this effect, nor have they found that hot flashes produce disturbed sleep. Therefore, sleep complaints in women at midlife should not routinely be attributed to hot flashes or to menopause.

Behavior Therapy↗

PubMed2005

Breast cancer, menopause, and long-term survivorship: critical issues for the 21st century.

Breast cancer accounts for 33% of all incident cancers in women in North America, and there are an estimated >2 million breast cancer survivors in the United States today. Ovarian hormones are intimately involved in the initiation and promotion of breast cancer development, with targeted endocrine therapies being the most widely used as anticancer treatment. It is not surprising that these treatments frequently cause persistent menopausal symptoms in breast cancer survivors. In addition, adjuvant chemotherapy often induces premature menopause in younger patients with breast cancer. Some women at high risk for the development of breast cancer (e.g., precancerous breast disease, carriers of deleterious hereditary predisposition genes) experience vasomotor symptoms as a result of tamoxifen therapy or preventive oophorectomy. Clinical management of menopausal symptoms in these settings is complicated by the relative prohibition of hormonal therapies and the fact that breast cancer-directed therapies often exacerbate these menopausal symptoms. Thus, this special population of women requires unique management strategies and deserves separate consideration.

Antineoplastic Agents↗

PubMed2005

Strategies and issues for managing menopause-related symptoms in diverse populations: ethnic and racial diversity.

Menopause is a naturally occurring "equal opportunity" event that every woman who lives beyond the age of approximately 52 years will experience. During the next 20 years, approximately 3.5 million African American women, 2 million Latinas, and 1 million Asian American women will enter the menopause. How a woman approaches the menopausal transition depends on a number of factors, from educational level to socioeconomic status; health-related factors, including stress; and marital status. Increasingly, the roles of race and ethnicity, as they relate to menopausal symptoms, are being explored. Understanding similarities and differences among women of color in perceptions, attitudes, and expectations surrounding the menopause can help provide culturally appropriate care and promote lifestyles that may decrease symptoms and increase quality of life. For example, minority women are usually the gatekeepers for healthcare for themselves and their families and have a highly developed social support network, often including extended family, a church community, and involvement in sororal or social organizations. In the future, research on menopausal symptoms among women of different racial/ethnic groups should focus on exploring in greater detail the effect of dietary factors and body mass index, additional evaluation of pituitary sensitivity, and use of complementary and alternative medicines in symptom management, with a better understanding of the risks and benefits of such therapies.

Complementary Therapies↗

PubMed2005

Lifestyle factors: are they related to vasomotor symptoms and do they modify the effectiveness or side effects of hormone therapy?

This article reviews and summarizes published literature in order to address the following questions: (1) Are lifestyle factors (alcohol use, cigarette exposure, and physical activity) and body mass index (BMI) related to the occurrence of vasomotor symptoms in perimenopausal and postmenopausal women? (2) Do lifestyle factors or BMI modify the effectiveness or side effects of menopausal hormone therapy (HT)? Information was culled from a nonstructured review of English-language literature. Low levels of alcohol consumption (< or =1 drink per day for women) do not have a measurable effect on occurrence of vasomotor symptoms; whether greater amounts of alcohol intake would promote vasomotor symptoms cannot be addressed by available literature. Most published studies report that active cigarette smoking is positively associated with vasomotor symptoms. However, a large study found that passive (but not active) smoking (i.e., secondhand smoke exposure) was related to vasomotor symptoms. Studies to date do not support a relation between physical activity and vasomotor symptoms. However, rates of vasomotor symptom reporting were low in these studies, potentially limiting the ability to detect an effect of physical activity. Greater BMI is a risk factor for more vasomotor symptom reporting. The scarcity of data that directly address whether lifestyle factors or BMI modify the effects of HT precludes a substantive response to this question at present. Available literature suggests that smoking and greater body weight are risk factors for vasomotor symptoms; women with vasomotor symptoms who smoke may benefit from smoking cessation, and women who are heavier than ideal body weight may benefit from weight reduction. Whether certain behaviors or BMI raise or lower the risks or benefits of HT remains largely unknown and should be the focus of future research.

Alcohol Drinking↗

PubMed2005

The impact of risk status, preexisting morbidity, and polypharmacy on treatment decisions concerning menopausal symptoms.

Because each menopausal treatment has a unique benefit-risk profile, deciding whether menopausal hormone therapy (HT) or another menopausal treatment is appropriate for an individual requires assessing the risks and benefits of each treatment as well as determining the patient's risk factors, comorbidities, and current medications. Simple summary metrics for assessing net treatment effects on multiple outcomes, such as the Women's Health Initiative's (WHI) global index, are not necessarily generalizable beyond the study population in which they were derived. However, trial evidence can be translated to individual decisions by transforming relative risks into absolute risks. The validity of generalizing relative risks found in clinical trials to groups with differing baseline risks depends on the homogeneity of relative risks across various risk strata. Subgroup analyses from the major clinical studies of HT found its relative risks for cardiovascular disease, hip fracture, breast cancer, colorectal cancer, and ovarian cancer to be relatively uniform across strata defined by age, race/ethnicity, antecedent risk status, or prior disease. The number of significant subgroup findings in these studies tended to match the number expected by chance alone. However, data are limited for many subgroups, especially those with comorbidities. Strata defined by the concurrent use of drugs that can interact with HT are not expected to be homogeneous, yet data on drug interactions are limited. More data are needed about the effects of menopausal treatments in diverse populations, and more attention is needed to translate this evidence into clinical practice and to develop tools to support informed decision making.

Estrogen Replacement Therapy↗

PubMed2005

Discontinuation of postmenopausal hormone therapy.

Current guidelines recommend that postmenopausal hormone therapy (HT) be used primarily for treatment of vasomotor and urogenital symptoms associated with the menopausal transition and that women use the lowest effective dose for the shortest time necessary. Vasomotor symptoms improve or resolve spontaneously within a few months to a few years of onset in the majority of women, suggesting that most women should be able to discontinue HT within a few years of starting treatment. Approximately 75% of women who try to stop are able to stop HT without major difficulty. However, some women who would like to stop HT are unable to do so, mainly owing to the development of vasomotor symptoms. Troublesome symptoms associated with stopping HT appear to be more common among women who start HT for treatment of symptoms, but they also are reported by women who started HT for other reasons, such as prevention of osteoporosis. Unfortunately, little information is available to guide physicians in helping women who have difficulty stopping HT. Many clinicians recommend slowly tapering HT or adding another drug for treatment of hot flashes, but the effectiveness of these approaches has not been evaluated. For women who cannot tolerate even a slow taper, the value of symptom relief likely outweighs any increased risks due to HT use.

Estrogen Replacement Therapy↗

PubMed2005

Bilateral oophorectomy and premature menopause.

The ovary is a complex metabolic organ. The follicles produce both androgens and estrogens, whereas the stromal tissue synthesizes androgens only. When menopause occurs, both androgen and estrogen levels decrease. The postmenopausal ovary remains a source of endogenous androgens that are converted to estrogen. The consequences of premature removal of the ovaries are not well known. The risks and benefits of menopausal hormone therapy (HT) in women with premature menopause have not been studied. Women who have had surgical menopause experience more severe symptoms and will need to stop estrogen therapy at some point in their lives. Intense symptoms such as hot flashes, night sweats, and insomnia will redevelop, so women should be given informed consent about the need for long-term use of HT and the greater difficulty in discontinuing therapy.

Estrogen Replacement Therapy↗

PubMed2005

A universal menopausal syndrome?

A variety of symptoms are reported frequently as being part of a menopausal syndrome. These include hot flashes, night sweats, menstrual irregularities, vaginal dryness, depression, nervous tension, palpitations, headaches, insomnia, lack of energy, difficulty concentrating, and dizzy spells. The question of whether and how symptoms occur together is important for women who want to know which symptoms can be attributed to menopause and which to aging generally or to other physical or psychosocial factors. To address this question, the present article examines the following avenues of research: (1) the clustering or grouping of symptoms; (2) the temporal association of different symptoms with stages of the menopausal transition; (3) the consistency of symptom reporting across cultures, race, and ethnicity; and (4) the consistency of risk factors for symptoms. Results of the factor analysis studies do not support a single syndrome consisting of menopausal and psychological or somatic symptoms. The prevalence of symptom reporting across the transition also argues against a menopausal syndrome because vasomotor symptoms follow a unique pattern that differs from that of other symptoms. Cross-cultural differences suggest that symptom reporting is not universal. Finally, although there is some overlap in risk factors for symptoms, menopausal status is more consistently related to vasomotor symptoms than to psychological or physical ones. Results of these investigations all argue against a universal menopausal syndrome. Future research should focus on how symptoms are interrelated, what factors are uniquely related to vasomotor symptoms, and identifying whether there is a subgroup of women who are more likely to report symptoms.

Aging↗