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Research recommendations
Pergamon
Experimental Gerontology, Vol. 29, Nos. 3/4, pp. 525-528, 1994 1994 ElsevierScienceLid Printed in the USA. All rights reserved 0531-5565/94 $6.00 + .00 0531-5565(94)E0023-U
Session VI. Research Directions
RESEARCH RECOMMENDATIONS ANDREW A. MONJAN, I FRANCIS L. BELLINO, 1 MARCIA G. ORY, 1 S H E R R Y SHERMAN 1 and SHARLENE WEISS 2'* 1National Institute on Aging, National Institutes of Health, Gateway Building, 7201 Wisconsin Ave., Bethesda, Maryland 20892 and 2National Institute for Nursing Research, National Institutes of Health, Westwood Building, Room 757, 5333 Westbard Avenue, Bethesda, MD 20892
MENOPAUSE-RELATEDresearch has generally focused on hormone therapy to alleviate postmenopausal health problems. Very little information is available regarding 1) the biological processes, particularly the mechanisms of ovarian follicular depletion, leading to menopause, and 2) the nature of the physiological and psychosocial changes during the pre- to postmenopausal transition. One of the principal goals of this NIH Workshop on Menopause was to generate a set of recommendations to guide research in this important area of women's health. The individual working groups, representing a wide variety of disciplines and interests, identified a large number of specific cross= cutting scientific questions to be addressed. NATURAL HISTORY OF MENOPAUSE The need for longitudinal community-based studies that observe women over time, from younger premenopausal to older postmenopausal ages, was deemed essential for both basic and clinical studies to advance our knowledge of the natural history Of menopause and to indicate promising interventions to modify potentially adverse shortand long-term sequelae. Life-course research is needed to elucidate the parallels between premenopausal women who have premenstrual symptoms and perimenopausal women who become symptomatic as they traverse menopause. This research may reveal important biological and behavioral continuities bridging pre- and postmenopause. The proposed cohort studies should also focus on specific ethnic and racial groups, especially those from under-represented populations. Proposed longitudinal studies should identify and utilize a standardized core data set to permit comparison between studies and to provide the epidemiologic basis in various subgroups of women for future randomized clinical trials. The need to develop new methodologies for assessing menopause-related changes and their clinical manifestations was underscored: Of critical importance is research that examines the complex interactions between sociocultural, physiological, and biobehavioral aging processes. Multidisciplinary collaborations of clinicians with basic scientists using state-of-the-art methodologies from Correspondence to: Andrew A. Monjan. * Current Address: University of Miami School of Medicine, Miami, FL 33101. 525
526
A.^. MONJAN et al.
molecular and cellular biology can greatly expedite progress in our understanding of the fundamental processes of menopause and lead to improved strategies for maintaining health in middle and old age. BASIC R E S E A R C H IN THE OVARIAN AND N E U R O E N D O C R I N E SYSTEMS Central to research on menopause is the need to acquire a better understanding of the factors and processes governing the depletion of ovarian follicles--a major determinant of the age at which natural menopause will occur. Important questions to be addressed concern the endocrine, paracrine, and neuronal factors that trigger the primordial follicle to start its development, and regulate the growth and atresia of growing follicles. A critical avenue to explore lies in elucidating the effect of age-related changes in ovarian-dependent factors and their impact on neuroendocrine rhythms and ovarian follicular processes, particularly during the pre- to postmenopausal transition. Appropriate animal and in vitro models are also needed to overcome the traditional limitations involved in conducting in vivo research in humans. E F F E C T OF M E N O P A U S E ON BONE BIOLOGY AND THE LOSS OF BONE MASS One of the most prominent consequences of oophorectomy in humans and animals is the rapid loss of bone mass. Although striking advances have been made in our understanding of the pathophysiology of bone loss induced by estrogen deficiency, there are important unanswered questions regarding the role of endogenous factors and exogenous lifestyle variables in modulating rates of bone remodelling and bone loss during the pre- to postmenopausal transition. A better understanding of these ancillary factors is required to promote the development of effective preventive and therapeutic strategies for maintaining skeletal integrity in later life. Specific avenues of research suggested were to elucidate 1) the cellular, biochemical, and molecular changes caused by reduced ovarian steroid action in the bone and hematopoietic marrow interface, and 2) the mechanisms underlying menopause-induced changes in the response of bone and bone cells to mechanical stress. The effects of menopause on nonosseous, skeletal tissues, and the development and/or exacerbation of osteoarthritis was identified as an important under-researched area. Also emphasized was the need to formulate new therapeutic strategies, including potential "tissue-specific" estrogen agonists that can prevent bone and bone marrow changes. E F F E C T OF M E N O P A U S E ON VASCULAR DISEASE Current data strongly suggest that altered levels or action of estrogen, progesterone, and other hormones or the relative relationship between estrogenic and androgenic compounds resulting from changes in ovarian function may play a fundamental role in the pathophysiology of vascular disease. Clarifying the effect of the altered endocrine milieu as women age is critically important to understand gender differences in atherogenesis and in the incidence of cardiovascular disease outcomes. Research on the effects of menopause and hormone therapy on nonlipid-mediated genomic and nongenomic mechanisms of cardiovascular and renal pathophysiology was identified as an important emerging area. Considerable emphasis was placed on the need for devel-
RESEARCH RECOMMENDATIONS
527
opment and/or refinements in promising technologies (such as carotid ultrasound) to evaluate cardiovascular status or events of interest. Another goal identified was that of increasing our understanding of the changes induced by menopause and hormone therapy on parameters of lipid and carbohydrate metabolism, which are more sensitive and specific indices or modulators of atherosclerosis. EFFECTS OF MENOPAUSE ON BODY COMPOSITION The independent contributions of menopause and age on body composition need to be delineated, as do relationships between changes in body composition and the development of age-related disease. Potential mechanisms that could explain changes in body composition include genetic factors, changes in neuroendocrine function, changes in energy balance, and in certain lifestyle (e.g., physical activity) and psychosocial factors. Studies in different ethnic and racial groups of the differential effects of menopause and age on changes in body composition and risk factors for diseases such as cardiovascular disease, diabetes, and osteoporosis could generate new information of significant public health importance. PSYCHOSOCIAL ASPECTS OF MENOPAUSE A better understanding of the interrelationships between the physiological changes and psychosocial functioning during the pre- to postmenopausal transition is of profound importance in understanding short-term symptomatology and long-term pathophysiology. Important questions to address include the effect of hormonal changes during the perimenopausal transition on cognitive affective functioning, depression, mood states, sleep, and sexual behavior, and the extent to which changes potentially attributable to menopause are independent of the 'normal' aging processes. Randomized controlled trials of behavioral interventions are necessary to determine the efficacy of symptom management strategies, such as exercise, diet, and stress management, and nonpharmacologic preparations, such as dietary phytoestrogens, on symptoms and disease risk factors in menopausal women. Studies to understand the impact of menopause in women experiencing other concurrent life transitions and stresses (e.g., retirement of self, spouse, or partner; elder care giving; and widowhood) were encouraged. Finally, the risk-benefit impact of hormone therapy on the individual and the health system needs to be carefully evaluated. Given the emphasis on containing health care costs, it is imperative to evaluate the economic costs (and changes in use of the health care system) as well as the benefits of hormone therapy (changes in the risk of chronic diseases commonly associated with menopause). MENOPAUSAL STATUS AND MANAGEMENT STRATEGIES The impact of hysterectomy and/or oophorectomy on other physiological processes needs to be characterized. Also important and still poorly characterized are the influence of the cultural context and the psychosocial impact of hysterectomy and/or oophorectomy. Medical alternatives to hysterectomy and a better understanding of the differences between natural and surgical menopause await investigation. Issues of compliance with hormone therapy appear to be related to the patient's understanding of the effects produced by these hormones, but far more complex factors appear to be in-
528
A.A. MONJAN e t al.
volved in decision making. The effects of progestins (which are used in combination with estrogen to prevent endometrial cancer) on the cardiovascular and skeletal systems are unknown and deserving of attention. Although progestins (in combination with estrogens in postmenopausal women) have been used for many years, the effective progestin dose threshold to protect the endometrium is still controversial. It is of critical importance to establish minimal dosages, and to develop strategies to achieve more direct targeting of therapeutics, to minimize negative side effects. DISSEMINATION OF INFORMATION TO THE PUBLIC Current information available to the public about menopause is often confusing, in large part due to our poor understanding of the menopausal process. Special efforts must be made to disseminate information from research findings to health care practitioners and to women at the earliest opportunity. Research should reflect the questions that women have about menopause, such as: the nature and variety of menopausal symptoms; the most appropriate strategies to manage troublesome symptoms; the advantages and disadvantages of oophorectomy; potential health conditions, diseases, therapies (e.g., chemotherapy for cancer), and behavioral practices that influence the mode and timing of the onset of menopause; and the long-term health consequences of reduced ovarian functioning.
Experimental Gerontology, Vol. 29, Nos. 3/4, pp. 525-528, 1994 1994 ElsevierScienceLid Printed in the USA. All rights reserved 0531-5565/94 $6.00 + .00 0531-5565(94)E0023-U
Session VI. Research Directions
RESEARCH RECOMMENDATIONS ANDREW A. MONJAN, I FRANCIS L. BELLINO, 1 MARCIA G. ORY, 1 S H E R R Y SHERMAN 1 and SHARLENE WEISS 2'* 1National Institute on Aging, National Institutes of Health, Gateway Building, 7201 Wisconsin Ave., Bethesda, Maryland 20892 and 2National Institute for Nursing Research, National Institutes of Health, Westwood Building, Room 757, 5333 Westbard Avenue, Bethesda, MD 20892
MENOPAUSE-RELATEDresearch has generally focused on hormone therapy to alleviate postmenopausal health problems. Very little information is available regarding 1) the biological processes, particularly the mechanisms of ovarian follicular depletion, leading to menopause, and 2) the nature of the physiological and psychosocial changes during the pre- to postmenopausal transition. One of the principal goals of this NIH Workshop on Menopause was to generate a set of recommendations to guide research in this important area of women's health. The individual working groups, representing a wide variety of disciplines and interests, identified a large number of specific cross= cutting scientific questions to be addressed. NATURAL HISTORY OF MENOPAUSE The need for longitudinal community-based studies that observe women over time, from younger premenopausal to older postmenopausal ages, was deemed essential for both basic and clinical studies to advance our knowledge of the natural history Of menopause and to indicate promising interventions to modify potentially adverse shortand long-term sequelae. Life-course research is needed to elucidate the parallels between premenopausal women who have premenstrual symptoms and perimenopausal women who become symptomatic as they traverse menopause. This research may reveal important biological and behavioral continuities bridging pre- and postmenopause. The proposed cohort studies should also focus on specific ethnic and racial groups, especially those from under-represented populations. Proposed longitudinal studies should identify and utilize a standardized core data set to permit comparison between studies and to provide the epidemiologic basis in various subgroups of women for future randomized clinical trials. The need to develop new methodologies for assessing menopause-related changes and their clinical manifestations was underscored: Of critical importance is research that examines the complex interactions between sociocultural, physiological, and biobehavioral aging processes. Multidisciplinary collaborations of clinicians with basic scientists using state-of-the-art methodologies from Correspondence to: Andrew A. Monjan. * Current Address: University of Miami School of Medicine, Miami, FL 33101. 525
526
A.^. MONJAN et al.
molecular and cellular biology can greatly expedite progress in our understanding of the fundamental processes of menopause and lead to improved strategies for maintaining health in middle and old age. BASIC R E S E A R C H IN THE OVARIAN AND N E U R O E N D O C R I N E SYSTEMS Central to research on menopause is the need to acquire a better understanding of the factors and processes governing the depletion of ovarian follicles--a major determinant of the age at which natural menopause will occur. Important questions to be addressed concern the endocrine, paracrine, and neuronal factors that trigger the primordial follicle to start its development, and regulate the growth and atresia of growing follicles. A critical avenue to explore lies in elucidating the effect of age-related changes in ovarian-dependent factors and their impact on neuroendocrine rhythms and ovarian follicular processes, particularly during the pre- to postmenopausal transition. Appropriate animal and in vitro models are also needed to overcome the traditional limitations involved in conducting in vivo research in humans. E F F E C T OF M E N O P A U S E ON BONE BIOLOGY AND THE LOSS OF BONE MASS One of the most prominent consequences of oophorectomy in humans and animals is the rapid loss of bone mass. Although striking advances have been made in our understanding of the pathophysiology of bone loss induced by estrogen deficiency, there are important unanswered questions regarding the role of endogenous factors and exogenous lifestyle variables in modulating rates of bone remodelling and bone loss during the pre- to postmenopausal transition. A better understanding of these ancillary factors is required to promote the development of effective preventive and therapeutic strategies for maintaining skeletal integrity in later life. Specific avenues of research suggested were to elucidate 1) the cellular, biochemical, and molecular changes caused by reduced ovarian steroid action in the bone and hematopoietic marrow interface, and 2) the mechanisms underlying menopause-induced changes in the response of bone and bone cells to mechanical stress. The effects of menopause on nonosseous, skeletal tissues, and the development and/or exacerbation of osteoarthritis was identified as an important under-researched area. Also emphasized was the need to formulate new therapeutic strategies, including potential "tissue-specific" estrogen agonists that can prevent bone and bone marrow changes. E F F E C T OF M E N O P A U S E ON VASCULAR DISEASE Current data strongly suggest that altered levels or action of estrogen, progesterone, and other hormones or the relative relationship between estrogenic and androgenic compounds resulting from changes in ovarian function may play a fundamental role in the pathophysiology of vascular disease. Clarifying the effect of the altered endocrine milieu as women age is critically important to understand gender differences in atherogenesis and in the incidence of cardiovascular disease outcomes. Research on the effects of menopause and hormone therapy on nonlipid-mediated genomic and nongenomic mechanisms of cardiovascular and renal pathophysiology was identified as an important emerging area. Considerable emphasis was placed on the need for devel-
RESEARCH RECOMMENDATIONS
527
opment and/or refinements in promising technologies (such as carotid ultrasound) to evaluate cardiovascular status or events of interest. Another goal identified was that of increasing our understanding of the changes induced by menopause and hormone therapy on parameters of lipid and carbohydrate metabolism, which are more sensitive and specific indices or modulators of atherosclerosis. EFFECTS OF MENOPAUSE ON BODY COMPOSITION The independent contributions of menopause and age on body composition need to be delineated, as do relationships between changes in body composition and the development of age-related disease. Potential mechanisms that could explain changes in body composition include genetic factors, changes in neuroendocrine function, changes in energy balance, and in certain lifestyle (e.g., physical activity) and psychosocial factors. Studies in different ethnic and racial groups of the differential effects of menopause and age on changes in body composition and risk factors for diseases such as cardiovascular disease, diabetes, and osteoporosis could generate new information of significant public health importance. PSYCHOSOCIAL ASPECTS OF MENOPAUSE A better understanding of the interrelationships between the physiological changes and psychosocial functioning during the pre- to postmenopausal transition is of profound importance in understanding short-term symptomatology and long-term pathophysiology. Important questions to address include the effect of hormonal changes during the perimenopausal transition on cognitive affective functioning, depression, mood states, sleep, and sexual behavior, and the extent to which changes potentially attributable to menopause are independent of the 'normal' aging processes. Randomized controlled trials of behavioral interventions are necessary to determine the efficacy of symptom management strategies, such as exercise, diet, and stress management, and nonpharmacologic preparations, such as dietary phytoestrogens, on symptoms and disease risk factors in menopausal women. Studies to understand the impact of menopause in women experiencing other concurrent life transitions and stresses (e.g., retirement of self, spouse, or partner; elder care giving; and widowhood) were encouraged. Finally, the risk-benefit impact of hormone therapy on the individual and the health system needs to be carefully evaluated. Given the emphasis on containing health care costs, it is imperative to evaluate the economic costs (and changes in use of the health care system) as well as the benefits of hormone therapy (changes in the risk of chronic diseases commonly associated with menopause). MENOPAUSAL STATUS AND MANAGEMENT STRATEGIES The impact of hysterectomy and/or oophorectomy on other physiological processes needs to be characterized. Also important and still poorly characterized are the influence of the cultural context and the psychosocial impact of hysterectomy and/or oophorectomy. Medical alternatives to hysterectomy and a better understanding of the differences between natural and surgical menopause await investigation. Issues of compliance with hormone therapy appear to be related to the patient's understanding of the effects produced by these hormones, but far more complex factors appear to be in-
528
A.A. MONJAN e t al.
volved in decision making. The effects of progestins (which are used in combination with estrogen to prevent endometrial cancer) on the cardiovascular and skeletal systems are unknown and deserving of attention. Although progestins (in combination with estrogens in postmenopausal women) have been used for many years, the effective progestin dose threshold to protect the endometrium is still controversial. It is of critical importance to establish minimal dosages, and to develop strategies to achieve more direct targeting of therapeutics, to minimize negative side effects. DISSEMINATION OF INFORMATION TO THE PUBLIC Current information available to the public about menopause is often confusing, in large part due to our poor understanding of the menopausal process. Special efforts must be made to disseminate information from research findings to health care practitioners and to women at the earliest opportunity. Research should reflect the questions that women have about menopause, such as: the nature and variety of menopausal symptoms; the most appropriate strategies to manage troublesome symptoms; the advantages and disadvantages of oophorectomy; potential health conditions, diseases, therapies (e.g., chemotherapy for cancer), and behavioral practices that influence the mode and timing of the onset of menopause; and the long-term health consequences of reduced ovarian functioning.