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a Biology of Aging Program, National Institute on Aging, Gateway Bldg., Bethesda, Maryland 20892-9205
b Division of Biological Sciences, University of California at Davis, Davis, California 95616-8536
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONBIOLOGICAL MECHANISMS UNDERLYING...PHYSIOLOGICAL AND...SUMMARYREFERENCES |
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aging, neuroendocrinology, ovary, pituitary hormones, steroid hormones
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONBIOLOGICAL MECHANISMS UNDERLYING...PHYSIOLOGICAL AND...SUMMARYREFERENCES |
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Research is the only way to answer these questions and to deepen our understanding so that we can begin to address the challenges presented by menopause. The amount and types of research that can be conducted directly in women are extremely limited for ethical, practical, and financial reasons. Therefore, we must turn to animal models to shed light on the biology of menopause. Animal species that experience a similar menopausal process at a stage of their life history comparable to that in women present advantages because of the ability to utilize tighter control of genetic constitution and variation in experimental populations and to perform invasive research under controlled experimental conditions. Whether a true animal model of human menopause exists will be clear only after extensive comparative studies. Nonprimate species show substantial differences in reproductive and reproductive aging processes compared with humans, but some of these species, when ovariectomized, may provide appropriate models for postmenopausal health problems [1–3]. Nonhuman primates (NHPs) hold great promise, because some species appear to undergo a process very similar to that which women experience across menopause. However, some important differences, such as substantially shorter postmenopausal life span and differences in the timing of hormonal changes during the menopausal transition, appear to exist. Until sufficient data are obtained, we cannot know whether these differences are genetically determined, species-related differences or whether they result from differences in the environment and/or nutrition of NHPs, nor do we know if these differences compromise the NHP as a model of human menopause.
The purpose of this workshop, the latest in a series on animal models of menopause sponsored by the National Institute on Aging (NIA) [3], was to review what is known about the female reproductive aging process in various species of monkeys, including hormone profiles during the menopausal transition, the occurrence of hot flashes, the extent of age-related and menopause-associated changes in hormone levels on metabolism, bone loss, and impaired cardiovascular and cognitive function. With this information, we will be able to evaluate which species of NHP are most likely to shed light on the mechanisms and repercussions of human menopause and to strategically encourage and fund further research that will lead to increased quality of life for postmenopausal women.
This workshop, held in January 2001, took the form of an advisory workshop for the NIA. Experts (workshop speakers: Dr. K.D. Carey, Southwest Foundation for Biomedical Research; Dr. Thomas Clarkson, Wake Forest University School of Medicine; Dr. Robert Freedman, Wayne State University; Dr. Ken Gould, Yerkes Regional Primate Research Center; Dr. Joseph Kemnitz, Wisconsin Regional Primate Research Center; Dr. Firyal Khan, University of Texas Medical School at Houston; Dr. Mark Lane, Gerontology Research Center, NIA; Dr. Bill Lasley, University of California at Davis; Dr. Naomi Rance, University of Arizona College of Medicine; Dr. M. Susan Smith, Oregon Regional Primate Research Center; Dr. Marc Tatar, Brown University; and Dr. Mary Lou Voytko, Wake Forest University School of Medicine) in particular scientific areas (female reproductive aging, neuroendocrine aging, bone physiology, vasomotor instability, metabolism, cardiovascular function, and cognitive function) presented the results of their studies using various NHP species (rhesus, baboon, chimpanzee, and cynomolgus) as well as similar studies from other laboratories. Workshop participants included an advisory panel (Dr. Phyllis Wise, University of Kentucky at Lexington [chair]; Dr. Lewis Kuller, University of Pittsburgh; Dr. Stavros Manolagas, University of Arkansas for Medical Sciences; Dr. Nanette Santoro, Albert Einstein College of Medicine; Dr. James Simpkins, University of North Texas Health Science Center at Fort Worth; and Dr. Jeanne Wei, Beth Israel Deaconess) that served as a subgroup of the National Advisory Council on Aging. Following the expert presentations and extensive discussion among all workshop participants, the advisory panel constructed a set of research recommendations (available at http://www.nia.nih.gov/research/meetings/primodelreport.htm) to the Director, NIA, to further develop this important area of research.
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BIOLOGICAL MECHANISMS UNDERLYING MENOPAUSE |
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TOPABSTRACTINTRODUCTIONBIOLOGICAL MECHANISMS UNDERLYING...PHYSIOLOGICAL AND...SUMMARYREFERENCES |
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Characterization of ovarian and pituitary function during female reproductive aging in rhesus monkeys, baboons, and chimpanzees is based on presentations by Dr. Bill Lasley (University of California at Davis), Dr. Firyal Khan (University of Houston), Dr. K.D. Carey (Southwest Foundation for Biomedical Research), Dr. Marc Tatar (Brown University), and Dr. Kenneth Gould (Yerkes Regional Primate Research Center). A moderate number of studies have examined the female reproductive aging process of NHPs, including studies of both captive [4–16] and free-ranging animals [17–19].
Rhesus monkey A recent study [15] revealed that urinary estrogen and progestin profiles of female rhesus monkeys during the menopausal transition are similar to those of women. However, certain hallmarks of the reproductive aging process in women may be absent in regularly cycling, older rhesus monkeys. Specifically, the monotropic rise in FSH, decline in inhibin B, and episodically high estrogen levels seen in regularly cycling, middle-aged women before the onset of irregular cycles [20, 21] are not apparent in middle-aged macaques before the onset of irregular menstrual cyclicity [16]. Using four groups of rhesus monkeys categorized by menstrual cycle status and pattern (three to six animals per group), the investigators concluded that in contrast to women, in whom menopause-related changes in hormonal outputs of the pituitary and ovary appear gradually, starting in middle-aged, regularly cycling women, older female rhesus show more abrupt changes, starting when cycles begin to become irregular [16]. Perhaps age-related changes play a more prominent role in the development of menopause in women than in rhesus monkeys. This type of study should be repeated and extended using larger groups of animals to confirm these interesting findings.
Baboon
Virtually no information is available in the published literature regarding the menopausal process in baboons. In the baboon, reproductive- and menopause-related research is facilitated by the ability to readily discern menstrual cycle status via the skin color and physical changes of the perineum rather than by the need to rely on blood or urinary hormonal measurements [22, 23]. An unpublished pilot study provided data showing that in middle-aged (
15 yr) female baboons with irregular cycles, as defined by the criteria of Chen et al. [24], when averaging short and long irregular cycles over the perimenopausal period, no change was observed in average length of cycle (34.4 days), nor was a difference observed in serum androstenedione, total or free testosterone, insulin-like growth factor (IGF)-I, or IGF binding protein-I. As in women, baboons with irregular cycles had a shorter follicular phase and were more frequently anovulatory. Relative to premenopause, FSH and LH were elevated in irregularly cycling animals; plasma progesterone, estrone, estradiol, and inhibin A were lower during the luteal phase; and inhibin B was lower in the follicular phase.
Several reproductive indices measured in wild baboons [19] were similar to those measured in captive animals (unpublished data from the Southwest Foundation for Biomedical Research). Wild and captive baboons both had the same exponential trajectory of adult mortality. Both populations were completely infertile at 25 yr of age. The mean menstrual cycle length for both is constant from 5 to 20 yr of age (
38 days in the wild and 33 days in captive populations). However, some differences between the wild and captive baboons were evident. A longer peak fertile period occurred in the wild (5–21 yr of age) relative to the captive animals (7–17 yr of age), which is likely due, at least in part, to husbandry practices that limit opportunities for mating in the captive population. Wild animals showed an abrupt decline in fertility, whereas captive animals showed a more gradual decline. Mean cycle irregularity markedly increased at 19 yr in captive animals, compared to 23 yr in wild baboons. In 18 captive baboons who survived beyond 24 yr, the mean age at menopause was 26.3 yr and the mean perimenopausal duration 7.4 yr, similar to humans [25].
Chimpanzee To our knowledge, only two studies examining hormonal changes in very old female chimpanzees have been published [5, 26]. The general conclusion based on the study of only 12 animals is that Pan troglodytes have menstrual cycles right up to the end of life, or that cycles terminate only within the last year of life. A small decline in cycle frequency occurred in animals older than 35 yr (8.6 cycles/yr) relative to animals from 15 to 25 yr (9.5 cycles/yr); the cycle length was longer in the older animals (35.6 vs. 32.2 days/cycle). Only the conception rate showed profound age-related differences (20% at 15–25 yr of age and <4% at >35 yr of age). A single P. paniscus [5], aged more than 40 yr (precise age was unknown, because the animal was captured in the wild when already postmature), was observed to be postmenopausal based on terminated menstrual cycles, elevated gonadotropins, and a response to GnRH challenge similar to that of a postmenopausal woman. Thus, the intact chimpanzee appears to be poorly suited as a model of human menopause, not only because of continued cycling until very late in life but also because of the very limited numbers of older females available for research. We are not aware of any studies regarding the consequences of ovariectomy, with or without estrogen replacement, in the middle-aged female chimpanzee in terms of bone density, cardiovascular function, and other physiologic systems associated with menopausal health problems.
Neuroendocrine System Changes Across Menopause
This discussion of aging of the reproductive neuroendocrine system is based on presentations by Dr. M. Susan Smith (Oregon Regional Primate Research Center) and Dr. Naomi Rance (University of Arizona).
Several ongoing, unpublished neuroendocrine studies related to female reproductive aging in rhesus monkeys at the Oregon Regional Primate Research Centers were described. The LH pulse amplitude of irregularly cycling monkeys was greater than that in premenopausal animals; in postmenopausal monkeys, the LH pulse pattern was similar to that in young, long-term ovariectomized female rhesus monkeys. Determination of changes in LH pulse frequency, which is more difficult because of variation in frequency throughout the cycle and low pulse amplitudes, are not yet complete. Expression of several genes involved in neurotransmitter synthesis or responsiveness to estrogen declined in various brain regions of middle-aged, irregularly cycling animals relative to young animals. Some of these changes were reversible by estrogen treatment, such as estrogen receptor 
in catecholaminergic brain stem areas, and level of choline acetyltransferase. Others, such as the norepinephrine transporter in the locus coeruleus, were not restored by estrogen treatment. The former category may reflect changes in hormone patterns more than the effects of age, whereas the latter category may reflect markers of aging [27]. In another study, the expression of melatonin receptor (Mel 1a) decreased in the suprachiasmatic nucleus in middle-aged monkeys before menopause, suggesting that age-related changes in the neuroendocrine circadian circuitry begin before menopause [28, 29].
Current studies using postmortem brain tissue from postmenopausal women may be confirmed and extended in the NHP model. For example, hypertrophied neuronal tissue from the infundibular nucleus of postmenopausal women express estrogen receptor, neurokinin B, and substance P mRNAs [30]. The GnRH gene expression increased in a separate subpopulation of neurons within the medial basal hypothalamus [31]. Additional studies using postmortem brain tissue from postmenopausal women documented a decrease in the numbers of neurons expressing pro-opiomelanocortin (POMC) gene transcripts [32]. Because of the diverse role of POMC in various physiologic processes, this loss may considerably affect the physiology of postmenopausal women. However, many inherent limitations exist in the use of human autopsy specimens. For example, because of the effects of stress on the reproductive axis, subject selection should be limited to patients experiencing sudden death and without a history of significant chronic illness. Collection of these materials is a slow process, and the acquisition of autopsy specimens from subjects with well-documented hormone replacement therapy is exceedingly difficult. More importantly, the interpretation of data comparing pre- and postmenopausal women is complicated by the presence of two major variables: age and ovarian status.
Because of these limitations, young ovariectomized cynomolgus monkeys are currently being used as a model to study the effects of hormonal manipulation on hypothalamic neuropeptide gene expression. This model has the advantages of removing the confounding influence of age and of allowing hormone replacement in regimens that mimic those given to postmenopausal women. These studies in monkeys also have obvious advantages compared with human studies. Invasive studies permit access to brain tissue to explore effects in the brain associated with loss of estrogen, either through natural menopause or via ovariectomy, and subsequent replacement of estrogen. Studies using brain tissue from ovariectomized cynomolgus monkeys suggest that neurokinin B mRNA [33], which is observed to be present in hypertrophied neurons of the infundibular nucleus in human autopsy specimens from postmenopausal women, was repressed by estrogen in the monkeys. In contrast, in the same study, no effect of ovariectomy and estrogen replacement was observed on POMC neurons in the infundibular nucleus, suggesting lack of regulation by estrogen.
An unanswered question that needs further study is the suitability of the ovariectomized young monkey as a model for the postmenopausal human. Although the ultimate result of both normal menopause and surgical menopause is the same (i.e., cessation of menstrual cycles and infertility), the repercussions on a woman's health may differ because of age and rate of loss of estradiol and other ovarian hormonal factors. Hence, changes in reproductive hormones may result in a broader spectrum of effects in an older individual than when they occur in a younger woman who is experiencing fewer age-related changes in other systems.
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PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL CHANGES ASSOCIATED WITH MENOPAUSE |
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TOPABSTRACTINTRODUCTIONBIOLOGICAL MECHANISMS UNDERLYING...PHYSIOLOGICAL AND...SUMMARYREFERENCES |
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This discussion of the metabolic characteristics of aging in male and female monkeys is based on presentations by Dr. Joseph Kemnitz (Wisconsin Regional Primate Research Center) and Dr. K.D. Carey (Southwest Foundation for Biomedical Research).
Rhesus monkey Longitudinal and cross-sectional measurements were made using primarily indoor-housed rhesus monkeys. Body weight was reasonably stable from 10 to 20 yr of age, with males weighing more than females [34]. Rhesus monkeys older than 25 yr tended to lose weight, primarily from loss of skeletal muscle [35]. Females had greater body fat relative to body weight [36]. Visceral fat deposition increased after menopause but appeared to be related more to age than to menopausal status [36]. Estrogen inhibited food intake in females in a dose-dependent manner [37]; progesterone attenuated the effects of estrogen when the two were administered together. Energy expenditure tended to be lower in the oldest group of females (age, 28–37 yr) [36].
Approximately 50% of rhesus monkeys older than 20 yr had abnormal glucose tolerance relative to young adults. Approximately half these monkeys exhibited hyperinsulinemia associated with increased adiposity, whereas the other half showed reduced insulin secretion in response to glucose challenges. Overall, females had better glucose tolerance and insulin secretion after glucose challenge than males [36]. Dehydroepiandrosterone (DHEA) declined gradually with age [38], and supplementation with DHEA lowered cholesterol in middle-aged rhesus monkeys [39].
Previous studies of metabolic parameters in middle-aged and older female rhesus monkeys generally provided limited documentation of the hormonal profile or their menopausal status. Furthermore, these studies used a cross-sectional rather than a longitudinal experimental design. Therefore, it is impossible to identify the temporal sequence of events in individual animals and their interrelationships with menopause. A better understanding may be forthcoming when two ongoing studies of caloric restriction (at the NIA Intramural Program and the Wisconsin Regional Primate Research Center) are complete. These studies maintain control groups that will yield substantive information regarding normative aging when completed. The female monkeys in these studies are currently 14–20 yr of age and are approaching a time when menopause-related symptoms and conditions will begin to occur.
Baboon In an unpublished study, a cohort of 26 nondiabetic female baboons (age, 9–18 yr) with body fat greater than 20% and exhibiting regular menstrual cycles as well as normal complete blood counts and serum chemistry profiles was used to examine the effect of increasing age and obesity on fasting lipids, glucose, and insulin levels. When examined 5 yr later, the 15 animals remaining in the cohort were still cycling regularly but exhibiting subtle signs of impending irregular cycles. Both weight and percentage body fat had increased, but only weight had increased significantly. Glucose had increased significantly, so that all animals were hyperglycemic. Despite a significant decrease in insulin, all but two animals remained hyperinsulinemic. Triglyceride levels were normal and did not change. A slight decrease had occurred in serum total cholesterol, but an increase in low-density lipoprotein (LDL) cholesterol, a significant decrease in high-density lipoprotein (HDL) cholesterol, and a significant increase in the LDL:HDL cholesterol ratio had also occurred. Thus, conditions associated with increased risk of coronary heart disease in aging women, such as obesity, altered lipoproteins, and increases in fasting glucose and insulin, also occur in aging female baboons.
Menopausal Hot Flashes
This discussion of menopausal hot flashes is based on the presentation by Dr. Robert Freedman (Wayne State University).
Rhesus monkeys are excellent models to study the menopausal hot flash, because their reproductive and thermoregulatory systems are very similar to those of humans. Like humans [40], core body temperature (Tc) in rhesus monkeys is regulated between an upper threshold for sweating and a lower threshold for shivering. Within the intervening thermoneutral zone, fine adjustments in Tc are effected by vasomotor control. Sweating is the primary means of evaporative cooling in both species. The histology, histochemistry, relative distribution, mean weighted density, and percentage body surface area containing sweat glands are very similar in rhesus monkeys and in humans [41]. Hypothalamic heating in rhesus monkeys produced a significant linear relationship between hypothalamic temperature and sweating rate, as most probably occurs in humans [42]. Thus, the anatomical and physiological similarities make the rhesus monkey an excellent analogue for the study of thermoregulatory phenomena such as hot flashes.
Two previous studies focused on hot flashes in monkeys. One [43] used rhesus monkeys (three adult females aged 9–14 yr) and was of relatively short duration (a few weeks) after ovariectomy with or without estrogen treatment. Spontaneous temperature fluctuations at the ear pinna were particularly prominent after ovariectomy, and estrogen-replacement therapy tended to reduce these fluctuations. However, statistical significance was unclear. In the other [44], two female ovariectomized stumptail macaques showed forehead temperature fluctuations that were significantly reduced by estrogen.
Cardiovascular Changes Preceding and Following Menopause
This discussion of cardiovascular changes preceding and following menopause is based on presentations by Dr. K.D. Carey (Southwest Foundation for Experimental Biology) and Dr. Thomas Clarkson (Wake Forest University School of Medicine).
Cardiovascular disease is the leading cause of morbidity and mortality in older women. Menopause and aging increase the risk for atherosclerosis and coronary artery disease, two major components of cardiovascular disease. An altered lipid profile is thought to be associated with this increased risk.
Baboon The middle-aged female baboon may be an appropriate model for the effects of reproductive aging on atherogenesis in humans. The baboon menstrual cycle is similar to the human cycle, and the baboon experiences a menopausal transition similar to that of women. On an atherogenic diet, increased LDL cholesterol (relative to that on a basal diet) was observed in regularly and irregularly cycling, middle-aged females, with only regularly cycling animals showing increased HDL cholesterol, resulting in a more atherogenic LDL:HDL cholesterol ratio in irregularly cycling animals [24]. Fatty streaks and occasional fibrous plaques were observed on the atherogenic diet, and the extent of lesions was positively correlated with the LDL:HDL cholesterol ratio. However, the lesions were not as extensive as in macaques on similar protocols. Animals with increased age and obesity, but not necessarily with irregular cycles, produced lipoprotein profiles that resemble those associated with irregular cycles.
Studies in ovariectomized female baboons have demonstrated that estrogen, either alone or in combination with progesterone, reduced plasma LDL cholesterol levels. Animals treated with estrogen plus progesterone had the least fatty streaks, whereas those treated with progesterone alone had the most [45].
Cynomolgus monkey Surgically postmenopausal cynomolgus monkeys on an atherogenic diet, like postmenopausal women, had elevated LDL cholesterol, reduced HDL cholesterol, and increased vasoconstrictor response and coronary artery atherosclerosis relative to control, intact monkeys fed the same diet for the same time [46]. Using continuous exposure to physiologic amounts of estrogen, with or without cyclically administered progestin, over 30 mo, coronary artery atherosclerosis was reduced to approximately half in animals treated with steroid hormone [47], largely independently of plasma lipid changes. The LDL cholesterol accumulation within coronary and other arteries in ovariectomized cynomolgus monkeys was significantly decreased by estrogen plus progestin treatment [48, 49].
In studies focused on vascular reactivity, surgically menopausal monkeys with no ovarian hormone replacement showed coronary artery vasoconstriction after an acetylcholine infusion, whereas their counterparts with physiologic replacement of estradiol had vasodilation after the acetylcholine infusion. Coadministration of progestin attenuated this effect [50, 51].
Physiologic effects of dietary interventions are more easily studied in NHPs, in which access to diet and environmental conditions are more rigorously controlled than in community-dwelling women. Either soy phytoestrogens or conjugated equine estrogens administered to ovariectomized cynomolgus monkeys on a moderately atherogenic diet decreased atherosclerotic plaque progression relative to controls; the conjugated equine estrogen was more effective [52].
In attempts to make the ovariectomized cynomolgus monkey an even better model for human menopause, androstenedione implants will be used to more closely replicate hormonal profiles of postmenopausal women.
Bone Changes Caused by Aging and Menopause
This discussion of bone changes caused by aging and menopause is based on presentations by Dr. Mark Lane (Gerontology Research Center, NIA) and Dr. Thomas Clarkson (Wake Forest University School of Medicine).
Three issues of interest for bone studies in middle-aged and older animals are age-related bone loss before menopause, bone loss following natural menopause or ovariectomy, and protection from postmenopausal bone loss by estrogen. Bone loss during aging, particularly in premenopausal monkeys, is not well characterized. Major concerns with early studies [53–55] that reported loss of bone mass with age in rhesus monkeys are the insufficient numbers of older animals studied; the failure to distinguish pre-, peri-, and postmenopausal animals; and the varied methodologies used to assess bone loss and the skeletal sites examined. A recent review article [56] provides an overview of the use of NHPs to study postmenopausal osteoporosis; results summarized from many studies show that the bone response to many interventional hormones and drugs in baboons, cynomolgus monkeys, or rhesus monkeys agrees well with currently available knowledge regarding the actions of these compounds in women.
Rhesus monkey Several recent studies have begun to address these concerns. One study [57] examined 178 female rhesus monkeys aged 2–34 yr. No evidence of change with age in total body and spine density was reported; however, small but significant reductions of bone mineral density (BMD) in radial sites were seen. The second study [58] utilized 58 female rhesus monkeys aged 4–30 yr and reported reduced bone mass in older postmenopausal monkeys at the total body, spine, and distal radius sites. Another study [59] reported slight but significant reductions in lumbar vertebrae BMD from 131 female rhesus skeletons aged 17–22 yr. Finally, a study in 20 premenopausal rhesus monkeys aged 8–23 yr [60] reported a significant age-associated bone loss at two radial sites, estimated at less than 5% per year in monkeys that reached peak bone mass, but not for total body or spine bone mass. The influence on bone remodeling of the approximately 10-fold larger amounts of calcium and vitamin D, and of the soy-based diet containing phytoestrogens, in monkey chow relative to the average human diet is unknown.
These data support a slight reduction in bone mass in females between the ages of peak bone mass and menopause. Thus, rhesus monkeys may represent a valuable model of human age-dependent bone loss. A major concern, however, is that unlike humans, female rhesus monkeys apparently do not lose significant vertebral bone mass before menopause. Whether the rate of bone loss accelerates after menopause in female rhesus monkeys is not known. Thus, additional studies of the peri- and postmenopause conditions are needed.
Cynomolgus monkey
Bone loss in cynomolgus monkeys occurred only when the animals were ovariectomized after reaching peak bone mass (12 yr of age) [61]. Cortical bone remodeling was stimulated by ovariectomy and decreased by estrogen treatment [62]. Initiating hormone replacement, even 2 yr following ovariectomy, protected against bone loss [63].
Cognitive Changes During Menopause
This discussion of cognitive changes during menopause is based on the presentation by Dr. Mary Lou Voytko (Wake Forest University School of Medicine).
Results from studies in women regarding the role of menopause in altering cognitive function relative to all other factors associated with middle age are conflicting. Most studies have been observational rather than prospective, randomized clinical trials. Thus, they are more susceptible to potential biases. Also, the majority of these studies have examined mixed populations (i.e., surgical and natural menopause) of women. This highlights the need to develop suitable animal models to achieve the controlled conditions that are likely to lead to more definitive results.
Several studies have focused on the effects of ovariectomy on cognitive abilities in NHPs. In one study, utilizing young ovariectomized cynomolgus monkeys so that the effect of estrogen loss could be explored in the absence of age changes, estrogen treatment modulated visuospatial attention function but not aspects of visual learning, cognitive flexibility, or spatial memory [64–66]. Another study showed that learning and performance of the spatial memory task, delayed response, was impaired in irregularly cycling or postmenopausal, middle-aged rhesus monkeys compared to middle-aged or young monkeys with regular menstrual cycles [67]. Similarly, in a small study using surgically menopausal middle-aged (age, 22 yr) rhesus monkeys, both delayed response performance and visuospatial attention function were altered in placebo-treated, but not in estrogen-treated, monkeys [68]. These observations in older monkeys are in contrast to observations in young monkeys, in which performance on the delayed response task was not responsive to ovariectomy or to treatment with estrogen [65]. Finally, rhesus monkeys (age, 8–27 yr) who had undergone early ovariectomy (age, 7–14 yr) showed a trend for worse performance in a visual recognition memory task but demonstrated significantly better performance in a spatial recognition span task in comparison to intact controls [69].
Various studies in postmenopausal women regarding the effects of estrogen or of estrogen plus progestin replacement on cerebral blood flow or increased activation patterns in specific brain regions [70–74] have provided only nonspecific information about response to estrogen in the primate brain. Clearly, additional studies using animal models are required to more fully appreciate the specific effects that these hormones exert on the functional activity and neurobiology of the brain. Two recent studies in rhesus monkeys indicate that ovariectomy reduced the density of tyrosine hydroxylase- and choline acetyltransferase-positive fibers in the prefrontal cortex and that either estrogen alone or estrogen plus progestin prevented some of this fiber loss [75, 76]. In addition, other preliminary studies in monkeys suggest that ovariectomy reduces the number and size of cholinergic neurons of the basal forebrain [77]. Preliminary functional imaging studies indicate that estrogen replacement enhances the functional activity of the cholinergic and dopaminergic systems [78] and that this enhancement continues to be realized for some time following estrogen withdrawal.
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SUMMARY |
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TOPABSTRACTINTRODUCTIONBIOLOGICAL MECHANISMS UNDERLYING...PHYSIOLOGICAL AND...SUMMARYREFERENCES |
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Apparent Similarities Between NHP and Human Menopause/Aging
Similarities in the female reproductive aging process between NHPs and humans that were presented and discussed at the workshop include 1) general parallelisms in urinary hormone profiles (estrogen, progestin, inhibin, and FSH) across the transition from regular through irregular to terminated cycles in NHPs; 2) progression from regular to irregular cycles in rhesus monkeys, baboons, and chimpanzees, and then to termination of menstrual cycles with at least several years of life remaining in rhesus monkeys and baboons; and 3) fertility in baboons and chimpanzees, which declines substantively in older cycling females.
Additional similarities are seen in nonreproductive measures between aging human and NHP females. These include age-related changes in metabolic parameters of rhesus monkeys and baboons that are similar to those in humans, such as gains in weight and increases in relative body fat content, with tendencies toward abnormal glucose tolerance and increased insulin resistance, up until old age, when body weight and fat decline. Levels of DHEA decline with age in rhesus monkeys, as is well established in humans. The apparent similarity of the internal temperature regulation system of NHPs and humans suggests that the NHP may be an appropriate model of hot flashes associated with menopause, permitting both invasive experimentation to understand the underlying biological mechanisms and potential preventative and interventional approaches to reduce the incidence of hot flashes in both peri- and postmenopausal women. Older cycling baboons show increased LDL and decreased HDL cholesterol relative to levels seen when 5 yr younger, suggesting an age-related increase in risk factors for cardiovascular disease. Although baboons appear to be less susceptible to atherogenesis than rhesus monkeys, fatty streaks, occasional fibrous plaques, and an atherogenic lipid profile were observed in baboons associated with a high-fat diet and irregular menstrual cycles, increased age, or increased obesity. Plasma LDL cholesterol and fatty streaks were responsive to estrogen treatment in ovariectomized baboons. Estrogen also reduces coronary artery atherosclerosis and reverses acetylcholine-induced vasoconstriction in ovariectomized cynomolgus monkeys fed a high-fat diet, but without a large effect on plasma lipid levels. Age-related changes in bone density have been reported; however, more studies are needed before we can determine whether age- or menopause-related changes occur in NHPs parallel to those in humans.
Whether cognitive decline occurs concomitant with reproductive decline and/or aging is unclear. Limited data gathered from studies of surgically or naturally menopausal NHPs suggest that estrogen states can modulate cognitive function in both young and old monkeys. However, the specific cognitive processes that may be influenced by estrogen may depend on age, with multiple domains being affected in older subjects. Although the findings of altered aspects of memory and attention processes in older, surgically menopausal monkeys mirror the findings obtained in several studies of nondemented postmenopausal women, it is difficult to directly relate the observations between monkeys and women because of differences in the instruments used to measure cognitive processes and the specific cognitive domains that have been measured between studies. Also, because of greater access to brain tissue, NHP studies are more likely to reveal underlying mechanisms for altered cerebral blood flow or brain activation patterns seen in imaging studies from women at various stages of the menopausal process, or the effects of estrogen in postmenopausal women. For example, several studies have demonstrated similarities in menopause- and age-related changes in gene expression in the brains of surgically menopausal monkeys compared to those observed in autopsy studies of postmenopausal women.
Research Approaches to Explore Apparent Differences Between NHP and Human Menopause/Aging
Important differences between NHP and human females must be considered. First, the length of the postmenopausal life span is considerably shorter in NHPs, probably not more than 6–7 yr in rhesus monkeys and baboons and less than 1 yr in chimpanzees, and relative to women, NHPs are much older when experiencing the menopausal process (Table 1). Whether this substantial difference in total and postmenopausal life span between NHPs and women results from diet or environmental factors, or whether this is a true genetically determined difference, is unclear. Are there ways to increase the average and maximum life span of these NHP species? We know that at the start of the 20th century, few women lived much past the age of menopause (50 yr). With the advent of enhanced knowledge regarding health-related biological processes and improved medical procedures, the average life span of women has increased substantially, whereas the age of menopause has not changed. Can something similar be done for NHPs? Perhaps through improved husbandry, diet, and medical care, their average life span can also be increased substantially, so that they enter menopause at a relatively younger age.
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Second, the timing and magnitude of changes in several key hormones related to human menopause appears to be different in NHPs. Preliminary data using a small cohort of rhesus monkeys suggests that the sentinel monotropic increase in FSH secretion and declining inhibin B level reported in normally cycling, middle-aged women did not occur in rhesus monkeys until cycles become irregular. This finding needs to be replicated with larger numbers of animals. Also, increased estrogen levels seen in perimenopausal women relative to midreproductive-aged women [21] have not been observed in irregularly cycling rhesus monkeys and baboons.
Third, seasonal menstrual cycles in rhesus monkeys may confound reproductive aging studies. Seasonality should be considered when interpreting studies of reproductive aging and the pathophysiology of menopause-related health problems and conditions.
Fourth, many of the studies exploring health and cognitive changes associated with surgical menopause, and the effects of estrogen on these changes, utilized young adult NHPs. Whether pathophysiologic changes associated with ovariectomy are independent of age at surgery is not known. It is reasonable to anticipate that older adult animals may respond differently than younger adults to ovariectomy and estrogen replacement because of age-related changes in the biological processes underlying tissue function. This important issue has not been adequately addressed. For example, the studies summarized at the workshop using ovariectomized cynomolgus monkeys involved relatively young animals (average age, 8–10 yr). That same laboratory has recently changed to somewhat older animals (age, >12 yr), so that animals achieve peak bone mass [56] before ovariectomy.
Finally, the numbers of appropriate older female NHPs available and useful for these studies are very limited. Investigators interested in research using NHPs who do not have direct access to adequate numbers of animals may consult with National Institutes of Health staff to determine what possibilities exist for obtaining appropriate animals (information regarding available animals may be obtained from NIA or National Center for Research Resources (NCRR) websites or staff contact information provided therein: NCRR, http://www.ncrr.nih.gov/compmed/cm_nprc.asp; NIA, http://www.nia.nih.gov/research/resources.htm).
Use of the NHP as a Model for Human Menopause
In conclusion, use of the NHP as a model for human menopause appears promising, but continued research is needed to confirm this. With an appropriate animal model, research on menopause will go forward to provide important new information for women, permitting a better understanding and anticipation of their menopausal experience as well as information to prevent or ameliorate menopause-associate health problems during their extensive postmenopausal life span.
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2 Correspondence: Francis Bellino, Biology of Aging Program, National Institute on Aging, 7201 Wisconsin Ave., Suite 2C231, Bethesda, MD 20892-9205. FAX: 301 402 0010; fb12a{at}nih.gov
Received: 5 March 2002.
First decision: 2 April 2002.
Accepted: 5 August 2002.
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