NIA Workshop on Primate Models of the Menopause

The Primate Models of the Menopause Workshop and Advisory Board meeting was held on January 10, 2001, at the NIH (Natcher Building, Conference Room D) from 8:00 a.m. - 4:00 p.m. Participants included presenters/discussants who are well versed in reproductive aging of primates, the Advisory Board members, and staff of the NIA, NHLBI, NICHD, NCRR, NINDS and other visitors. The meeting was organized by Drs. Frank Bellino and Phyllis Wise and chaired by Dr. Wise. The workshop agenda is provided in Appendix I. Names and affiliations of the presenters and Advisory Board are listed in Appendix II.

Executive Summary

As a result of the workshop presentations on physiologic, hormonal and cycle changes across the perimenopause and in naturally and surgically menopausal female non-human primates (NHP), related discussions among the presenters and the Advisory Board members, and deliberations of the Advisory Board, four main areas of focus for future studies were identified. These were:

1. understanding the basic process of aging in NHP,
2. enhancing our understanding of the mechanisms of the perimenopausal transition and associated pathophysiologic outcomes,
3. research focused on the postmenopausal period, and
4. investigations that utilize the power of gene expression profiling and proteomics in enhancing our understanding of the aging process and the menopause.

The Advisory Board voiced the opinion that primatologists interested in aging and the menopause should be thoroughly familiar with basic concepts and the latest information on the biology of aging in other species. The need for expanded and stable funding for the maintenance and study of aging primate colonies cannot be underestimated. Finally, special review groups should be constituted to review research applications dealing with animal models of menopause because of the largely descriptive nature of this research at this stage.

Background and Current Status

The meeting opened with welcoming and introductory remarks by Drs. Frank Bellino and Phyllis Wise. Dr. Bellino summarized the report of the previous Advisory Board, which had met in 1994 and reviewed the goals of the current meeting. Participants noted that since the last advisory meeting, several advances had occurred in our understanding of the menopause. First, that primates undergo the menopause has become clear since more older females have been maintained in NIH Regional Primate Research Centers. Until recently most older females were euthanized before this biological change was observed. The investment by the NIA to pay for housing and maintenance of this resource has been modest. Considering these circumstances, researchers must be applauded for pursuing studies that are costly and labor- and time-intensive, while being uncertain of the stability of funding and the instability of the supply of NHP. Second, the focus on the pre- and peri-menopausal period of female reproductive aging is relatively new. This may be driven by the exciting new data from the human perimenopausal transition. Some of the early descriptive studies suggest that human and some primate species share some events in common. Third, the limited availability of middle-aged and old NHP compromises the power of the studies that can be performed in these species. It appears unlikely that female reproductive aging can be studied effectively in the severely limited numbers of older chimpanzees (Pan troglodytes) in current captive populations. 

Suggested Future Areas of Emphasis

1. Studies focused on understanding the basic process of somatic aging in NHP and its relationship to the timing of the menopause. It is clear that an understanding of the NHP menopause, its timing relative to somatic aging, the mechanisms that regulate this timing, and whether NHP are a good model for the human menopause depend on our knowledge of the process of somatic aging in the NHP. Discussion revealed that little is known about the rate and mechanisms of somatic aging of various organ systems in NHP. Current information would suggest that the menopause occurs near the end of the NHP average lifespan. However, it is unclear whether this is the case because NHP may not be maintained under optimal nutritional or environmental conditions, or if more aggressive medical and surgical approaches will significantly extend average lifespan. Information obtained during the workshop suggests that the NHP diet is high in fiber, calcium, vitamin D and soy, and low in fat. This appears to be a diet that is not comparable to that of most humans and may obscure comparison with humans. At the present time, it is unclear whether this diet is optimal for the health or longevity of NHP. If conditions could be optimized so that these animals live longer, somatic aging may occur later while the timing of the menopause is likely to stay fixed. This would then be more similar to the relationship between human somatic and reproductive aging. Studies that focus on the somatic aging process itself would allow investigators to better understand the framework within which the menopause occurs.
    
2. Studies focused on enhancing our understanding of the mechanisms of the perimenopausal transition and associated pathophysiologic outcomes. Perimenopause hormonal data in baboons and rhesus were presented at the workshop. These appear generally similar to human perimenopausal hormonal data; the perimenopausal rise in FSH well documented in women appears to occur in irregularly cycling baboons, but was not observed in rhesus until the postmenopause. For this and other reasons (ease of monitoring reproductive cycles and estrogen status externally; lack of seasonal cycles; similarity of captive and wild baboons in age-dependent mortality and fertility rates and cycle irregularity; moderate to relatively large numbers of older, genetically characterized females available at Southwest Foundation for Biomedical Research), baboons appear particularly promising. However, since the number of studies that have examined the perimenopausal period is extremely limited, it is impossible to determine whether one or more NHP species will serve as an appropriate model of the human menopause. Future investigations should consider the entire hypothalamic-pituitary-ovarian axis, not just the ovary, and concentrate on invasive, mechanistic measurements of parameters that cannot be followed in humans such as brain neurotransmitter dynamics, changes in ovarian follicular development and maturation, etc. It will be important to perform studies in which the responsiveness of the hypothalamic-pituitary-ovarian axis is tested through careful manipulation of the endocrine environment through administration of gonadotropins, GnRH agonists or antagonists, or selective steroid hormone receptor agonists or antagonists. Care should be taken to use validated hormonal assays in specific NHP species, compare bound and free steroid hormone with the human female, carefully compare the reproductive hormonal patterns with humans, and evaluate the effect of seasonality in reproductive cycles in those species with seasonal cycles.
    
3. Research focused on the postmenopausal period. The postmenopausal period in most women lasts at least one-third of their entire lifespan and is associated with significant health problems in many physiological systems. Information presented at the workshop showed that, in contrast to women, NHP go through the natural menopause at ages very close to their average lifespan and thus have a much shorter postmenopausal span. Therefore, it is important to explore whether the NHP is a good model for postmenopausal health problems and conditions. Investigation of the natural postmenopausal period in NHP awaits studies to optimize lifespan by changes in nutrition and environment under which they are maintained, and more aggressive medical attention. These studies should be pursued. It appears prohibitively expensive to study the currently short postmenopausal period solely through studies of old, naturally menopausal animals since these animals are likely to be more frail and have more health problems than early postmenopausal women, and the numbers available for research are small.
   
   To minimize problems associated with studying the postmenopausal period in NHP outlined above, surgically- or pharmacologically-induced ovariectomy may be viable options to induce menopause. Attention must be paid to the age of ovariectomy, since the response in young animals may differ from that in middle-aged animals. This needs to be studied further. In addition, the continued presence (pharmacological menopause) or absence (surgical menopause) of the ovary may affect observations in end organs after menopause because of potential bioregulatory factors secreted from the postmenopausal ovary. The use of animals that have been ovariectomized at appropriate ages either surgically or through the use of pharmacological agents that reversibly inhibit ovarian function should yield insights into the effects of the postmenopausal period on the central nervous system, cardiovascular, immune and gastrointestinal system, bone and mineral metabolism, behavior, learning and cognition.
    
4. Investigations that utilize the power of gene expression profiling and proteomics in enhancing our understanding of the aging process and the menopause. With the advances in our knowledge of the human genome and with the high homology of the human and NHP genome and chromosomal structure, major advances in the biology of aging and the menopause should result from the use of gene expression microarray technology and proteomics. Focus on the use of these methods is recommended. The importance of proper use of these methods and proper statistical and bioinformatic analyses of such data cannot be over-emphasized.

Additional Recommendations

5. Greater inclusion of gerontologic expertise in NHP studies of the peri- and postmenopause. The Advisory Board believes that there is a need for primatologists interested in aging and the menopause to be thoroughly familiar with basic concepts and latest information on biology of aging in other species. This could be achieved through workshops that all investigators in NIA-subsidized Centers attend on an annual basis. These meetings could (1) review the latest findings of investigators, much like was done at this meeting and (2) provide presentations by investigators who are studying the basic process of aging or the menopause in other species. In this manner, primatologists will be able to share resources and information, and design collaborative future studies that take advantage of existing knowledge derived from aging in other species.
    
6. Need for expanded and stable funding. The need for expanded and stable funding for the maintenance and study of aging primate colonies cannot be underestimated. Studies of aging are inherently expensive. However, little progress will be made without the financial commitment of the NIA to Primate Centers such that selected NHP species can be maintained to old age. In the future, the availability of research naïve, nulliparous and multiparous animals will in part determine the rate of progress in our understanding of whether the NHP menopause is useful in the study of the human menopause. From the data presented, longitudinal and cross-sectional aging studies using rhesus, cynomolgus and baboon should be encouraged. For example, the apparent lack of baseline information regarding bone density changes with age, menopause and bone site is crucial to understand mechanisms underlying menopausal bone loss and effects of supplementary estrogen. If the goal is to understand the biology of aging as well as the menopause, males must be maintained. In contrast, it appears unlikely that financial support of chimpanzees will be very fruitful since the availability of this species is so limiting. We would strongly suggest that a mechanism of long-term financial support (longer than 5 years) be developed to achieve stable support of the resource. Clearly, biological material must be banked and shared. The ways that blood, urine, organs, tissues, and cells are preserved should be optimized for as many investigators as possible. This will depend upon the state of the science at the time and the studies proposed by funded investigators.
    
7. Need for appropriate review of research that is descriptive in nature. Frequently, CSR study sections favor hypothesis-driven research. Unfortunately, research in NHP menopause is still at the stage where descriptive research is critical and necessary before the proper hypotheses can be formulated. The advisory committee recommends that the NIA consider whether special study sections (i.e. special emphasis panels) should be formed to review proposals in the study of the menopause in NHP.

Summary

In summary, information presented and discussed at the workshop support the hypothesis that female reproductive aging in the NHP is a more appropriate model for the human menopausal process and its connections with menopause-related health problems than other non-human species. The Advisory Board believes that considerably more research studies are required before it will be possible to know whether:

1. one NHP species is most appropriate,
2. one species will model one aspect of the menopause while another species will model a different aspect of the menopause, and
3. the timing and relationship of somatic and reproductive aging are similar in NHP and humans.

The amount of time and effort required to achieve the goals outlined in this report will depend on the financial resources devoted to this important topic, the ability to recruit more outstanding scientists to plan and conduct these studies, and the ability to make sufficient numbers of appropriate animals available.

Apendix I.  NIA Primate Models of Menopause Workshop Agenda

January 10, 2001
Natcher Conference Center, Room D
National Institutes of Health, Bethesda, MD

Appendix II. Participants in the NIA Primate Models of Menopause Workshop

Speakers

Dr. K.D.Carey
Southwest Foundation for Biomedical Research
PO BOX 760549
West Loop at 410 at Military Drive
San Antonio, TX 78245
Phone: 210 258-9460
Fax: 210 670-3323

Thomas B. Clarkson, D.V.M.
Comparative Medicine Clinical Research Center
Wake Forest University School of Medicine
Medical Center Boulevard
Winston-Salem, North Carolina 27157-1040 USA
Phone: 336 716-1570
Fax: 336 716-1601

Robert R. Freedman, Ph.D.
Wayne State University SOM
275 E. Hancock
Detroit, MI 48201
Phone: 313 577-1857
Fax: 313 577-8382

Dr. Ken Gould
5809 Cobb Meadow
Norcross, GA. 30093-4026
Phone: 404 727-7714 or 770 921-9422
Fax: 770 931-7502.

Joseph W. Kemnitz, Ph.D.
Wisconsin RPRC
University of Wisconsin-Madison
1220 Capitol Court
Madison, WI 53715-1299
Phone: 608 263-3588
Fax: 608 263-4031

Firyal Khan, PhD
Department of Obstetrics Gynecology and Reproductive Science
University of Texas Medical School -Houston
6431 Fannin
Houston TX 77030
Phone: 713 500-6383
Fax: 713 500-0795

Mark A. Lane, Ph.D.
Nutritional and Molecular Physiology Unit
Laboratory of Neurosciences
National Institute on Aging
National Institute of Health
5600 Nathan Shock Drive
Baltimore, MD 21224
Phone: 410 558-8481
Fax: 410 558-8323

Bill Lasley, PhD
Institute of Toxicology and Environmental Health
Old Davis Road
University of California at Davis
Davis, CA 95616
Phone: 530 752-8506
Fax: 530 752-5300

Naomi Rance, M.D., Ph.D.
Department of Pathology
University of Arizona College of Medicine
1501 N. Campbell
Tucson, Arizona 85724
Phone: 520 626-6099
Fax: 520 626-1027

M. Susan Smith, Ph.D.
Oregon Regional Primate Research Center
505 NW 185th Avenue
Beaverton, OR 97006
Phone: 503 690-5300
Fax: 503 690-5569

Marc Tatar, PhD
Department of Ecology and Evolutionary Biology
Box G-W
Brown University
Providence, RI 02912
Phone: 401 863-3455
Fax: 401 863-2166

Mary Lou Voytko, Ph.D.
Department of Pathology
Section on Comparative Medicine
Wake Forest University School of Medicine
Medical Center Boulevard
Winston-Salem, NC 27157-1040
Phone: 336 716-1523
Fax: 336 716-1515

Advisory Committee

Lewis H. Kuller, MD, DrPH
University Professor of Public Health
Department of Epidemiology
University of Pittsburgh
Graduate School of Public Health
130 DeSoto Street, Room A526
Pittsburgh, PA 15261
Phone: 412 624-3054
Fax: 412 624-7397

Stavros C. Manolagas, M.D., Ph.D.
University of Arkansas for Medical Sciences
Division of Endocrinology and Metabolism and the
UAMS Center for Osteoporosis and Metabolic Bone Diseases
4301 West Markham, Slot 587
Little Rock, AR 72205
Phone: 501 686-5130
Fax: 501 686-8148

Nanette Santoro, M.D.
Division of Reproductive Endocrinology
Albert Einstein College of Medicine
1300 Morris Park Avenue
Bronx, NY 10461
Phone: 718 430-3152
Fax: 718 430-8586

James W. Simpkins, Ph.D.
Department of Pharmacology & Neuroscience
University of North Texas Health Science Center-Fort Worth
3500 Camp Bowie Blvd.
Fort Worth, Texas 76107- 2699
Phone: 817 735-2063
Fax: 817 735-2091

Jeanne Y. Wei, M.D., Ph.D.
Gerontology Division
Beth Israel Deaconess Medical Center
330 Brookline Ave.
Boston, MA 02215
Phone: 617 667-2332
Fax: 617 667-3346

Phyllis M. Wise, Ph.D.
University of Kentucky
Department of Physiology
MS 509 Chandler Medical Center
800 Rose Street
Lexington, KY 40536-0298
Phone: 859 323-6045
Fax: 859 323-1070