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Genetics and Menopause
New Developments to Improve Clinical Outcomes

Lee P. Shulman, MD

It is estimated that in the next decade, 40 million women will be menopausal, thus requiring a completely different approach in the training of women's health care professionals. Such a change in population demographics comes at a time of great discovery in reproductive biology and medicine: the ongoing work of the Human Genome Project. The Human Genome Project and industry-based research have led to profound changes in our knowledge of genetics, disease, and organic processes. However, it is critical to know that the work of the Human Genome Project will not only help delineate the etiology of disease and lead to more accurate diagnosis and, eventually, effective therapies and prevention, but will also unlock the secrets of developmental biology that will help us better understand the processes that control development, organic function, and, ultimately, organic dysfunction and cellular and organic death.

THE GENETICS OF MENOPAUSE
We have well described the process of perimenopausal and menopausal development in women, and yet we know little of the causative factors of these changes. Again, the age-old conundrum returns. What are the roles of genetics and environment in the menopausal process? We recognize that some women experience severe vasomotor instability at the time of menopause, whereas others have no such problems but experience severe osteoporosis correlating with the dimunition of endogenous estrogen production. Conversely, other women experience no such changes but succumb to cardiovascular disease or Alzheimer's dementia at a relatively early age. Unfortunately, we are currently unable to explain such clear differences in the process and extent of the menopausal transition. It is hoped that the continuing work of the Human Genome Project will help identify those genetic factors and, thus, those environmental factors that affect the onset and severity of specific menopausal problems. Those genes and proteins that may be associated with more benign menopausal changes are also sought. In this way, it is hoped that more effective, safe, and targeted therapies will be developed for women with particular menopause-related problems.

POSITIVE BEGINNINGS
Despite our almost primitive level of understanding of the impact and interactions of genes on disease and health management, the care of women has already been positively affected by the work of the Human Genome Project and other genetic centers. From improved detection of chlamydia infections to more accurate assessment of genetic disease risk, the practice of obstetrics and gynecology has already been considerably improved by these early developments and advances. Even in the extensive and diverse field of menopausal management, genetics studies have begun to provide critical information that will eventually serve to help better delineate menopause-related risks and identify individuals who will benefit from specific therapeutic modalities.

Symptom Relief
It is clear that estrogen replacement therapies provide relief from vasomotor symptoms and vulvovaginal atrophy in postmenopausal women. A current controversy is whether soy products and other botanical products may provide similar and, presumably, benign treatment of these conditions. A large multicenter trial sponsored by the National Institutes of Health is currently underway to rigorously evaluate the claims of botanical product manufacturers. Nonetheless, other investigators have started to clarify what role, if any, soy and other botanical products have in the management of patients' perimenopausal and postmenopausal symptoms. Potter and colleagues found that intake of soy protein at several isoflavone concentrations for 6 months decreased the risk factors associated with cardiovascular disease in a cohort of postmenopausal women.¹ However, only the higher isoflavone-containing product protected against spinal bone loss. In addition, Glazier and Bowman reviewed 74 studies on the efficacy of phytoestrogens in the care and management of menopausal women.² They found that, although these products provided some relief of various menopausal symptoms, the clinically proven health benefits of prescribed hormone replacement regimens currently far outweigh those of phytoestrogens, and thus there was insufficient evidence to recommend the use of phytoestrogens in place of traditional estrogen supplementation, or to make recommendations to women about specific phytoestrogen products.

Long-term Health Issues
Having considered hormone replacement therapy (HRT) to be an important part of the primary and secondary prevention of cardiovascular disease for the past 2 decades, recent academic and societal pronouncements have called this seminal concept into question. Indeed, many researchers and clinicians now acknowledge that these more recent studies fail to demonstrate a secondary cardioprotective effect for HRT, and that the current data concerning primary prevention do not provide convincing support for (or against) such an association. However, genetics studies have considerably added to our understanding of cardiovascular risk and have begun to provide more insights into the factors that lead some patients to profound disease and early mortality and others to a more benign clinical cardiovascular course.

Elevated high-density lipoprotein (HDL) levels have long been associated with reduced risk for cardiovascular disease. However, a recent study by Agerholm-Larsen and colleagues has found that a common mutation in the cholesteryl ester transfer protein gene actually reverses this beneficial association and serves to increase the risk of cardiovascular disease in women with elevated HDL cholesterol levels.³ In a related field of study, Psaty and colleagues found that a prothrombin gene variation had a nearly 11-fold (statistically significant) increased risk of nonfatal myocardial infarction compared with those who did not possess the allele.⁴ The authors believe that if further studies confirmed this finding and find other gene variations and mutations associated with adverse cardiovascular outcomes, a better assessment of the risks and benefits of HRT in postmenopausal women would be accomplished.

Finally, the use of HRT has been shown to have a clear and beneficial effect on bone mineral density (BMD) and is associated with a statistically significant and clinically relevant reduction in the risk of fracture among postmenopausal women. Nonetheless, genetics studies have already begun to help better identify menopausal women at even greater risk for BMD loss and fracture and the development and use of more targeted therapeutic interventions to prevent and treat postmenopausal osteoporosis. Hunter and colleagues used a twin-study paradigm to demonstrate that genetic and environmental influences differ significantly in pre- and postmenopausal groups for BMD, but not for calcaneal ultrasound findings.⁵ The authors reported that, although the total variance in BMD is greater in the postmenopausal group, there is considerable evidence that the same genes are involved. Their findings stress the importance of accounting for menopause-gene interactions in the genetic analysis of data on osteoporosis.

To this end, a prospective study by McGuigan and colleagues evaluated the prediction of osteoporotic bone fractures by bone densitometry and COLIA 1 genotyping.⁶ Earlier studies had identified a polymorphism affecting an Sp 1 binding site in the COLIA 1 gene that predicted BMD and osteoporotic fractures in several populations. In this study of men and women, COLIA 1 genotyping predicted fractures independently of bone mass and interacted favorably with bone densitometry to help identify women who are at high or low risk of incurring osteoporotic fractures.

GENETICS EVOLUTION
The debate concerning optimal menopausal management paradigms and the selection of those women who may most benefit from them will surely continue. The integration of genetic information will undoubtedly improve our ability to promote safe and effective hormone replacement interventions and to ensure that they are provided to women who will likely benefit from them. Whether it is the production of pharmaceutical products that target specific organ systems or the development of effective screening programs that permit the detection of women who may not gain the salutary and secondary benefits of HRT, genetics studies will be at the forefront of hormone- and age-targeted research for the foreseeable future. This supplement is one of the first of its kind to address the genetic impact of the various issues surrounding the evaluation and care of the perimenopausal and postmenopausal woman. I can only hope this collection of articles by leading experts in the field of menopause and mature women's health care will be quickly surpassed by future supplements that herald our increasing understanding of these genetic and environmental processes.

REFERENCES

1. Potter SM, Baum JA, Teng H, et al. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr. 1998;68(6 Suppl): 1375S-1379S.
2. Glazier MG, Bowman MA. A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy. Arch Intern Med. 2001;161:1161-1172.
3. Agerholm-Larsen B, Nordestgaard BG, Steffensen R, et al. Elevated HDL cholesterol is a risk factor for ischemic heart disease in white women when caused by a common mutation in the cholesteryl ester transfer protein gene. Circulation. 2000;101:1907-1912.
4. Psaty BM, Smith NL, Lemaitre RN, et al. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA. 2001;285:906-913.
5. Hunter DJ, de Lange M, Andrew T, et al. Genetic variation in bone mineral density and calcaneal ultrasound: a study of the influence of menopause using female twins. Osteoporos Int. 2001;12:406-411.
6. McGuigan FE, Armbrecht G, Smith R, et al. Prediction of osteoporotic fractures by bone densitometry and COLIA1 genotyping: a prospective, population-based study in men and women. Osteoporos Int. 2001;12:91-96.

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