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Prevention during the menopause is critical for good health: skin studies support protracted hormone therapy
Prevention during the menopause is critical for good health: skin studies support protracted hormone therapy Frederick Naftolin, M.D., D.Phil. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
Estrogen replacement therapy maintains the skin. Similar effects must be investigated in other organ systems. (Fertil Steril威 2005;84:293– 4. ©2005 by American Society for Reproductive Medicine.)
The article by Wolff et al. (1) presents a plausible case for protective effects of timely (early and continuous) hormone replacement therapy (HT; begun for symptoms) (2) on the skin. This is of note because the skin is the largest organ and its health is vital to many facets of healthy living in our aging population. It supports earlier investigations (3, 4) and beckons further prospective clinical trials and molecular investigation of the basis and limitations of skin protection afforded by HT. But, if recently changed guidelines on hormone use in the menopause (5, 6) had been followed by Wolff’s subjects, the question of a salutary effect of estrogen on the postmenopausal woman’s skin might have been moot. The use of timely HT would be a dead issue due to misapprehension of the results of recent randomized clinical trials on HT (menopausal hormone treatment given in the absence of symptoms) (2). These randomized clinical trials studied the effects on the heart of starting estrogen or estrogen plus progestin in women more than a decade after the menopause. Thus, subjects were, on average, in their mid-60s at the start of HT (7–9). Because they were long past the protection conferred by ovarian hormones they were not truly healthy at the start of the randomized clinical trials (7–9). Nevertheless, the untoward outcomes of starting HT at late age have been inappropriately taken to discourage HT use starting in the menopausal transition (10, 11). If the new guidelines had been applied there would probably not have been enough subjects taking HT early and long enough to show differences from nonusers for effects of HT on the heart, brain (cognition, affect, immune system, dystrophies), and metabolic systems as well as the skin. Yet, all of these effects have been shown in preclinical and observational and prospective randomized clinical studies (11). Thus, evidence of important preventative effects of estrogen would be lost.
Received March 24, 2005; revised and accepted April 26, 2005. Reprint requests: Frederick Naftolin, M.D., D.Phil., Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, FMB 331, P.O. Box 208063, New Haven, Connecticut 06520 (FAX: 203-387-6068; E-mail: frederick.naftolin@ yale.edu).
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.04.018
This recent deviation from the accepted application of randomized clinical trials needs rethinking (12). We have just completed a century in which the lifespan of the average human in industrialized countries has doubled. Through the employment of our frontal lobes that have been enhanced by natural selection, we developed and applied basic public health measures, including vaccination, and invented and developed industrial means of furnishing effective antibiotics (13). These few things have forever changed the world and its future; there is no going back. Because of these changes, the demography of the world is in flux. The results are being felt in every possible sphere. Many of these effects are in the fields of health and longevity, and they play out in the areas of economics, sociology, and geopolitics. What, exactly, is our position? Humans are now the only species to regularly live to twice their reproductive age. Because the gain is postreproductive, it is outside of the bounds of natural selection (14). To my knowledge, there is no known mechanism of developing adaptive responses in the postreproductive period (15). This, plus the retirement of acute illness (hemorrhage, infection, birth and maternal accidents) from the list of major causes of death, has resulted in leading causes of death in industrialized countries that, with the exception of motor accidents, are all chronic ailments: cardiovascular disease/stroke, metabolic ailments, bone-wasting, cancer, depression, and brain dystrophy (16, 17). We have passed from the century of treatment to the century of prevention. We had better get our priorities right in this regard; just as the developing world is facing a tide of young people, industrialized countries are facing a veritable tsunami of aging people and we need to plan for them. Because there are not adaptive mechanisms for the postreproductive period, we need to understand that the wholesale appearance of failure of the ovaries in the aging population will not cause a new set of adaptive behaviors to appear. Rather, the same behavior that was adaptive for reproduction, and therefore was conserved and honed through the ages, will be called on to respond to the menopause. However, these previously adaptive behaviors are
Fertility and Sterility姞 Vol. 84, No. 2, August 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
293
often maladaptive in the postreproductive period. In brief, they include increased arterial vascular stiffness and resistance, increased blood lipids, increased bone mineral loss, increased inflammatory responses to injury, “disordered brain function,” insulin resistance, and other changes that magnify the effects of aging (13). The resulting chronic ailments are now the chief causes of death. As motioned in the Wolff et al. (1) report, among the derangements after menopause are changes in collagen and glycoseaminoglycans that allow the connective tissues to lose their turgor (3, 4, 18, 19) and reparative function, thus increased scarring and pressure sores may be in the cards for those that cannot ward off injury and immobilization. Estrogen is the main architect of the reproductive phenotype of women. Its actions maintain women’s fitness for reproductive success and estrogen’s decrease in the puerperium is accompanied by responses in tissues that are adaptive, including vascular stiffening and resistance, lipid and bone mobilization, disrupted mentation and sleep, and vasomotor instability (13). Estrogen’s pervasive influence and the importance of reproductive fitness are signified by the presence of estrogen response elements in the majority of genes in the human genome (A. Fadiel and F. Naftolin, unpublished). It makes sense that timely and continuing estrogen replacement (HT) in the postreproductive period might be helpful in warding off the appearance of maladaptive physiologic changes. As well, because estrogens are powerful antioxidants, they may slow the progress of aging, per se. Yet, if we accept the new health guidelines prompted by misapprehensions of the results of the studies mentioned, we might never seriously consider, let alone test, the possibilities exemplified by the Wolff et al. (1) report. Women would be treated for a few years at most and then, by the time that the outcomes of their chronic ailments were perceived, any opportunity for prevention by estrogen would have passed. That is the lesson of the Women’s Health Initiative, Heart and Estrogen/ Progestin Replacement Study, and Estrogen Replacement and Artherosclerosis Trial studies: untimely intervention is worse than no intervention at all (11). Unfortunately, they did not test the value of timely intervention, which is prevention. So, as menopausal symptoms warn of estrogen deficiency, the article by Wolff et al. (1) is a kind of “canary in the tunnel” that is singing out to warn us of the need to test the idea of prevention by timely estrogen treatment. We must rethink the current American position on prevention of menopausal complications by estrogen and thereby afford women the scientific rigor that they deserve (10). The Wolff et al. article again tosses down the gauntlet. Who will pick it up? Some new studies are in process (20) but more will be needed. REFERENCES 1. Wolff EF, Narayan D, Taylor HS. Long-term effects of hormone therapy on skin rigidity and wrinkles. Fertil Steril 2005;84:285– 8.
294
Naftolin
2. Naftolin F, Schneider HPG, Sturdee DW, Birkhauser M, Brincat MP, Gambacciani M, et al. Guidelines for hormone treatment of women in the menopausal transition and beyond. Position Statement by the Executive Committee of the International Menopause Society. Climacteric 2004;7:333–7. 3. Raine-Fenning NJ, Brincat MP, Muscat-Baron Y. Skin aging and menopause: implications for treatment. Am J Clin Dermatol 2003;4: 371– 8. 4. Maheux R, Naud F, Rioux M, Genier R, Lemay A, Guy J, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gynecol 1994; 170:642–9. 5. North American Menopause Society. Recommendations for estrogen and progestogen use in peri- and postmenopausal women: October 2004 position statement of The North American Menopause Society. Menopause 2004;11:589 – 600. 6. The Practice Committee of the American Society for Reproductive Medicine. Estrogen and progestogen therapy in postmenopausal women. Fertil Steril 2004;81:231– 41. 7. Hsia J, Simon JA, Lin F, Applegate NB, Vogt MT, Hunninghake D, et al. Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease: the Heart and Estrogen/Progestin Replacement Study. Circulation 2000;102:2228 –32. 8. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Schumaker SA, Snyder TA, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–9. 9. Writing Group for the Women’s Healthy Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33. 10. Naftolin F, Taylor HS, Karas R, Brinton E, Newman I, Clarkson TB, et al. The Women’s Health Initiative (WHI) could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steril 2004;81:1498 –501. 11. Harman SM, Brinton EA, Clarkson T, Heward CB, Hecht HS, Karas RH, et al. Is the WHI relevant to HT started in the perimenopause? Endocrine 2004;24:195–202. 12. Shapiro S. Effects of HT on the risks of breast cancer and cardiovascular disease: the validity of the epidemiological evidence. In: Schneider HPG, Naftolin F, eds. Climacteric medicine—where do we go? Abingdon, UK: Parthenon Publishing, 2005:166 –74. 13. Naftolin F, Richman S. Menopause: lack of Darwinian adaptation drives its physiology. In: Schneider HPG, Naftolin F, eds. Climacteric medicine—where do we go? Abingdon, UK: Parthenon Publishing, 2005:4 – 8. 14. Darwin C. The voyage of the Beagle. New York: E.P. Dutton & Co., Inc., 1936. 15. Naftolin F, Whitten P, Keefe D. An evolutionary perspective on the climateric and menopause. Menopause 1994;4:223–5. 16. National Center for Health Statistics. Vital Statistics of the United States, 1992, Vol. II. Mortality, Part A. 17. Ries LA, Wingo PA, Miller DS, Howe HL, Weir HK, Rosenberg HM, et al. The annual report to the nation on the status of cancer, 1973–1997, with a special section on colorectal cancer. Cancer 2000;88(10):2398 – 424. 18. Huszar G, Cabrol D, Naftolin F. The relationship between myometrial and cervical functions in pregnancy and labor. In: Huszar G, ed. The physiology and biochemistry of the uterus in pregnancy and labor. Boca Raton, FL: CRC Press, 1986:287–306. 19. Kleissl HP, VanderRest M, Naftolin F, Glorieux FH, DeLeon A. Collagen changes in the human uterine cervix at parturition. Am J Obstet Gynecol 1978;130:748 –53. 20. Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, et al. KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric 2005;8:3–12.
Stopping hormone therapy prematurely harms the skin and more
Vol. 84, No. 2, August 2005
Estrogen replacement therapy maintains the skin. Similar effects must be investigated in other organ systems. (Fertil Steril威 2005;84:293– 4. ©2005 by American Society for Reproductive Medicine.)
The article by Wolff et al. (1) presents a plausible case for protective effects of timely (early and continuous) hormone replacement therapy (HT; begun for symptoms) (2) on the skin. This is of note because the skin is the largest organ and its health is vital to many facets of healthy living in our aging population. It supports earlier investigations (3, 4) and beckons further prospective clinical trials and molecular investigation of the basis and limitations of skin protection afforded by HT. But, if recently changed guidelines on hormone use in the menopause (5, 6) had been followed by Wolff’s subjects, the question of a salutary effect of estrogen on the postmenopausal woman’s skin might have been moot. The use of timely HT would be a dead issue due to misapprehension of the results of recent randomized clinical trials on HT (menopausal hormone treatment given in the absence of symptoms) (2). These randomized clinical trials studied the effects on the heart of starting estrogen or estrogen plus progestin in women more than a decade after the menopause. Thus, subjects were, on average, in their mid-60s at the start of HT (7–9). Because they were long past the protection conferred by ovarian hormones they were not truly healthy at the start of the randomized clinical trials (7–9). Nevertheless, the untoward outcomes of starting HT at late age have been inappropriately taken to discourage HT use starting in the menopausal transition (10, 11). If the new guidelines had been applied there would probably not have been enough subjects taking HT early and long enough to show differences from nonusers for effects of HT on the heart, brain (cognition, affect, immune system, dystrophies), and metabolic systems as well as the skin. Yet, all of these effects have been shown in preclinical and observational and prospective randomized clinical studies (11). Thus, evidence of important preventative effects of estrogen would be lost.
Received March 24, 2005; revised and accepted April 26, 2005. Reprint requests: Frederick Naftolin, M.D., D.Phil., Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, FMB 331, P.O. Box 208063, New Haven, Connecticut 06520 (FAX: 203-387-6068; E-mail: frederick.naftolin@ yale.edu).
0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2005.04.018
This recent deviation from the accepted application of randomized clinical trials needs rethinking (12). We have just completed a century in which the lifespan of the average human in industrialized countries has doubled. Through the employment of our frontal lobes that have been enhanced by natural selection, we developed and applied basic public health measures, including vaccination, and invented and developed industrial means of furnishing effective antibiotics (13). These few things have forever changed the world and its future; there is no going back. Because of these changes, the demography of the world is in flux. The results are being felt in every possible sphere. Many of these effects are in the fields of health and longevity, and they play out in the areas of economics, sociology, and geopolitics. What, exactly, is our position? Humans are now the only species to regularly live to twice their reproductive age. Because the gain is postreproductive, it is outside of the bounds of natural selection (14). To my knowledge, there is no known mechanism of developing adaptive responses in the postreproductive period (15). This, plus the retirement of acute illness (hemorrhage, infection, birth and maternal accidents) from the list of major causes of death, has resulted in leading causes of death in industrialized countries that, with the exception of motor accidents, are all chronic ailments: cardiovascular disease/stroke, metabolic ailments, bone-wasting, cancer, depression, and brain dystrophy (16, 17). We have passed from the century of treatment to the century of prevention. We had better get our priorities right in this regard; just as the developing world is facing a tide of young people, industrialized countries are facing a veritable tsunami of aging people and we need to plan for them. Because there are not adaptive mechanisms for the postreproductive period, we need to understand that the wholesale appearance of failure of the ovaries in the aging population will not cause a new set of adaptive behaviors to appear. Rather, the same behavior that was adaptive for reproduction, and therefore was conserved and honed through the ages, will be called on to respond to the menopause. However, these previously adaptive behaviors are
Fertility and Sterility姞 Vol. 84, No. 2, August 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
293
often maladaptive in the postreproductive period. In brief, they include increased arterial vascular stiffness and resistance, increased blood lipids, increased bone mineral loss, increased inflammatory responses to injury, “disordered brain function,” insulin resistance, and other changes that magnify the effects of aging (13). The resulting chronic ailments are now the chief causes of death. As motioned in the Wolff et al. (1) report, among the derangements after menopause are changes in collagen and glycoseaminoglycans that allow the connective tissues to lose their turgor (3, 4, 18, 19) and reparative function, thus increased scarring and pressure sores may be in the cards for those that cannot ward off injury and immobilization. Estrogen is the main architect of the reproductive phenotype of women. Its actions maintain women’s fitness for reproductive success and estrogen’s decrease in the puerperium is accompanied by responses in tissues that are adaptive, including vascular stiffening and resistance, lipid and bone mobilization, disrupted mentation and sleep, and vasomotor instability (13). Estrogen’s pervasive influence and the importance of reproductive fitness are signified by the presence of estrogen response elements in the majority of genes in the human genome (A. Fadiel and F. Naftolin, unpublished). It makes sense that timely and continuing estrogen replacement (HT) in the postreproductive period might be helpful in warding off the appearance of maladaptive physiologic changes. As well, because estrogens are powerful antioxidants, they may slow the progress of aging, per se. Yet, if we accept the new health guidelines prompted by misapprehensions of the results of the studies mentioned, we might never seriously consider, let alone test, the possibilities exemplified by the Wolff et al. (1) report. Women would be treated for a few years at most and then, by the time that the outcomes of their chronic ailments were perceived, any opportunity for prevention by estrogen would have passed. That is the lesson of the Women’s Health Initiative, Heart and Estrogen/ Progestin Replacement Study, and Estrogen Replacement and Artherosclerosis Trial studies: untimely intervention is worse than no intervention at all (11). Unfortunately, they did not test the value of timely intervention, which is prevention. So, as menopausal symptoms warn of estrogen deficiency, the article by Wolff et al. (1) is a kind of “canary in the tunnel” that is singing out to warn us of the need to test the idea of prevention by timely estrogen treatment. We must rethink the current American position on prevention of menopausal complications by estrogen and thereby afford women the scientific rigor that they deserve (10). The Wolff et al. article again tosses down the gauntlet. Who will pick it up? Some new studies are in process (20) but more will be needed. REFERENCES 1. Wolff EF, Narayan D, Taylor HS. Long-term effects of hormone therapy on skin rigidity and wrinkles. Fertil Steril 2005;84:285– 8.
294
Naftolin
2. Naftolin F, Schneider HPG, Sturdee DW, Birkhauser M, Brincat MP, Gambacciani M, et al. Guidelines for hormone treatment of women in the menopausal transition and beyond. Position Statement by the Executive Committee of the International Menopause Society. Climacteric 2004;7:333–7. 3. Raine-Fenning NJ, Brincat MP, Muscat-Baron Y. Skin aging and menopause: implications for treatment. Am J Clin Dermatol 2003;4: 371– 8. 4. Maheux R, Naud F, Rioux M, Genier R, Lemay A, Guy J, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gynecol 1994; 170:642–9. 5. North American Menopause Society. Recommendations for estrogen and progestogen use in peri- and postmenopausal women: October 2004 position statement of The North American Menopause Society. Menopause 2004;11:589 – 600. 6. The Practice Committee of the American Society for Reproductive Medicine. Estrogen and progestogen therapy in postmenopausal women. Fertil Steril 2004;81:231– 41. 7. Hsia J, Simon JA, Lin F, Applegate NB, Vogt MT, Hunninghake D, et al. Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease: the Heart and Estrogen/Progestin Replacement Study. Circulation 2000;102:2228 –32. 8. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Schumaker SA, Snyder TA, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–9. 9. Writing Group for the Women’s Healthy Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33. 10. Naftolin F, Taylor HS, Karas R, Brinton E, Newman I, Clarkson TB, et al. The Women’s Health Initiative (WHI) could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steril 2004;81:1498 –501. 11. Harman SM, Brinton EA, Clarkson T, Heward CB, Hecht HS, Karas RH, et al. Is the WHI relevant to HT started in the perimenopause? Endocrine 2004;24:195–202. 12. Shapiro S. Effects of HT on the risks of breast cancer and cardiovascular disease: the validity of the epidemiological evidence. In: Schneider HPG, Naftolin F, eds. Climacteric medicine—where do we go? Abingdon, UK: Parthenon Publishing, 2005:166 –74. 13. Naftolin F, Richman S. Menopause: lack of Darwinian adaptation drives its physiology. In: Schneider HPG, Naftolin F, eds. Climacteric medicine—where do we go? Abingdon, UK: Parthenon Publishing, 2005:4 – 8. 14. Darwin C. The voyage of the Beagle. New York: E.P. Dutton & Co., Inc., 1936. 15. Naftolin F, Whitten P, Keefe D. An evolutionary perspective on the climateric and menopause. Menopause 1994;4:223–5. 16. National Center for Health Statistics. Vital Statistics of the United States, 1992, Vol. II. Mortality, Part A. 17. Ries LA, Wingo PA, Miller DS, Howe HL, Weir HK, Rosenberg HM, et al. The annual report to the nation on the status of cancer, 1973–1997, with a special section on colorectal cancer. Cancer 2000;88(10):2398 – 424. 18. Huszar G, Cabrol D, Naftolin F. The relationship between myometrial and cervical functions in pregnancy and labor. In: Huszar G, ed. The physiology and biochemistry of the uterus in pregnancy and labor. Boca Raton, FL: CRC Press, 1986:287–306. 19. Kleissl HP, VanderRest M, Naftolin F, Glorieux FH, DeLeon A. Collagen changes in the human uterine cervix at parturition. Am J Obstet Gynecol 1978;130:748 –53. 20. Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, et al. KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric 2005;8:3–12.
Stopping hormone therapy prematurely harms the skin and more
Vol. 84, No. 2, August 2005