917
EDITORIALS
One reason is a deep-seated resistance among doctors. In the UK, most women first consult a general practitioner and are in any case dependent on the GP for continued prescriptions. In the Glasgow series14 over 90% consulted their GP about menopausal symptoms; 20% were given nothing more than reassurance and only 6% were referred to a hospital clinic. Only 10% of the women in this study and 16% of the nurses were aware that there were menopause clinics in Glasgow. Of the 72% who received some form of drug treatment, one third were given psychotropic agents while two-thirds received specific oestrogen therapy prescribed for their climacteric
complaints. disquieting finding in the Glasgow survey women who have undergone and hysterectomy oophorectomy before the age of 40 are known to be at high risk of osteoporosis15 and Another
was
More than hot flushes Climacteric
can be traced back to the of the ancient Egyptians, who organotherapy prescribed penis of ass for impotence.2000 years later Brown-Sequard reported rejuvenation of both himself and his wife with canine testicular juice.2 Attempts were also made at that time to treat climacteric symptoms either with human or animal ovarian grafts inplanted into retroperitoneal fat3 (which, not surprisingly, failed) or with ovarian extracts (ovarian juice or powdered ovaries made up as tablets).4 When ovarian steroids were isolated in the 1920s, they were used in women with severe menopausal symptoms and to suppress lactation. Specific oestrogen treatment for the menopause became a practical proposition when a preparation containing conjugated equine oestrogens was licensed in the USA in 1942, but the results of the first double-blind placebo-controlled trial that confirmed a beneficial effect of oestrogens on climacteric 5 symptoms were not published until 1950.5 Postmenopausal oestrogen therapy (commonly known as hormone replacement therapy, HRT) relieves vasomotor and urogenital symptoms of the menopause, prevents postmenopausal loss of bone mineral content, and reduces the incidence of hip, radial, and vertebral fractures.66 Epidemiological studies have shown that risk of death from coronary heart disease (CHD) is reduced by about 50%,’the effect being greatest in women with a premature menopause,10 in whom the mortality from CHD is otherwise increased. 11Although confirmation of these findings ultimately depends on results from randomised controlled trials-and the National Institutes of Health has announced plans for such a trial—the benefits of HRT are well established. Why, therefore, is HRT not widely prescribed? Only 9% of postmenopausal women in London13 and 3% in Glasgow14 receive HRT for more than 3 years.
therapy
that, although
cardiovascular disease," many such women were not offered treatment at a sufficiently early stage to prevent these conditions. Even when HRT was prescribed "there was little evidence of women and their general practitioners opting for long duration HRT". A similar lack of enthusiasm was evident in London,l3 where 26-5% of women attending a hospital clinic found their GP "uninterested" and a further 9-5% "totally unhelpful". Even when doctors prescribe oestrogen therapy they seldom do so for more than a few months. Doctors in the USA are no more sympathetic. Only 7% of family practitioners and 37 % of gynaecologists prescribe HRT for prevention of osteoporosis.16 Prescribing habits for the menopause vary widely in different parts of the country: the national average is about 15% but in Boston only 3% of all menopausal receive HRT and in New Haven, women Connecticut, 6%. The presumed adverse effects of oestrogens probably deter many women and their doctors from starting or continuing treatment. 60% of respondents in a Cambridge, UK, study18 expressed concern about side-effects, including the risk of cancer, even though endometrial cancer can be prevented by progestagens and any increase in breast cancer is both controversiall9 and insignificant by comparison with the reduction in cardiovascular mortality and
osteoporosis. The regular withdrawal bleeding with cyclical oestrogen/progestagen therapy is often unacceptable. 26% of the Glasgow women14 said that withdrawal bleeding made therapy unacceptable and 47% stated that it was a minor disadvantage. Only 26 % felt that it was not troublesome. 80% of Brighton, UK, GPs felt that continuation of menstrual bleeding was a major disadvantage of HRT. 20 To increase the low prescribing rate of HRT for those who need it, more doctors need to be informed about the true benefits and risks. A serious obstacle is the tendency to equate the natural oestrogens used to treat the menopause with the
918
synthetic oestrogens present in oral contraceptives, despite their different structures and effects. Women who would benefit most from treatment are those with a premature menopause,7,8 a history of long-term amenorrhoea, low body weight, or low dietary intake of calcium, and also smokers and those with a family history of osteoporosis.21 That an early menopause predisposes to the premature onset of cardiovascular disease1O,11 reinforces the need for treating such women as soon as premature ovarian failure is diagnosed. Contrary to popular belief, many of the risk factors for coronary heart disease are indications for HRT and not contraindications-smoking,22 hyperlipidaemia,23 and a history of CHD are reasons to start treatment and contraindications to stopping it. HRT increases the long-term survival of women with established coronary atherosclerosis.24 Compliance would be improved by individualising treatment. The minimum effective dose of oestrogen should be prescribed initially-0-625 mg of conjugated equine oestrogens is sufficient to prevent osteoporosis.25 Irrespective of dose, oral oestrogens are not necessarily first-line treatment for all women. For example, transdermal oestradiol may be a more logical choice for those with a history of side-effects from oral contraceptives. The type and dose of progestagen are likewise important. Since progestagens are given to protect the endometrium they are not mandatory in women after hysterectomy-a fact overlooked by the 47% of Los Angeles gynaecologists who prescribed combined oestrogen/progestagen therapy to such women.26 Progestagens derived from 17a-hydroxyprogesterone give rise to fewer side-effects than the 19-nortestosterone derivatives.z’ The frequency of withdrawal bleeding can be reduced by giving progestagens every 3 months and not monthly. 28 A low-dose progestagen can also be given every day without interruption and, although 80% may experience some initial menstrual irregularity, this generally subsides after the first 6 months.29 A new synthetic steroid, tibolone, which displays weak oestrogenic, androgenic, and progestagenic activity in animals may offer many of the advantages of conventional HRT without the disadvantage of withdrawal bleeding or oestrogenic side-effects. This drug alleviates climacteric symptoms3° and prevents without the osteoporosis3’ stimulating endometrium.32 These features make tibolone highly acceptable to women in their 60s and 70s who are generally intolerant of conventional HRT, especially if this entails return of menstrual bleeding. Climacteric replacement therapy is not the secret of eternal youth, but it is much more than treatment of hot flushes. The challenge for the 1990s is to identify those women who would benefit most and to ensure that they receive adequate therapy. 1. Utian WH. Scientific basis for post menopausal estrogen therapy. In: Beard RJ, ed. The menopause: a guide to current research and practice. Baltimore: University Park Press, 1976: 176.
2. Brown Sequard (1895). Cited in DeMerre LJ. The female sex hormones. New York: Vantage Press, 1954. 3. Sauvé L. Les greffes ovariennes. Envisagées au point de vue de la pratique chirurgicale. Paris: G Steintied, 1909. 4. Bra M (1895). Cited in: DeMerre LJ. The female sex hormones. New York: Vantage Press, 1954. 5. Greenblatt RB, Barfield WE, Garner JF, Calk GL, Harrod JP.
Evaluation of an estrogen, androgen, estrogen-androgen combination and a placebo in the treatment of the menopause. J Clin Endocrinol
1950; 10: 1547-58. Jensen GF, Christiansen C, Transbol I. Fracture frequency and bone preservation in postmenopausal women treated with estrogen. Obstet Gynecol 1982; 60: 493-96. 7. Rosenberg L, Armstrong B, Jick H. Myocardial infarction and estrogen therapy in post-menopausal women. N Engl J Med 1976; 23: 1256-59. 8. Ross RK, Paganini-Hill A, Mack TM, Arthur M, Henderson BE. Menopausal oestrogen therapy and protection from death from ischaemic heart disease. Lancet 1981; i: 858-60. 9. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991; 325: 756-62. 10. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and risk of coronary heart disease in women. N Engl J Med 1987; 316: 1105-10. 11. Higano M, Robinson RW, Cohen WD. Increased incidence of 6.
cardiovascular disease in castrated women. N Engl J Med 1963; 268: 1123-25. 12. Healy B. The Yentl syndrome. N Engl J Med 1991; 325: 274-76. 13. Garnett T, Mitchell A, Studd J. Patterns of referral to a menopausal clinic. J R Soc Med 1991; 84: 128-30. 14. Barlow DH, Grosset KA, Hart H, Hart DM. A study of the experience of Glasgow women in the climacteric years. Br J Obstet Gynecol 1989; 96: 1192-97. 15. Richelson LS, Wahner HW, Melton LJ III, Riggs BL. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 1984; 311: 1273-75. 16. Grisso JA, Baum CR, Turner B. What do physicians do to prevent osteoporosis? J Bone Min Res 1990; 5: 213-19. 17. Sarrel P. In: Ginsburg J, ed. The circulation in the female—from the cradle to the grave. Carnforth, Lanes: Parthenon, 1989: 85. 18. Draper J, Roland M. Perimenopausal women’s views on taking hormone replacement therapy to prevent osteoporosis. Br Med J 1990; 300: 786-88. 19. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991; 151: 67-72. 20. Shears R-M. Brighton practitioners’ attitude to HRT. Practitioner 1989; 233: 147-9. 21. Lindsay R, Hart DM, Abdalla H, Dempster D. Pathogenesis of postmenopausal osteoporosis. In: Notelovitz M, Van Keep P, eds. The climacteric in perspective. Carnforth, Lanes: Parthenon, 1986: 79-85. 22. Wilson PWF, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking and cardiovascular morbidity in women over 50. N Engl J Med 1985; 313: 1038-43. 23. Bush TL, Barrett-Conner E, Cowan LD. Cardiovascular morbidity and non contraceptive use of estrogens in women: results from the Lipid Research Clinic Program follow up study. Circulation 1987; 75: 1102-09. 24. Sullivan JM, Vander Zwang R, et al. Estrogen replacement and coronary artery disease. Arch Intern Med 1990; 150: 2557-62. 25. Lindsay R, Hart DM, Clark DM. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol
1984; 63: 759-63. RK, Paganini-Hill A, Roy S,
26. Ross
et
al. Past and present
preferred
prescribing practices of hormone replacement therapy amongst Los Angeles gynecologists. Am J Publ Health 1988; 78: 516-19. 27. Dennerstein L, Burrows G. Psychological effects of progestogens in the post-menopausal years. Maturitas 1986; 8: 101-06. 28. Kemp JF, Fryer JA, Baber RJ. An alternative regimen of hormone replacement therapy to improve patient compliance. Aust N Z J Obstet Gynaecol 1989; 29: 66-69. 29. Weinstein L, Bewtra C, Gallagher JC. Evaluation of continuous low-dose regimen of estrogen progestin for treatment of the menopausal patient. Am J Obstet Gynecol 1990; 162: 1534-39. 30. Nevinny-Stickel J. Double-blind cross-over study with Org OD 14 and placebo in postmenopausal patients. Arch Gynecol 1983; 234: 27-31. 31. Yeusens P, Dequeker J, Gielen J, Schot LPC. Non-linear increase in vertebral density induced by a synthetic steroid (Org OD 14) in women with established osteoporosis. Maturitas 1991; 13: 155-62. 32. Multicentre study of effects of Org OD 14 on endometrium, vaginal cytology and cervical mucus in post-menopausal and oophorectomised women.
Maturitas
1984; 5: 281-86.
EDITORIALS
One reason is a deep-seated resistance among doctors. In the UK, most women first consult a general practitioner and are in any case dependent on the GP for continued prescriptions. In the Glasgow series14 over 90% consulted their GP about menopausal symptoms; 20% were given nothing more than reassurance and only 6% were referred to a hospital clinic. Only 10% of the women in this study and 16% of the nurses were aware that there were menopause clinics in Glasgow. Of the 72% who received some form of drug treatment, one third were given psychotropic agents while two-thirds received specific oestrogen therapy prescribed for their climacteric
complaints. disquieting finding in the Glasgow survey women who have undergone and hysterectomy oophorectomy before the age of 40 are known to be at high risk of osteoporosis15 and Another
was
More than hot flushes Climacteric
can be traced back to the of the ancient Egyptians, who organotherapy prescribed penis of ass for impotence.2000 years later Brown-Sequard reported rejuvenation of both himself and his wife with canine testicular juice.2 Attempts were also made at that time to treat climacteric symptoms either with human or animal ovarian grafts inplanted into retroperitoneal fat3 (which, not surprisingly, failed) or with ovarian extracts (ovarian juice or powdered ovaries made up as tablets).4 When ovarian steroids were isolated in the 1920s, they were used in women with severe menopausal symptoms and to suppress lactation. Specific oestrogen treatment for the menopause became a practical proposition when a preparation containing conjugated equine oestrogens was licensed in the USA in 1942, but the results of the first double-blind placebo-controlled trial that confirmed a beneficial effect of oestrogens on climacteric 5 symptoms were not published until 1950.5 Postmenopausal oestrogen therapy (commonly known as hormone replacement therapy, HRT) relieves vasomotor and urogenital symptoms of the menopause, prevents postmenopausal loss of bone mineral content, and reduces the incidence of hip, radial, and vertebral fractures.66 Epidemiological studies have shown that risk of death from coronary heart disease (CHD) is reduced by about 50%,’the effect being greatest in women with a premature menopause,10 in whom the mortality from CHD is otherwise increased. 11Although confirmation of these findings ultimately depends on results from randomised controlled trials-and the National Institutes of Health has announced plans for such a trial—the benefits of HRT are well established. Why, therefore, is HRT not widely prescribed? Only 9% of postmenopausal women in London13 and 3% in Glasgow14 receive HRT for more than 3 years.
therapy
that, although
cardiovascular disease," many such women were not offered treatment at a sufficiently early stage to prevent these conditions. Even when HRT was prescribed "there was little evidence of women and their general practitioners opting for long duration HRT". A similar lack of enthusiasm was evident in London,l3 where 26-5% of women attending a hospital clinic found their GP "uninterested" and a further 9-5% "totally unhelpful". Even when doctors prescribe oestrogen therapy they seldom do so for more than a few months. Doctors in the USA are no more sympathetic. Only 7% of family practitioners and 37 % of gynaecologists prescribe HRT for prevention of osteoporosis.16 Prescribing habits for the menopause vary widely in different parts of the country: the national average is about 15% but in Boston only 3% of all menopausal receive HRT and in New Haven, women Connecticut, 6%. The presumed adverse effects of oestrogens probably deter many women and their doctors from starting or continuing treatment. 60% of respondents in a Cambridge, UK, study18 expressed concern about side-effects, including the risk of cancer, even though endometrial cancer can be prevented by progestagens and any increase in breast cancer is both controversiall9 and insignificant by comparison with the reduction in cardiovascular mortality and
osteoporosis. The regular withdrawal bleeding with cyclical oestrogen/progestagen therapy is often unacceptable. 26% of the Glasgow women14 said that withdrawal bleeding made therapy unacceptable and 47% stated that it was a minor disadvantage. Only 26 % felt that it was not troublesome. 80% of Brighton, UK, GPs felt that continuation of menstrual bleeding was a major disadvantage of HRT. 20 To increase the low prescribing rate of HRT for those who need it, more doctors need to be informed about the true benefits and risks. A serious obstacle is the tendency to equate the natural oestrogens used to treat the menopause with the
918
synthetic oestrogens present in oral contraceptives, despite their different structures and effects. Women who would benefit most from treatment are those with a premature menopause,7,8 a history of long-term amenorrhoea, low body weight, or low dietary intake of calcium, and also smokers and those with a family history of osteoporosis.21 That an early menopause predisposes to the premature onset of cardiovascular disease1O,11 reinforces the need for treating such women as soon as premature ovarian failure is diagnosed. Contrary to popular belief, many of the risk factors for coronary heart disease are indications for HRT and not contraindications-smoking,22 hyperlipidaemia,23 and a history of CHD are reasons to start treatment and contraindications to stopping it. HRT increases the long-term survival of women with established coronary atherosclerosis.24 Compliance would be improved by individualising treatment. The minimum effective dose of oestrogen should be prescribed initially-0-625 mg of conjugated equine oestrogens is sufficient to prevent osteoporosis.25 Irrespective of dose, oral oestrogens are not necessarily first-line treatment for all women. For example, transdermal oestradiol may be a more logical choice for those with a history of side-effects from oral contraceptives. The type and dose of progestagen are likewise important. Since progestagens are given to protect the endometrium they are not mandatory in women after hysterectomy-a fact overlooked by the 47% of Los Angeles gynaecologists who prescribed combined oestrogen/progestagen therapy to such women.26 Progestagens derived from 17a-hydroxyprogesterone give rise to fewer side-effects than the 19-nortestosterone derivatives.z’ The frequency of withdrawal bleeding can be reduced by giving progestagens every 3 months and not monthly. 28 A low-dose progestagen can also be given every day without interruption and, although 80% may experience some initial menstrual irregularity, this generally subsides after the first 6 months.29 A new synthetic steroid, tibolone, which displays weak oestrogenic, androgenic, and progestagenic activity in animals may offer many of the advantages of conventional HRT without the disadvantage of withdrawal bleeding or oestrogenic side-effects. This drug alleviates climacteric symptoms3° and prevents without the osteoporosis3’ stimulating endometrium.32 These features make tibolone highly acceptable to women in their 60s and 70s who are generally intolerant of conventional HRT, especially if this entails return of menstrual bleeding. Climacteric replacement therapy is not the secret of eternal youth, but it is much more than treatment of hot flushes. The challenge for the 1990s is to identify those women who would benefit most and to ensure that they receive adequate therapy. 1. Utian WH. Scientific basis for post menopausal estrogen therapy. In: Beard RJ, ed. The menopause: a guide to current research and practice. Baltimore: University Park Press, 1976: 176.
2. Brown Sequard (1895). Cited in DeMerre LJ. The female sex hormones. New York: Vantage Press, 1954. 3. Sauvé L. Les greffes ovariennes. Envisagées au point de vue de la pratique chirurgicale. Paris: G Steintied, 1909. 4. Bra M (1895). Cited in: DeMerre LJ. The female sex hormones. New York: Vantage Press, 1954. 5. Greenblatt RB, Barfield WE, Garner JF, Calk GL, Harrod JP.
Evaluation of an estrogen, androgen, estrogen-androgen combination and a placebo in the treatment of the menopause. J Clin Endocrinol
1950; 10: 1547-58. Jensen GF, Christiansen C, Transbol I. Fracture frequency and bone preservation in postmenopausal women treated with estrogen. Obstet Gynecol 1982; 60: 493-96. 7. Rosenberg L, Armstrong B, Jick H. Myocardial infarction and estrogen therapy in post-menopausal women. N Engl J Med 1976; 23: 1256-59. 8. Ross RK, Paganini-Hill A, Mack TM, Arthur M, Henderson BE. Menopausal oestrogen therapy and protection from death from ischaemic heart disease. Lancet 1981; i: 858-60. 9. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. N Engl J Med 1991; 325: 756-62. 10. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and risk of coronary heart disease in women. N Engl J Med 1987; 316: 1105-10. 11. Higano M, Robinson RW, Cohen WD. Increased incidence of 6.
cardiovascular disease in castrated women. N Engl J Med 1963; 268: 1123-25. 12. Healy B. The Yentl syndrome. N Engl J Med 1991; 325: 274-76. 13. Garnett T, Mitchell A, Studd J. Patterns of referral to a menopausal clinic. J R Soc Med 1991; 84: 128-30. 14. Barlow DH, Grosset KA, Hart H, Hart DM. A study of the experience of Glasgow women in the climacteric years. Br J Obstet Gynecol 1989; 96: 1192-97. 15. Richelson LS, Wahner HW, Melton LJ III, Riggs BL. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 1984; 311: 1273-75. 16. Grisso JA, Baum CR, Turner B. What do physicians do to prevent osteoporosis? J Bone Min Res 1990; 5: 213-19. 17. Sarrel P. In: Ginsburg J, ed. The circulation in the female—from the cradle to the grave. Carnforth, Lanes: Parthenon, 1989: 85. 18. Draper J, Roland M. Perimenopausal women’s views on taking hormone replacement therapy to prevent osteoporosis. Br Med J 1990; 300: 786-88. 19. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991; 151: 67-72. 20. Shears R-M. Brighton practitioners’ attitude to HRT. Practitioner 1989; 233: 147-9. 21. Lindsay R, Hart DM, Abdalla H, Dempster D. Pathogenesis of postmenopausal osteoporosis. In: Notelovitz M, Van Keep P, eds. The climacteric in perspective. Carnforth, Lanes: Parthenon, 1986: 79-85. 22. Wilson PWF, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking and cardiovascular morbidity in women over 50. N Engl J Med 1985; 313: 1038-43. 23. Bush TL, Barrett-Conner E, Cowan LD. Cardiovascular morbidity and non contraceptive use of estrogens in women: results from the Lipid Research Clinic Program follow up study. Circulation 1987; 75: 1102-09. 24. Sullivan JM, Vander Zwang R, et al. Estrogen replacement and coronary artery disease. Arch Intern Med 1990; 150: 2557-62. 25. Lindsay R, Hart DM, Clark DM. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol
1984; 63: 759-63. RK, Paganini-Hill A, Roy S,
26. Ross
et
al. Past and present
preferred
prescribing practices of hormone replacement therapy amongst Los Angeles gynecologists. Am J Publ Health 1988; 78: 516-19. 27. Dennerstein L, Burrows G. Psychological effects of progestogens in the post-menopausal years. Maturitas 1986; 8: 101-06. 28. Kemp JF, Fryer JA, Baber RJ. An alternative regimen of hormone replacement therapy to improve patient compliance. Aust N Z J Obstet Gynaecol 1989; 29: 66-69. 29. Weinstein L, Bewtra C, Gallagher JC. Evaluation of continuous low-dose regimen of estrogen progestin for treatment of the menopausal patient. Am J Obstet Gynecol 1990; 162: 1534-39. 30. Nevinny-Stickel J. Double-blind cross-over study with Org OD 14 and placebo in postmenopausal patients. Arch Gynecol 1983; 234: 27-31. 31. Yeusens P, Dequeker J, Gielen J, Schot LPC. Non-linear increase in vertebral density induced by a synthetic steroid (Org OD 14) in women with established osteoporosis. Maturitas 1991; 13: 155-62. 32. Multicentre study of effects of Org OD 14 on endometrium, vaginal cytology and cervical mucus in post-menopausal and oophorectomised women.
Maturitas
1984; 5: 281-86.
