Editorial

Safety of post-menopausal hormone replacement

I

t remains surprising that hormone replacement

therapy (HRT) for the post-menopausal woman has not met with general acceptance. A recent consensus view' stated that the risk-benefit and costbenefit ratios favoured the majority of women considering long term hormone replacement from when oestrogen deficiency symptoms commence, or menstruation ceases. H R T may prevent or retard the onset of the most common cause of death in women (coronary heart disease), a major cause of morbidity (osteoporosis), and a cause of serious impairment of quality of life for women (perimenopausal symptoms). Contributory factors to physician reluctance to prescribe H R T may include the disadvantage to the patient of the recommencement of monthly withdrawal bleeding. Second, there is concern over the possible carcinogenic effects of oestrogen and progestogen replacement. Third, since oral preparations especially may disproportionately stimulate hepatic protein synthesis and thus increase circulating coagulation factors and renin substrate (the 'first pass' effect), there is disquiet about these metabolic effects leading to an increased risk of atherosclerosis, hypertension and thromboembolic disease. It is the purpose of the following commentary to alleviate some of these anxieties and reassure about the safety of post-menopausal oestrogen replacement therapy. Indeed a history of endometrial and breast carcinoma, existing cardiovascular disease, and prior thromboembolism have all been cited as absolute contraindications to oestrogen replacement. Data are accumulating which refute these assertions. Recently Dupont and Page2 published a metaanalysis on the subject of breast carcinoma and oestrogen replacement and reported that the overall risk of breast cancer associated with oestrogen therapy was 1.07. In order to explain the variations in estimated risks between the 28 studies cited in their analysis, these authors also examined the effects of type, duration and dosage of treatment. The risk of breast cancer for women who took 0.625 mg per day or less of conjugated oestrogens (CE) was 1.08 times that of

women not administered this therapy (95% confidence intervals, 0.96-1.2). In contrast, women receiving 1.25 mg per day or more of CE exhibited a relative risk of 2.0 or less in all studies. With regard to these latter studies, other risk factors may have varied between studies and thus estimating the overall risk with this higher dosage was difficult. Certainly the study of Bergkvist et aL3 conducted on a large cohort of women implied that breast cancer risk varied with the type and daily dosage of oestrogen. That is, low dosage administration of conjugated oestrogens did not increase the risk whereas oestradiol preparations were associated with a 20 per cent increase in breast cancer risk that increased significantly with duration of exposure. The study published by Colditz et aL4 based upon a ten year prospective cohort observed a significantly elevated risk among current users of HRT (relative risk 1.36, confidence intervals, 1.11 to 1.67), whereas past users of H R T were not at an increased risk (relative risk 0.98, confidence intervals, 0.81-1.18). The latter group were also considered not to be protected from breast carcinoma, which would have been expected if the association with current use were due to increased detection. This issue has since been disputed in correspondence following the r e p ~ r t . ~ Benign breast disease is a further source of controversy as to the safety of oestrogen replacement. Again Dupont and Page2 provide persuasive evidence that menopausal therapy with conjugated oestrogens (0.625 mg per day or less) does not augment breast cancer risk among women with benign breast disease. T o date there is no published evidence to suggest that hormone replacement increases the incidence of breast cancer in patients with a strong family history of breast cancer.6 There is no theoretical reason to presume that progestogens should decrease breast cancer risk. In breast tissue cell division occurs mainly in the latter half of the menstrual cycle when progesterone levels are r a i ~ e d . Two ~ studies have appeared in the literature3,*that considered the effect of both oestrogen and progestogens on the risk ofbreast cancer. Gambrel1

Correspondence 20: Professor D. L. Healy, Monash Department Obstetrics & Gynaecology and Menstrual/MenopauseClinic, Monash Medical Centre, Level 5, 246 Clayton Road, Clayton, Victoria 3168, Australia. POST-MENOPAUSAL HORMONE REPLACEMENT

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disease was reported by Henderson et a1.l' er al.%reported a decrease in breast cancer risk with The benefit with regard to coronary heart disease the addition of progestogens to HRT. Bergkvist et aL3 is consistent with the effect of oestrogens to lower lowobserved a fourfold rise in breast cancer risk among density lipoprotein (LDL) cholesterol and raise highpatients taking combined hormone replacement for density lipoprotein (HDL) cholesterol. However, only between six and nine years (but based on data from between 25 and 50 per cent of this beneficial effect only ten women). It is likely that selection bias operates is through changes in LDL and HDLZoand the effect for women administered H R T since they are more of oestrogens a n d or progestogens on newly-recognised likely to undergo breast examination. Since there is lipoproteins implicated in coronary heart disease, such no clear evidence that progestogens decrease risks of as oxidised LDL and LDL-related lipoprotein (Lp,) breast carcinoma there is no indication for their use is unclear.21The addition of progestogens may reverse in women who have had their uterus removed. some of the beneficial effects of H R T on HDL, but Even more contentious is the issue of prescribing not upon LDL, where the decrease may be accentuH R T to women who have been successfully treated ated.22 Moreover, combined oestrogen-progestogen for endometrial and breast carcinoma. Although treatment may have an additional benefit on triglyassumed to be absolute contraindications there are no cerides than H R T Other effects of H R T data to substantiate this ~ a r n i n gIn . ~1986, Creasman independent of serum lipids include changes in insulin et al. lo published data from patients who received HRT and glucose metabolism, prostaglandin actions and after treatment for endometrial cancer (stage 1). arterial blood These last changes relate to direct Despite it being a non-randomised study the known vasodilatory actions of oestradiol on vessel walls and prognostic features of the disease were similar between endothelium. Whether progestogens as combined therthe oestrogen treated and non-oestrogen treated apies change these potential risk factors is unknown. groups. Patients who received H R T appeared to be There is agreement in the literature that protected from recurrence (p = 0.0336). progestogens given daily for 12 or more days per Three physiological situationsg support the month (to women with a uterus) will reduce their consideration of HRT in women previously treated for excess risk of endometrial carcinoma associated with breast cancer. First, the survival of the pregnant woman with breast cancer is similar to that of the non long term post-menopausal unopposed oestrogen pregnant woman once a correction for age and stage use.z4-26Studies continue to determine precisely which combined continuous oestrogen-progestogenregimens of disease has been made." Second, subsequent pregwill give equal protection. The correct advice for the nancies do not increase recurrence rates.12 Third, patient who is amenorrhoroeic after the new day randomised studiesl3 have not shown a benefit from surgery operation of endometrial ablationhesection is prophylactic oophorectomy with regard to time of recurrence or survival in premenopausal women with quite unknown at present. breast cancer. It thus seems entirely reasonable to at There are of course other beneficial effects of HRT least discuss the risks and benefits of H R T with in the post-menopausal woman. HRT reduces the rate women who have been treated for breast carcinoma of bone loss after menopause and has been associated and who are suffering from considerable postwith a 60 per cent fall in the rate of hip fracture and menopausal symptoms. coincident m~rbidity.'~ At present one of the There is good evidence that HRT is protective remaining controversies in the prevention of osteoagainst cardiovascular disease. Agreement among porosis is whether postmenopausal HRT should be recent epidemiological reports demonstrates a reducuniversal or restricted to those women at high risk.28 tion in the order of 40 to 50 per cent in the risk of Alternative routes of oestrogen administration may provide effective oestrogen supplementation and avoid ischaemic heart disease for women administered postand raised serum menopausal HRT.14-16 In 1985, Stampfer et ~ 1 . ' ~ the increase in bile lithogeni~ity,2~ levels of renin substrate and clotting factors, these reported data after four years of follow-up and observed that H R T reduced the risk of coronary heart disease. latter being implicated in the development of hyperSimultaneously'8 results from the Framingham Study tension and thromboembolism. Certainly, transdermal implied that the risk was increased! Now after up to delivery of oestrogen fulfills these r e q ~ i r e m e n t s . ~ ~ - ~ ~ Despite the current enthusiasm for oestrogen ten years of follow-up, the former group16 have reported an overall relative risk (after correction for replacement therapy and reassuring safety data in the age and other risk factors) of major coronary heart literature it has been repeatedly stated r e ~ e n t l y ~ ' * ~ ~ - ~ ~ disease in current users of H R T of 0.56 (95 per cent that only a large randomised clinical trial will confidence intervals, 0.40-0.80). Current H R T usage adequately address the biases which inevitably enter was not associated with any change in the risk of the current modes of study (case-control, crossstroke. Supporting evidence for a reduced mortality sectional, prospective-cohort). Meanwhile, the riskfrom coronary heart disease and also cerebrovascular benefit assessment will vary according to any given Aust NZ J Med 1992; 22 CRITCHLEY ET AL. 104

woman’s medical history and indiiridual characteristics. Each potential candidate for hormone replacement therapy should be fully informed about the current state of knowledge and hence exercise a role in any decisions about future therapy. H. 0. D. CRITCHLEY Lecturer, Monash University, Department of Obstetrics and Gynaecology, E. A. FARRELL Director, Menopause Unit, Monash Medical Centre, D. L. HEALY Professor, Monash University, Department of Obstetrics and Gynaecology, Clayton, Vic.

References 1. MacLennan AH (for the Australian Menopause Society). Hormone replacement therapy and the menopause. Med J Aust 1991; 155: 43-4. 2. Dupont WD, Page DL. Menopausal estrogen replacement and breast cancer. Arch Intern Med 1991; 151: 67-72. 3. Bergkvist L, Adami H-0, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 1989; 321: 293-7. 4. Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE. Prospective study of estrogen replacement therapy and risk ofbreast cancer in postmenopausal women. JAMA 1990; 264: 2648-53. 5. Dupont WD. Estrogen replacement therapy and risk of breast cancer. JAMA 1991; 265: 1824. 6. MacLennan AH. Hormone replacement therapy and the menopause. Correspondence reply. Med J Aust 1991; 155: 351. 7. Anderson TJ, Ferguson DJP, Raab GM. Cell turnover in the ‘resting’ human breast: influence of parity, contraceptive pill, age and laterality. Br J Cancer 1982; 46: 376-82. 8. Gambrel1 RD, Maier RC, Sanders BJ. Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users. Obstet Gynecol 1983; 62: 435-43. 9. Creasman WT. Estrogen replacement therapy: is previously treated cancer a contraindication? Obstet Gynecol 1991; 77: 308-12. 10. Creasman WT, Henderson D, Hinshw W, Clarke-Pearson DL. Estrogen replacement therapy in the patient treated for endometrial carcinoma. Obstet Gynecol 1986; 67: 326-30. 11. King RM, Welch JS, Martin JK, Coulam CB. Carcinoma of the breast associated with pregnancy. Surg Gynecol Obstet 1985; 160: 228-32. 12. Ribeiro G, Jones DA, Jones M. Carcinoma of the breast associated with pregnancy. Br J Surg 1986; 73: 607-9. 13. Ravdin RG, Lewison EF, Slack NH, Gardner B, State D, Fisher B. Results of a clinical trial concerning the worth of prophylactic oophorectomy for breast carcinoma. Surg Gynecol Obstet 1970; 131: 1055-64. 14. Bush TL, Barrett-Connor E, Cowan LD et al. Cardiovascular mortality and noncontraceptiveuse of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987; 75: 1102-9. POST-MENOPAUSAL HORMONE REPLACEMENT

15. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991; 20: 47-63. 16. Stampfer MJ, Colditz GA, Willett WC et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten year followup from the Nurses’ Health Study. N Engl J Med 1991; 325: 756-62. 17. Srampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985; 313: 1044-9. 18. Wilson PWF, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med 1985; 313: 1038-43. 19. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991; 151: 75-8. 20. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991; 265: 1861-7. 21. Crook D, Stevenson JC. Progestogens, lipid metabolism and hormone replacement therapy. Brit J Obstet Gynaecol 1991; 98: 749-50. 22. Goldman L, Tosteson ANA. Uncertainty about postmenopausal estrogen. Time for action, not debate. N Engl J Med 1991; 325: 800-2. 23. Stevenson JC. Osteoporosis and cardiovascular disease in women: converging paths? Lancet 1990; 336: 1121-2. 24. Whitehead MI, McQueen J, King RJB, Campbell S. Endometrial histology and biochemistry in climacteric women during oestrogenlprogestogen therapy. J Roy SOCMed 1979; 72: 322-7. 25. Studd JWW, Thom MH, Paterson MEL, Wade-Evans T . The prevention and treatment of endometrial pathology in postmenopausal women receiving exogenous estrogens. In: The menopause and postmenopause. Eds. Pasetto N, Paoletti R, Ambrus JL. 1980 M T P Press, Lancaster, 127-139. 26. Voigt LF, Weiss NS, Chu J, Daling JR, McKnight B, Van Belle G. Progestogen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet 1991; 338 274-7. 27. Kiel DP, Felson DT, Anderson JJ, Wilson PWF, Moskowitz MM. Hip fracture and the use of estrogens in postmenopausal women. The Framingham Study. New Engl J Med 1987; 317: 1169-74. 28. Nordin BEC, Need AG, Chatterton BE, Horowitz M, Cleghorn DB. Bone density screening for osteoporosis. Lancet 1990; 336: 1327-28. 29. Van Erpecum KJ, Van Berge Henegouwen GP, Verschoor L, Stoelwinder B, Willekens FLH. Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women. Gastroenterology 1991; 100: 482-8. 30. Chetkowski RJ, Meldrum DR, Steingold KA, et al. Biologic effects of transdermal estradiol. N Engl J Med 1986; 314: 1615-20. 31. De Lignieres B, Basdevant A, Thomas G. et al. Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab 1986; 62: 536-41. 32. Pattison NS, Uptin T, Knox B, France J. Transdermal wstrogen for postmenopausal women: a double blind crossover comparative study with ethinyl oestradiol. Aust NZ J Obstet Gynaecol 1989; 29: 62-5. 33. Barren-Connor E. Postmenopausal estrogen and prevention bias. Ann Intern Med 1991; 115: 455-6. 34. Moon TE. Estrogens and disease prevention. Arch Intern Med 1991; 151: 17-8. 35. Vandenbroucke JP. Postmenopausal oestrogen and cardioprotection. Lancet 1991; 337: 833-4. Aust NZ J Med 1992; 22

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