- Email: [email protected]
Heart rate variability and hormone replacement therapy
was 2·81 (1·15–6·89) and for serous tumours was 2·03 (1·04–3·97). Women developing invasive mucinous ovarian cancers were less likely to have used oestrogen HRT but more likely to have used oral contraceptives.4 Beral also pooled six studies of cutaneous melanoma and one of ocular melanoma and estimated an increased risk of 1·4 (1·2–1·7) for ever users of HRT.2 She said that oestrogen and progestagen oral contraceptives increased the risk of hepatocellular cancer, and the apparent decrease in colorectal cancer for current users of HRT could relate to a healthy user effect. Selections and exclusions in studies, early drop out of intolerant and susceptible women, and a possible latent period of 20 years or more could lead to serious underestimations of risks of all cancers, including breast cancer. Large increases in women’s cancer registrations have occurred in the past 40 years in countries where hormones are taken with rises and temporary falls after changes in prescribing patterns. Stampfer and Persson stated that the addition of progestagens to oestrogenonly HRT may increase breast cancer risks. To emphasise monitored adherence to progestagen-taking to reduce the risk of endometrial cancer therefore seems unwise when nonhormonal managements of menopausal symptoms or osteoporosis are available. Studies in animals have shown that oestrogens and progestagens are carcinogenic, either by acting alone or as co-carcinogens. These hormones induce cancer not only in hormone target organs such as mammary gland, uterus, pituitary gland, and ovaries, but also in liver, lymphoid tissues, adrenal glands, and kidneys.5 Although epidemiologists may be uncertain of the meaning of their results, millions of women are being prescribed hormones with a certainty that is not justified by the evidence. *Ellen C G Grant, Elizabeth H Price, C Michael Steel *20 Coombe Ridings, Kingston-upon-Thames KT2 7JU, UK; Department of Medical Microbiology, Royal London Hospital, London; and Department of Medical Sciences, University of St Andrews, St Andrews 1
Clinical Synthesis Panel on HRT. Hormone replacement therapy. Lancet 1999; 354: 152–55. 2 Beral V. Use of hormone replacement therapy and the subsequent risk of cancer. J Epidemiol Biostat 1999 (in press). 3 Kaufman DW, Kelly JP, Welch WR, et al. Noncontraceptive estrogen use and epithelial ovarian cancer. Am J Epidemiol 1989; 130: 1142–51. 4 Risch HA. Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol 1996; 63: 254–57.
THE LANCET • Vol 354 • October 9, 1999
5
Li JJ. Perspectives in hormonal carcinogenesis: animal models to human disease. In: Huff J, Boyd J, Barrett JC, eds. Cellular and molecular mechanisms of hormonal carcinogenesis. Environmental influences. New York: Wiley-Liss, 1996: 447–54.
HRT
n
Heart rate Total power (beats/min) (ms2 )
Norethisterone Medrogestrone Medroxyprogesterone Levonorgestrel Chlormadinone
4 4 2 2 1
69·7 (0·8) 77·6 (6·5) 69·2 (3·6) 69·4 (0·6) 70·3
1601 (595) 904 (423) 372 (209) 983 (510) 353
Data are means (SE) unless otherwise indicated.
Women on progestagen-containing HRT
Heart rate variability and hormone replacement therapy Sir—Christopher Hayward and colleagues (July 17, p 256)1 suggest that, in our study investigating the effects of progestagen-containing hormone replacement therapy (HRT) on heart rate variability,2 the modulation of beneficial cardiovascular effects of oestradiol by progestagen is not only dependent on the presence of progestagens but also the specific type of progestagen used. In addition, the route of application may play an important part. Seely and colleagues3 have shown that intravaginal, natural progesterone does not negate the oestrogen-induced reductions of systemic blood pressure, whereas medroxyprogesterone counterbalances the beneficial effects induced by oestrogen on cardiovascular targets. 1 Furthermore, our data, stratified by progestagen compound, suggest that medroxyprogesterone acetate is not the only progestagen that attenuates heart rate variability. Although not statistically powerful enough because of the small number of women studied, assessment of mean heart rate and total power (a measure of heart rate variability) indicates higher heart rate and lower total power in women on progestagencontaining HRT for all progestagens studied (table), compared with women on oestrogen replacement therapy and those without HRT.2 Hayward and colleagues underestimate an important issue of our study: progestagens not only negate beneficial effects of oestrogen replacement on heart rate variability, but even increase heart rate above and reduce heart rate variability below values in women without HRT. 2 We believe that this reduction of heart rate variability in our women on progestagen-containing HRT is of importance. The homogeneous and extensive reduction of heart rate variability is evident despite our small study population, 2 whereas because of high interindividual variability large samples are usually necessary to show differences in autonomic regulation of heart rate.4 Nevertheless, our findings should be interpreted with caution
because the prognostic relevance of reduced heart rate variability as a surrogate for increased mortality has been shown in patients after myocardial infarction, 4 but is still a matter of debate for the estimation of prognosis during drug therapy in other populations. Research on the impact of HRT on cardiovascular risk has mainly focused on the beneficial actions of oestrogen on the cardiovascular system. 5 However, progestagencontaining HRT is routine. Opposing effects of progestagens on beneficial cardiovascular effects of oestrogens have been recognised, which may even change prognostic markers beyond control levels,2 depending on the particular compound, mode (eg, cyclical, continuous), and route of application. However, additional aspects (eg, control of oestrogeninduced growth of the endometrium and of vaginal bleeding during HRT) beyond the view of the cardiologist should be considered. Michael Christ, Karen Seyffart, Hanns-Christian Tillmann, *Martin Wehling Institute of Clinical Pharmacology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, D-68135 Mannheim, Germany (e-mail: [email protected]) 1
Hayward CS, Webb CM, Collins P. Hormone replacement therapy and heart-rate variability. Lancet 1999; 354: 256. 2 Christ M, Seyffart K, Wehling M. Attenuation of heart-rate variability in postmenopausal women on progestin-containing hormone replacement therapy. Lancet 1999; 353: 1939–40. 3 Seely EW, Walsh BW, Gerhard MD, Williams GH. Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women. Hypertension 1999; 33: 1190–94. 4 La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998; 351: 478–84. 5 Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340: 1801–11.
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Clinical Synthesis Panel on HRT. Hormone replacement therapy. Lancet 1999; 354: 152–55. 2 Beral V. Use of hormone replacement therapy and the subsequent risk of cancer. J Epidemiol Biostat 1999 (in press). 3 Kaufman DW, Kelly JP, Welch WR, et al. Noncontraceptive estrogen use and epithelial ovarian cancer. Am J Epidemiol 1989; 130: 1142–51. 4 Risch HA. Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol 1996; 63: 254–57.
THE LANCET • Vol 354 • October 9, 1999
5
Li JJ. Perspectives in hormonal carcinogenesis: animal models to human disease. In: Huff J, Boyd J, Barrett JC, eds. Cellular and molecular mechanisms of hormonal carcinogenesis. Environmental influences. New York: Wiley-Liss, 1996: 447–54.
HRT
n
Heart rate Total power (beats/min) (ms2 )
Norethisterone Medrogestrone Medroxyprogesterone Levonorgestrel Chlormadinone
4 4 2 2 1
69·7 (0·8) 77·6 (6·5) 69·2 (3·6) 69·4 (0·6) 70·3
1601 (595) 904 (423) 372 (209) 983 (510) 353
Data are means (SE) unless otherwise indicated.
Women on progestagen-containing HRT
Heart rate variability and hormone replacement therapy Sir—Christopher Hayward and colleagues (July 17, p 256)1 suggest that, in our study investigating the effects of progestagen-containing hormone replacement therapy (HRT) on heart rate variability,2 the modulation of beneficial cardiovascular effects of oestradiol by progestagen is not only dependent on the presence of progestagens but also the specific type of progestagen used. In addition, the route of application may play an important part. Seely and colleagues3 have shown that intravaginal, natural progesterone does not negate the oestrogen-induced reductions of systemic blood pressure, whereas medroxyprogesterone counterbalances the beneficial effects induced by oestrogen on cardiovascular targets. 1 Furthermore, our data, stratified by progestagen compound, suggest that medroxyprogesterone acetate is not the only progestagen that attenuates heart rate variability. Although not statistically powerful enough because of the small number of women studied, assessment of mean heart rate and total power (a measure of heart rate variability) indicates higher heart rate and lower total power in women on progestagencontaining HRT for all progestagens studied (table), compared with women on oestrogen replacement therapy and those without HRT.2 Hayward and colleagues underestimate an important issue of our study: progestagens not only negate beneficial effects of oestrogen replacement on heart rate variability, but even increase heart rate above and reduce heart rate variability below values in women without HRT. 2 We believe that this reduction of heart rate variability in our women on progestagen-containing HRT is of importance. The homogeneous and extensive reduction of heart rate variability is evident despite our small study population, 2 whereas because of high interindividual variability large samples are usually necessary to show differences in autonomic regulation of heart rate.4 Nevertheless, our findings should be interpreted with caution
because the prognostic relevance of reduced heart rate variability as a surrogate for increased mortality has been shown in patients after myocardial infarction, 4 but is still a matter of debate for the estimation of prognosis during drug therapy in other populations. Research on the impact of HRT on cardiovascular risk has mainly focused on the beneficial actions of oestrogen on the cardiovascular system. 5 However, progestagencontaining HRT is routine. Opposing effects of progestagens on beneficial cardiovascular effects of oestrogens have been recognised, which may even change prognostic markers beyond control levels,2 depending on the particular compound, mode (eg, cyclical, continuous), and route of application. However, additional aspects (eg, control of oestrogeninduced growth of the endometrium and of vaginal bleeding during HRT) beyond the view of the cardiologist should be considered. Michael Christ, Karen Seyffart, Hanns-Christian Tillmann, *Martin Wehling Institute of Clinical Pharmacology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, D-68135 Mannheim, Germany (e-mail: [email protected]) 1
Hayward CS, Webb CM, Collins P. Hormone replacement therapy and heart-rate variability. Lancet 1999; 354: 256. 2 Christ M, Seyffart K, Wehling M. Attenuation of heart-rate variability in postmenopausal women on progestin-containing hormone replacement therapy. Lancet 1999; 353: 1939–40. 3 Seely EW, Walsh BW, Gerhard MD, Williams GH. Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women. Hypertension 1999; 33: 1190–94. 4 La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998; 351: 478–84. 5 Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340: 1801–11.
1303