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Oestrogen therapy for myocardial ischaemia in women
COMMENTARY
Oestrogen therapy for myocardial ischaemia in
women
See page 133
The past 5-10 years have seen a great deal of research into the pathogenesis and treatment of coronary heart disease (CHD) in women, this surge of interest being due to the realisation that risk factors and clinical courses of CHD in women differ from those in men. One big difference is the increase in risk of CHD after women become postmenopausal, which is thought to be due to cessation of ovarian oestrogen production. Epidemiological studies indicate that postmenopausal oestrogen therapy reduces the risk of CHD by as much as 50%. However, the effects of oestrogen on plasma lipoprotein concentrations (a rise in high density and a fall in low density lipoprotein cholesterol) explain only a small part of oestrogen’s beneficial effects on risk of CHD. One intriguing mechanism by which oestrogen may reduce the risk of CHD is by its direct effects on heart and coronary artery function. Postmenopausal oestrogen therapy not only inhibits progression of coronary artery atherosclerosis but also affects coronary artery reactivity and cardiovascular hemodynamics. Rosano et al take the story further by showing that oestrogen treatment of postmenopausal women can reduce or prevent symptoms of myocardial ischaemia. Unfortunately, they did not examine the pathophysiological mechanisms responsible for these effects. The methods exist, and we now need studies of the effects of oestrogen on coronary artery reactivity, heart contractility, and peripheral arterial function in women and in laboratory animals. Without these data reports such as the one by Rosano et al will not permit clinically confident generalisations about oestrogen treatment and reduction in CHD risk. Rosano et al speculate that oestrogen may be a useful treatment for stable angina in women. One should certainly pause for thought before stopping oestrogen treatment in a woman at high risk of myocardial infarction. However, little is known about this hormone’s effects on thrombosis. High doses of ethinyloestradiol in old-style oral contraceptives increased the risk of cerebral and coronary vascular disease (presumably by promoting thrombosis) in premenopausal women. Current doses of oestrogens given to postmenopausal women are much lower and are not thought to increase the risk of arterial thrombosis but this concern has yet to be finally removed by careful epidemiological studies of postmenopausal oestrogens and arterial thrombosis. Meanwhile we should hesitate to recommend oestrogen for angina, in doses and by routes that result in pharmacological concentrations, especially since good alternatives such as glyceryl trinitrate and calcium-channel blockers are available. It is not clear from Rosano’s results that oestrogen affords protection against myocardial ischaemia beyond that of conventional treatment.
J Koudy Williams Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina, USA
128
Turner’s
syndrome and chromosome Y
See page 140
Of the known chromosome mosaics those involving X and Y are by far the most common. A structural aberration of X or Y is frequently accompanied by a second stem line displaying a 45,X complement. If the abnormal sex chromosome shows ring formation or a complex rearrangement the 45,X line will predominate. Conventional cytogenetic techniques may well miss cells containing the structurally abnormal sex chromosome.2 The detection of such low frequency mosaicisms (micromosaicism) in Turner’s syndrome or gonadal dysgenesis has attracted attention because the very high in utero lethality of the 45,X condition, largely restricted to cases lacking a second cell line, has led to the hypothesis that most if not all live-born 45,Xs are mosaics.3,4 However, even after the investigation of two tissues some 25% of live-born Turner’s syndrome patients remained apparent non-mosaic 45,X.2 One possible explanation is that conventional cytogenetics are not sensitive enough to detect the mosaicism. Furthermore, dysgenetic gonads in individuals whose genome contains Y chromosome material are at increased risk of neoplasia, and this may be a special problem for patients with Turner’s syndrome who are put on growth hormone therapy. Molecular techniques now permit identification of Ychromosomal DNA content in a second cell line even in micromosaics.3-6 In this issue of The Lancet Kocova et al report the detection of Y chromosome sequences by polymerase chain amplification with SRY-gene-specific primers followed by Southern analysis of PCR products. They claim that one cell containing SRY can be detected among 100 000 XX cells by this method. Among 18 patients with Turner’s syndrome positive signals for SRY were detected in 6. Surprisingly, after amplification of alphoid Y centromeric repeats no definite signals were. Even more surprisingly, 1 SRY-positive patient was 45,X/46,XX and another 45,X/47,XXX on conventional cytogenetic investi-
gation. In Y-derived chromosomes marker sequences which map to distal Yp or Yq may be lost during the formation of these chromosomes although their centromeric sequences are preferentially retained.7 Does this mean that in the SRY-positive cases, reported in this paper, the centromeric sequences were deleted? As a mode of origin one would then have to assume, for example, a coincident abnormal XY interchange and loss of one X chromosome by anaphase lag in the first and malsegregation in the second case. Witt and co-workers6 have compared amplification of alphoid centromeric repeats of the Y and the X chromosomes and of the SRY sequence. In 28 patients with Turner’s syndrome, the pattern of signal distribution after amplification of a fragment of the SRY gene was identical to that of the Y-specific alphoid repeats and no findings conflicting with conventional cytogenetic results were noted. Those studying Y mosaicism, including Kocova et al, tend to emphasise sensitivity-but what about accuracy? In conventional cytogenetics the detection of mosaicism depends on several factors, including numbers of cells examined, numbers and types of tissues, culture techniques used, and in vivo or in vitro selection against one of the cell lines.2 Sensitivity addresses just one of these factors. The absence of mosaicism in blood does not exclude mosaicism in other tissues. There is recent evidence that human fetal blood derives from the yolk sac and not from the embryo
Oestrogen therapy for myocardial ischaemia in
women
See page 133
The past 5-10 years have seen a great deal of research into the pathogenesis and treatment of coronary heart disease (CHD) in women, this surge of interest being due to the realisation that risk factors and clinical courses of CHD in women differ from those in men. One big difference is the increase in risk of CHD after women become postmenopausal, which is thought to be due to cessation of ovarian oestrogen production. Epidemiological studies indicate that postmenopausal oestrogen therapy reduces the risk of CHD by as much as 50%. However, the effects of oestrogen on plasma lipoprotein concentrations (a rise in high density and a fall in low density lipoprotein cholesterol) explain only a small part of oestrogen’s beneficial effects on risk of CHD. One intriguing mechanism by which oestrogen may reduce the risk of CHD is by its direct effects on heart and coronary artery function. Postmenopausal oestrogen therapy not only inhibits progression of coronary artery atherosclerosis but also affects coronary artery reactivity and cardiovascular hemodynamics. Rosano et al take the story further by showing that oestrogen treatment of postmenopausal women can reduce or prevent symptoms of myocardial ischaemia. Unfortunately, they did not examine the pathophysiological mechanisms responsible for these effects. The methods exist, and we now need studies of the effects of oestrogen on coronary artery reactivity, heart contractility, and peripheral arterial function in women and in laboratory animals. Without these data reports such as the one by Rosano et al will not permit clinically confident generalisations about oestrogen treatment and reduction in CHD risk. Rosano et al speculate that oestrogen may be a useful treatment for stable angina in women. One should certainly pause for thought before stopping oestrogen treatment in a woman at high risk of myocardial infarction. However, little is known about this hormone’s effects on thrombosis. High doses of ethinyloestradiol in old-style oral contraceptives increased the risk of cerebral and coronary vascular disease (presumably by promoting thrombosis) in premenopausal women. Current doses of oestrogens given to postmenopausal women are much lower and are not thought to increase the risk of arterial thrombosis but this concern has yet to be finally removed by careful epidemiological studies of postmenopausal oestrogens and arterial thrombosis. Meanwhile we should hesitate to recommend oestrogen for angina, in doses and by routes that result in pharmacological concentrations, especially since good alternatives such as glyceryl trinitrate and calcium-channel blockers are available. It is not clear from Rosano’s results that oestrogen affords protection against myocardial ischaemia beyond that of conventional treatment.
J Koudy Williams Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina, USA
128
Turner’s
syndrome and chromosome Y
See page 140
Of the known chromosome mosaics those involving X and Y are by far the most common. A structural aberration of X or Y is frequently accompanied by a second stem line displaying a 45,X complement. If the abnormal sex chromosome shows ring formation or a complex rearrangement the 45,X line will predominate. Conventional cytogenetic techniques may well miss cells containing the structurally abnormal sex chromosome.2 The detection of such low frequency mosaicisms (micromosaicism) in Turner’s syndrome or gonadal dysgenesis has attracted attention because the very high in utero lethality of the 45,X condition, largely restricted to cases lacking a second cell line, has led to the hypothesis that most if not all live-born 45,Xs are mosaics.3,4 However, even after the investigation of two tissues some 25% of live-born Turner’s syndrome patients remained apparent non-mosaic 45,X.2 One possible explanation is that conventional cytogenetics are not sensitive enough to detect the mosaicism. Furthermore, dysgenetic gonads in individuals whose genome contains Y chromosome material are at increased risk of neoplasia, and this may be a special problem for patients with Turner’s syndrome who are put on growth hormone therapy. Molecular techniques now permit identification of Ychromosomal DNA content in a second cell line even in micromosaics.3-6 In this issue of The Lancet Kocova et al report the detection of Y chromosome sequences by polymerase chain amplification with SRY-gene-specific primers followed by Southern analysis of PCR products. They claim that one cell containing SRY can be detected among 100 000 XX cells by this method. Among 18 patients with Turner’s syndrome positive signals for SRY were detected in 6. Surprisingly, after amplification of alphoid Y centromeric repeats no definite signals were. Even more surprisingly, 1 SRY-positive patient was 45,X/46,XX and another 45,X/47,XXX on conventional cytogenetic investi-
gation. In Y-derived chromosomes marker sequences which map to distal Yp or Yq may be lost during the formation of these chromosomes although their centromeric sequences are preferentially retained.7 Does this mean that in the SRY-positive cases, reported in this paper, the centromeric sequences were deleted? As a mode of origin one would then have to assume, for example, a coincident abnormal XY interchange and loss of one X chromosome by anaphase lag in the first and malsegregation in the second case. Witt and co-workers6 have compared amplification of alphoid centromeric repeats of the Y and the X chromosomes and of the SRY sequence. In 28 patients with Turner’s syndrome, the pattern of signal distribution after amplification of a fragment of the SRY gene was identical to that of the Y-specific alphoid repeats and no findings conflicting with conventional cytogenetic results were noted. Those studying Y mosaicism, including Kocova et al, tend to emphasise sensitivity-but what about accuracy? In conventional cytogenetics the detection of mosaicism depends on several factors, including numbers of cells examined, numbers and types of tissues, culture techniques used, and in vivo or in vitro selection against one of the cell lines.2 Sensitivity addresses just one of these factors. The absence of mosaicism in blood does not exclude mosaicism in other tissues. There is recent evidence that human fetal blood derives from the yolk sac and not from the embryo