REVIEW ARTICLE
Am J Cardiovasc Drugs 2002; 2 (6): 401-413 1175-3277/02/0006-0401/$25.00/0 © Adis International Limited. All rights reserved.
Turner Syndrome and the Heart Cardiovascular Complications and Treatment Strategies Claus Højbjerg Gravholt Medical Department M (Endocrinology and Diabetes) and Medical Research Laboratories, Aarhus Kommunehospital, Aarhus University Hospital, Aarhus, Denmark
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. History and Introduction . . . . . . . . . . . . . . . . . . . . . . 2. Congenital Malformations of the Heart and the Great Vessels 3. Hypertension and Ischemic Heart Disease . . . . . . . . . . . 4. Aortic Dissection . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Growth Hormone Treatment and the Heart . . . . . . . . . . . 6. Hormone Replacement Therapy and the Heart . . . . . . . . 7. Cardiovascular Management in Turner Syndrome . . . . . . .
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401 401 403 406 407 407 408 409
Turner syndrome is a condition usually associated with reduced final height, gonadal dysgenesis, and thus insufficient circulating levels of female sex steroids, and infertility. A number of other signs and symptoms are seen more frequently with the syndrome. With respect to cardiac function, congenital malformations of the heart and the great vessels, hypertension and ischemic heart disease, and increased risk of aortic dissection are all conditions that the pediatrician or the physician caring for females with Turner syndrome should keep in mind. Many girls and adolescents with Turner syndrome receive growth hormone (GH) treatment, which has so far been an effective and well-tolerated therapy. Nevertheless, because of the experience from acromegaly, the physician should monitor blood pressure and perform echocardiography, together with clinical examinations by a cardiologist at regular intervals. During adulthood most women with Turner syndrome are faced with premature menopause and the need for female hormone replacement therapy (HRT). During clinical evaluation of girls and women with Turner syndrome, these conditions and complications should be kept under surveillance. Here the cardiovascular complications of Turner syndrome are reviewed. The risk of congenital heart defects such as bicuspid aortic valves, aortic coarctation, other valve abnormalities, and septal defect is increased. Likewise, the risk of aortic dissection at a young age is increased, as is the risk of hypertension, ischemic heart disease, and stroke. GH therapy does not seem to adversely affect the heart, although longer-term follow-up studies are needed. In short-term studies, HRT lowers blood pressure, while any effect on the risk of ischemic heart disease has not been evaluated. Treatment with GH and HRT are discussed in relation to the heart and great vessels. Presently, the pathophysiology of the congenital cardiovascular malformation in Turner syndrome is unexplained, although different theories exist. Recommendations for clinical practice are given, including life-long surveillance of cardiac function, aortic diameter and blood pressure.
1. History and Introduction Turner syndrome derives its name from the American physician Henry H. Turner of Oklahoma City, Oklahoma.[1] In a report in Endocrinology in 1938 he described seven patients with several characteristic features of the syndrome, such as infantilism, cubitus valgus and congenital webbing of the neck. Since the
initial report a number of abnormalities have been recognized in association with the syndrome. The cardinal stigmata are growth retardation with reduced final height, gonadal insufficiency and infertility. Further congenital malformations and conditions are given in table I, with tentative frequencies, based on a number of references.
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Table I. Abnormalities associated with Turner syndrome with tentative frequencies[2-6] Feature 1. Retarded growth and reduced final height
Frequency (%) 95-100
2. Gonadal dysgenesis no pubertal development infertility chronic estrogen deficiency androgen insufficiency
85 98 95-98 ?
3. Endocrine disturbances glucose intolerance type 2 diabetes mellitus type 1 diabetes mellitus thyroiditis elevated hepatic enzymes hypertension android body composition
15-50 10 2-3 15 50-80 30-50 ?
4. Physical abnormalities a) Eyes epicanthus nearsightedness strabismus ptosis b) Ears infection of middle ear hearing defects deformity of external ear c) Mouth micrognathia (small mandibular bone) high arched palate abnormal dental development d) Neck low posterior hairline broad short-appearing neck pterygium colli (webbed neck) excess loose skin in the back of the neck of neonates e) Thorax broad chest (shield chest) with apparently wide-spaced nipples inverted nipples f) Skin, nails and hair increased skin ridge count lymphedema of hands and feet at birth (or later) multiple pigmented nevi nail hypoplasia vitiligo alopecia g) Skeleton bone age retardation decreased bone mineral content cubitus valgus short fourth metacarpal
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20 20 15 10 60 30 15 60 35 ? 40 40 25 25
30 5 30 25 25 10 5 5 85 80 50 35
genu valgum congenital hip (sub)luxation scoliosis Madelungs deformity h) Heart bicuspid aortic valves coarctation of the aorta aortic dilation/aneurysm other cardiac malformations i) Kidneys horseshoe kidney abnormal positioning or duplication of renal pelvis, ureters or vessels renal aplasia
35 20 10 5 13-34 4-14 2? 1-6 10 15 3
5. Psychosocial problems emotional immaturation specific learning problems mental problems
40-85 40 25
6. Other failure to thrive during first year of life
50
Turner syndrome is caused by an absent or structurally abnormal X chromosome. The typical karyotype in Turner syndrome is 45,X; i.e. one X chromosome is missing. Most women with Turner syndrome, however, are not carrying the ‘typical’ karyotype of 45,X, but have several different variants all causing the clinical signs of Turner syndrome. The most frequently occurring karyotypes are 45,X, karyotypes with an isochromosome of X [i(Xq) or i(Xp)], the mosaic karyotype of 45,X/46,XX, and karyotypes containing an entire Y chromosome or parts thereof. The 45,X karyotype was found in only 48% of all live-born females with Turner syndrome during the period 1970–1995.[5] The prevalence has never been firmly established, but a number of cytogenetic studies have given estimates ranging from 25–210 per 100 000 females,[7-10] and most seem to agree on a hypothetical proportion of about 50 per 100 000 girls in Caucasian populations (figure 1). In the future, it is possible that the number of girls being born with Turner syndrome will decrease because of increased use of prenatal diagnostic measures (amniocentesis, chorionic villus sampling [CVS], ultrasonography, triple-bloodsample testing, etc.). However, treatment and prevention measures are hampered by a considerable delay in diagnosis;[11] in Denmark the median age at diagnosis is 15 years when considering all girls and women diagnosed between 1920 and 2000 (figure 2). This means that many girls and women are treated rather late in life, and some are never diagnosed. Turner syndrome is often complicated by congenital cardiovascular malformations, hypertension, ischemic heart disease, Am J Cardiovasc Drugs 2002; 2 (6)
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80
Prevalence of Turner Syndrome per 100 000 liveborn girls
70
60
50
40
30
20
10
0 1920
1930
1940
1950
1960
1970
1980
1990
2000
Year
Fig. 1. Recorded prevalence of Turner syndrome per 100 000 live-born girls by year of birth from 1910 to 2000 in Denmark. The broken line indicates the hypothetical prevalence of 50 per 100 000 live-born girls (data from the Danish Cytogenetic Central Register).
and aortic dilation with or without aortic aneurysm. These associated features are responsible for considerable morbidity, and premature death in a number of patients. Today, most girls and adolescents with Turner syndrome are treated with growth hormone (GH) to increase final height[12] and estrogens to induce puberty, and after the advent of menarche, progestogens are added 10–12 days every month to simulate the cyclic events of the normal menstrual cycle. Since GH and hormone replacement therapy (HRT) may exert significant cardiovascular effects, complications relating to the heart and effects on the heart of this treatment given to women and girls with Turner syndrome are reviewed. 2. Congenital Malformations of the Heart and the Great Vessels An association between Turner syndrome and congenital cardiovascular malformations has been known from early on. In the early series focusing on heart defects, emphasis was primarily on coarctation of the aorta;[13-15] pulmonary stenosis was also © Adis International Limited. All rights reserved.
noted (possibly due to ‘contamination’ of study groups by patients likely to have Noonan syndrome),[15,16] as well as less severe congenital malformations of the heart,[4,17,18] especially with the 45,X karyotype.[4,19-21] In addition, many case reports have described specific, uncommon malformations linked to the syndrome. Although the congenital malformations of the heart have been recognized for many years, a number of studies during recent years have meticulously documented these malformations in relatively unselected populations, and approximate frequencies are available[4,18,22-24] (table II). Congenital cardiovascular malformations occur more frequently in unselected populations of individuals with Turner syndrome than in the background population. The malformations normally involve only the vessels of the left side of the heart and show a very characteristic pattern when compared with that of the general population.[23,24] A recent Italian study found congenital cardiac malformations in 136 of 594 (22.9%) patients with Turner syndrome.[24] This figure corroborates previous findings in unselected groups of patients, in whom congenital cardiac leAm J Cardiovasc Drugs 2002; 2 (6)
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Median = 15 years Range = 0−86 years n = 746
120
100
Number
80
60
40
20
0 0
10
20
30
40
50
60
70
80
Age at diagnosis (years) Fig. 2. Delay in diagnosis of Turner syndrome. The x-axis illustrates the number of patients with Turner syndrome at the chronological age of diagnosis. Bars illustrate 2.5-year periods. Data are from the Danish Cytogenetic Central Register from 1910– 2000. Data include all diagnosed females with a karyotype that can be associated with Turner syndrome.
sions were found in 20–40% of.[4,23,25,26] Notably, a number of patients have more than one structural malformation. In a recent large study, it was shown that cardiac malformations were more prevalent among the subgroup of patients with 45,X (39%) than among those with karyotypes that include an isochromosome (Xq) [11–12%] (mosaic or not).[23] In the large Italian study it was also found that cardiac malformations were more prevalent among patients with 45,X (30%) than among patients with X mosaicism (24%) and X chromosome structural abnormalities (iXq, r[X], del[X], etc.) [11%].[24] The study group was sufficiently large to permit formal statistical evaluation of the risk of congenital malformations between these three major groups of karyotypes, with more malformations occurring among patients with 45,X than among the group of patients with X chromosome structural abnormalities (relative risk [RR] 2.7; 95% confidence interval [CI] 1.8–4.2), but with a comparable number of malformations among patients with 45,X and X mosaicism (RR 1.2; 95% CI 0.8–1.9).[24] Thus it seems that karyotypes involving structural abnormalities of the X chromosome confer some protection towards cardiac malformations. Likewise, in a registry study of all Danish patients with Turner syndrome, the 45,X karyotype was most frequently associated with congenital malformations, including cardiac malformations.[5] In the same study, cardiovascular morbidity not related to congenital malformations of the heart (such as acute © Adis International Limited. All rights reserved.
myocardial infarction, hypertension and arteriosclerosis) were more frequently associated with karyotypes other than 45,X. The same pattern was seen for endocrine diseases, primarily hypothyroidism and type 1 and 2 diabetes mellitus, indicating that the many different karyotypes involved in Turner syndrome may lead to different disease patterns, congenital as well as acquired.[5] It may be speculated that the increased morbidity due especially to endocrine disease is part of the explanation for the increased morbidity due to cardiovascular diseases. Concerning other karyotypes (i.e. karyotypes with rings and markers or Y chromosomal material) known to result in clinical Turner syndrome, current numbers are too small to allow formal statistical comparison with the 45,X karyotype. A bicuspid aortic valve is the most common finding and is seen in 13–34% of patients, with Turner syndrome compared with only 1–2% in the general population[27] (figure 3). Although some individuals present with a systolic murmur or an ejection click on clinical examination, many (perhaps the majority) are not identified clinically, but only echocardiographically.[22,23] Bicuspid aortic valves are seen with most karyotypes, but predominantly with the 45,X karyotype.[23,24] Coarctation of the aorta is present in 4−14% of all patients with Turner syndrome (figure 3), and predominates in patients with the ‘classical’ karyotype of 45,X. Most patients with aortic coarctation are diagnosed early, because of the relative severity of the condition. Coarctation occurs more than 350-fold more frequently in patients with Turner syndrome than in the general population.[5] Today, patients with clinically significant coarctation are operated on early, either with resection and end-to-end anastomosis, or subclavian flap operation, while some undergo primary percutaneous balloon dilatation with or without stenting. Other malformations affecting the valves have also been reported, such as aortic valve stenosis, aortic valve regurgitation, mitral valve prolapse, mitral valve stenosis and cleft mitral valve. Furthermore, atrial septal defect, ventricular septal defect and persistent ductus arteriosus are seen in 1–6% of patients.[4,23,24] Surgery, or coronary catheterization if possible, should be undertaken wherever required. Clinical follow-up is necessary in most or all patients. In any case, all patients with either bicuspid valves, septal defects or other valvular diseases should be informed of the risk of infectious endocarditis in relation to minor surgery, including dental work, and be issued with proper antibiotic prophylaxis when necessary. Rarely, hypoplastic left heart syndrome has also been described,[23,28] which leads to early death if untreated.[23] The incidence of any given malformation differs from study to study (table II). These differences are probably not important, since it is clear that any figure given in the literature is grossly Am J Cardiovasc Drugs 2002; 2 (6)
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Table II. Incidence of congenital malformations in patients with Turner syndrome. Data have been compiled from five trials with apparent unbiased inclusion of patients and presented as number of patients affected/total number examined (%) Congenital malformation
Incidence in clinical trials Miller et al.[22] Dawson-Falk et al.[18] (n = 35)a (n = 40)b 5/40 (12.5) 2/35 (6) 5/40 (12.5) 1/40 (2.5) 12/35 (34) 7/40 (17.5) 2/35 (6) 2/40 (5) 1/40 (2.5)
Gotzsche et al.[4] (n = 179)a 18/179 (10)
Aortic coarctation Dilated ascending aorta Hypoplastic aortic arch Bicuspid aortic valve 25/179 (14) Mitral valve prolapse or regurgitation 1/179 (0.6) Interrupted inferior vena cava with azygos continuation Cardiac dextroposition 1/40 (2.5) 1/179 (0.6) Aortic valve disease (stenosis and/or 19/179 (11) incompetence) Partial anomalous pulmonary venous drainage 1/179 (0.6) Ventricular septal defect Atrioventricular septal defect Pulmonary valve abnormality (stenosis, 2/179 (1) regurgitation) Persistent ductus arteriosus 2/179 (1) a Patients were examined only with clinical examination and echocardiography. b Patients were examined by magnetic resonance imaging scan and echocardiography. c Patients were examined with clinical examination, ECG, chest x-ray and transthoracic echocardiography.
elevated in comparison with the background population. Thus, any individual with Turner syndrome should always be seen by a cardiologist and at least have echocardiography performed. Depending on the findings on echocardiography, some patients should also be examined by magnetic resonance imaging (MRI) scan, and rarely invasive examination, such as right- and/or leftsided cardiac catheterization, might be necessary. The cause of congenital heart defects in Turner syndrome remains unknown. Various investigators have presented different views on the subject depending on whether they see congenital malformation of the heart in Turner syndrome as a true malformation, linked to the expression of a specific gene or cluster of genes, possibly being X-linked (a gene or genes escaping X inactivation), or the result of disruption of normal embryonic developmental events, and thus not caused by the karyotype itself. Since patients with 45,X karyotype are predominantly affected by congenital cardiovascular malformations, as well as by lymphedema (and thus webbed neck), deficient development of lymphatics has been proposed as a causative factor. In utero, developing lymph channels distend secondary to failed emptying of jugular lymph sacs into central veins. It is suggested that these distended lymph channels encroach on the heart and great vessels, in this way mechanically inducing congenital heart defects.[20,21,29] The development of coarctation of the aorta may be due to a combination of maldevelopment of lymphatics and de© Adis International Limited. All rights reserved.
Sybert[25] (n = 244)a 34/244 (14)
Mazzanti & Cacciari[24] (n = 594)c 41/594 (6.9) 17/594 (2.9)
33/244 (14) 6/244 (2)
74/594 (12.5) 53/594 (8.9)
14/244 (6)
19/594 (3.2)
1/244 (0.5)
17/594 (2.9) 3/594 (0.5) 1/594 (0.2)
12/244 (5)
1/244 (0.5)
creased left-sided blood flow in utero (through the aorta), leading to increased flow through the pulmonary artery and the ductus arteriosus, which may induce development of a shelf or flange, leading to later coarctation.[20] Recent intriguing observations show that cardiac hypoplasia, along with lung hypoplasia, is widespread among Turner syndrome fetuses recognized because of massive hydrops or large nuchal hygromas.[30] The authors examined 117 Turner syndrome fetuses (32% definitely verified by karyotyping, the rest due to typical stigmata), ad found more than 90% of the fetuses to have heart weights below the 2.5 centile, and suggested that myocardial hypoplasia is a primary defect in Turner syndrome leading cardiac pump inadequacy impeding venous return and thereby elevating venous pressure, and that the resulting venous hypertension could lead to diminished lymphatic outflow, and, eventually to hydrops formation. The phenotype would thus result in intra-uterine death or, if only minimally restricted heart growth was seen, the fetus could survive to birth.[30] The study leaves several questions unanswered: is cardiac and lung hypoplasia present in live-born Turner syndrome; is the hypoplasia linked to other congenital malformations of the heart; is the hypoplasia actually leading to lymphedema, or is it vice-versa, etc. Other researchers have speculated whether one or more genes on the missing X chromosome are causative. It is supposed that such a gene (or genes) would be one of the many genes on the X chromosome known to normally escape X inacAm J Cardiovasc Drugs 2002; 2 (6)
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Aortic dissection
Aortic coarctation
Fig. 3. Typical congenital malformations seen in Turner syndrome, i.e. coarctation of the aorta and bicuspid aortic valves. The figure also illustrates the occurrence of aortic dilation and dissection. It is noteworthy that the presence of congenital malformations and/or systemic hypertension is not a prerequisite for the development of dilation and dissection of the aorta.
tivation,[31] a situation leading to haploinsufficiency of the gene (or genes) and the gene product. The recently reported cloning of the SHOX gene (short stature homeobox-containing gene or PHOG [pseudoautosomal homeobox-containing osteogenic gene]) from the pseudoautosomal region (PAR1) on the X and Y chromosome,[32,33] responsible for part of the reduced growth seen in Turner syndrome and in the Leri-Weil syndrome, and perhaps especially the disproportionate growth, has spurred enthusiasm, and work is in progress to identify genes responsible for other parts of the Turner phenotype. A gene on chromosome 16 responsible for the lymphedema in the lymphedema-distichiasis syndrome has been described.[34] Very recent work has suggested that at least one lymphogenic gene is present on the short arm of the X chromosome (Xp) distal to Xp11 between the genes of Duchenne muscular dystrophy and monoamine oxidase A.[35] The concept of chromosomal imbalance, and thus disturbed pairing during mitosis, has also been implicated.[35] 3. Hypertension and Ischemic Heart Disease Thirty percent of girls with Turner syndrome have mild hypertension on 24-hour ambulatory blood pressure monitoring, and as many as 50% have an abnormal diurnal blood pressure profile.[36] Hypertension is also prominent in women with Turner syndrome, who have significantly elevated blood pressure com© Adis International Limited. All rights reserved.
pared with an age-matched control group,[37] and as many as 50% have clinical hypertension.[6,37] The nocturnal fall in diastolic blood pressure is blunted in many compared with controls, and an increase is seen with HRT, as well as in systolic night/day ratio. The significance of this is unknown. It seems that women with Turner syndrome are ‘non-dippers’, i.e. have a diminished reduction of blood pressure during the night.[37] A blunted nocturnal fall in blood pressure in hypertensive women has been shown to predict future major cardiovascular events.[38] In women with essential hypertension, non-dippers have an increased left ventricular mass which is considered to be an independent marker of cardiovascular morbidity and mortality.[39,40] In Turner syndrome, compared with controls, 24-hour, day, and night heart rate is significantly elevated,[37] which could be suggestive of the presence of parasympathetic neuropathy. At present there are no longitudinal studies of blood pressure and hypertension in patients with Turner syndrome. There is a definite need for such studies. Furthermore, it is essential to establish the effect of treatment and to determine which drugs to choose as first- and second-line treatment. Previously, the incidence of ischemic heart disease was not found to be increased in patients with Turner syndrome, despite reports of increased plasma levels of cholesterol,[41] increased blood pressure, and congenital cardiac malformations. Recently, in the Turner syndrome population in Denmark (n = 594), however, ischemic heart disease (acute myocardial infarction and arteriosclerosis) was found more frequently in an epidemiological register study of morbidity.[5] The RR of disease was increased to 2.1 (95% CI 1.2–3.4), while hypertension occurred with an RR of 2.9 (95% CI 1.2–6.0), and cerebrovascular diseases of 2.7 (95% CI 1.04–5.3). In a clinical study, we could not detect any difference in measures of lipid status between a group of untreated women with Turner syndrome before treatment and a control group.[42] Compensated hypothyroidism is associated with coronary artery disease and elevated plasma levels of low-density lipoprotein-cholesterol and apolipoprotein B.[43,44] This may help explain part of the increased risk of cardiovascular disease in Turner syndrome,[5] since hypothyroidism and thyroid antibody formation are common in Turner syndrome, especially in a subgroup with an isochromosome of the long arm of the X chromosome [i(Xq)].[45-57] In a recent cross-sectional study of 145 women with Turner syndrome, 14% had hypothyroidism; in a subgroup of women with an isochromosome (iXq), an impressive 37.5% had hypothyroidism, emphasizing the grossly elevated risk of the condition linked to this karyotype.[58] Am J Cardiovasc Drugs 2002; 2 (6)
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4. Aortic Dissection The association of aortic dissection and Turner syndrome has been acknowledged for many years.[23] More than 60 case reports of aortic dilation or dissection, some of which were fatal, have been described.[26,59-85] In most cases, risk factors were present. In the general population, risk factors for aortic dissection include the following: systemic hypertension, which is present in up to 90% of cases;[86,87] Marfan and Ehlers-Danloss syndrome, where mutations in the fibrillin and the collagen type III gene are present, respectively, (which are also conditions with increased risk of dilation, aneurysm and rupture); congenital bicuspid or unicommissural aortic valves (especially for type I and II dissections);[27,86] and coarctation of the aorta.[86,87] In addition, pregnancy, trauma and iatrogenic trauma (cannulation or incision trauma during cardiopulmonary bypass procedures) are risk factors.[86,87] Other, rarer, risk factors include temporal arteritis, connective tissue disease, cystic medial necrosis of the aorta, syphilitic aortitis, and fibromuscular dysplasia.[87] Usually, but not always, these risk factors (other than Turner syndrome) are known to be present in the reported cases of aortic dissection in Turner syndrome.[26,68] At the same time, the prevalence and the nature of cardiovascular malformations have been described in several studies (see section 2).[4,18,23,24,88] Aortic root dilation, which is a risk factor for later rupture, is often seen and seems to be associated with elevated systolic blood pressure.[6] Undoubtedly, Turner syndrome should be included in this list of risk factors for aortic dissection. At present, no abnormalities of the aortic wall have been identified in Turner syndrome. Cystic medial necrosis, similar to the changes found in Marfan syndrome, has been described in some (for review see Lin et al.[26]), but not in all cases. No biochemical or genetic abnormalities have been described in Turner syndrome thus far. Pregnancy is a rare event in patients with Turner syndrome.[89,90] Owing to an increasing number of egg donation programs, more patients can be expected to go through pregnancy in the future.[91] Because of the pregnancy-associated changes in blood pressure, cardiac work load, etc., the risk of aortic dissection is likely to be increased. Uneventful cases of pregnancy have been reported;[89,92,93] however, fatal and nonfatal cases due to aortic dissection have also been described.[94-97] Prospective studies are needed to establish the exact risk of aortic dissection, to identify patients at an elevated risk, and, if possible, to introduce procedures and/or medicine to lower the risk, both during pregnancy and during normal life. © Adis International Limited. All rights reserved.
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5. Growth Hormone Treatment and the Heart Short stature is a key feature of Turner syndrome. Growth retardation can be identified prenatally[98-100] and growth remains subnormal not only during the first years of life[99,100] but throughout childhood. The normal pubertal growth spurt is absent in Turner syndrome,[101] even in the 15% of girls with spontaneous puberty.[102] The rationale for starting GH treatment is not a lack of GH secretion, but rather reduced final height. Although the results of different studies are equivocal and the spontaneous and stimulated GH secretion has been found by some to be diminished,[103,104] others have found normal GH secretion.[105-107] Treatment with GH has generally been found to be well tolerated in most patients. However, in Turner syndrome supraphysiological (or pharmacological) GH doses are used, resulting in circulating insulin-like growth factor (IGF)-1 values often in the acromegalic range, in comparison with conditions such as hypopituitarism (including the GH axis), chronic kidney failure, and other conditions. The reason for high-dose GH treatment is to overcome the apparent GH or IGF resistance present in Turner syndrome,[108] and thus increase height appropriately.[12] Safety of treatment clearly remains important. This has to be seen in the light of the increased cardiovascular morbidity and mortality in acromegaly,[109] a pathological condition with chronically elevated GH and IGF-I levels, where cardiac function is improved with restoration of normal GH values.[110] Different aspects of the safety of GH administration have been studied. Studies have shown that insulin resistance is induced by GH treatment in Turner syndrome[12,111,112] and reversed when GH treatment is stopped.[12] The induction of insulin resistance is of considerable concern, since the prevalence of type 2 diabetes mellitus is increased in Turner syndrome,[5] and a prolonged period of hyperinsulinemia could potentially lead to overt diabetes mellitus. So far, no long-term (more than 5 years) studies have addressed the issue of late effects of GH-induced hyperinsulinemia. Total and regional body composition is altered in Turner syndrome, with more body fat and less muscle mass,[113] and is modified during GH treatment, with a reduction in truncal fat and an increase in muscle mass, presumably favorable changes normally associated with a reduction in cardiovascular risk. However, it is doubtful whether these changes persist after cessation of GH treatment. Few studies have addressed the effect of GH treatment on the heart. This is of special interest because of the increased occurrence of cardiovascular malformations, aortic dilation and coronary heart disease later in life in Turner syndrome.[4,5,18,23,26,37,114] In a recent study very high doses of GH were used in a subgroup of patients for, on average, 7 years.[12] Am J Cardiovasc Drugs 2002; 2 (6)
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6. Hormone Replacement Therapy and the Heart The chronic estrogen deficiency known to affect many adult women with Turner syndrome is likely to be associated with cardiovascular morbidity. It is generally assumed that treatment with estrogens not only confers cardioprotection through a lowering of harmful circulating lipids, but also through direct antioxidant effects,[117] a change in the vascular reactivity[118] and its interaction with vascular smooth muscle.[119,120] Part of the increased cardiovascular morbidity and mortality in Turner syndrome could therefore be explained by non-use of estrogens. At present, no long-term studies have assessed the effect of HRT on the heart and on the increased mortality seen in Turner syndrome. It might be speculated that HRT would have positive effects on aortic ‘stiffness’ in the long term,[121] but any direct effect on the aortic wall has not been described. Far from all patients receive HRT during adulthood, and many adolescents are introduced to estrogens rather late, in order to achieve the highest final height. Recently, there has been speculation that the standard HRT dose given to women with Turner syndrome © Adis International Limited. All rights reserved.
(estradiol 2mg or equivalent) is too low. This speculation has been based on the fact that when trying to establish a ripe endometrium for egg donation, patients need estradiol 4mg, or more, for a prolonged period.[90] Hypertension is frequent among patients with Turner syndrome (see section 3), and treatment with female HRT causes a small but significant reduction in the 24-hour diastolic pressure and the diastolic day pressure and a near significant fall in systolic day pressure.[37] In postmenopausal women with hypertension, treatment with estrogen, with or without gestagen, has been shown to decrease 24-hour ambulatory blood pressure in shortterm studies.[122] Although lipid abnormalities have been found in a few, but not in most studies (see section 3), changes have been found during HRT in one study, with a significant, albeit small, fall in high-density lipoprotein-cholesterol, while other lipid variables were unchanged;[42,123] another study found lipids to be unaffected by HRT.[121] There are no long-term studies of the effect of HRT on cardiovascular morbidity and mortality in Turner syndrome. In healthy, postmenopausal women (aged 50–75 years) without prior cardiovascular disease the results from the recent Women’s Health Initiative randomized trial show that HRT should not be initiated for primary intervention of cardiovascular disease.[124] In addition to an increased risk of cardiovascular disease in the treated group, the results showed increases in the risk of breast cancer, stroke, and pulmonary embolism, and a decreased risk of fractured and colorectal cancer amongst actively treated women.[124] In postmenopausal women with a previous cardiovascular event (secondary intervention), HRT has proved to have no effect on cardiovascular mortality and morbidity.[125] In postmenopausal women with a previous stroke, has
Survival
No signs of left ventricular hypertrophy or evidence of worsening of hypertension were found in these girls. However, two girls with pre-existing left-sided obstruction (congenital abnormal aortic and mitral valve, respectively) developed significant valve stenosis, and thus possibly left ventricular hypertrophy, and were excluded from further statistical analysis. This could suggest that pre-existing valve abnormalities might be a risk factor for developing left ventricular hypertrophy. At inclusion, many girls with Turner syndrome had relatively increased systolic and diastolic blood pressure in comparison with normal reference values, but at the end of the study there was a slight decrease in the ageadjusted diastolic blood pressure. In a recent cross-sectional study of girls with Turner syndrome receiving either no treatment (mostly young girls), GH or GH in combination with estradiol and a progestogen, 17% had elevated blood pressure in comparison with age-matched reference data.[115] Furthermore, by 24hour blood pressure evaluation, it was shown that 57% of all girls had a blunted nocturnal fall in blood pressure (‘non-dippers’).[31,116] This is a situation often encountered in hypertension and diabetes mellitus, and thought to be indicative of autonomous neuropathy, and in adult women with hypertension (without Turner syndrome) it is considered an independent risk factor for later development of cardiovascular events.[31] It remains to be seen if there are any long-term effects of GH treatment on the cardiovascular system. It is recommended that long-term followup is continued in previous and ongoing GH treatment trials for increasing final height.
Median survival: Turner syndrome 70 years Background population 78 years
0
20
40
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80
Age (years)
Fig. 4. Kaplan-Meier survival plot of females with Turner syndrome versus the back[125]
ground population.
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Survival
mellitus has in many cases been found to be an accompanying cause of death.[128] Thus, increased mortality may be due to a number of reasons: congenital malformations leading to premature death (e.g. coarctation of the aorta); osteoporosis, because of lack of replacement therapy; hormonal or metabolic disease, especially type 2 diabetes mellitus; ischemic heart disease; chronic estrogen deficiency, due to insufficient HRT. At present, there is a lack of longitudinal, observational and interventional studies in adults with Turner syndrome. It is not known how long-term HRT affects cardiovascular morbidity and mortality. Likewise, the question of when to stop HRT, if ever, is unresolved.
Median survival: 45,X 66 years Other karyotypes 72 years p < 0.02 0
20
40
60
80
100
Age (years)
Fig. 5. Kaplan-Meier survival plot of females with Turner syndrome with the 45,X [125]
7. Cardiovascular Management in Turner Syndrome
karyotype versus females with Turner syndrome with any other karyotype.
HRT has been unsuccessful, albeit not deleterious, as secondary intervention.[126] Previous research has documented that adult women with Turner syndrome are characterized by several features: glucose intolerance, deficient insulin secretion, thyroid and hepatic abnormalities, android body composition, decreased physical fitness and elevated blood pressure, with a specific increase in the night/day ratio. Thus, several features of the metabolic syndrome (syndrome X)[127] are present in Turner syndrome, and a comparison with the hormonal and metabolic profile of relatives of patients with type 2 diabetes mellitus is warranted. It should also be pointed out that women with Turner syndrome have a decreased life expectancy (figure 4), especially those with the 45,X karyotype (figure 5).[128-130] The RR of death has been found to be high (4.16; 95% CI 3.22–5.39), especially from causes such as aortic dissection, ischemic heart disease, congenital malformations of the heart, epilepsy and pneumonia,[130] while the rate of malignancy has been found to be low in three studies.[5,128,130] Diabetes
In the clinical practice careful monitoring of glucose metabolism, weight, thyroid function, bones, hepatic function and blood pressure should be performed in patients with Turner syndrome. A cardiovascular risk profile should be determined at diagnosis, and the patient should be informed about risks and benefits from GH and HRT. Patients should be seen by a cardiologist and have echocardiography performed, together with clinical examination (table III). When pubertal induction is taking place, it may be prudent to perform a new cardiovascular assessment, and likewise in adulthood.[131] If any congenital cardiac malformation is present, this should be dealt with appropriately (see section 2), relevant examinations and tests performed, and the patient should be followed up at regular intervals. Endocarditis prophylaxis should be given in case of bicuspid aortic valves, and in case of any surgical procedures having to be performed. The potential consequences of GH treatment on the heart and great vessels should be discussed, as well as consequences of HRT, and perhaps especially the consequences of not taking HRT. Based on the available literature, HRT is highly recommended during adulthood. The unsolved problem of who will eventually develop dilation of the aorta, and thus be at great risk of later aortic dis-
Table III. Cardiovascular management of patients with Turner syndrome Echocardiography at diagnosis should be performed in all patients If congenital cardiac malformations are diagnosed, these should be dealt with appropriately, including: surgery, if deemed clinically necessary; regular clinical examinations (echocardiography, MRI scan, blood tests, BP, etc.); prophylaxis for infectious endocarditis (visits at the dentist, minor surgery, etc.) The potential consequences of growth hormone treatment should be evaluated The benefits and drawbacks of HRT should be discussed with the patient at a relevant age; at present, HRT is recommended Evaluation of the aorta, with emphasis on aortic dilation, and the subsequent risk of aortic dissection Cardiac monitoring prior to assisted reproductive therapy or spontaneous pregnancy, and during pregnancy Risk of ischemic heart disease BP at every visit at the physician BP = blood pressure; HRT = hormone replacement therapy; MRI = magnetic resonance imaging.
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section, leaves the patient and her physician in a situation where repeat echocardiography, at present, is the only solution. Currently, it is not known how frequently echocardiography (and/or MRI) should be performed. In adulthood, a new cardiovascular risk assessment should be performed, and at every visit blood pressure should be monitored. It is recommended that special precautionary steps be taken before and during pregnancy, whether spontaneous or assisted, with cardiac monitoring (heart auscultation, blood pressure, echocardiography and/or MRI [only on vital indication during pregnancy]) at regular intervals. Since general physicians only infrequently encounter patients with Turner syndrome, it is recommended that the care and treatment of Turner syndrome is centralized in outpatient clinics devoted to the care of these girls and women.
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Acknowledgements Claus Højbjerg Gravholt is supported by a research fellowship by the University of Aarhus, by a grant from the Danish Diabetes Association, and the Danish Health Research Council, grant number 9600822 (Aarhus University – Novo Nordisk Center for Research in Growth and Regeneration). Lone Svendsen, Karen Mathiasen, Joan Hansen, Lone Korsgaard, Iben Christensen, Kirsten Nyborg, Inga Bisgaard, and Merete Møller are thanked for expert technical help. Line Gether and Solveig Skærlund are thanked for expert secretarial help.
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Correspondence and offprints: Dr Claus Højbjerg Gravholt, Medical Department M (Endocrinology and Diabetes), Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark. E-mail:
[email protected]
Am J Cardiovasc Drugs 2002; 2 (6)