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Endocrine Care |
Research Center for Endocrinology and Metabolism (K.L.-W.), Department of Gynecology (I.B.), and Section of Preventive Cardiology (L.W.), Sahlgrenska University Hospital, Göteborg, Sweden
Address all correspondence and requests for reprints to: Kerstin Landin-Wilhelmsen, M.D., Ph.D., Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: kerstin.landin{at}sahlgrenska.se
Abstract
Turner syndrome (TS) is caused by an X chromosome aberration and is characterized by endogenous estrogen deficiency secondary to ovarian dysgenesis and short stature. Our aim was to study the prevalence of cardiovascular malformations and cardiovascular risk factors (blood pressure, blood lipids and glucose, coagulation factors, social factors, smoking habits) in adults with Turner syndrome in comparison with a female random population sample. One hundred women with Turner syndrome (aged 16–71 yr) underwent physical examination, echocardiography, electrocardiography, and blood sampling. Seventy-one of them were matched for age [mean age, 33.7 ± 11 yr (range, 25–64)] with a random population sample (n = 213) of women [mean age, 34.8 ± 9 yr (range, 25–64)] from the World Health Organization’s Monitoring of Trends and Determinants in Cardiovascular Diseases Project, Göteborg. Six percent of Turner syndrome women were smokers compared with 25% in the population (P < 0.001). Turner syndrome women were relatively heavier and had a lower degree of leisure time physical activity than controls (P < 0.001). Diabetes and treatment for hypertension were present in 3 and 22% among Turner syndrome women vs. 2% (not significant) and 3% (P < 0.001) in controls, respectively. Cardiovascular malformations were found among 17% in Turner syndrome women (45,X dominated) vs. 0.5% in controls (P < 0.001). Systolic but not diastolic blood pressure was higher in Turner syndrome women. No differences were seen in serum total cholesterol, high- or low-density lipoprotein cholesterol, triglycerides, lipoprotein (a), or plasma fibrinogen concentrations between patients and controls. Diabetes or hypertension was not related to karyotype. In conclusion, congenital cardiovascular malformations were frequent. Most cardiovascular risk factors (glucose and lipid levels, fibrinogen, smoking habits) were not increased, but hypertension was more common in Turner syndrome women.
TURNER SYNDROME (TS) is caused by loss of all or part of an X chromosome and is characterized by estrogen deficiency secondary to ovarian dysgenesis and short stature. Morbidity secondary to diabetes mellitus, hypertension, ischemic heart disease, and stroke is increased in TS according to a recent Danish survey (1). Cardiac malformations are frequently found (2, 3, 4, 5). It has also been reported that hypertension, glucose intolerance, and disturbed lipid metabolism are more common in girls and young women with TS (6, 7, 8, 9, 10). However, Lanes et al. (11) showed that girls with TS had a normal lipid profile, which was not altered after treatment with either GH or estrogen.
The purpose of the present study was to analyze the prevalence of cardiovascular risk factors, especially diabetes mellitus, blood lipids, fibrinogen, and cardiovascular malformations, as well as sex hormones in a large group of adult TS women and compare them with a random population sample of similar age from the same region. The results are also related to karyotype in TS.
Subjects and Methods
Patients
During the period 1995–2000, 100 women with TS were studied in the Departments of Internal Medicine and Obstetrics and Gynecology at Sahlgrenska University Hospital in Göteborg, Sweden. The patients were recruited by means of an advertisement in the national TS patient newspaper and via a letter from us to the chief endocrinologists and gynecologists in Sweden. The patients were invited to participate in a voluntary screening program during 2 days. Mean age was 31 ± 12 yr (range, 16–71). The reference population included a random population sample of women aged 25–64 yr (see below); 71 of the TS women could be matched for age with women from that sample for laboratory analyses. The mean age among these 71 women was 33.7 ± 11 yr (range, 25–64).
The two genetic laboratories in the region hold registers of TS women; however, for ethical reasons, it was not possible to recruit patients via these registers. According to these laboratories, there were 175 women aged 16 yr or older with TS in the total population of 604,500 in the region (1 TS woman per 3500 women). As stated above, 100 women accepted the invitation to take part in the study. It is known that some of the missing women have moved out of the area, but some women who were not diagnosed at the genetic laboratories in the region had moved in from other parts of the country. It is estimated that the present study accounted for approximately 50% of the TS women in the region.
The chromosomal analyses were based on medical records available from 1955–2000. Forty-nine women had 45,X, 27 women had mosaicism, and 24 women had structural abnormalities.
Ninety-one percent of the TS women were currently on hormone replacement therapy (HRT) substitution [estrogen (17-ß-estradiol), 2 mg], but only 62% had taken HRT continuously since pubertal induction. Thirty-three percent of all TS women had received GH treatment for a mean of 49 ± 18 months, and 96% of TS women younger than 25 yr had received GH. Fifty-eight percent had received androgens during puberty induction. GH was terminated several years previously in the 71 TS women included in the laboratory analyses and at least 1 year previously in the TS women aged 16–24 yr.
Controls
A random population sample of women aged 25–64 yr (n = 740) was recruited from the World Health Organization’s Monitoring of Trends and Determinants in Cardiovascular Diseases (MONICA) Project, Göteborg, in 1995 (12). This project includes cardiovascular risk factor screening. Of these women, 3 controls were randomly selected per each TS woman (n = 213) and matched for age (mean, 34.8 ± 9 yr). Twenty-nine TS women were excluded from the comparison of laboratory variables because of lack of control women for matching (28 women younger than 25 yr and 1 woman older than 64 yr). Because congenital malformations and other diseases do not decrease with age, in the age range in question, the entire reference series (n = 100) could be used for these comparisons. Thirty-one percent of the controls took oral contraceptives, and 16% older than 45 yr took HRT (17-ß-estradiol, 2 mg).
Lifestyle factors
Past and present health status, social status, occupation, and smoking habits were asked for. A nonsmoker was a person who had never smoked or occasionally smoked less than one cigarette per day. Smokers were asked not to smoke during the morning before their examination and blood sampling. Physical activity during leisure time was graded from 1 to 3 (from low to high) according to a standardized and validated questionnaire (13).
Anthropometry
Body weight was measured to the nearest 0.1 kg in the fasting state with the subject in underwear and without shoes. Body height was measured barefoot and to the nearest 1 cm. Body mass index (BMI) was calculated as body weight divided by height squared (kg/m2). Waist circumference was measured with a soft tape midway between the lowest rib margin and the iliac crest in the standing position. The hip circumference was measured over the widest part of the gluteal region, and the waist/hip ratio was calculated.
Blood pressure and cardiac evaluations
Blood pressure was measured with a mercury sphygmomanometer to the nearest 2 mm Hg on the right arm in the sitting position after 10 min of rest. Disappearance of Korotkoff sounds (phase V) was used to determine diastolic pressure. A cuff size corresponding to the circumference of the right arm was chosen. Electrocardiography and echocardiography were performed on all TS patients.
Biochemical analyses
Fasting venous blood samples were drawn from an antecubital vein in the morning after an overnight fast. The samples were drawn on day 5 in the menstrual cycle in all control women with regular bleedings. After centrifugation, all samples were frozen and stored at -70 C until analyses, which were performed within 1 year. The same laboratory and methods were used for both patients and controls. Concentrations of serum total cholesterol, high-density lipoprotein cholesterol, and triglycerides were determined enzymatically (Boehringer, Mannheim, Germany). Low-density lipoprotein cholesterol was calculated according to Friedewald’s formula adjusted to SI units (14). Lipoprotein (a) [Lp(a)] was determined using a RIA kit (Pharmacia, Uppsala, Sweden). Serum insulin was determined with a RIA method (Phadebas, Pharmacia), and blood glucose was determined with a glucose-6-phosphate dehydrogenase method (Kebo Lab, Stockholm, Sweden).
Fibrinogen was analyzed with 9 volumes of blood drawn into 1 volume of 0.13 M trisodium citrate, according to a polymerization method described by von Clauss (15). Plasminogen activator inhibitor type 1 (PAI-1) antigen was analyzed with kits from Biopool (Umeå, Sweden).
Serum estradiol was determined by enzyme immunoassay using luminometry (Amerlite E2–60, Amersham Pharmacia Biotech, Little Chalfont, UK). SHBG was determined by an immunoradiometric assay (Farmos Group Ltd., Oulunsalo, Finland), and serum testosterone was determined by a nonextraction competitive RIA using an antiserum against a T-19-carboxymethyl adduct to BSA (Radioassay System Laboratories, ICN Biochemicals, Inc., Costa Mesa, CA).
Ethical considerations
The study was approved by the Ethical Committee at Göteborg University, and all participants gave their informed consent. Human rights were also approved according to the Helsinki Declaration.
Statistical analyses
Means and standard deviations were calculated with conventional
methods. Differences between patients and controls were tested with
Student’s t test and the Mantel-Haenszel
2 test. Simple correlations were calculated
with Pearson’s method. Multiple stepwise regression models were used
to test interaction between factors. A P value less than
0.05 (two-sided test) was considered statistically significant.
Results
Anthropometry and lifestyle factors
Anthropometric data, smoking habits, social factors, and degree of
physical activity for TS women and controls are listed in Table 1
. Body height and weight were lower
(P < 0.001) but BMI and waist/hip ratio were higher
(P < 0.01) in TS women than in controls. Smoking and
physical activity were less common in TS women than in controls
(P < 0.001). TS women worked or studied more
frequently than controls (P < 0.001). The number of
women married or living together was similar (Table 1).
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Treated hypertension was more common among TS women than controls
whether it was based on the 71 age-matched or all 100 TS women
(P < 0.001). The number of hypertensive TS women was
22% among the 71 age-matched women and 20% among all 100 TS women
(P < 0.001). Systolic (P < 0.001) but
not diastolic blood pressure was higher in patients than in controls
(Table 2). Mean blood pressure levels in
TS women with antihypertensive treatment were similar to those in TS
women without treatment. No newly diagnosed diabetics or hypertensives
were detected at the examination. Of 20 hypertensive TS women, 6 had
cardiac malformations; in the remaining women, no secondary
hypertension was found.
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). Three TS patients had type II
diabetes. Fasting plasma insulin did not differ from controls, and
fasting blood glucose was normal in TS women (Table 2). Blood lipids and coagulation factors
Blood lipids or fibrinogen did not differ between patients
and controls (Table 2). Total cholesterol increased with increasing age
in both patients and controls. There were no differences in the various
blood lipids between TS women and controls irrespective of
whether or not the latter had HRT.
PAI-1 antigen was 29.0 ± 29.0 mU/liter in TS women but was not
measured in controls (Table 2). However, the PAI-1 antigen
concentrations in the present study did not differ from PAI-1 activity
levels in healthy women in previous studies from our laboratory
(16). PAI-1 antigen correlates positively with PAI-1
activity, and both are associated with cardiovascular disease
(17, 18). No differences in PAI-1 antigen levels were
found between hypertensive and normotensive women in the TS sample.
Hormones
Serum estradiol and testosterone did not differ, and SHBG was
lower (P < 0.05) in TS women than in controls (Table 2). Postmenopausal control women without HRT had lower serum estradiol
concentrations (0.17 ± 0.26 nmol/liter) than those with HRT
(0.33 ± 0.52 nmol/liter). TS women did not differ from the
latter.
In TS patients, there was no correlation between the concentrations of serum estradiol and total, low-density lipoprotein, high-density lipoprotein cholesterol, or triglycerides.
Cardiovascular malformations
Seventeen (17%) of all 100 TS women had cardiovascular
malformations according to medical history and echocardiography
performed during the present investigation. This was considerably
higher than the 0.5% among the controls (P < 0.001)
or in the general population. Six TS women were operated on for aortic
coarctation. One woman had this diagnosis but was free from cardiac
symptoms and had not been operated on. One woman was operated on for
mitral valvular insufficiency. Four TS women had mild aortic
insufficiency, two had aortic stenosis, and another had mild aortic and
tricuspid insufficiency. Two TS women had bicuspid aortic valves. In
the 17 women with cardiovascular malformations, the karyotype was
monosomy in 15, which was significantly more common than in the rest of
the TS women (P < 0.001), and structural abnormalities
in 2 (Table 3). Six of these 17 women
(35%) were also treated for hypertension. One TS woman died at 28 yr
of age from acute aortic dissection. She was treated for hypertension,
and echocardiography 3 years earlier had shown mild aortic
insufficiency.
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Karyotype
Eighty-eight percent of the TS women with cardiovascular
malformations had monosomy (45,X), but among diabetics and
hypertensives, the karyotype pattern varied (Table 3).
Discussion
Blood pressure and cardiovascular malformations
In this study, cardiovascular malformations and treated hypertension, but not diabetes, were common in a fairly large cohort of adult women with TS when compared with a random population sample. A random population sample must be considered as the best available control group in this case.
In spite of the increased prevalence of treated hypertension in TS women, the measured diastolic blood pressure was similar to that in controls. This indicates that the TS patients were well controlled. The repeated checks by physicians might have led to drug treatment to a higher extent than would occur in the general population. Careful control of the blood pressure is important, because TS patients have an increased prevalence of cardiovascular malformations. This is especially important because of the high risk of aortic dissection (19). One young woman died from aortic dissection in this series. Aortic coarctation is a frequent congenital malformation in TS (4, 5). It is well known that these patients may suffer sustained hypertension even after a successful operation. However, most TS women had essential hypertension. Others (7, 9, 10) have also reported an increased prevalence of hypertension in both young and adult TS women. Hypertension was reported in 20% of adult TS women with the 45,X karyotype and in 14% of those having the mosaic pattern in another study, but cardiovascular malformations were uncommon (20). Ischemic heart disease and stroke are common in TS according to a Danish survey (1). We did not find that or increased levels of the most important risk factors for ischemic heart disease, but there were only nine TS women older than 50 yr of age in our study.
Diabetes, body composition, and physical activity
Diabetes was rare and plasma insulin was not higher in TS women than in controls. Hyperinsulinemia with normal blood glucose is often seen in the insulin-resistant state as a result of compensatory mechanisms in hepatic glucose metabolism. An increased prevalence of insulin resistance has been reported in TS (21, 22) as well as diabetes and glucose intolerance in smaller groups of TS patients (6, 7, 8, 9, 10, 23). BMI and waist/hip ratio were higher in the Danish TS women than in the present study (27 vs. 26 kg/m2 and 0.88 vs. 0.82, respectively) (10). Both degree of obesity and its central location as revealed by high waist/hip ratio as well as physical activity are of importance for glucose metabolism and insulin sensitivity (16, 20, 21, 22, 23, 24). The present TS women were relatively heavier, had more centrally located body fat, and were less physically active than controls. Furthermore, in a previous report regarding a sample of the present study group, we found lower lean body mass in TS women compared with controls: 60% compared with 72% of total body weight (25). In spite of these precipitating factors, diabetes was not frequent among the TS women. HRT was used to a high extent (91%) in the present TS women. BMI was also low (23 kg/m2) in the smaller study by Sylvén (20), in which 5% had diabetes mellitus and only 42% were on HRT. The karyotype did not differ between those with and without diabetes in that study or the present study. In the report by Holl et al. (8), 6 of 25 adult women had impaired glucose tolerance and 1 had diabetes. HRT was used by 92%, and BMI was similar to that in the present study. The effect of estrogens on glucose metabolism has varied (10, 26). The low number of diabetic TS women in most studies precludes firm conclusions regarding any increased diabetes prevalence in TS.
Blood lipids, coagulation factors, and smoking
Blood lipids were similar in TS women and controls in the present study, which was also reported in TS girls (11). GH treatment led to decreased concentrations of total and low-density lipoprotein cholesterol in that study (11). There were no differences in blood lipids between TS women with or without HRT in the present study, which is in accordance with a previous report (20). Similarly, Gravholt et al. (10) did not find any lipid abnormalities in TS women and found no change on HRT. However, they reported an increased morbidity in cardiovascular disease in TS and suggested that TS women had tendencies to a "metabolic syndrome" (1).
Lp(a) cholesterol is an independent risk factor for cardiovascular disease (27). Lp(a) did not differ between patients and controls in the present study, which corroborates an earlier, smaller study in TS girls (11). Lp(a) has been reported to increase after GH treatment in hypopituitary adults (28), but this was not seen in TS girls after GH treatment (11, 29). Fibrinogen is also an independent risk factor for cardiovascular disease and especially for stroke (30). Fibrinogen increases with increasing age (31) and is strongly correlated to smoking (30). Neither fibrinogen nor PAI-1 antigen was increased, and smoking was uncommon, in the present study.
Hormones and social factors
Ninety-one percent of TS women were on HRT in the present study. The TS women, both with and without HRT, had serum estradiol concentrations similar to the controls both when compared with all controls and when compared with postmenopausal women with HRT. Hence, the present findings show that the HRT dose in TS (2 mg of 17-ß-estradiol) gives a serum estradiol concentration that is equivalent to that in a healthy female population.
A lower SHBG concentration in the TS women than in controls might be explained by the more frequent HRT substitution among TS women. Their somewhat higher waist/hip ratio might also play a role in the lower SHBG.
The TS women were working or were students to a greater extent than the controls, and they were married or living together with a man to the same extent as the controls, indicative of a normal social life.
In conclusion, most cardiovascular risk factors [glucose and lipid metabolic levels, Lp(a), fibrinogen, and smoking habits] were not increased, but hypertension and low physical activity were overrepresented. However, congenital cardiovascular malformations, mostly found in TS women with 45,X, aortic coarctation, and dissection call for attention. A thorough cardiac evaluation is recommended, especially in the event of pregnancy.
Acknowledgments
We thank Georg Lappas for statistical help.
Footnotes
This study was supported by grants from the Swedish Social and Welfare Board and the Faculty of Medicine, Göteborg University. Funding of research and development was from Västra Götaland and Ingabritt and Arne Lundberg Research Fund.
Abbreviations: BMI, Body mass index; HRT, hormone replacement therapy; Lp(a), lipoprotein (a); PAI-1, plasminogen activator inhibitor type 1; TS, Turner syndrome.
Received March 1, 2000.
Accepted May 7, 2001.
References
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