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BRIEF REPORT |
Endocrine Division (M.E.-M., K.L.-W.), Departments of Internal Medicine, and Obstetrics and Gynecology (I.B., C.H.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden; Department of Endocrinology (K.B.), Malmö University Hospital, Lund University, SE-20502 Malmö, Sweden; and Section of Preventive Cardiology (L.W.), Göteborg University, SE-41250 Göteborg, Sweden
Address all correspondence and requests for reprints to: Kerstin Landin-Wilhelmsen, M.D., Ph.D., Endocrine Division, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: kerstin.landin{at}sahlgrenska.se.
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Abstract |
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Women with TS (n = 91; mean age, 37.7 ± 11 yr) were compared with an age-matched female random population sample (n = 228). At baseline, 15 (16%) TS women were treated for hypothyroidism, and elevated serum TSH was found in another eight (9%). As a result, hypothyroidism was more common in women with TS (25%) than in controls (2%; P < 0.0001). Serum free T4 was lower (P = 0.02), and serum TSH was higher (P < 0.0001) in TS women than in age-matched controls. Of all TS women with hypothyroidism, 10 (43%) had an elevated thyroid peroxidase antibody titer vs. 15 (22%) of those without hypothyroidism (P < 0.05), evenly distributed between the karyotype 45,X and mosaicism. A high body mass index, but not a family history or blood lipids, was associated with hypothyroidism in TS. After the 5-yr follow-up, an additional 11 (16%) developed hypothyroidism, of whom four (36%) had elevated thyroid peroxidase. Altogether, 34 (37%) TS women had hypothyroidism after the 5-yr follow-up.
Autoimmune hypothyroidism was common, with an annual incidence of 3.2% in TS. Thyroid function should be checked regularly in TS.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The purpose of the present study was to analyze the prevalence and incidence of hypothyroidism in a large cohort of TS women in comparison with a random population sample of similar age. The results of the 5-yr follow-up of thyroid function in TS are reported. Furthermore, fluorescence in situ hybridization (FISH), a sensitive method, was used to detect mosaicism to study whether hypothyroidism was associated with a special cell line in TS.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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A random population sample of women aged 25–64 yr (n = 740) was recruited from the World Health Organization MONICA (MONItoring of trends and determinants in CArdiovascular diseases) Project in 1995 in Göteborg (15), including cardiovascular risk factor screening in 38 countries around the world. Age-matched controls (n = 228; mean age, 37.3 ± 9 yr) were available for 91 TS women.
Estrogen hormone replacement therapy (HRT) (17-ß-estradiol, 2 mg) was currently being given to 95% of the TS women. Of the controls, 31% were taking oral contraceptives, and 16% above 45 yr of age were taking HRT (17-ß-estradiol, 2 mg).
Subjects and methods
Data on a family history of thyroid disease among TS women was requested during the investigation. A sibling, mother, father, aunt, uncle, grandmother, or grandfather with a thyroid disease was registered as a positive family history of thyroid disease.
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 (in kilograms) divided by height (in meters) squared. 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 to hip ratio was calculated. The clinical examination including the thyroid was performed by the same endocrinologists (K.L.-W. and K.B.) in the two cities throughout the study period.
Fasting venous blood samples were drawn from an antecubital vein in the morning after an overnight fast. The samples were drawn on d 5 in the menstrual cycle in all control women with regular bleedings. All TS women had their HRT washed out for 2 months before this study. After centrifugation, all samples were frozen and stored at –70 C until analysis, which was performed within 1 yr. Concentrations of serum free T4 and TSH were measured with an immunometric method with luminometry (Johnson & Johnson, La Jolla, CA), and thyroid peroxidase antibody (TPO) concentrations were determined with the BRAHMS luminometric test anti-TPO (Henning, Berlin, Germany). The reference levels for free T4 were (SI units in parentheses) 0.86–2.18 ng/dl (11–28 pmol/liter) in 1995–1999 and 0.86–1.71 ng/dl (11–22 pmol/liter) after 1999, whereas reference levels were 0.1–3.0 µU/ml (0.1–3.0 mU/liter) in 1995–1999 and 0.2–4.0 µU/ml (0.2–4.0 mU/liter) after 1999 for serum TSH and less than 100 U/ml (kU/liter) for TPO antibody concentration until 2003, when the level changed to less than 60 U/ml (kU/liter). The data were corrected for the relevant reference interval. Blood lipids were determined enzymatically (Boehringer, Mannheim, Germany).
The chromosomal findings were based on medical records. The karyotype was defined after analysis of 30 cells. Briefly, the FISH procedure was as follows. Buccal mucosal cells were fixed in a 3:1 absolute ethanol to acetic acid mixture at room temperature for 15 min. The DNA probes for chromosomes X (DXZ1) and Y (DYZ3) were directly labeled with green fluorochrome (Spectrum Green, Vysis Inc., Downers Grove, IL) and orange fluorochrome (Spectrum Orange, Vysis Inc.), respectively. Ten microliters of the DNA probe mixture were added. A coverslip was attached and sealed with rubber cement, and the samples were incubated at 80 C for 5 min on a heat block for denaturation. The hybridization and washes were performed mainly as described previously (16, 17). In short, the hybridization was performed at 37 C in a moist chamber for 3–4 h. The slides were washed at 42 C in 50% formamide/2x sodium saline citrate (SSC) (pH 7.6) for 15 min, followed by 2x SSC (pH 7.0) for 10 min, and finally 0.1% Nonidet P-40/2x SSC (pH 7.0) for 5 min. The samples were allowed to air dry, 10 µl of 4',6-diamidino-2-phenylindole II counterstain (Vysis Inc.) were applied, and a coverslip was attached. The analysis was performed on a Nikon microscope equipped with 4',6-diamidino-2-phenylindole (360 nm), fluorescein isothiocyanate filter (490 nm), and tetramethylrhodamine isothiocyanate filter (570 nm). An average of 214 ± 86 (mean ± SD) nuclei were scored per patient.
In those cases in which FISH revealed another cell line that was not diagnosed with the conventional karyotype, the karyotyping of an additional 100 cells was performed to: 1) confirm the FISH analysis, and/or 2) characterize the second sex chromosome.
The chromosome status was based on the combined picture of FISH and karyotyping. The isochromosome group included individuals with 45,X/46,X,i(X)(q10).
All TS women had their thyroid function checked annually. Furthermore, after 5 yr, a thorough examination with blood samples for thyroid, liver, and kidney function; vitamins; hormones; and other blood variables was performed, in addition to a cardiac ultrasound, bone measurement, body composition, hearing test, etc. An examination by an endocrinologist and a gynecologist was also performed. Other results, apart from thyroid data, will be reported later.
Ethical considerations
The study was approved by the Ethics Committees at Göteborg and Lund Universities, and all the participants gave their informed consent. Human rights were also approved according to the Helsinki Declaration.
Statistical analyses
Means and SD values were calculated with conventional methods. Differences between patients and controls were tested with Student’s t test, and differences between noncontinuous variables among TS women were tested with Mantel-Haentzel’s 
2 test. Differences within TS subjects after follow-up were tested with Wilcoxon’s signed rank test. Simple correlations were calculated with Pearson’s method. Multiple stepwise regression models were used to test interactions between factors.
A P value less than 0.05 (two-sided test) was considered statistically significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. As expected, TS women were shorter than age-matched women from the population. Body weight was lower, but BMI and waist to hip ratio were higher than in controls. BMI was higher among TS women with hypothyroidism than in TS women without hypothyroidism (27.1 ± 4.7 vs. 25.0 ± 4.3 kg/m2; P < 0.05). Smoking was less prevalent in TS, and one of the smokers had hypothyroidism. Continuous HRT was being given to 95% of all TS patients and to those with hypothyroidism.
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). Serum free T4 was lower than the reference level in 3% of the TS women with elevated TSH.
The TPO antibody titer varied widely [range, 0–4200 U/ml (kU/liter)] (Table 1). An elevated TPO antibody concentration was found more frequently in TS women with hypothyroidism (43%) than in women without hypothyroidism (22%; P < 0.05). The TPO concentration correlated positively with serum TSH (r = 0.18; P = 0.03). No correlation was found between serum TPO concentration and age or the serum free T4 concentration in TS.
There were no differences in total cholesterol, high- or low-density lipoprotein cholesterol, or serum triglycerides between TS women and controls (Table 1). Hypothyroidism did not influence blood lipid levels, except in one TS woman who had twice the total cholesterol levels and four times the triglyceride levels and hypothyroidism. After T4 substitution, her blood lipids normalized.
Six of the TS women with hypothyroidism and seven of those without it had a positive family history of thyroid disease (not significant).
The karyotype pattern and FISH data are given in Table 2. A nonmosaic karyotype 45,X was found in 52% of the TS women, whereas a mosaic karyotype was found in 48%. TS women with isochromosome, 45,X/46,X,i(X)(q10), were studied as a subgroup. However, nothing singled them out in terms of thyroid data. There was no correlation between the frequency of 45,X cells in an individual and serum TPO, TSH, or free T4 concentrations, respectively. Elevated TPO concentrations were evenly distributed between the karyotype 45,X and mosaicism (Table 2).
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). Hypothyroidism increased with increasing age. Figure 1 shows the annual results of serum TSH in the remaining 57 TS women who were not hypothyroid at the start or after the 5-yr follow-up. Serum TSH increased within the normal range during follow-up. TPO was elevated in 11 (19%) of these TS women. Serum free T4 was unaltered.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The repeated checks by physicians might have led to the detection of hypothyroidism and the administration of T4 substitution, to a larger extent, than would normally occur in the general population.
However, the present prevalence of hypothyroidism among TS women is similar to that in previous reports from studies of adult TS women (3, 14, 18).
In line with earlier studies (7, 10, 13, 14), we found that the main etiology was autoimmune hypothyroidism. This was, in turn, associated with the Turner disease and not with a family history of thyroid disease, contrary to what was reported by Wilson et al. (13). Elevated TPO antibody concentrations are more frequently associated with hypothyroidism than hyperthyroidism. The TPO concentrations correlated positively with serum TSH in the present study. The clinical symptoms seldom led the TS patients or the controls to seek medical attention (19, 20). Interestingly, premature ovarian failure in general, especially due to endometriosis, is also associated with thyroid disorders and elevated TPO antibody concentrations (21). An idiopathic cause was more common than TS as a cause of premature ovarian failure in a British survey (22).
Elevated blood lipids were not associated with hypothyroidism, in agreement with a Danish study of adult TS (23). However, BMI was higher among TS women with hypothyroidism. Smoking and HRT were negatively correlated to TPO concentrations in a recent report in a female population but were not associated with thyroid disease (24). Smoking was uncommon among the TS women, and only one had hypothyroidism, which could not explain the high prevalence of hypothyroidism in TS. It has been suggested that cyanide in tobacco smoke blocks the iodine uptake, leading to lower serum TSH levels in smokers (25).
The present, first prospective study of TS revealed a high yearly incidence (3.2%) of hypothyroidism in TS. Nearly half of the subjects had elevated TPO antibody concentrations. This has also been reported in another study in a normal population, where positive TPO antibodies predispose to hypothyroidism (19).
Hypothyroidism increased with increasing age in TS, and it is possible to speculate about whether most TS women will develop hypothyroidism with time. Figure 1, which shows increasing serum TSH with time, still within the normal range, in TS women who were not hypothyroid at the start or after the 5-yr follow-up, supports an additional increase in incidence. At least those TS women with elevated TPO (19%) in that group appear to run a particularly high risk of hypothyroidism at future follow-ups.
Our hypothesis was that hypothyroidism was related to monosomy, i.e. the 45,X karyotype. This has been seen in congenital heart disease and hearing loss, but not in osteoporosis and fractures, in the present TS women (26, 27, 28). However, there was no correlation between the percentage of cells with a 45,X karyotype in an individual determined by FISH and the number of cases of hypothyroidism. A gain in the long (q) arm together with a loss of a short (p) arm of the X-chromosome may be of importance for the development of autoimmunity. This has also been seen in other studies, mainly in children with TS (11, 14, 29, 30, 31). However, elevated TPO concentrations were evenly distributed between the different karyotype variants. The risk of developing hypothyroidism therefore appears to be high for all TS women, independent of karyotype.
This means that, even if an individual with a TS karyotype may generally run an elevated risk of developing hypothyroidism, the actual risk is also dependent on the (autosomal) genetic background in which the TS karyotype happens to appear. This hypothesis is further strengthened by the observation by Wilson et al. (13) that there is a correlation between a positive family history of hypothyroidism, or at least elevated TPO antibody concentrations, and the risk that a TS woman will develop hypothyroidism. Autoimmune hypothyroidism is also common in the general female population (24), which speaks in favor of different genes being involved. The specific genetic cause is still unknown. Taken together, this implies that genes on other chromosomes are probably also important for hypothyroidism.
In conclusion, this is the first longitudinal study to show that autoimmune hypothyroidism was common in TS women and after a 5-yr follow-up in TS women. The annual incidence of hypothyroidism was 3.2% in TS. Thyroid function must be checked regularly in women with TS.
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Acknowledgments |
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Footnotes |
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First Published Online December 28, 2004
Abbreviations: BMI, Body mass index; FISH, fluorescence in situ hybridization; HRT, hormone replacement therapy; SSC, sodium saline citrate; TPO, thyroid peroxidase; TS, Turner syndrome.
Received June 30, 2004.
Accepted December 20, 2004.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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