http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(3): 250–253 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2013.872236
TURNER’S SYNDROME
The influence of hormonal replacement and growth hormone treatment on the lipids in Turner syndrome Tomasz Jerzy Irzyniec1,2 and Wacław Jez_ 3 1
Department of Health Promotion and Community Nursing, Medical University of Silesia, Katowice, Poland, 2Department of Nephrology/ENDO Hospital of the Ministry of Interior Affairs, Katowice, Poland, and 3Out-patient Clinic for Women with Turner Syndrome, Specialist Hospital No 2. Bytom, Poland Abstract
Keywords
Aim: Women with Turner syndrome (TS) have a risk of developing cardiovascular diseases. We assessed the lipid and carbohydrate metabolism in TS-women in the context of current hormone replacement therapy (HRT) and growth hormone (GH) treatment during childhood. Methods: The information were collected from medical documentation and anamnesis of 165 TS-women (24.9 ± 7.7 yr) between 1995 and 2011. The patients underwent a pituitary-gonadal axis assessment together with measurements of total cholesterol (TC), high- (HDL) and low(LDL) density lipoproteins, triglycerides (TG), and glucose levels. Results: Only 58% of women were using HRT. No differences were found in the levels of the lipid components and glucose in women who were undergoing HRT compared to those without it. Compared to TS-women without (n ¼ 113), prior GH treatment in 34 TS-women positively influenced the lipid parameters: TC 5.0 ± 1.1 versus 4.6 ± 0.9 mmol/l (p ¼ 0.03), HDL 1.5 ± 0.5 versus 1.4 ± 0.4 mmol/l (p40.05), LDL 3.3 ± 0.9 versus 2.9 ± 0.7 mmol/l (p ¼ 0.03), and TG 1.1 ± 0.6 versus 0.8 ± 0.3 g/l (p ¼ 0.009), respectively. Conclusions: (1) HRT does not affect lipid metabolism in TS-women. (2) The use of GH in TS-children favorably influences their lipid profile in adulthood.
Hormonal therapy, lipids, Turner Syndrome
Turner syndrome (TS) is characterized by the loss of all or part of one sex chromosome and occurs in 1 in 2500 live-born females, leading to growth failure, gonadal insufficiency and cardiac anomalies [1]. Women with TS are substantially shorter than their healthy counterparts, but have higher body mass indices (BMI). In addition, higher blood pressure and disorders in lipid metabolism are characteristic of TS-women [2,3]. The changes in the lipid metabolism in TS-women have not been well studied. They have also never been juxtaposed with karyotype, age and in terms of their effects on cardiovascular risk factors. TS-women have trace concentrations of estrogens and excessive uncontrolled gonadotropins secretion [4]. Estrogen replacement therapy is necessary for TS-patients for many reasons [5,6]. Hormone replacement therapy (HRT) in cases of gonadal insufficiency, positively impacts the lipid balance, causing inter alia, an increase in high-density lipoprotein (HDL) levels, and a slight decrease in low-density lipoprotein (LDL) and total cholesterol (TC) levels [7]. However, biphasic period stimulation (estrogen/ progestogen) can be initiated only after having confirmed that TS-women have reached their maximum height. Treatment with growth hormone plays a significant role in the development of insulin resistance. Despite some metabolic side Address for correspondence: Tomasz Jerzy Irzyniec, MD, PhD, Department of Health Promotion and Community Nursing, Medical University of Silesia, ul. Głowackiego 10, 40 – 052 Katowice, Poland. Tel: +48 32 782-72-21. Fax: +48 32 782-73-00. E-mail: [email protected]
Received 29 November 2012 Revised 26 October 2013 Accepted 2 December 2013 Published online 8 January 2014
effects, treatment with GH seems to have indisputable benefits when the reduced height of TS-women is taken into account [8,9]. Previous reports have surmised that gonadal hormones are not the primary factor influencing insulin resistance or lipid imbalance, which are the causative factors of cardiovascular diseases. Instead, it is the early treatment with GH that causes these imbalances [10]. In our previous work, we found that a large group of TSwomen, do not comply with doctors’ orders regarding hormonal treatment [11]. Therefore, by analyzing gonadal hormone concentrations and assessing risk factors for cardiovascular diseases, we sought to determine if HRT actually decreases the risk of occurrence of cardiovascular diseases. Fortuitously, only a part of TS-women were treated with GH [12], which enabled us to conduct a comparative study of TS-women who had been treated with GH and those who were not treated. The objective of this study was to assess lipid and carbohydrate metabolism in TS-women in the context of HRT as well as GH treatment during childhood.
20 14
Introduction
History
Methods One hundred and sixty-five TS-women between the ages of 18 and 53 (mean 24.9 ± 7.7 yr) were included in the study. The presence of TS was confirmed by karyotyping [13]. The information about current HRT and previous GH use was obtained from medical documentation and anamnesis, which was conducted by the same group of investigators throughout the period of 16 years. The gonadotropins (FSH, LH) and 17b-estradiol (E2) concentrations were measured in all TS women. FSH and LH
Turner syndrome, lipids
DOI: 10.3109/09513590.2013.872236
levels were determined using a radioimmunoassay and E2 levels using immunoradiometric methods. We also measured TC, HDL, LDL, triglycerides (TG) and glucose concentrations. Blood pressure, body weight and BMI were measured for all subjects. The collected data were statistically analyzed using Statistica 9.0 for Windows XP (StatSoft, USA). The results were reported as the mean value ± standard deviation (SD). We used an unpaired t test to compare the results. The results of hormonal tests were compared using the Mann–Whitney U test. The bilateral test of differences between two structural indicators was applied to evaluate the statistical characteristics of the frequency of occurrence of particular values. The Tau–Kendal test was used for correlation analysis. A p value50.05 was used for statistical significance.
Results Table 1 presents the baseline test results of the 165 TS-women, of which 88 (53.3%) have the typical 45,X karyotype. TS-women with the 45,X karyotype did not significantly differ from those displaying other karyotypes in terms of the analyzed parameters. Table 2 shows that 96 out of the 165 TS-women (58.2%) reported that they were currently being treated with HRT. In these women, we did not observe statistically significant differences in lipid parameters. Glucose concentration was only slightly, but not significantly, lower (p¼0.0804). In both groups, there was a comparable percentage of women with monosomy 45,X (52.1 versus 55.1%) and treated with GH in childhood (22.9 versus 18.8%). It is assumed that the concentration of 17b-estradiol in the Table 1. Clinical and laboratory characteristics of the study population of 165 women with Turner syndrome. Means ± SD (range). Parameters
Values
Age [years] Height [cm] Weight [kg] BMI [kg/m2] Systolic pressure [mmHg] Diastolic pressure [mmHg] FSH [IU/l] LH [IU/l] E2 [pmol/l] Cholesterol [mmol/l] HDL [mmol/l] LDL [mmol/l] TG [g/l] Glucose [mmol/l]
24.9 ± 7.7 (18–53) 145 ± 7.1 (123–172) 50 ± 9.8 (28.8–80) 23.8 ± 4.2 (14.2–36.2) 119 ± 16 (80–185) 81 ± 11 (60–125) 37 ± 23.4 (0.5–132) 23.3 ± 17.8 (1–93) 116 ± 128 (10–228) 4.9 ± 1 (2.6–10.7) 1.4 ± 0.5 (0.2–3) 3.3 ± 0.9 (1.4–7.1) 1.08 ± 0.57 (0.24–3) 5.09 ± 0.84 (3.2–10.6)
Table 2. Selected parameters in TS-women who declared HRT application (HRT+) versus TS-women who did not declare it (HRT). Means ± SD. Parameters
HRT + n ¼ 96
HRT-n ¼ 69
p Value
Age [years] Height [cm] Weight [kg] BMI [kg/m2] Systolic pressure [mmHg] Diastolic pressure [mmHg] FSH [IU/l] LH [IU/l] E2 [pmol/l] Cholesterol [mmol/l] HDL [mmol/l] LDL [mmol/l] TG [g/l] Glucose [mmol/l]
24.6 ± 7.1 145.6 ± 6.9 49.5 ± 8.9 23.3 ± 4 118 ± 16 81 ± 11 31.8 ± 22.1 20.9 ± 17.4 135 ± 147 4.9 ± 1 1.4 ± 0.4 3.3 ± 0.8 1.02 ± 0.51 4.99 ± 0.7
25.3 ± 8.4 144.3 ± 7.3 50.8 ± 11 24.4 ± 4.5 121 ± 16 81 ± 11 44.2 ± 23.3 26.6 ± 18.1 90 ± 100 4.9 ± 1.2 1.4 ± 0.5 3.2 ± 0.9 1.16 ± 0.63 5.22 ± 1
NS NS NS NS NS NS 0.0007 0.04 0.0303 NS NS NS NS 0.0804
blood of women in reproductive age should exceed 110 pmol/l. We analyzed selected parameters in 96 TS-women who declared HRT use and divided them into a group in which E2 110 pmol/l (n ¼ 34) and a group with E25110 pmol/l (n ¼ 62). TS-women from the first group had significantly higher concentrations of E2 than from the second one (284 ± 163 versus 52 ± 36 pmol/l, respectively; p50.0001). However, statistically significant differences in other biochemical and hormonal parameters were not found. There were 35 women in this study who had been treated with GH during childhood. We found notable differences in height, BMI and concentrations of cholesterol, triglycerides, FSH and E2 in women treated with GH compared to the non-treated subjects; however, the latter population had a higher average age (21.5 ± 4.6 versus 26.1 ± 8.1 yr, respectively; p¼0.0012). Subjects were age-matched for comparison (Table 3). Women treated with GH in childhood were slightly taller than their peers who did not receive the treatment. In both groups, there were a comparable percentage of women with the 45,X karyotype (58.8 versus 55.2%) and reporting HRT use (61.7 versus 54.5%, respectively). We found notable differences in the lipid profile. We also observed higher FSH concentrations in the GH-treated group (p¼0.0066). Correlations In all of the groups of TS-women, the FSH and LH concentrations were positively, while FSH and E2 negatively correlated. No correlations between hormonal and lipid metabolism parameters were found in any of the groups of TS-women. Only the group with plasma E2 concentrations higher than 110 pmol/l exhibited a negative correlation between E2 and body mass (Tau ¼ 0.2528; p¼0.0355) as well as between E2 and diastolic blood pressure (Tau ¼ 0.2788; p¼0.0204). This group was also characterized by a positive correlation between E2 and glucose concentrations (Tau ¼ 0.2358; p¼0.0499). Summary of results The risk factors of cardiovascular disease were investigated in 165 TS-women based on their current use/non-use of HRT as well as GH during childhood. We did not find any differences in the lipid profiles between women based on their use of HRT, in spite of the presence of higher concentrations of estradiol and lower of gonadotropins. The above-mentioned differences were not noted during the separate analysis of women who were using HRT in which E2 110 pmol/l and a group with E25110 pmol/l. Table 3. The parameters in women with Turner syndrome treated with GH in childhood (GH+) and women not treated (GH). Both groups matched according to the age of subjects. Means ± SD. Parameters
GH+n ¼ 34
GHn ¼ 113
p Value
Age [years] Height [cm] Weight [kg] BMI [kg/m2] Systolic pressure [mmHg] Diastolic pressure [mmHg] FSH [IU/l] LH [IU/l] E2 [pmol/l] Cholesterol [mmol/l] HDL [mmol/l] LDL [mmol/l] TG [g/l] Glucose [mmol/l]
21.7 ± 4.6 147.2 ± 7.7 49 ± 8.7 22.6 ± 3.7 118 ± 17 79 ± 10 48 ± 26.8 26 ± 16.4 147 ± 160 4.6 ± 0.9 1.4 ± 0.4 2.9 ± 0.7 0.83 ± 0.3 5.12 ± 0.67
23.6 ± 4.6 144.6 ± 6.6 49.2 ± 9.6 23.5 ± 4 119 ± 15 81 ± 11 35.7 ± 21.4 23.3 ± 18.1 117 ± 138 5 ± 1.1 1.5 ± 0.5 3.3 ± 0.9 1.13 ± 0.64 5.02 ± 0.59
NS 0.0584 NS NS NS NS 0.0066 NS NS 0.0346 NS 0.0312 0.0092 NS
NS – the lack of statistical significance. NS – the lack of statistical significance.
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T. J. Irzyniec & W. Jez_
Favorable differences in the lipid profile were observed in TS-women, who had been treated with GH during childhood. Although they had similar concentrations of estradiol, TS-women who were treated with GH in childhood had higher levels of gonadotropins.
Discussion Our study population of TS women had a pro-atherogenic phenotype, which has been widely described by other authors [2,14]. Some studies have shown that monosomy 45,X [15] and the paternal X chromosome are the factors associated with higher atherogenicity [16,17]. We compared the subjects with 45,X monosomy to those displaying other karyotypes and did not observe any differences in the lipids parameters. The impact of estrogens on metabolism of lipids is well established. Estrogens diminish lipids oxidation and increase the synthesis of triglycerides. Changes in the content of serum lipids explain the increase in HDL levels and the slight decrease in LDL and TC levels. The TG concentration and the storage of lipids also increase [7]. In a high percentage of women, the non-use or insufficient use of HRT aggravates the risk of atheromatosis. HRT is known to prevent type 2 diabetes in menopausal women. However, this beneficial influence does not protect against cardiovascular diseases [18]. The benefit of HRT on the lipid balance in TS-women was noted. The favorable effects of HRT on the lipid profile in TSwomen were previously described by Ostberg [19] who noted that the increase in HDL level and decrease in glucose concentration did not change the TC level. However, there are reports that suggest that HRT does not have any beneficial impact on lipid balance [20]. In our study, we did not observe any differences in lipid metabolism parameters in women who use HRT compared to those who do not. The timing, duration and compliance with HRT treatment among the HRT-treated subjects were sometimes difficult to establish. Nevertheless, our finding that HRT-treated TS-women with estradiol concentrations either above or below 110 pmol/l had no differences in lipid parameters supports the hypothesis that HRT does not have a beneficial impact on the lipids. However, we cannot exclude that HRT has a positive effect on carbohydrate metabolism, which is suggested by the decreasing trend in glucose concentration. GH influences carbohydrate metabolism when in excess, decreases the use of carbohydrates, and hinders the uptake of glucose by cells. This GH-induced insulin resistance seems to be caused by impaired post-receptor insulin activity, which ultimately leads to secondary hyperinsulinism [21]. Women with TS display higher insulin resistance, which is a karyotype-dependent factor [22]. Insulin resistance is also an early metabolic defect in girls with TS. The application of GH has become a standard in treating young girls with Turner syndrome, despite certain metabolic side effects. The treatment with GH causes a loss in insulin sensitivity, which returns to pre-therapy levels when treatment is stopped [23]. We found evidence in the literature showing that the levels of insulin resistance remain for several years after finishing the therapy with GH, but the b-cell activity and the fasting insulin concentrations are higher than before the onset of treatment. In addition, changes in lipid metabolism were observed. TC and HDL levels were higher at 6 months after ending therapy than immediately after its cessation. The authors concluded that GH has a positive impact on the lipid profile in TS-women. Five years after the end of GH therapy, the beneficial influence of this hormone was still visible [10]. In addition, Wooten and Bondy have reported that young girls with TS aged 13.6 ± 3.7 yr with prior GH treatment have less abdominal fat and better lipid profile compared to untreated patients [24].
Gynecol Endocrinol, 2014; 30(3): 250–253
From the group of 165 TS-women, we evaluated those who had been treated with GH during childhood. The selection of a group in which a large percentage of women were not treated with GH was possible because we began our observation in 1995 and included women who were adults at the time. If we assume that GH therapy was standardized in Poland around 1990, it becomes obvious why some of them were never treated with GH. We do not have any data regarding the duration for which these subjects had undergone treatment, although we can assume that it must have ended by the age of 16 at the latest. The treatment with GH during childhood was as per doctors’ orders. The mean age in this group [GH(+)] was 21.7 yr, so the time that had passed since the therapy had ended was at least 5 years. We sought to compare this group with the other TS-women. Subjects were age matched for comparison. The percentage of women who used HRT and displayed 45,X monosomy were comparable in both the GH(+) and GH() groups. We noted a beneficial lipid profile in the GH(+) women. Therefore, we conclude that the effect of GH treatment on the lipid profile is relevant, and not only visible, which was stated by Bannink et al. [10], whereas the negative impact on the glucose metabolism was not observed. In addition, we observed significantly higher concentrations of gonadotropins in the GH(+) group, which suggests that their demand on HRT is higher. The results of the correlation analysis indicate a positive correlation between E2 and glucose concentrations, which is well known. The negative correlation between the E2 concentration and body mass as well as between E2 and diastolic blood pressure in TS-women with an E2 concentration 110 pmol/l indicates a beneficial effect of estradiol on the above-mentioned parameters. However, estradiol does not influence the lipid metabolism parameters in TS-women.
Conclusions (1) The application of HRT in women with Turner syndrome does not affect the lipid metabolism. (2) The use of GH in TS-children favorably influences their lipid profile in adulthood.
Declaration of interest The authors report no declarations of interest.
References 1. Stochholm K, Juul S, Juel K, et al. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897–902. 2. Kozłowska-Wojciechowska M, Jez_ W, Zdrojewski T, Chwojnicki K. Are young women with Turner syndrome at greater risk of coronary artery disease? Eur J Cardiovasc Prev Rehabil 2006;13:467–9. 3. Hjerrild BE, Holst JJ, Juhl CB, et al. Delayed b-cell response and glucose intolerance in young women with Turner syndrome. BMC Endocr Disord 2011;11:6. 4. Styne DM, Grumbach MM. Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Melmed S, Polonsky KS, Reed Larsen P, Kronenberg HM, eds. Williams textbook of endocrinology. 12th ed. Philadelphia: Saunders Elsevier; 2011:1054–201. 5. Bondy CA. Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92:10–25. 6. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010;95:1487–95. 7. Bulun SE. Physiology and pathology of the female reproductive axis. In: Melmed S, Polonsky KS, Reed Larsen P, Kronenberg HM, eds. Williams textbook of endocrinology. 12th ed. Philadelphia: Saunders Elsevier; 2011:581–660. 8. Pinsker JE. Clinical review: Turner syndrome: updating the paradigm of clinical care. J Clin Endocrinol Metab 2012;97:994–1003.
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9. Gravholt CH. Clinical practice in Turner syndrome. Nat Clin Pract Endocrinol Metab 2005;1:41–52. 10. Bannink EM, van der Palen RL, Mulder PG, de Muinck KeizerSchrama SM. Long-term follow-up of GH-treated girls with Turner syndrome: metabolic consequences. Horm Res 2009;71:343–9. 11. Jez_ W, Irzyniec T. Hormonal replacement therapy in women with Turner’s syndrome in Poland: analysis of 176 cases. Gynecol Endocrinol 2009;25:546–50. 12. Irzyniec T, Jez_ W, Piszczek R. Height correlation analysis between women with Turner syndrome, their sisters and parents. Endokrynol Pol 2008;59:140–5. 13. Jez_ W, Irzyniec T, Pyrkosz A. Selected problems of the diagnosis of Turner’s syndrome. Przeg Lek 2007;64:130–3. 14. Giordano R, Forno D, Lanfranco F, et al. Metabolic and cardiovascular outcomes in a group of adult patients with Turner’s syndrome under hormonal replacement therapy. Eur J Endocrinol 2011;164: 819–26. 15. Van PL, Bakalov VK, Bondy CA. Monosomy for the X-chromosome is associated with an atherogenic lipid profile. J Clin Endocrinol Metab 2006;91:2867–70. 16. Van PL, Bakalov VK, Zinn AR, Bondy CA. Maternal X chromosome, visceral adiposity and lipid profile. JAMA 2006;295:1373–4. 17. El-Mansoury M, Barrenas ML, Bryman, et al. Chromosomal mosaicism mitigates stigmata and cardiovascular risk factors in Turner syndrome. Clin Endocrinol 2007;66:744–51.
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18. Kanaya AM, Herrington D, Vittinghoff E. HERS Study. Glycemic effects of postmenopausal hormone therapy: the heart and estrogen/progestin replacement study. A randomized, doubleblind, placebo-controlled trial. Ann Intern Med 2003;138:1–9. 19. Ostberg JE, Storry C, Donald AE, et al. A dose-response study of hormone replacement in young hypogonadal women: effects on intima media thickness and metabolism. Clin Endocrinol 2007;66: 557–64. 20. Nabhan ZM, Dimeglio LA, Qi R, et al. Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a pilot comparative study. J Clin Endocrinol Metab 2009;94:2009–14. 21. Melmed S, Kleinberg D, Ho K. Pituitary physiology and diagnostic evaluation. In: Melmed S, Polonsky KS, Reed Larsen P, Kronenberg HM, eds. Williams textbook of endocrinology. 12th ed. Philadelphia: Saunders Elsevier; 2011:175–228. 22. Salgin B, Amin R, Yuen K, et al. Insulin resistance is an intrinsic defect independent of fat mass in women with Turner’s syndrome. Horm Res 2006;65:69–75. 23. Mazzanti L, Bergamaschi R, Castiglioni L, et al. Turner syndrome, insulin sensitivity and growth hormone treatment. Horm Res 2005; 64:51–7. 24. Wooten N, Bakalow VK, Hill S, Bondy CA. Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome. J Clin Endocrinol Metab 2008;93: 2109–14.
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TURNER’S SYNDROME
The influence of hormonal replacement and growth hormone treatment on the lipids in Turner syndrome Tomasz Jerzy Irzyniec1,2 and Wacław Jez_ 3 1
Department of Health Promotion and Community Nursing, Medical University of Silesia, Katowice, Poland, 2Department of Nephrology/ENDO Hospital of the Ministry of Interior Affairs, Katowice, Poland, and 3Out-patient Clinic for Women with Turner Syndrome, Specialist Hospital No 2. Bytom, Poland Abstract
Keywords
Aim: Women with Turner syndrome (TS) have a risk of developing cardiovascular diseases. We assessed the lipid and carbohydrate metabolism in TS-women in the context of current hormone replacement therapy (HRT) and growth hormone (GH) treatment during childhood. Methods: The information were collected from medical documentation and anamnesis of 165 TS-women (24.9 ± 7.7 yr) between 1995 and 2011. The patients underwent a pituitary-gonadal axis assessment together with measurements of total cholesterol (TC), high- (HDL) and low(LDL) density lipoproteins, triglycerides (TG), and glucose levels. Results: Only 58% of women were using HRT. No differences were found in the levels of the lipid components and glucose in women who were undergoing HRT compared to those without it. Compared to TS-women without (n ¼ 113), prior GH treatment in 34 TS-women positively influenced the lipid parameters: TC 5.0 ± 1.1 versus 4.6 ± 0.9 mmol/l (p ¼ 0.03), HDL 1.5 ± 0.5 versus 1.4 ± 0.4 mmol/l (p40.05), LDL 3.3 ± 0.9 versus 2.9 ± 0.7 mmol/l (p ¼ 0.03), and TG 1.1 ± 0.6 versus 0.8 ± 0.3 g/l (p ¼ 0.009), respectively. Conclusions: (1) HRT does not affect lipid metabolism in TS-women. (2) The use of GH in TS-children favorably influences their lipid profile in adulthood.
Hormonal therapy, lipids, Turner Syndrome
Turner syndrome (TS) is characterized by the loss of all or part of one sex chromosome and occurs in 1 in 2500 live-born females, leading to growth failure, gonadal insufficiency and cardiac anomalies [1]. Women with TS are substantially shorter than their healthy counterparts, but have higher body mass indices (BMI). In addition, higher blood pressure and disorders in lipid metabolism are characteristic of TS-women [2,3]. The changes in the lipid metabolism in TS-women have not been well studied. They have also never been juxtaposed with karyotype, age and in terms of their effects on cardiovascular risk factors. TS-women have trace concentrations of estrogens and excessive uncontrolled gonadotropins secretion [4]. Estrogen replacement therapy is necessary for TS-patients for many reasons [5,6]. Hormone replacement therapy (HRT) in cases of gonadal insufficiency, positively impacts the lipid balance, causing inter alia, an increase in high-density lipoprotein (HDL) levels, and a slight decrease in low-density lipoprotein (LDL) and total cholesterol (TC) levels [7]. However, biphasic period stimulation (estrogen/ progestogen) can be initiated only after having confirmed that TS-women have reached their maximum height. Treatment with growth hormone plays a significant role in the development of insulin resistance. Despite some metabolic side Address for correspondence: Tomasz Jerzy Irzyniec, MD, PhD, Department of Health Promotion and Community Nursing, Medical University of Silesia, ul. Głowackiego 10, 40 – 052 Katowice, Poland. Tel: +48 32 782-72-21. Fax: +48 32 782-73-00. E-mail: [email protected]
Received 29 November 2012 Revised 26 October 2013 Accepted 2 December 2013 Published online 8 January 2014
effects, treatment with GH seems to have indisputable benefits when the reduced height of TS-women is taken into account [8,9]. Previous reports have surmised that gonadal hormones are not the primary factor influencing insulin resistance or lipid imbalance, which are the causative factors of cardiovascular diseases. Instead, it is the early treatment with GH that causes these imbalances [10]. In our previous work, we found that a large group of TSwomen, do not comply with doctors’ orders regarding hormonal treatment [11]. Therefore, by analyzing gonadal hormone concentrations and assessing risk factors for cardiovascular diseases, we sought to determine if HRT actually decreases the risk of occurrence of cardiovascular diseases. Fortuitously, only a part of TS-women were treated with GH [12], which enabled us to conduct a comparative study of TS-women who had been treated with GH and those who were not treated. The objective of this study was to assess lipid and carbohydrate metabolism in TS-women in the context of HRT as well as GH treatment during childhood.
20 14
Introduction
History
Methods One hundred and sixty-five TS-women between the ages of 18 and 53 (mean 24.9 ± 7.7 yr) were included in the study. The presence of TS was confirmed by karyotyping [13]. The information about current HRT and previous GH use was obtained from medical documentation and anamnesis, which was conducted by the same group of investigators throughout the period of 16 years. The gonadotropins (FSH, LH) and 17b-estradiol (E2) concentrations were measured in all TS women. FSH and LH
Turner syndrome, lipids
DOI: 10.3109/09513590.2013.872236
levels were determined using a radioimmunoassay and E2 levels using immunoradiometric methods. We also measured TC, HDL, LDL, triglycerides (TG) and glucose concentrations. Blood pressure, body weight and BMI were measured for all subjects. The collected data were statistically analyzed using Statistica 9.0 for Windows XP (StatSoft, USA). The results were reported as the mean value ± standard deviation (SD). We used an unpaired t test to compare the results. The results of hormonal tests were compared using the Mann–Whitney U test. The bilateral test of differences between two structural indicators was applied to evaluate the statistical characteristics of the frequency of occurrence of particular values. The Tau–Kendal test was used for correlation analysis. A p value50.05 was used for statistical significance.
Results Table 1 presents the baseline test results of the 165 TS-women, of which 88 (53.3%) have the typical 45,X karyotype. TS-women with the 45,X karyotype did not significantly differ from those displaying other karyotypes in terms of the analyzed parameters. Table 2 shows that 96 out of the 165 TS-women (58.2%) reported that they were currently being treated with HRT. In these women, we did not observe statistically significant differences in lipid parameters. Glucose concentration was only slightly, but not significantly, lower (p¼0.0804). In both groups, there was a comparable percentage of women with monosomy 45,X (52.1 versus 55.1%) and treated with GH in childhood (22.9 versus 18.8%). It is assumed that the concentration of 17b-estradiol in the Table 1. Clinical and laboratory characteristics of the study population of 165 women with Turner syndrome. Means ± SD (range). Parameters
Values
Age [years] Height [cm] Weight [kg] BMI [kg/m2] Systolic pressure [mmHg] Diastolic pressure [mmHg] FSH [IU/l] LH [IU/l] E2 [pmol/l] Cholesterol [mmol/l] HDL [mmol/l] LDL [mmol/l] TG [g/l] Glucose [mmol/l]
24.9 ± 7.7 (18–53) 145 ± 7.1 (123–172) 50 ± 9.8 (28.8–80) 23.8 ± 4.2 (14.2–36.2) 119 ± 16 (80–185) 81 ± 11 (60–125) 37 ± 23.4 (0.5–132) 23.3 ± 17.8 (1–93) 116 ± 128 (10–228) 4.9 ± 1 (2.6–10.7) 1.4 ± 0.5 (0.2–3) 3.3 ± 0.9 (1.4–7.1) 1.08 ± 0.57 (0.24–3) 5.09 ± 0.84 (3.2–10.6)
Table 2. Selected parameters in TS-women who declared HRT application (HRT+) versus TS-women who did not declare it (HRT). Means ± SD. Parameters
HRT + n ¼ 96
HRT-n ¼ 69
p Value
Age [years] Height [cm] Weight [kg] BMI [kg/m2] Systolic pressure [mmHg] Diastolic pressure [mmHg] FSH [IU/l] LH [IU/l] E2 [pmol/l] Cholesterol [mmol/l] HDL [mmol/l] LDL [mmol/l] TG [g/l] Glucose [mmol/l]
24.6 ± 7.1 145.6 ± 6.9 49.5 ± 8.9 23.3 ± 4 118 ± 16 81 ± 11 31.8 ± 22.1 20.9 ± 17.4 135 ± 147 4.9 ± 1 1.4 ± 0.4 3.3 ± 0.8 1.02 ± 0.51 4.99 ± 0.7
25.3 ± 8.4 144.3 ± 7.3 50.8 ± 11 24.4 ± 4.5 121 ± 16 81 ± 11 44.2 ± 23.3 26.6 ± 18.1 90 ± 100 4.9 ± 1.2 1.4 ± 0.5 3.2 ± 0.9 1.16 ± 0.63 5.22 ± 1
NS NS NS NS NS NS 0.0007 0.04 0.0303 NS NS NS NS 0.0804
blood of women in reproductive age should exceed 110 pmol/l. We analyzed selected parameters in 96 TS-women who declared HRT use and divided them into a group in which E2 110 pmol/l (n ¼ 34) and a group with E25110 pmol/l (n ¼ 62). TS-women from the first group had significantly higher concentrations of E2 than from the second one (284 ± 163 versus 52 ± 36 pmol/l, respectively; p50.0001). However, statistically significant differences in other biochemical and hormonal parameters were not found. There were 35 women in this study who had been treated with GH during childhood. We found notable differences in height, BMI and concentrations of cholesterol, triglycerides, FSH and E2 in women treated with GH compared to the non-treated subjects; however, the latter population had a higher average age (21.5 ± 4.6 versus 26.1 ± 8.1 yr, respectively; p¼0.0012). Subjects were age-matched for comparison (Table 3). Women treated with GH in childhood were slightly taller than their peers who did not receive the treatment. In both groups, there were a comparable percentage of women with the 45,X karyotype (58.8 versus 55.2%) and reporting HRT use (61.7 versus 54.5%, respectively). We found notable differences in the lipid profile. We also observed higher FSH concentrations in the GH-treated group (p¼0.0066). Correlations In all of the groups of TS-women, the FSH and LH concentrations were positively, while FSH and E2 negatively correlated. No correlations between hormonal and lipid metabolism parameters were found in any of the groups of TS-women. Only the group with plasma E2 concentrations higher than 110 pmol/l exhibited a negative correlation between E2 and body mass (Tau ¼ 0.2528; p¼0.0355) as well as between E2 and diastolic blood pressure (Tau ¼ 0.2788; p¼0.0204). This group was also characterized by a positive correlation between E2 and glucose concentrations (Tau ¼ 0.2358; p¼0.0499). Summary of results The risk factors of cardiovascular disease were investigated in 165 TS-women based on their current use/non-use of HRT as well as GH during childhood. We did not find any differences in the lipid profiles between women based on their use of HRT, in spite of the presence of higher concentrations of estradiol and lower of gonadotropins. The above-mentioned differences were not noted during the separate analysis of women who were using HRT in which E2 110 pmol/l and a group with E25110 pmol/l. Table 3. The parameters in women with Turner syndrome treated with GH in childhood (GH+) and women not treated (GH). Both groups matched according to the age of subjects. Means ± SD. Parameters
GH+n ¼ 34
GHn ¼ 113
p Value
Age [years] Height [cm] Weight [kg] BMI [kg/m2] Systolic pressure [mmHg] Diastolic pressure [mmHg] FSH [IU/l] LH [IU/l] E2 [pmol/l] Cholesterol [mmol/l] HDL [mmol/l] LDL [mmol/l] TG [g/l] Glucose [mmol/l]
21.7 ± 4.6 147.2 ± 7.7 49 ± 8.7 22.6 ± 3.7 118 ± 17 79 ± 10 48 ± 26.8 26 ± 16.4 147 ± 160 4.6 ± 0.9 1.4 ± 0.4 2.9 ± 0.7 0.83 ± 0.3 5.12 ± 0.67
23.6 ± 4.6 144.6 ± 6.6 49.2 ± 9.6 23.5 ± 4 119 ± 15 81 ± 11 35.7 ± 21.4 23.3 ± 18.1 117 ± 138 5 ± 1.1 1.5 ± 0.5 3.3 ± 0.9 1.13 ± 0.64 5.02 ± 0.59
NS 0.0584 NS NS NS NS 0.0066 NS NS 0.0346 NS 0.0312 0.0092 NS
NS – the lack of statistical significance. NS – the lack of statistical significance.
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Favorable differences in the lipid profile were observed in TS-women, who had been treated with GH during childhood. Although they had similar concentrations of estradiol, TS-women who were treated with GH in childhood had higher levels of gonadotropins.
Discussion Our study population of TS women had a pro-atherogenic phenotype, which has been widely described by other authors [2,14]. Some studies have shown that monosomy 45,X [15] and the paternal X chromosome are the factors associated with higher atherogenicity [16,17]. We compared the subjects with 45,X monosomy to those displaying other karyotypes and did not observe any differences in the lipids parameters. The impact of estrogens on metabolism of lipids is well established. Estrogens diminish lipids oxidation and increase the synthesis of triglycerides. Changes in the content of serum lipids explain the increase in HDL levels and the slight decrease in LDL and TC levels. The TG concentration and the storage of lipids also increase [7]. In a high percentage of women, the non-use or insufficient use of HRT aggravates the risk of atheromatosis. HRT is known to prevent type 2 diabetes in menopausal women. However, this beneficial influence does not protect against cardiovascular diseases [18]. The benefit of HRT on the lipid balance in TS-women was noted. The favorable effects of HRT on the lipid profile in TSwomen were previously described by Ostberg [19] who noted that the increase in HDL level and decrease in glucose concentration did not change the TC level. However, there are reports that suggest that HRT does not have any beneficial impact on lipid balance [20]. In our study, we did not observe any differences in lipid metabolism parameters in women who use HRT compared to those who do not. The timing, duration and compliance with HRT treatment among the HRT-treated subjects were sometimes difficult to establish. Nevertheless, our finding that HRT-treated TS-women with estradiol concentrations either above or below 110 pmol/l had no differences in lipid parameters supports the hypothesis that HRT does not have a beneficial impact on the lipids. However, we cannot exclude that HRT has a positive effect on carbohydrate metabolism, which is suggested by the decreasing trend in glucose concentration. GH influences carbohydrate metabolism when in excess, decreases the use of carbohydrates, and hinders the uptake of glucose by cells. This GH-induced insulin resistance seems to be caused by impaired post-receptor insulin activity, which ultimately leads to secondary hyperinsulinism [21]. Women with TS display higher insulin resistance, which is a karyotype-dependent factor [22]. Insulin resistance is also an early metabolic defect in girls with TS. The application of GH has become a standard in treating young girls with Turner syndrome, despite certain metabolic side effects. The treatment with GH causes a loss in insulin sensitivity, which returns to pre-therapy levels when treatment is stopped [23]. We found evidence in the literature showing that the levels of insulin resistance remain for several years after finishing the therapy with GH, but the b-cell activity and the fasting insulin concentrations are higher than before the onset of treatment. In addition, changes in lipid metabolism were observed. TC and HDL levels were higher at 6 months after ending therapy than immediately after its cessation. The authors concluded that GH has a positive impact on the lipid profile in TS-women. Five years after the end of GH therapy, the beneficial influence of this hormone was still visible [10]. In addition, Wooten and Bondy have reported that young girls with TS aged 13.6 ± 3.7 yr with prior GH treatment have less abdominal fat and better lipid profile compared to untreated patients [24].
Gynecol Endocrinol, 2014; 30(3): 250–253
From the group of 165 TS-women, we evaluated those who had been treated with GH during childhood. The selection of a group in which a large percentage of women were not treated with GH was possible because we began our observation in 1995 and included women who were adults at the time. If we assume that GH therapy was standardized in Poland around 1990, it becomes obvious why some of them were never treated with GH. We do not have any data regarding the duration for which these subjects had undergone treatment, although we can assume that it must have ended by the age of 16 at the latest. The treatment with GH during childhood was as per doctors’ orders. The mean age in this group [GH(+)] was 21.7 yr, so the time that had passed since the therapy had ended was at least 5 years. We sought to compare this group with the other TS-women. Subjects were age matched for comparison. The percentage of women who used HRT and displayed 45,X monosomy were comparable in both the GH(+) and GH() groups. We noted a beneficial lipid profile in the GH(+) women. Therefore, we conclude that the effect of GH treatment on the lipid profile is relevant, and not only visible, which was stated by Bannink et al. [10], whereas the negative impact on the glucose metabolism was not observed. In addition, we observed significantly higher concentrations of gonadotropins in the GH(+) group, which suggests that their demand on HRT is higher. The results of the correlation analysis indicate a positive correlation between E2 and glucose concentrations, which is well known. The negative correlation between the E2 concentration and body mass as well as between E2 and diastolic blood pressure in TS-women with an E2 concentration 110 pmol/l indicates a beneficial effect of estradiol on the above-mentioned parameters. However, estradiol does not influence the lipid metabolism parameters in TS-women.
Conclusions (1) The application of HRT in women with Turner syndrome does not affect the lipid metabolism. (2) The use of GH in TS-children favorably influences their lipid profile in adulthood.
Declaration of interest The authors report no declarations of interest.
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