Turner syndrome (TS), primarily characterized by premature ovarian insufficiency, is a disease resulting from a complete or partial absence of the second X chromosome. This study aims to describe the prevalence of metabolic comorbidities in TS patients of different ages and karyotypes.
MethodsThe medical history, diagnosis, physical examination, laboratory examination and imaging examination data of 145 TS patients were obtained from the medical files.
Results(1) In total, 4.1% of the TS patients in this cohort were diagnosed with hypertension, and elderly patients had higher blood pressure. (2) 6.9% of patients were diagnosed with diabetes, and monosomic TS had a lower TyG index. (3) The prevalence of dyslipidemia and fatty liver was 20.0% and 16.7% respectively. TS patients treated with recombinant human growth hormone (rhGH) had significantly higher LDL-C and Apo-A1 levels. (4) The prevalence of hyperuricemia was 27.6%, and higher uric acid levels were observed in young patients and those receiving rhGH treatment. A total of 17.2% of patients were diagnosed with liver dysfunction. (5) The prevalence of low bone mass, which was higher in elderly patients and those without rhGH treatment, was 53.8% in TS patients older than 19 years.
ConclusionsTS patients have a higher prevalence of metabolic comorbidities, including dyslipidemia, fatty liver, hyperuricemia, liver dysfunction and low bone mass. RhGH treatment in childhood had some positive effects on glucose, lipid and bone metabolism in young adulthood. Therefore, additional attention should be given to metabolic comorbidities in TS patients at high risk.
El síndrome de Turner (TS), caracterizado principalmente por insuficiencia ovárica prematura, es una enfermedad resultante de la ausencia completa o parcial del segundo cromosoma X. Este estudio tiene como objetivo describir la prevalencia de comorbilidades metabólicas en pacientes con TS de diferentes edades y cariotipos.
MétodosSe obtuvieron los antecedentes médicos, los diagnósticos, los datos del examen físico, las pruebas de laboratorio y los estudios de imagen de 145 pacientes con TS a partir de sus expedientes clínicos.
Resultados(1) En total, el 4,1% de los pacientes con TS en esta cohorte fueron diagnosticados con hipertensión, y los pacientes de mayor edad presentaron una presión arterial más elevada. (2) El 6,9% de los pacientes fueron diagnosticados con diabetes, y los pacientes con TS monosómica presentaron un índice TyG más bajo. (3) La prevalencia de dislipidemia y enfermedad hepática grasa fue del 20,0 y 16,7%, respectivamente. Los pacientes con TS tratados con hormona de crecimiento humana recombinante (rhGH) mostraron niveles significativamente más altos de c-LDL y Apo-A1. (4) La prevalencia de hiperuricemia fue del 27,6%, observándose niveles más elevados de ácido úrico en pacientes jóvenes y en aquellos que recibieron tratamiento con rhGH. En total, el 17,2% de los pacientes fueron diagnosticados con disfunción hepática. (5) La prevalencia de masa ósea baja fue del 53,8% en pacientes con TS mayores de 19 años, siendo mayor en los pacientes de edad avanzada y en aquellos que no recibieron tratamiento con rhGH.
ConclusionesLos pacientes con TS presentan una mayor prevalencia de comorbilidades metabólicas, incluidas dislipidemia, enfermedad hepática grasa, hiperuricemia, disfunción hepática y baja masa ósea. El tratamiento con rhGH durante la infancia tuvo ciertos efectos positivos sobre el metabolismo de la glucosa, los lípidos y los huesos en la adultez joven. Por lo tanto, se debe prestar especial atención a las comorbilidades metabólicas en pacientes con TS de alto riesgo.
Turner syndrome (TS), primarily characterized by premature ovarian insufficiency, is a sex chromosome abnormality defined by the presence of one X chromosome and complete or partial absence of the second X chromosome, with an estimated prevalence of 25–50 per 100,000 female live births.1 Approximately half of TS patients have the most typical karyotype, 45, X, whereas the remaining TS patients have a variety of karyotypes.2
TS affects multiple organs of patients throughout their lifetime. The most prominent feature of TS is premature ovarian insufficiency, resulting in a hypo-estrogenic state with elevated follicle-stimulating hormone (FSH). Thus, for the majority of patients, hormone replacement therapy (HRT) is recommended until menopause. Another noticeable physical feature is short stature, with a mean height of 137.8–143.7cm. To improve the final height of patients, recombinant human growth hormone (rhGH) therapy is recommended, which is usually continued until bone age greater than 14.1
Estrogen and FSH are critical factors influencing metabolic health. Thus, there are growing concerns about metabolic comorbidities in TS patients, including hypertension, abnormal glucolipid metabolism, purine metabolism and bone metabolism, which may be one of the reasons for the decreased lifespan of TS patients. However, previous studies have shown very high variability in prevalence, possibly owing to huge differences in age, karyotype, rhGH treatment and race.3–5 Thus, additional information on this issue is still needed, and it is important to provide and synthesize all these data through a large cohort.
This study was one of the largest monocentric cohort studies on metabolic comorbidities of TS worldwide. We summarized the real-world data on metabolic comorbidities from 145 TS inpatients to describe the common metabolic comorbidities of TS patients throughout their lifetime.
Patients and methodsPatientsA total of 145 TS patients from the Department of Endocrinology in Peking Union Medical College Hospital (PUMCH) were included. Therein, 65 patients with monosomy (45, X) were divided into the Monosomic TS Group, and other 80 TS patients with all other karyotypes were divided into Other TS Group.1
When discussing the differences in metabolic features as they aged, 145 patients were divided into three groups: 15–19, 20–29 and 30–50 years old. When discussing the effects of rhGH on metabolic features, 145 patients were divided into a Non-rhGH Group and a RhGH Group.
All the subjects in this study met the inclusion criteria1: age was greater than or equal to 15 years, so rhGH therapy had been stopped for more than 1 year; and2 genetic diagnosis of TS was confirmed by karyotyping.1 The study protocol (I-22PJ192) was approved by the Ethics Committees of PUMCH.
Data collectionMedical history, diagnostic, physical examination, laboratory examination and imaging examination data were obtained from the medical files in digital medical records system of PUMCH. All TS inpatients who met the above inclusion criteria were included without any selection bias. In cases where a patient had multiple hospitalizations, only the most recent admission record was considered, ensuring that each individual was included only once.
Physical, laboratory and imaging examinationThe physical examination included body mass index (BMI) and blood pressure. BMI was calculated as BMI=weight (kg)/height (m)2. Laboratory examinations included serum insulin-like growth factor-1 (IGF-1), thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), FSH, luteinizing hormone (LH), fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (LDL-C), apolipoprotein a1 (APO-A1), apolipoprotein b (APO-B), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), direct bilirubin (DBil), total bilirubin (TBil), creatinine, urea and uric acid. The triglyceride glucose (TyG) index was calculated as TyG=ln [TG (mg/dl)*FBG (mg/dl)/2]. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry; the results included the femoral neck (FN), total hip, 2nd to 4th lumbar spine (L2–L4) and 1st to 4th lumbar spine (L1–L4). A liver assessment was performed using liver ultrasound.
Diagnoses of comorbiditiesThe diagnoses of metabolic syndrome, hypertension, diabetes/prediabetes and hyperlipemia were made according to the appropriate guidelines.6–15 Hypertension was defined according to the guidelines of World Health Organization (WHO) and International Society of Hypertension: either SBP ≥140mmHg and/or DBP ≥90mmHg in adults or either SBP and/or DBP ≥95th percentile in patients aged 15–18 years.6–8 Diabetes and prediabetes were diagnosed according to the guideline of WHO and Chinese Diabetes Society: FBG levels were defined as follows: normal, less than 6.1mmol/L; impaired fasting glucose (IFG), 6.1–7.0mmol/L; and diabetes, greater than or equal to 7.0mmol/L. Two-hour postprandial glucose levels were defined as follows: normal, less than 7.8mmol/L; impaired glucose tolerance (IGT), 7.8–11.0mmol/L; and diabetes, above or equal to 11.0mmol/L.14,15 Hyperlipemia was defined according to guideline of Chinese Medical Association: TC >5.2mmol/L, LDL-C >3.4mmol/L, HDL-C <1.0mmol/L or TG >1.7mmol/L.9–11 The diagnosis of metabolic syndrome was made according to the Chinese Society of Diabetology and the Chinese Society of Pediatrics.12,13 The adults with three or more following metabolic abnormalities were defined as metabolic syndrome: (1) BMI ≥25.0kg/m2; (2) either SBP ≥140mmHg and/or DBP ≥90mmHg; (3) either FPG ≥6.1mmol/L and/or 2-h postprandial glucose levels ≥7.8mmol/L; (4) either TG ≥1.7mmol/L and/or HDL-C <0.9mmol/L in men or <1.0mmol/L in women. For patients aged 15–18 years, metabolic syndrome was defined as a satisfying waist circumference ≥90th percentile and meeting any two of the remaining four criteria: (1) FPG ≥6.1mmol/L and/or 2-h postprandial glucose ≥7.8mmol/L; (2) either SBP or DBP ≥95th percentile; (3) LDL-C <1.03mmol/L or non-HDL-C ≥3.76mmol/L; or (4) TG ≥1.47mmol/L. A diagnosis of fatty liver was made by ultrasound. Low bone mass was defined as a Z value less than or equal to −2.0 in patients aged 19–50 years compared with a Chinese nationwide BMD database.16,17 The proportion of low bone mass was not calculated in patients aged less than 19 years because of the lack of BMD reference values.
The diagnosis of complications refers to International Classification of Diseases-10. Ear diseases included otitis media and conductive hearing loss. The thyroid diseases included chronic thyroiditis and subclinical hypothyroidism. Cardiac diseases, including noncompaction cardiomyopathy, mitral valve prolapse, mitral valve redundancy, mitral regurgitation, bicuspid aortic valve, aortic regurgitation, aortic stenosis, coarctation of the aorta, widening of the coronary sinus and pericardial effusion, were diagnosed by echocardiography. Kidney diseases were diagnosed by renal ultrasonography and included horseshoe kidney, polycystic kidney, solitary kidney, reduction in kidney volume, caliectasis, pyelectasis, separation of the renal pelvis, kidney stone, hydronephrosis and renal cysts. The spine deformities included kyphosis and scoliosis.
Statistical analysisThe data in this study are presented as the number (%) or mean±standard deviation, as appropriate. Student's t test or Welch's t test was used to compare continuous variables. The chi-square test or Fisher's exact test was used to compare categorical variables. The multivariate logistic regression model was used for the associations between metabolic comorbidities and clinical features. IBM SPSS software (version 26) was used to analyze the data. A P value ≤0.05 was considered to indicate statistical significance.
ResultsDemographic characteristicsThe cohort included 145 TS patients, as shown in Table S1; 65 (44.8%) patients had 45, X monosomy, and 80 (55.2%) patients had other karyotypes: 56 mosaicism, 14 isochromosomes (Xq), and 10 others.
The demographic characteristics of the patients in the cohort are shown in Table 1. The patients had a mean age of 22.26±7.05 years. The participants had a mean height of 150.77±8.44cm and a mean weight of 50.8±9.36kg. Overall, 91 (62.8%) patients received rhGH treatment before 14 years old for an average period of 3.03±2.13 years, and 115 (79.3%) of those patients received HRT for an average period of 4.66±4.54 years. At their last follow-up, these patients were in a hypo-estrogenic state (estradiol: 37.89±49.95pg/ml) with considerably elevated FSH (61.30±40.34IU/L) and LH (18.36±12.91IU/L) levels. And 91 (62.8%) patients received rhGH treatment before 14 years old for an average period of 3.03±2.13 years.
Characteristics of the Turner syndrome cohort.
| All TS | Monosomic TS | Other TS | P | |
|---|---|---|---|---|
| Number of subjects | 145 | 65 | 80 | – |
| Age, years | 22.26±7.05 | 23.22±7.75 | 21.48±6.37 | 0.140 |
| Height, cm | 150.77±8.44 | 150.59±8.03 | 150.91±8.79 | 0.822 |
| Weight, kg | 50.80±9.36 | 49.61±8.78 | 51.78±9.76 | 0.168 |
| rhGH treatment, number | 91(62.8%) | 40(61.5%) | 51(63.7%) | 0.863 |
| rhGH treatment, years* | 3.03±2.13 | 3.16±2.39 | 2.92±1.92 | 0.615 |
| HRT, number | 115(79.3%) | 51(78.5%) | 64(80.0%) | 0.839 |
| HRT, years* | 4.66±4.54 | 4.82±4.46 | 4.54±4.63 | 0.747 |
| IGF-1, ng/ml | 282.09±115.89 | 283.95±90.05 | 280.54±134.69 | 0.890 |
| Estradiol, pg/ml | 37.89±49.95 | 34.19±30.54 | 40.80±61.21 | 0.098 |
| LH, IU/L | 18.36±12.91 | 17.87±12.31 | 18.75±13.43 | 0.702 |
| FSH, IU/L | 61.30±40.34 | 64.10±43.88 | 59.12±37.52 | 0.487 |
| FT3, pg/ml | 3.39±0.44 | 3.35±0.43 | 3.42±0.45 | 0.353 |
| FT4, ng/dl | 1.46±1.58 | 1.61±2.37 | 1.33±0.20 | 0.322 |
| TSH, μIU/ml | 3.89±3.58 | 3.61±2.35 | 4.11±4.30 | 0.429 |
| Ear diseases | 11(7.6%) | 5(7.7%) | 6(7.5%) | >0.999 |
| Thyroid diseases | 76(52.4%) | 38(58.5%) | 38(47.5%) | 0.189 |
| Cardiac disease | 12/57(21.1%) | 9/29(31.0%) | 3/28(10.7%) | 0.060 |
| Kidney diseases | 12/45(26.7%) | 4/17(23.5%) | 8/28(28.6%) | >0.999 |
| Spine deformities | 7(4.8%) | 2(3.1%) | 5(6.3%) | 0.460 |
The above data were presented as number (%) or mean±standard deviation. Statistical analyses were performed to compare the difference between Monosomic TS Group and Other TS Group.
Abbreviations: TS: Turner syndrome; rhGH: recombinant human growth hormone; HRT: hormone replacement therapy; IGF-1: insulin-like growth factor-1; LH: luteinizing hormone; FSH: follicle-stimulating hormone; FT3: free triiodothyronine; FT4: free thyroxine; TSH: thyroid stimulating hormone.
For most of TS patients, their FT3, FT4 and TSH levels were within the normal range, with or without thyroid replacement therapy. Thyroid diseases (52.4%) were the most common nonmetabolic comorbidities in TS patients, followed by kidney diseases (26.7%) and cardiac diseases (21.1%).
Metabolic comorbidities of TS at different agesThe metabolic comorbidities of TS at different ages are shown in Table 2. Among the 145 TS patients, 1.4% had metabolic syndrome. The prevalence of hypertension was 4.1% in this cohort, and patients aged 30–50 years had significantly higher SBP than younger patients. Approximately 9.0% of patients were diagnosed with diabetes or prediabetes; more specifically, 10 (6.9%) had diabetes, 2 (1.4%) had IFG, and 1 (0.7%) had IGT. The prevalence of diabetes slightly increased with age (5.7% vs. 7.8% vs. 8.3%), without significant difference. TS patients aged 30–50 years seemed to have higher FBG levels and TyG index than younger patients, but the difference was not significant. The prevalence of dyslipidemia and fatty liver was 20.0% and 16.7%, respectively. Specifically, the prevalence of hypertriglyceridemia, hypercholesteremia, LDL-C >3.4mmol/L and HDL-C <1.0mmol/L was 5.6%, 17.2%, 9.0% and 3.4%, respectively. There were no significant differences in BMI; TG, TC, LDL-C or LDL-C levels among the different age groups. The prevalence of hyperuricemia was 27.6%, and uric acid levels significantly decreased with age. The prevalence of hyperuricemia was 40.0% in TS patients aged 15–19 years, 21.6% in 20–29 years old, and 4.2% in 30–50 years old. The prevalence of liver dysfunction was 17.2%, and there were no significant differences in AST, ALT, GGT, TBil or DBil levels among the different age groups.
Metabolic comorbidities in TS patients in different ages.
| All ages TS | 15–19 years old | 20–29 years old | 30–50 years old | P | |
|---|---|---|---|---|---|
| Number | 145 | 70 | 51 | 24 | – |
| Age, years | 22.26±7.05 | 16.91±1.52 | 23.35±2.23 | 35.50±4.58 | – |
| Metabolic syndrome | |||||
| Metabolic syndrome | 2(1.4%) | 1(1.4%) | 1(2.0%) | 0(0%) | 0.790 |
| Blood pressure | |||||
| Hypertension | 6(4.1%) | 3(4.3%) | 2(3.9%) | 1(4.2%) | >0.999 |
| SBP, mmHg | 113.19±15.73 | 113.69±15.21 | 107.19±15.11 | 122.19±14.09 | 0.008 |
| DBP, mmHg | 73.68±10.07 | 74.92±10.27 | 70.52±10.14 | 76.25±8.63 | 0.119 |
| Glucose metabolism | |||||
| Diabetes/pre-diabetes | 13(9.0%) | 6(8.6%) | 5(9.8%) | 2(8.3%) | >0.999 |
| Diabetes | 10(6.9%) | 4(5.7%) | 4(7.8%) | 2(8.3%) | 0.860 |
| Impaired fasting glucose | 2(1.4%) | 1(1.4%) | 1(2.0%) | 0(0%) | 0.793 |
| Impaired glucose tolerance | 1(0.7%) | 1(1.4%) | 0(0%) | 0(0%) | 0.583 |
| FBG, mmol/L | 5.14±1.63 | 4.96±1.14 | 5.18±1.72 | 5.60±2.43 | 0.278 |
| TyG index | 8.14±0.55 | 8.14±0.49 | 8.06±0.63 | 8.32±0.53 | 0.250 |
| Lipid metabolism | |||||
| Hyperlipidemias | 29(20.0%) | 12(17.1%) | 9(17.6%) | 8(33.3%) | 0.163 |
| Hypertriglyceridemia | 8(5.6%) | 3(4.3%) | 3(5.9%) | 2(8.3%) | 0.748 |
| Hypercholesteremia | 25(17.2%) | 10(14.3%) | 8(15.7%) | 7(29.2%) | 0.234 |
| LDL-C >3.4mmol/L | 13(9.0%) | 6(8.6%) | 4(7.8%) | 3(12.5%) | 0.795 |
| HDL-C <1.0mmol/L | 5(3.4%) | 2(2.9%) | 1(2.0%) | 2(8.3%) | 0.344 |
| Fatty liver | 6/36(16.7%) | 4/14(28.6%) | 2/11(18.2%) | 0/11(0%) | 0.108 |
| BMI, kg/m2 | 22.35±3.95 | 22.94±4.38 | 21.54±3.48 | 22.38±3.39 | 0.159 |
| TC, mmol/L | 4.60±0.82 | 4.58±0.79 | 4.53±0.75 | 4.80±1.05 | 0.477 |
| TG, mmol/L | 0.96±0.46 | 0.96±0.42 | 0.91±0.49 | 1.07±0.47 | 0.453 |
| HDL-C, mmol/L | 1.55±0.36 | 1.55±0.40 | 1.54±0.33 | 1.57±0.30 | 0.963 |
| LDL-C, mmol/L | 2.54±0.71 | 2.51±0.67 | 2.48±0.72 | 2.74±0.81 | 0.376 |
| Apo-A1, g/L | 1.50±0.33 | 1.40±0.27 | 1.54±0.36 | 1.56±0.33 | 0.358 |
| Apo-B, g/L | 0.82±0.22 | 0.84±0.22 | 0.81±0.20 | 0.82±0.25 | 0.933 |
| Purine metabolism | |||||
| Hyperuricemia | 40(27.6%) | 28(40.0%) | 11(21.6%) | 1(4.2%) | 0.002 |
| uric acid, μmol/L | 311.94±88.50 | 343.88±83.29 | 294.10±80.61 | 250.89±82.57 | <0.001 |
| Liver function | |||||
| Liver dysfunction | 25(17.2%) | 13(18.6%) | 7(13.7%) | 5(20.8%) | 1.000 |
| ALT, U/L | 23.24±17.93 | 25.95±22.75 | 20.63±10.78 | 21.25±13.84 | 0.235 |
| AST, U/L | 26.88±18.03 | 30.50±24.67 | 24.11±7.36 | 22.95±8.44 | 0.136 |
| GGT, U/L | 37.75±44.89 | 38.43±49.32 | 32.73±33.05 | 46.28±54.24 | 0.575 |
| TBil, μmol/L | 10.81±4.29 | 11.06±5.03 | 10.10±3.26 | 11.64±3.91 | 0.294 |
| DBil, μmol/L | 3.30±1.62 | 3.48±1.89 | 3.04±1.06 | 3.34±1.75 | 0.343 |
| Renal function | |||||
| Creatinine, μmol/L | 55.16±10.21 | 55.15±10.13 | 54.72±10.80 | 56.09±9.47 | 0.866 |
| Urea, mmol/L | 3.92±1.31 | 3.67±1.10 | 4.12±1.39 | 4.20±1.62 | 0.104 |
| Bone metabolism | |||||
| Number | 85 | 33 | 35 | 17 | – |
| Low bone mass | 8/52(53.8%) | N/A | 14(40.0%) | 14(82.4%) | 0.001 |
| FN BMD, g/cm2 | 0.78±0.12 | 0.78±0.12 | 0.78±0.12 | 0.76±0.11 | 0.745 |
| Hip BMD, g/cm2 | 0.78±0.11 | 0.80±0.11 | 0.76±0.11 | 0.79±0.09 | 0.377 |
| L1–L4 BMD, g/cm2 | 0.91±0.12 | 0.90±0.10 | 0.92±0.14 | 0.91±0.13 | 0.898 |
| L2–L4 BMD, g/cm2 | 0.91±0.13 | 0.90±0.13 | 0.92±0.14 | 0.92±0.13 | 0.822 |
| FN Z-score | −1.00±0.91 | N/A | −0.95±0.90 | −1.06±0.97 | 0.687 |
| Hip Z-score | −1.34±0.80 | N/A | −1.36±0.82 | −1.24±0.80 | 0.650 |
| L1–L4 Z-score | −1.27±0.94 | N/A | −1.13±0.91 | −1.49±1.00 | 0.235 |
| L2–L4 Z-score | −1.36±0.96 | N/A | −1.29±0.98 | −1.48±0.98 | 0.529 |
The above data were presented as number (%) or mean±standard deviation. Statistical analyses were performed to compare the difference among 15–19 years old group, 20–29 years old group and 30–50 years old group. Bold font P represents P values which are statistically significant.
Abbreviations: TS: Turner syndrome; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG: fasting blood glucose; TyG: triglyceride glucose index; BMI: body mass index; TC: total cholesterol; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; APO-A1: apolipoprotein a1; APO-B: apolipoprotein b; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transpeptidase; TBil: total bilirubin; DBil: direct bilirubin; FN: femoral neck; L1: 1st lumbar vertebra; L4: 4th lumbar vertebra; L2: 2rd lumbar vertebra; N/A: not applicable; BMD: bone mineral density.
A total of 85 patients in the cohort underwent BMD assessments, and 53.8% of patients older than 19 years were diagnosed with low bone mass. The prevalence of low bone mass was 40.0% in TS patients aged 20–29 years, whereas it increased to 82.4% in 30–50 years old. The FN BMD, Hip BMD or L1-L4 BMD of TS patients remained stable from 15 to 50 years old, but the FN Z score and L1–L4 Z score were lower in TS patients aged 30–50 years than younger patients.
Metabolic comorbidities of TS patients with different karyotypesThe metabolic comorbidities of TS patients with different karyotypes are shown in Table 3. The prevalence of metabolic comorbidities was similar between the Monosomic TS Group and the Other TS Group. The prevalence of diabetes was 4.6% in the Monosomic TS Group and 8.8% in the Other TS Group, with no statistical significance. The TyG index was significantly higher in the Other TS Group (8.02±0.58 vs. 8.24±0.51). The prevalence of dyslipidemia was 15.4% in the Monosomic TS Group and 23.8% in the Other TS Group, with no statistical significance. However, in patients aged 15–19 years, the Monosomic TS Group had a lower prevalence of dyslipidemia and LDL-C and Apo-B levels than the Other TS Group. The Monosomic TS Group had a similar prevalence of liver dysfunction as the Other TS Group (16.9% vs. 17.5%), but the Monosomic TS Group had higher TBil and DBil levels. There were no significant differences in the prevalence of hyperuricemia and uric acid, creatinine and urea levels between two groups.
Metabolic comorbidities in TS patients with different karyotypes.
| All ages | 15–19 years old | 20–29 years old | 30–50 years old | |||||
|---|---|---|---|---|---|---|---|---|
| Monosomic TS | Other TS | Monosomic TS | Other TS | Monosomic TS | Other TS | Monosomic TS | Other TS | |
| Number | 65 | 80 | 26 | 44 | 27 | 24 | 12 | 12 |
| Age, years | 23.22±7.75 | 21.48±6.37 | 16.77±1.48 | 17.00±1.56 | 23.26±2.30 | 23.46±2.19 | 37.08±4.85 | 33.92±3.85 |
| Metabolic syndrome | ||||||||
| Metabolic syndrome | 0(0%) | 2(2.5%) | 0(0%) | 1(2.3%) | 0(0%) | 1(4.2%) | 0(0%) | 0(0%) |
| Blood pressure | ||||||||
| Hypertension | 3(4.6%) | 3(3.8%) | 2(7.7%) | 1(2.3%) | 1(3.7%) | 1(4.2%) | 0(0%) | 1(8.3%) |
| SBP, mmHg | 113.06±13.98 | 113.27±16.90 | 113.83±13.07 | 113.63±16.45 | 108.58±16.12 | 106.07±14.72 | 119.43±9.96 | 124.33±16.91 |
| DBP, mmHg | 72.32±9.92 | 74.56±10.17 | 73.83±9.49 | 75.46±10.79 | 69.33±12.12 | 71.47±8.55 | 74.86±5.24 | 77.33±10.77 |
| Glucose metabolism | ||||||||
| Diabetes/pre-diabetes | 4(6.2%) | 9(11.3%) | 2(7.7%) | 4(9.1%) | 1(3.7%) | 4(16.7%) | 1(8.3%) | 1(8.3%) |
| Diabetes | 3(4.6%) | 7(8.8%) | 1(3.8%) | 3(6.8%) | 1(3.7%) | 3(12.5%) | 1(8.3%) | 1(8.3%) |
| Impaired fasting glucose | 0(0%) | 2(2.5%) | 0(0%) | 1(2.3%) | 0(0%) | 1(4.2%) | 0(0%) | 0(0%) |
| impaired glucose tolerance | 1(1.5%) | 0(0%) | 1(3.8%) | 0(0%) | 0(0%) | 0(0%) | 0(0%) | 0(0%) |
| FBG, mmol/L | 5.02±1.73 | 5.24±1.54 | 4.65±0.51 | 5.15±1.37 | 5.14±1.73 | 5.23±1.75 | 5.65±3.20 | 5.56±1.72 |
| TyG index | 8.02±0.58 | 8.24±0.5# | 7.96±0.50 | 8.23±0.47 | 7.99±0.68 | 8.15±0.55 | 8.21±0.47 | 8.40±0.58 |
| Lipid metabolism | ||||||||
| Hyperlipidemias | 10(15.4%) | 19(23.8%) | 1(3.8%) | 11(25.0%)# | 6(22.2%) | 3(12.5%) | 3(25.0%) | 5(41.7%) |
| Hypertriglyceridemia | 3(4.6%) | 5(6.3%) | 1(3.8%) | 2(4.5%) | 1(3.7%) | 2(8.3%) | 1(8.3%) | 1(8.3%) |
| Hypercholesteremia | 9(13.8%) | 16(20.0%) | 1(3.8%) | 9(20.5%) | 6(22.2%) | 2(8.3%) | 2(16.7%) | 5(41.6%) |
| LDL-C >3.4mmol/L | 4(6.2%) | 9(11.3%) | 0(0%) | 6(13.6%) | 3(11.1%) | 1(4.2%) | 1(8.3%) | 2(16.7%) |
| HDL-C <1.0mmol/L | 3(4.6%) | 2(2.5%) | 1(3.8%) | 1(2.3%) | 1(3.7%) | 0(0%) | 1(8.3%) | 1(8.3%) |
| Fatty liver | 2/18(11.1%) | 4/18(22.2%) | 1/7(14.3%) | 3/7(42.9%) | 1/5(20.0%) | 1/6(16.7%) | 0/6(0%) | 0/5(0%) |
| BMI, kg/m2 | 21.84±3.49 | 22.75±4.26 | 22.36±3.98 | 23.28±4.61 | 21.49±3.25 | 21.60±3.80 | 21.55±3.01 | 23.14±3.65 |
| TC, mmol/L | 4.47±0.87 | 4.71±0.78 | 4.34±0.77 | 4.70±0.78 | 4.61±0.79 | 4.42±0.69 | 4.38±1.24 | 5.14±0.76 |
| TG, mmol/L | 0.91±0.48 | 1.00±0.44 | 0.89±0.47 | 0.99±0.40 | 0.89±0.51 | 0.94±0.48 | 1.01±0.46 | 1.12±0.50 |
| HDL-c, mmol/L | 1.55±0.37 | 1.55±0.35 | 1.61±0.44 | 1.51±0.37 | 1.49±0.31 | 1.63±0.36 | 1.58±0.38 | 1.56±0.25 |
| LDL-c, mmol/L | 2.44±0.71 | 2.62±0.71 | 2.24±0.58 | 2.64±0.68# | 2.61±0.75 | 2.27±0.64 | 2.39±0.82 | 3.02±0.71 |
| Apo-A1, g/L | 1.46±0.36 | 1.53±0.29 | 1.55±0.40 | 1.31±0.14 | 1.42±0.27 | 1.79±0.44 | 1.47±0.55 | 1.60±0.16 |
| Apo-B, g/L | 0.75±0.20 | 0.88±0.22# | 0.69±0.15 | 0.92±0.21# | 0.82±0.18 | 0.79±0.26 | 0.68±0.29 | 0.90±0.21 |
| Purine metabolism | ||||||||
| Hyperuricemia | 16(24.6%) | 24(30.0%) | 11(42.3%) | 17(38.6%) | 5(18.5%) | 6(25.0%) | 0(0%) | 1(8.3%) |
| uric acid, μmol/L | 307.88±79.34 | 315.24±95.76 | 340.17±76.98 | 346.22±87.97 | 301.12±70.53 | 285.75±92.28 | 232.12±59.51 | 264.55±96.47 |
| Liver function | ||||||||
| Liver dysfunction | 11(16.9%) | 14(17.5%) | 7(26.9%) | 6(13.6%) | 3(11.1%) | 4(16.7%) | 1(8.3%) | 4(33.3%) |
| ALT, U/L | 23.03±21.94 | 23.42±13.82 | 26.50±31.86 | 25.60±14.82 | 21.74±11.67 | 19.38±9.77 | 18.42±10.72 | 24.08±16.38 |
| AST, U/L | 27.92±23.72 | 26.06±11.92 | 35.05±36.55 | 27.88±14.12 | 24.55±6.75 | 23.61±8.15 | 21.10±7.00 | 24.64±9.57 |
| GGT, U/L | 30.11±29.57 | 43.53±53.21 | 32.94±39.57 | 41.83±54.91 | 27.53±22.30 | 38.22±41.52 | 29.86±17.06 | 56.73±67.21 |
| TBil, μmol/L | 12.06±4.75 | 9.75±3.57# | 12.78±6.21 | 9.98±3.84# | 10.60±2.69 | 9.50±3.79 | 14.00±4.14 | 9.48±2.06# |
| DBil, μmol/L | 3.70±1.90 | 2.97±1.27# | 4.18±2.37 | 3.06±1.40# | 3.05±0.93 | 3.02±1.20 | 4.15±2.10 | 2.60±0.93# |
| Renal function | ||||||||
| Creatinine, μmol/L | 55.94±9.15 | 54.50±11.03 | 55.96±8.41 | 54.64±11.13 | 55.30±9.24 | 54.08±12.50 | 57.35±11.01 | 54.83±7.93 |
| Urea, mmol/L | 4.04±1.30 | 3.82±1.32 | 3.72±1.17 | 3.64±1.06 | 4.27±1.01 | 3.95±1.73 | 4.22±2.10 | 4.18±1.17 |
| Bone metabolism | ||||||||
| Number | 38 | 47 | 11 | 22 | 19 | 16 | 8 | 9 |
| Low bone mass | 14/27(51.9%) | 14/25(56.0%) | N/A | N/A | 7(36.8%) | 7(43.8%) | 7(87.5%) | 7(77.8%) |
| FN BMD, g/cm2 | 0.77±0.12 | 0.78±0.12 | 0.78±0.13 | 0.79±0.12 | 0.79±0.11 | 0.78±0.14 | 0.72±0.12 | 0.79±0.11 |
| Hip BMD, g/cm2 | 0.77±0.10 | 0.79±0.12 | 0.78±0.10 | 0.80±0.12 | 0.76±0.10 | 0.76±0.13 | 0.77±0.11 | 0.81±0.06 |
| L1–L4 BMD, g/cm2 | 0.91±0.12 | 0.91±0.12 | 0.90±0.11 | 0.91±0.10 | 0.92±0.11 | 0.91±0.18 | 0.89±0.18 | 0.92±0.07 |
| L2–L4 BMD, g/cm2 | 0.92±0.13 | 0.91±0.14 | 0.90±0.12 | 0.91±0.13 | 0.93±0.11 | 0.91±0.17 | 0.91±0.18 | 0.94±0.07 |
| FN Z-score | −0.96±0.92 | −1.05±0.92 | N/A | N/A | −0.80±0.91 | −1.14±0.90 | −1.23±1.00 | −0.92±0.98 |
| Hip Z-score | −1.31±0.83 | −1.37±0.78 | N/A | N/A | −1.24±0.80 | −1.53±0.85 | −1.40±1.03 | −1.13±0.63 |
| L1–L4 Z-score | −1.25±0.96 | −1.31±0.93 | N/A | N/A | −1.14±0.75 | −1.13±1.17 | −1.47±1.37 | −1.51±0.57 |
| L2–L4 Z-score | −1.30±0.95 | −1.43±0.99 | N/A | N/A | −1.21±0.77 | −1.40±1.24 | −1.50±1.33 | −1.46±0.60 |
The above data were presented as number (%) or mean±standard deviation.
Bold font value and # represents P<0.05 between Monosomic TS Group and Other TS Group.
Abbreviations: TS: Turner syndrome; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG: fasting blood glucose; TyG: triglyceride glucose index; BMI: body mass index; TC: total cholesterol; TG: triglyceride; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; APO-A1: apolipoprotein a1; APO-B: apolipoprotein b; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transpeptidase; TBil: total bilirubin; DBil: direct bilirubin; FN: femoral neck; L1: 1st lumbar vertebra; L4: 4th lumbar vertebra; L2: 2rd lumbar vertebra; N/A: not applicable; BMD: bone mineral density.
A total of 38 patients in the Monosomic TS Group and 47 in the Other TS Group underwent BMD assessments. The prevalence of low bone mass in TS patients older than 19 years was similar between the two groups (51.9% vs. 56.0%). Moreover, there was also no significant difference in the BMD or Z score of the FN, Hip or L1-L4 between the two groups.
Metabolic comorbidities of TS patients with or without rhGH treatmentA total of 91 patients received rhGH treatment, and 54 patients did not; their metabolic features are shown in Table S2. Approximately 4.4% of patients in RhGH Group were diagnosed with diabetes, lower than 11.1% in Non-rhGH Group. For patients aged 15–19 years, the prevalence of diabetes in RhGH Group was lower than Non-rhGH Group (1.9% vs. 18.8%). Regarding lipid metabolism, TS patients in RhGH Group had significantly higher HDL-C (1.44±0.31 vs. 1.61±0.37mmol/L) and Apo-A1 (1.40±0.30 vs. 1.59±0.33g/L) levels than those in Non-rhGH Group. Slightly lower BMI, TG, LDL-C, Apo-B levels and higher TC levels were also observed in the RhGH Group, but these differences were not statistically significant. Moreover, the patients in the RhGH Group had a higher prevalence of hyperuricemia (36.3% vs. 13.0%) and higher uric acid levels (325.48±86.70 vs. 284.52±86.74mol/L) than those in the Non-rhGH Group.
A total of 53 patients in the RhGH Group and 32 in the Non-rhGH Group underwent BMD assessments. The prevalence of low bone mass in TS patients older than 19 years was significantly lower in the RhGH Group (39.3% vs. 70.8%). The FN Z scores were significantly higher in the RhGH Group (−1.42±0.84 vs. −0.65±0.83). Moreover, higher Hip Z scores, L1–L4 Z scores and L2–L4 Z scores were also observed in the RhGH Group, but the differences were not statistically significant.
The associations between metabolic comorbidities and clinical featuresAs shown in Table S3, the multivariate logistic regression model showed that age, karyotype, BMI, FBG, blood pressure, rhGH treatment and HRT were not independent factors for dyslipidemia, fatty liver and liver dysfunction. The independent factors for hyperuricemia were age and hypertension, and for low bone mass were age and HRT.
DiscussionTS patients in this cohort typically exhibit a hormonal pattern of hypergonadotropic hypogonadism. This real-world cohort study highlighted the significant effect of estrogen and X chromosome haploinsufficiency on glucose, lipid, and bone metabolism in female. In this young cohort with an average age of 22 years, a total of 4.1% of the TS patients were diagnosed with hypertension, 6.9% with diabetes, 20.0% with dyslipidemia, and 27.6% with hyperuricemia, indicating the severity of metabolic issues in the TS population. The prevalence of fatty liver and liver dysfunction were 16.7% and 17.2%, highlighting the need for greater attention to liver health. Bone metabolism was even more concerning, with more than half of the patients diagnosed with low bone mass, which was even higher in elderly TS patients and those without rhGH treatment.
Metabolic syndrome is characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. The prevalence of metabolic syndrome was 1.4% in these Chinese TS patients, which was lower than anticipated, likely influenced by the relatively young age (22.26±7.05 years) of this cohort. Estrogen is recognized for its role in regulating glucose homeostasis, primarily affecting the liver and muscle.18 In our real-world cohort, the prevalence of diabetes was 6.9%, which was lower than the 16%–78% previously reported,5,19 possibly also due to the young age. Previous epidemiological studies revealed that TS patients have an approximately 10-fold increase in type 1 diabetes prevalence and an approximately 4-fold increase in type 2 diabetes incidence.1 Reduced beta-cell function and decreased insulin secretion in TS patients may be plausible explanations for the high risk of diabetes or prediabetes.19 Nevertheless, for TS patients prone to metabolic risks, adopting a healthy lifestyle throughout their lifespan, regularly monitoring metabolic indicators and preventing multiple metabolic abnormalities remain crucial.20,21 Moreover, in our cohort, the prevalence of diabetes slightly increased with age from 5.7% to 7.8% and then to 8.3%, indicating the need for increased attention given to middle-aged and elderly patients (over 30 years old). TS patients aged 30–50 years had a slightly increased TyG index, which means that they had higher insulin resistance than younger patients, another factor contributing to their elevated risk of developing diabetes or prediabetes. Additionally, a higher TyG index is associated with a higher risk of cardiovascular events, which calls for additional attention from physicians and patients. The prevalence of diabetes in the TS of the RhGH Group seemed lower than that in Non-rhGH Group, especially in young patients (15–19 years old), highlighting the importance of rhGH in childhood.
The prevalence of dyslipidemia and fatty liver was 20.0% and 16.7%, respectively. Obesity, insulin resistance, and low estrogen levels, which are common in TS patients, have recently been recognized as important contributors to fatty liver.22,23 Additionally, TS patients in our cohort showed a higher TC, TG, LDL-C and lower HDL-C. In this cohort, approximately 9.0% of patients had a LDL-C level higher than 3.4mmol/L. Recent studies have confirmed that the retention of LDL-C and Apo-B containing lipoproteins within the arterial wall is the critical initiating event in the process of atherogenesis, and cardiovascular risk decreases following an increase in the absolute LDL-C concentration.24,25 Thus, individualized management of dyslipidemia based on total cardiovascular risk assessment is crucial for each TS patient. Previous studies have shown that rhGH therapy has a positive effect on body fat and abnormal glycolipid profiles in TS children. In our cohort, approximately 63% of TS patients received rhGH therapy before 14 years of age, and those without rhGH had a worse lipid profile, as indicated by significantly lower LDL-C and Apo-A1 levels and slightly higher TC and LDL-C levels. Therefore, abnormal lipid metabolism in TS patients could be improved by rhGH treatment, which demonstrated a significant benefit in improving the linear growth of TS patients during rhGH treatment.
The prevalence of liver dysfunction was 17.2% in TS patients. In addition to HRT, metabolic mechanisms and autoimmune pathogenesis are recognized as the main causes of liver dysfunction.26 Thus, HRT should not be interrupted in patients with TS with liver dysfunction.22,26 Regular screening of liver function in TS patients is needed during follow-up.22 The majority of the TS patients in our cohort had normal renal function, and 27.6% of them had hyperuricemia. Uricosuric effects of estrogen and progestogen treatment had been proved in previous studies, and these TS patients show hypergonadotropic hypogonadism but inadequate HRT in their adulthood, which might be a very important reason for their high prevalence of hyperuricemia, highlighting the potential benefit of HRT.27,28 This study revealed that the TS patients in the RhGH Group had a higher prevalence of hyperuricemia and higher uric acid levels. Previous study also found TS children exhibited a gradual increase in uric acid levels after rhGH treatment, which was related to the first year of stanozolol treatment.29 Moreover, the age and blood pressure were found as the independent risk factors for hyperuricemia, and besides, previous study have identified BMISDS, HOMA-IR, glucose, and eGFR as other factors.29 Overall, regular screening of uric acid is needed for early detection and treatment, especially for individuals who receive rhGH or androgen, and who do not receive HRT. Low bone mass is a common comorbidity in TS patients. In our real-world cohort, 87 TS patients underwent BMD assessment using dual-energy X-ray absorptiometry. Among the patients older than 19 years, 53.8% were diagnosed with low bone mass, which is higher than the 23.8%–27.9% reported in a previous study.5,30 Many factors, including low estrogen levels, high FSH levels, overweight status, and obesity, might affect BMD.31 In this study, we identified the age and HRT (estrogen and FSH levels) as the independent factors for low bone mass. In the healthy female population, BMD decreases with age after reaching peak BMD values.16 The main cause of higher prevalence of low bone mass in TS patients should be low estrogen levels and high FSH levels.31 We found that the BMD Z score was lower in TS patients aged 30-50 years, and the BMD in TS patients did not increase as in healthy females before reaching peak BMD values, possibly due to low estrogen levels and inadequate HRT (4.66±4.54 years). Inadequate HRT might also explain why our cohort had a younger mean age (22.3 vs. 37.7 years) but a higher prevalence of low bone mass than the Canadian cohort (53.8% vs. 27.9%).30 Population databases showed that the prevalence of fractures increased approximately 1.35-fold to 2.16-fold compared with that in healthy females.3,32 The common causes included low bone mass, selective thin cortical bone, hearing impairment and imbalanced bone remodeling.33–35 Notably, the efficacy of HRT in reducing fracture risk was confirmed previously. Therefore, screening of BMD and improving compliance with HRT are needed, especially for TS patients at high risk of fracture. Furthermore, rhGH therapy may be another factor. The patients in the RhGH Group had a lower prevalence of low bone mass and higher FN BMD and FN Z score than those in the Non-rhGH Group. However, in our cohort, only 63% of patients received rhGH treatment for an average of 3 years. In summary, our data highlight the importance of adequate rhGH and HRT treatment for TS patients.
To the best of our knowledge, this study was one of the largest monocentric cohort studies on metabolic comorbidities of TS, highlighting the significance of rhGH treatment in TS children by demonstrating the beneficial effects of rhGH treatment on glucolipid and bone metabolism. Also, there are several limitations. This was a retrospective cohort study, so some missing data could not be assessed. For instance, waist circumferences were not recorded in some patients. And only half of the patients in our cohort underwent a BMD assessment, and those with a higher risk of low bone mass might be more willing to undergo screening, which might lead to an overestimation of the prevalence of low bone mass. Besides, TS is a disease with considerable heterogeneity. This study provides a general description based only on karyotype or age. Notably, there are significant individual variations among patients even within the same group. Third, we did not establish a healthy control group in this study. Compared with the normal reference range, the use of these data in healthy people might lead to an underestimation of the severity of metabolic comorbidities in TS patients. Additionally, over the lengthy study period, several features of metabolic comorbidities might have changed.
In conclusion, TS patients exhibit a typically hormonal pattern of hypergonadotropic hypogonadism, and have a higher prevalence of metabolic comorbidities, including dyslipidemia, fatty liver, hyperuricemia, liver dysfunction and low bone mass. RhGH treatment in childhood had some positive effects on glucose, lipid and bone metabolism in young adulthood. Therefore, additional attention should be given to metabolic comorbidities in TS patients, especially in those at high risk.
CRediT authorship contribution statementAll authors contributed to the study conception and design. Material preparation and data collection were performed by Shan Xiao, Zhibo Zhou and Xiaoyuan Guo. Data analyses were performed by Shan Xiao and Yiling He. The first draft of the manuscript was written by Zhibo Zhou. Shi Chen, Hongbo Yang, Hui Pan and Huijuan Zhu commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Ethical considerationsThe study protocol (I-22PJ192) was approved by the Ethics Committees of Peking Union Medical College Hospital.
FundingThis work was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0506800), STI2030—MajorProjects2021ZD0200500, the National High Level Hospital Clinical Research Funding under Grant (2022-PUMCH-A-249 and 2022-PUMCH-B-016) and National Key Clinical Specialty Capacity Improvement Project.
Conflict of interestThe authors of this manuscript declare that they have no conflict of interest.
We extend special thanks to Dr. Yuelun Zhang from Peking Union Medical College Hospital for his generous and expert assistance in the methodologies and statistics of this study.
The following are the supplementary data to this article:
