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The association of testosterone sex hormone


J Bone Miner Metab DOI 10.1007/s00774-016-0803-6

ORIGINAL ARTICLE

The association of?testosterone, sex hormone?binding globulin, and?insulin?like growth factor?1 with?bone parameters in?Korean men aged 50?years or older
Hye?Jung?Kim1?· Hyung?Suk?Koo2?· Young?Sang?Kim3? ?· Moon?Jong?Kim3?· Kwang?Min?Kim4?· Nam?Seok?Joo4?· Ji?hee?Haam3?

Received: 28 July 2016 / Accepted: 31 October 2016 ? The Japanese Society for Bone and Mineral Research and Springer Japan 2016

Abstract? Testosterone and insulin-like growth factor-1 (IGF-1) are essential factors for the maintenance of bone health in men. However, the results for the association of testosterone and IGF-1 with bone parameters were not consistent in prior studies. We evaluated the relationship of testosterone, sex hormone-binding globulin (SHBG), and IGF-1 with bone mineral density (BMD) and bone turnover markers (BTMs) in Korean men. We enrolled 1227 men aged ≥50?years in this cross-sectional study. Serum levels of total testosterone (TT), SHBG, IGF-1, osteocalcin, and C-terminal cross-linking telopeptide of type I collagen (CTX) were measured. Free testosterone (FT) was calculated using Vermeulen’s method. BMD was measured by dual-energy X-ray absorptiometry. TT level was not related to BMD or BTMs in the unadjusted model; however, after adjusting for SHBG and IGF-1, the association between TT and BTMs was significant (β? =? ?0.139 for osteocalcin and β? =? ?0.204 for CTX). SHBG levels were negatively associated with lumbar BMD, and positively associated with BTMs in all models. As SHBG level increased, the prevalence of osteopenia or osteoporosis defined by BMD significantly increased (OR of 1SD change, 1.24). IGF-1 levels were significantly related
* Young?Sang Kim zeroup@cha.ac.kr
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with BMD, but not with BTMs. Meanwhile, FT levels were positively associated with BMD and negatively associated with BTMs. In conclusion, SHBG levels were independently related with bone parameters and osteopenia in men aged ≥50?years. IGF-1 levels were positively associated with BMD, but not with BTMs. SHBG may play a role in regulating age-related bone loss in men after middle-age. Keywords? Insulin-like growth factor-1?· Testosterone?· Sex hormone-binding globulin?· Bone mineral density?· Biochemical markers of bone turnover

Introduction
Growth hormone (GH) and sex steroids play major roles in bone growth and development in childhood and adolescence [1]. These hormones are also essential for the maintenance of bone health in male adults. Adult GH deficiency causes bone loss with low bone turnover and elevates the risk of fractures [2]. In the same way, studies on men with castration or androgen deprivation therapy indicated that sex steroids deficiency causes rapid bone loss [3, 4]. Bone loss begins at 19 or 20 years of age and gradually continues to old age in Korean men [5]. The age-related change is also observed in GH/insulin-like growth factor (IGF) axis and gonad. The levels of IGF-1, the main mediator of GH, fall with age [6]. Similarly, the levels of testosterone, especially the free form, decline with age [7–9]. Therefore, various studies have investigated whether IGF-1 and testosterone are associated with age-related bone loss. In clinical studies, low IGF-1 levels were related with reduced bone mineral density (BMD) in men [10, 11]. Low level of testosterone was also associated with bone loss in other studies [12–14].



Department of?Family Medicine, Green-cross I-MED, 06647?Seoul, South Korea Department of?Family Medicine, Dongguk University Bundang Oriental Hospital, 13601?Seongnam, South Korea Department of?Family Medicine, CHA Bundang Medical Centre, CHA University, 59 Yatap?ro, Bundang?gu, 13496?Seongnam?Si, Gyeonggi?do, South Korea Department of?Family Practice and?Community Health, School of?Medicine, Ajou University, 16499?Suwon, South Korea

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J Bone Miner Metab

Recently, the relationship between testosterone and bone metabolism was contradicted by some studies [15–17]. The European Male Ageing Study (EMAS) reported that testosterone was not associated with the parameters of bone metabolism in middle-aged and elderly men [15, 17]. One of the studies showed that sex hormone-binding globulin (SHBG) and IGF-1, instead of total testosterone (TT) or free testosterone (FT), were significantly related with biochemical bone turnover markers (BTMs) [15]. Hence, the association of testosterone and IGF-1 with bone metabolism should be investigated further. The purpose of this cross-sectional study was to evaluate the relationship of testosterone, SHBG, and IGF-1 with BMD and bone turnover in Korean men aged ≥50?years.

BMD and?biochemical measurements BMD was measured in the lumbar spine (L1–L4), total hip, and femoral neck using dual-energy X-ray absorptiometry (Hologic Discovery-W; Hologic, Bedford, MA, USA). Osteoporosis was diagnosed if the T-score of the 3 sites was ?2.5 or less; and osteopenia was diagnosed if the T-score was ?1.0 or less. Fasting blood samples were drawn from the antecubital area in the morning. Serum samples were stored at 4?°C and analyzed within a day of sampling. All serum analyses were performed on a daily basis. Calcium, phosphate, glucose and lipid profiles were tested using an automatic analyzer (Hitachi 7600; Hitachi, Tokyo, Japan). All participants had normal values for serum calcium and phosphorus. Serum osteocalcin and C-terminal cross-linking telopeptide of type I collagen (CTX) were assessed as biochemical markers for bone formation and resorption, respectively. Serum osteocalcin was measured using an Elecsys N-MID Osteocalcin kit (Roche Diagnostics, Mannheim, Germany) by electrogenerated chemiluminescence with intra- and interassay coefficients of variation of 1.2–4.0 and 1.7–6.5%, respectively. Serum CTX was measured using an Elecsys β-CrossLapskit (Roche Diagnostics) by chemiluminescence immunoassay with intra- and interassay coefficients of variation of 1.2–4.7 and 1.5–5.7%, respectively. TT was measured by radioimmunoassay using Coat-a-Count? Total Testosterone kit (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA). Serum concentrations of SHBG (Roche Diagnostics), and IGF-1 (DPC, Los Angeles, CA, USA) were analyzed by electrochemiluminescent immunoassay. FT was calculated by the method described by Vermeulen et?al. based on equilibrium binding equations using the serum concentrations of TT and SHBG [18]. Statistical analysis

Materials and?methods
Study design and?study population This cross-sectional study was conducted in the Health Promotion Center of CHA Bundang Medical Center. All participants voluntarily took part in our study without any reward, and submitted informed consent. A total of 1257 men aged ≥50?years consented to participate in an agerelated module that included hormone assay, BMD and BTMs. Those who were receiving androgen therapy or osteoporosis treatment were excluded (N? =?17). In addition, those with abnormal liver, kidney, or thyroid function (N? =?8), history of stroke, angina, myocardial infarction and malignancy (N?=?13) were also excluded. Finally, 1227 men were included in our study. This study was approved by the Institutional Review Board of CHA Bundang Medical Center in Korea (BD2013-081). Measurements We collected information on medical history and lifestyle habits using a self-report questionnaire. Smoking history was categorized into non-, ex-, and current smokers. Drinking history was divided into current alcohol consumption or not. Exercise was classified into routine (moderate to strenuous intensity, ≥3 times a week) and non-routine. Height and weight were measured in a standing position without shoes and were recorded to the first decimal point in centimeters and kilograms, respectively. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. Waist circumference was measured midway between the lower rib margin and the iliac crest in a standing position. Blood pressure was measured after resting for 10?min in a sitting position using an automatic sphygmomanometer.

All analyses were conducted using SPSS 23.0 statistical analysis software (IBM, Armonk, NY, USA). For descriptive analysis, the results were expressed as a median (interquartile range) or as a number (proportion). For the parametric statistical analyses, variables showing skewed distributions were logarithmically transformed. Linear regression analyses were used to assess the relationship of testosterone and IGF-1 with BMD and BTMs in the models with and without controlling for potential confounders. After the crude model (Model 1) was set, age and BMI was adjusted in Model 2. Model 3 additionally included the variables of glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, drinking, smoking, exercise, and history of diabetes.

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J Bone Miner Metab Table?1??General characteristics of study subjects N?=?1227 Age Smoking ?Non-smoker ?Current smoker ?Ex-smoker Drinking Routine exercise Hypertension Diabetes Body mass index (kg/m2) Waist circumference (cm) Systolic BP (mmHg) Diastolic BP (mmHg) Glucose (mmol/L) Total cholesterol (mmol/L) Triglyceride (mmol/L) HDL cholesterol (mmol/L) Total testosterone (nmol/L) SHBG (nmol/L) Free testosterone (nmol/L) IGF-1 (nmol/L) Bone mineral density (g/cm2) ?Lumbar spine (L1–4) ?Total hip ?Femoral neck Osteopenia Osteoporosis Bone turnover markers ?Osteocalcin (ng/mL) ?CTX (ng/mL) 57.0 (53.0–62.0) 314 (25.6%) 410 (33.4%) 503 (41.0%) 857 (69.8%) 590 (48.1%) 402 (32.8%) 188 (15.3%) 24.5 (22.6–26.2) 86.5 (81.0–92.0) 123.0 (114.0–132.0) 77.0 (70.0–84.0) 5.55 (5.11–6.16) 5.02 (4.48–5.65) 1.37 (0.96–1.93) 1.25 (1.07–1.47) 16.10 (12.80–20.30) 44.90 (34.84–59.16) 0.27 (0.22–0.33) 20.89 (16.38–25.30) 0.986 (0.891–1.095) 0.981 (0.897–1.064) 0.766 (0.695–0.845) 517 (42.1%) 42 (3.4%) 14.71 (11.80–18.23) 0.42 (0.28–0.58) Table?2??Association of each hormonal factor with bone mineral density and bone turnover markers Model BMD LS TT ?1 ?2 ?3 SHBG ?1 ?2 ?3 IGF-1 ?1 ?2 ?3 FT ?1 ?2 ?3 TH FN BTMs OC CTX

?0.014 0.027 0.041

?0.016 0.048 0.066*

?0.030 0.029 0.044

?0.009 ?0.021 ?0.040 0.112** 0.121** 0.104** 0.003 0.006 0.013

?0.055 ?0.064* ?0.086** 0.080** 0.128** 0.098** 0.044 0.023 0.036

?0.114** ?0.147** ?0.154** ?0.081** ?0.033 ?0.039 ?0.073* ?0.014 ?0.022 0.103** 0.098** 0.084** 0.070* 0.083** 0.091** 0.149** 0.088** 0.075** 0.097** 0.076** 0.081** 0.176** 0.111** 0.099**

0.088** ?0.104** ?0.145** 0.058* ?0.112** ?0.177** 0.062*

?0.118** ?0.180**

All values represent the standardized coefficients of regression analyses. Model 1 is crude model. Model 2 additionally adjusted for the variables of age and BMI. Model 3 additionally adjusted for the variables of glucose, TC, HDL cholesterol, drinking, smoking, exercise, and history of diabetes. Single and double asterisks represent P?<?0.05 and P?<?0.01, respectively. The levels of SHBG and CTX are logarithmically transformed. Single and double asterisks represent P?<?0.05 and P?<?0.01, respectively TT total testosterone, FT free testosterone, SHBG sex hormone-binding globulin, IGF insulin-like growth factor, BMI body mass index, LS lumbar spine, BMD bone mineral density, TH total hip, FN femoral neck, OC osteocalcin, CTX C-terminal telopeptide of type I collagen, TC total cholesterol, HDL high-density lipoprotein

Data are expressed as median (interquartile range) or number (proportion) BP blood pressure, HDL high-density lipoprotein, SHBG sex hormone-binding globulin, IGF insulin-like growth factor, CTX C-terminal telopeptide of type I collagen

Results
The general characteristics of the participants are summarized in Table?1. The median age was 57?years. The median levels of TT, SHBG, FT, and IGF-1 were 16.1, 44.9, 0.27, and 20.9?nmol/L, respectively. The association between the variables and bone parameters were assessed. Age was negatively correlated with nonvertebral BMD and positively correlated with CTX. BMI was strongly associated with bone parameters (positively with BMD and negatively with BTMs). Glucose levels were negatively correlated with BTMs, and HDL cholesterol levels were negatively correlated with BMDs. FT and IGF-1 levels decreased with age (r? =? ?0.185 and ?0.265, respectively). Table?2 shows the association between each hormonal factor and bone parameters. The levels of TT were not related with BMD or BTMs in the unadjusted model (Model 1). The TT level was negatively associated

In addition, the hormones and their interaction terms were simultaneously included in regression models. First, regression models included TT, SHBG, IGF-1, and the interaction terms between two or three variables. The other models then included FT, IGF-1, and the interaction term. Next, the odds ratios of the hormonal factors for osteopenia or osteoporosis were estimated using logistic regression analyses. The same variables as those included in the linear regression models were considered in the logistic regression models. For all analyses, P?<?0.05 was considered statistically significant.

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Table?3??Regression models including total testosterone, sex hormone-binding globulin, insulin-like growth factor-1, and the interaction terms between the hormonal factors to show the association with bone mineral density and bone turnover markers BMD LS TH FN BTMs OC CTX Model 1 ?FT ?IGF-1 Model 2 ?FT ?IGF-1 Model 3 ?FT ?IGF-1

J Bone Miner Metab Table?4??Regression models including free testosterone, insulin-like growth factor-1, and the interaction term between the hormonal factors to show the association with bone mineral density and bone turnover markers BMD LS TH FN BTMs OC CTX

Model 1 ?TT 0.066 0.091* 0.080* ?0.139** ?0.204** ?SHBG ?0.147** ?0.176** ?0.171** 0.212** 0.238** ?IGF-1 0.096** 0.128** 0.154** 0.058 0.068* Model 2 ?TT 0.094* 0.089* 0.068 ?0.153** ?0.239** ?SHBG ?0.139** ?0.081* ?0.070 0.227** 0.291** ?IGF-1 0.105** 0.097** 0.118** 0.047 0.037 Model 3 ?TT 0.105** 0.098* 0.076* ?0.161** ?0.246** ?SHBG ?0.140** ?0.069 ?0.060 0.216** 0.277** ?IGF-1 0.091** 0.086** 0.106** 0.048 0.046 All values represent the standardized coefficients of regression analyses. Model 1 included TT, SHBG, IGF-1 and the interaction terms between TT and SHBG, between TT and IGF-1, between SHBG and IGF-1, and among the 3 variables. Model 2 additionally adjusted for the variables of age and BMI. Model 3 additionally adjusted for the variables of glucose, TC, HDL cholesterol, drinking, smoking, exercise, and history of diabetes. Single and double asterisks represent P?<?0.05 and P?<?0.01, respectively. The levels of SHBG and CTX are logarithmically transformed. Single and double asterisks represent P?<?0.05 and P?<?0.01, respectively TT total testosterone, SHBG sex hormone-binding globulin, IGF insulin-like growth factor, BMI body mass index, LS lumbar spine, BMD bone mineral density, TH total hip, FN femoral neck, OC osteocalcin, CTX C-terminal telopeptide of type I collagen, TC total cholesterol, HDL high-density lipoprotein

0.061* 0.101** 0.079** 0.095** 0.087** 0.080**

0.081** 0.139** 0.070* 0.082** 0.076** 0.069*

0.070* 0.170** 0.052 0.109** 0.056* 0.096**

?0.107** 0.013 ?0.114** 0.012 ?0.120** 0.020

?0.155** 0.056 ?0.179** 0.031 ?0.185** 0.046

All values represent the standardized coefficients of regression analyses. Model 1 included FT, IGF-1 and the interaction term between FT and SHBG. Model 2 additionally adjusted for the variables of age and BMI. Model 3 additionally adjusted for the variables of glucose, TC, HDL cholesterol, drinking, smoking, exercise, and history of diabetes. Single and double asterisks represent P?<?0.05 and P?<?0.01, respectively. The levels of CTX are logarithmically transformed. Single and double asterisks represent P?<?0.05 and P?<?0.01, respectively FT free testosterone, IGF insulin-like growth factor, BMI body mass index, LS lumbar spine, BMD bone mineral density, TH total hip, FN femoral neck, OC osteocalcin, CTX C-terminal telopeptide of type I collagen, TC total cholesterol, HDL high-density lipoprotein

with CTX level only in the adjusted models (β? =? ?0.084 in Model 3). SHBG level was negatively related with BMD at 3 sites and positively related with BTMs in unadjusted model (Model 1). In adjusted models, the association between SHBG levels and BMD was significant only at the lumbar area (β? =? ?0.081 and ?0.072 in Model 2 and Model 3, respectively). IGF-1 level was significantly related with BMDs at 3 sites in all models. However, IGF-1 level was not associated with BTMs. The levels of FT was positively associated with BMD and negatively associated with BTMs in all models. The levels of TT, SHBG, IGF-1, and their interaction terms were included in regression models (Table?3). Similar to the relationship between each hormonal factor and bone parameters, IGF-1 levels were positively associated with BMD, but not significantly associated with BTMs. The TT levels were positively associated with lumbar spine (LS) BMD and negatively associated with BTMs in all the regression models including the variables of SHBG and IGF-1. The SHBG levels were negatively associated

with LS BMD and positively associated with BTMs in the models. In addition, 1SD change of SHBG level increased the level of osteopenia or osteoporosis defined by BMD in 24% (OR 1.24; 95% CI 1.04–1.46). The levels of FT, IGF-1, and their interaction term were included in regression models (Table?4). Both FT and IGF-1 levels were positively related with BMD. However, FT levels, but not IGF-1 levels, were significantly associated with BTMs. In the logistic regression models including FT and IGF-1, the increase in IGF-1 levels decreased the prevalence of osteopenia/osteoporosis defined by BMD (OR per 1SD increase 0.87; 95% CI 0.77–0.99).

Discussion
The current study demonstrated the association of IGF-1 and testosterone with BMD, BTMs and osteopenia/osteoporosis. SHBG levels and calculated FT levels were significantly related with BMD and BTMs. SHBG levels were also significantly associated with the prevalence of osteopenia/osteoporosis. IGF-1 levels were associated with BMD but not with BTMs. Testosterone has direct effects on the androgen receptor of bone cells and has indirect effects on bone cells

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J Bone Miner Metab

after conversion to estradiol and dihydrotestosterone via estrogen receptors [19]. Testosterone inhibits the function of osteoclasts and stabilizes osteoblasts [19]. Hence, serum testosterone levels have been expected to be positively associated with bone health. However, a few studies reported a significant relationship between TT levels and BMD [20, 21]. In our study, TT levels without adjusting for SHBG were not related to BMD and BTMs. These findings are in agreement with previous studies [15, 22, 23]. Instead, our study showed a significant association between FT levels and bone markers. Similar to our results, some studies also considered FT levels as a major determinant of BMD [24, 25]. Since testosterone strongly binds to SHBG, the function of testosterone mainly derives from unbound or weakly bound forms. Therefore, FT levels rather than TT levels may be related to bone metabolism. In our study, SHBG levels were independently associated with BMD and BTMs. Our results are in line with the results of previous studies [12, 23]. Recent studies reported that higher levels of SHBG, but not sex steroids, increased the risk of fracture [26, 27]. Until now, direct effects of SHBG on bone metabolism have not been unveiled. Estradiol plays an important role in bone metabolism not only in women but also in men [28]. Despite having a weaker affinity for SHBG than testosterone, estradiol also binds to SHBG [29]. Therefore, the increase in SHBG serum concentration lowers the bioavailable estradiol level and may inhibit the function of estradiol on bone metabolism. However, at least, SHBG does not merely serve to regulate the free concentration of steroids. It became clear that the cell membranes of selected tissues contained a receptor for SHBG [30]. The role of the receptor for SHBG should be investigated further. A positive association between IGF-1 and BMD was also reported in prior studies [10, 11, 22]. The relationship between the GH/IGF-1 system and bone metabolism may be explained by the established mechanisms. IGF-1 stimulates both osteoblasts and osteoclasts. IGF-1 reduces osteoblast apoptosis and promotes osteoblastogenesis [31]. Simultaneously, osteoclasts express IGF-1 receptors and are influenced directly by IGF-1. Thus, administration of GH or IGF-1 induced an increase in BMD and BTMs in clinical trials [32, 33]. However, the association between IGF-1 and BTMs was controversial in observational studies. In agreement with the results of the clinical trials, some observational studies reported a positive association between IGF-1 levels and BTMs in men [15, 34, 35]. However, higher rates of bone remodeling were negatively associated with bone health in middle-aged and older men [15], although one of the studies included young men [35]. Another study found a positive association between IGF-1 levels and BTMs was prominent in healthy adult men aged <55?years [34]. A further study also reported that IGF-1 levels were not related with bone

turnover in elderly men [36]. Hence, the effects of IGF-1 on bone metabolism may be more apparent in younger men compared to older men. In our study, an association between IGF-1 levels and BTMs was not demonstrated in men aged ≥50. Further research may expand the study subjects to various age groups including younger population. Similar to our study, some researchers considered both sex hormone and GH/IGF-1 axis simultaneously as factors related to bone metabolism. However, only a single study analyzed the association of bone makers with each hormonal factor with adjustment for the other hormones [15]. Unlike our results, IGF-1 levels were positively associated with BTMs after adjustment for the other hormone levels and confounders. Although this study did not show an association between IGF-1 levels and BMD, higher levels of BTMs were related with lower BMD. In our study, the hormonal factors and their interactions were considered in the analyses. As mentioned previously, the levels of SHBG and calculated FT, not IGF-1 levels, were significantly related with BTMs. The difference in results between the studies may be caused by the difference in ethnic group and age range. The interaction between hormones should be considered in further studies. Our study had several limitations. First, since the study was cross-sectional, IGF-1 or testosterone could not be guaranteed as a predisposing factor for current bone status. However, the mechanisms of hormone action in bone have been substantially described. Further longitudinal studies may help overcome this limitation. Second, our study was performed in a single center. Although our results could not be generalized, a large sample may support the value of our results. Third, we did not measure some variables, such as estradiol, vitamin D, parathyroid hormone, IGF binding proteins and additional bone turnover markers. Procollagen type I N-terminal propeptide is considered a sensitive marker of bone formation; however, osteocalcin is still an important bone remodeling marker [37]. Finally, improved methods to measure TT and FT were not introduced. Testosterone is most accurately measured by mass spectrometry, which is considered the standard for clinical research based on steroid assays [38]. A direct method of FT assay should be considered in future studies. In conclusion, SHBG levels were independently related with bone parameters and osteopenia/osteoporosis in men aged ≥50?years. IGF-1 levels were positively associated with BMD, but not with BTMs. These associations were the same after adjustment for interaction between the hormone levels. It may be suggested that SHBG plays a role in regulating age-related bone loss in men after middle-age. Further longitudinal studies are required to evaluate the differences in bone loss according to the serum levels of both IGF-1 and testosterone.

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Acknowledgements? The authors thank to all staffs of CHA Health Promotion Center for the quality control of our data. Compliance with ethical standards? Conflict of interest? None of the authors has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the contents of the paper.

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