http://informahealthcare.com/tam ISSN: 1368-5538 (print), 1473-0790 (electronic) Aging Male, Early Online: 1–5 ! 2015 Informa UK Ltd. DOI: 10.3109/13685538.2015.1034686

ORIGINAL ARTICLE

Vitamin D is significantly associated with total testosterone and sex hormone-binding globulin in Malaysian men Kok-Yong Chin1, Soelaiman Ima-Nirwana1, and Wan Zurinah Wan Ngah2 Department of Pharmacology and 2Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia

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Abstract

Keywords

Objective: Cross-sectional studies in the Caucasian population have shown a significant relationship between vitamin D and testosterone levels, but data in the Asian population are limited. This study aimed to determine the association between vitamin D and testosterone levels in Malaysian men. Methods: Chinese and Malay men (n ¼ 382) aged 20 years or above residing in the Klang Valley, Malaysia were recruited. Their fasting blood was collected for serum testosterone, sex hormone-binding globulin (SHBG) and 25-hydroxyvitamin D (25(OH)D) assays. Relationship between 25(OH)D and testosterone levels was analyzed using multiple regression analysis. Testosterone and SHBG levels among subjects with different vitamin D status were compared using univariate analysis. Confounders such as age, ethnicity and body mass index (BMI) were adjusted. Results: 25(OH)D was significantly and positively associated with total testosterone and SHBG levels before and after adjustment for age and ethnicity (p50.05). Only association with SHBG remained significant after further adjustment for BMI (p50.05). Total testosterone and SHBG values displayed an increasing trend from subjects with vitamin D deficiency to those with optimal level (p50.05). The trend was attenuated after adjustment for BMI (p40.05). Conclusion: 25(OH)D is significantly associated with total testosterone and SHBG in Malaysian men but this association is BMI-dependent.

Men, sex hormone-binding globulin, testosterone, vitamin D

Introduction Most of the vitamin D in our body is synthesized cutaneously upon exposure to ultraviolet B irradiation in the sunlight and the rest is absorbed from our diet. Vitamin D is hydroxylated in the liver into 25-hydroxyvitamin D (25(OH)D), which is the major circulating form in the blood. In the kidney, 25(OH)D is hydroxylated again into the metabolically active form, 1,25-dihydroxyvitamin D (1,25(OH)2D) [1,2]. In classifying individual vitamin D status, the cut-off values are based on 25(OH)D level in the blood [3]. The classical roles of vitamin D in maintaining bone health and regulating calcium metabolism are well established [4]. Recent epidemiological studies have also uncovered relationships between vitamin D and autoimmune diseases, cardiovascular diseases, cancer, depression and diabetes mellitus [5,6]. Vitamin D exerts its physiological functions through vitamin D receptor (VDR) [7,8]. The discovery of Address for correspondence: Prof. Dr Soelaiman Ima Nirwana, Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia. Tel: +603-91455002. Fax: +60391456633. E-mail: [email protected]

History Received 17 February 2015 Revised 20 March 2015 Accepted 24 March 2015 Published online 25 May 2015

vitamin D receptor and metabolizing enzymes in the human testis, ejaculatory tract and mature spermatozoa has prompted scientific interest in the role of vitamin D on male reproduction [9]. This is supported by a previous observation that VDR knockout mice develop hypergonatropic hypogonadism, reduced testicular weight, abnormal testicular histology and reduced number of functional sperms [10]. Cross-sectional studies on the relationship between vitamin D and testosterone have revealed heterogenous results. Although some studies have shown a positive relationship between them [11,12], others have indicated that the relationship is not significant [13]. Similarly, studies on the effects of vitamin D supplementation on testosterone levels have yielded conflicted results. The study by Pilz et al. has shown that vitamin D supplementation increases testosterone level, but the findings by Jorde et al. are negative [14,15]. There are no Asian data as all studies aforementioned have been performed in the Caucasian population. On this premise, the current study was performed to determine the relationship between serum 25(OH)D and testosterone (total, bioavailable and free fractions) levels in Malaysian men aged 20 years or above. Previously, we have determined the vitamin D level and its association

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with bone health and indicators of calcium metabolism in this population [16]. The hypothesis of this study was that the relationship between 25(OH)D and testosterone would be significant in Malaysian men. This study would bridge the gap in knowledge on the relationship between 25(OH)D and testosterone in the Asian population, so that a better understanding of the role of vitamin D in men is obtained.

0.86–1.19% for inorganic phosphate, 3.1–8.0% for SHBG, 2.80–3.60% for PTH and 4.60–8.70% for 25(OH)D. Vitamin D status of the subjects was determined based on the cut-off values put forward by the Endocrine Society of the United States [20]. Subjects were classified as having vitamin D deficiency if the 25(OH)D level was below 50 nmol/l and as having vitamin D insufficiency if the level was between 51 and 74 nmol/l.

Materials and methods

Statistical analysis

Study design

Normality of the data was determined using the Kolmogorov-Smirnov test. Skewed data were transformed using conventional methods (square root or logarithmic transformation) to improve the normality. Serum inorganic phosphate and intact parathyroid levels remained skewed after transformation and were analyzed using non-parametric test. The comparison of characteristics between Malay and Chinese subjects was performed using independent t-test for normally-distributed data and the Mann-Whitney U-test for skewed data. The association between 25(OH)D and testosterone levels was assessed using multiple linear regression with adjustment for confounding factors. Three models were generated, whereby Model 1 was unadjusted, Model 2 was adjusted for age and ethnicity, and Model 3 was further adjusted for BMI. Strength of association was determined using standardized regression coefficient (b). The comparison of testosterone and SHBG levels among subjects with different vitamin D status was performed using univariate analysis with adjustment for potential confounding variables. Model 1 was adjusted for age and ethnicity. Model 2 was further adjusted for BMI. Pairwise comparison was conducted using the Sidak test. Statistical analysis was executed using Statistical Package for Social Sciences (SPSS) version 20.0 (IBM, Armonk, NY). Significant value was set at p50.05.

This cross-sectional study conducted between September 2009 and September 2011 recruited community-living men aged 20 years and above residing in the Klang Valley (Kuala Lumpur and its environs). Purposive sampling was adopted, in which invitation with inclusion and exclusion criteria was advertised via major newspapers, radio broadcast, flyers, public announcement in community centers and religious places. Men included in this study were free from malignancy, hypogonadism and conditions indicative of dysregulation in calcium metabolism, such as abnormal total calcium, inorganic phosphate and parathyroid hormone levels. Before giving written consent to participate, subjects were briefed about the details of this study. The protocol of the study had been reviewed and approved by the Research Ethics Committee of Universiti Kebangsaan Malaysia Medical Centre (Study Code: UKM-AP-TKP-09-2009) [17,18]. Subjects attended the screening sessions held at Universiti Kebangsaan Malaysia and local community centers. They answered a demographic questionnaire. Physical examination and medical history taking were performed by qualified physicians. Age was determined from records on subject’s identification card and ethnicity was self-declared. Height without shoes recorded to the nearest 1 cm was determined using a portable stadiometer (Seca, Hamburg, Germany). Body weight with light clothing recorded to the nearest 0.1 kg was measured using a weighing scale (Tanita, Tokyo, Japan). Body mass index (BMI) was calculated as per the convention: BMI (kg/m2) ¼ body weight in kg divided by the square of height in m. Subjects underwent an overnight fast of at least 8 h before attending the screening session. Blood collection was performed by physicians or phlebotomists between 8:30 am and 10:30 am. Serum was extracted via centrifugation (3000 rpm, 15 min, 4  C) and stored at 70  C until analyzed. Serum testosterone level was determined using ADVIA Centaur (Siemens Healthcare Diagnostics, Deerfield, IL) based on chemiluminescence method. Serum free and bioavailable testosterone levels were determined using Sodergard’s formula [19]. Serum total calcium and inorganic phosphate levels were measured using ADVIA 2400 (Siemens Healthcare Diagnostics, Deerfield, IL) based on colorimetric method. Serum sex hormone-binding globulin (SHBG) (IBL International, Hamburg, Germany), intact parathyroid hormone (PTH) (IBL International, Hamburg, Germany) and 25(OH)D (IDS, Tyne and Wear, UK) levels were assayed using sandwiched enzyme-linked immunoassay. The interassay coefficient of variation for the assays were 5.00–6.32% for total testosterone, 1.10–1.17% for total calcium,

Results After the exclusion of 18 statistical outliers, data from 382 subjects (39% Malays and 61% Chinese) were available for analysis. The Malay subjects had significantly lower age, height, sex hormone-binding globulin and 25(OH)D levels compared to the Chinese subjects (p50.05). The serum total calcium, inorganic phosphate, bioavailable and free testosterone levels were significantly lower in the Chinese compared to the Malay subjects (p50.05) (Table 1). This warranted adjustment for ethnicity for the subsequent analysis. According to the criteria set by the Endocrine Society, 23.0% subjects had vitamin D deficiency, 67.8% subjects had insufficiency and 9.2% had normal vitamin D level. Multiple regression analysis indicated that serum 25(OH)D was significantly and positively associated with total testosterone (p50.05). The association persisted after adjustment for age and ethnicity (p50.05). However, after further adjustment for BMI, the association between serum 25(OH)D and total testosterone became not significant (p40.05). The associations between 25(OH)D and free and bioavailable testosterone were not significant before and after adjustments (p40.05). The association between serum 25(OH)D and SHBG level were positive and significant

Vitamin D and testosterone

DOI: 10.3109/13685538.2015.1034686

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Table 1. Characteristics of the subjects. Malays (n ¼ 149)

Age (years) Height (cm) Body weight (kg) Body mass index (kg/m2) Serum total calcium (mmol/l) Serum inorganic phosphate (mmol/l)* Serum intact parathyroid (pg/ml)* Serum total testosterone (nmol/l) Serum bioavailable testosterone (nmol/l) Serum free testosterone (nmol/l) Serum sex hormone-binding globulin (nmol/l) Serum 25-hydroxyvitamin D (nmol/l)

Chinese (n ¼ 233)

Overall (n ¼ 382)

Mean

SD

Mean

SD

Mean

SD

p Value

38.61 166.00 69.54 25.18 2.30 1.15 45.7 19.7 11.5 0.41 43.0 55.0

17.19 6.51 14.36 4.58 0.12 0.13 20.5 6.4 3.4 0.12 22.8 11.7

46.56 168.36 67.96 23.97 2.23 1.09 45.7 19.0 10.7 0.38 46.9 60.3

13.44 6.28 11.29 3.65 0.10 0.18 17.9 6.2 3.3 0.12 25.2 10.8

43.46 167.44 68.58 24.44 2.26 1.11 45.7 19.3 11.0 0.39 45.4 58.2

15.48 6.47 12.58 4.08 0.11 0.17 18.9 6.3 3.4 0.12 24.3 11.4

50.001 50.001 0.413 0.010 50.001 50.001 0.623 0.312 0.017 0.045 0.086 50.001

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Comparison in the characteristics between Chinese and Malay subjects was made using independent t-test for normally distributed data and MannWhitney U-test for skewed data (marked*). Bolded p values are significant.

Table 2. The association between 25-hydroxyvitamin D and testosterone and sex hormone-binding globulin.

Serum Serum Serum Serum

total testosterone bioavailable testosterone free testosterone sex hormone-binding globulin

Model 1 b

p

Model 2 b

p

Model 3 b

p

0.127 0.035 0.02 0.216

0.013 0.492 0.691 50.001

0.158 0.047 0.047 0.162

0.003 0.332 0.349 0.001

0.087 0.018 0.018 0.092

0.071 0.717 0.714 0.039

Multiple linear regression is used to study the relationship between 25-hydroxyvitamin D (predictor) and testosterone and sex hormone-binding globulin (dependent variables). Model 1 contains only the predictor. Model 2 is adjusted for age and ethnicity. Model 3 is further adjusted for body mass index. Strength of association is represented by standardized regression coefficient (b). Bolded p values are significant.

before and after adjustment for age, ethnicity and BMI (p50.05) (Table 2). The total testosterone level was significantly lower in subjects having vitamin D deficiency compared to those having insufficiency and normal level (p50.05). Similar trend was observed in SHBG level, whereby vitamin Ddeficient subjects had significantly lower SHBG level compared to vitamin D-insufficient subjects and normal subjects (p50.05). In addition, the SHBG level of vitamin Dinsufficient subjects was significantly lower compared to normal subjects (p50.05). The differences in total testosterone and SHBG became not significant after adjustment for BMI (p40.05) (Figure 1). The levels of free and bioavailable testosterone did not differ significantly among subjects with different vitamin D status (p40.05) (data not shown).

Discussion The current study found that there was a significant and positive association between serum 25(OH)D and total testosterone level, and between 25(OH)D and SHBG. Adjustment for BMI reduced the strength of the relationship between 25(OH)D and total testosterone, indicating that it was not independent of BMI. Free and bioavailable testosterone was not related to 25(OH)D level. As an increase in 25(OH)D was associated with elevations of both total testosterone and SHBG, this resulted in no net increase in the bioavailability of testosterone, as reflected in the lack of association between free and bioavailable testosterone and 25(OH)D. Increased BMI is an indicator of obesity [21].

Obesity is associated with decreased testosterone level, mediated by reduced SHBG level due to insulin resistance [22]. Lower testosterone also causes obesity [22,23]. On the other hand, vitamin D is fat soluble and is sequestered into fat tissue [24]. A previous study revealed that a higher BMI caused decreased 25(OH)D level but a lower 25(OH)D did not cause increased BMI [25]. These observations suggest a complex role of BMI in the relationship between testosterone and vitamin D. Studies on the relationship between 25(OH)D and testosterone levels in the Caucasian men revealed heterogenous results. Studies performed by Nimptsch et al. [11] on 1362 men (aged 40–75 years) in the Health Professionals Follow-up Study, Wehr et al. [12] on 2299 German men (aged 62 ± 11 years) in the Ludwigshafen Risk and Cardiovascular Health Study, and Lee et al. [26] on 3051 men (aged 40–79 years) in the European Male Ageing Male study revealed a significant positive relationship between total testosterone and 25(OH)D levels. Nimptsch et al. [11] and Lee et al. [26] also observed a positive relationship between free testosterone and 25(OH)D levels, which was not seen in the current study. Lee et al. [26] discovered that the positive relationship between 25(OH)D and testosterone was attenuated after multiple adjustments (inclusive of BMI). On the other hand, studies by Hammoud et al. [27] on 170 healthy men (aged 29 ± 8.5 years), RamlauHansen et al. [28] on 307 Danish men (aged 18–21 years) and Chen et al. [13] on 55 Australian men (aged 58.1 ± 12.9 years) revealed no significant relationship between total testosterone and 25(OH)D. The discrepancy could be due to differences in population and sample size. Despite the lack of correlation

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Figure 1. Testosterone and sex hormone-binding globulin levels among subjects with different vitamin D status. The letters indicate significant difference between the marked group with (a) the vitamin D deficiency group and (b) the vitamin D insufficiency group. Univariate analysis is performed to compare the serum total testosterone and sex hormone-binding globulin level between subjects with different vitamin D status. Model 1 is adjusted for age and ethnicity. Model 2 is further adjusted for body mass index. A p value 50.05 is considered significant.

with 25(OH)D, total testosterone was associated significantly with 1,25(OH)2D in the study of Chen et al. [13]. Although associations between 25(OH)D and free and bioavailable testosterone were not significant in this study, other studies had shown otherwise [11,26]. In a noteworthy study by Lerchbaum et al. [29] involving 200 healthy men (aged 20–58 years), subjects were divided according to quintiles of 25(OH)D levels. Men in the lower quintiles and the highest quintile had significantly higher risk of being hypogonadal compared to men in quintile 4 (optimal 25(OH)D level: 82–102 nmol/l) [29]. Thus, they suggested the relationship between 25(OH)D and testosterone levels was Ushaped, whereby both low and very high 25(OH)D levels were linked to hypogonadism [29]. Only 9.3% of the subjects in the current study had sufficient vitamin D level, hence similar findings could not be obtained. Wehr et al. [12] found a significant association between 25(OH)D and SHBG in men even after adjustment for age and BMI. Ramlau-Hansen et al. [28] also noted that median of SHBG was higher at higher 25(OH)D level. The current study was in agreement with these two studies. In contrast, the correlation between SHBG and 25(OH)D was not significant in the study of Chen et al. [13]. Testosterone and vitamin D have been implicated in various medical conditions, such as osteoporosis, cardiovascular diseases, metabolic syndrome and mortality [6,30]. The results of this study suggest that the overlapping influence of testosterone and vitamin D could be caused partly by the interlacing relationship between the two factors. Testosterone replacement therapy carries side effects, such as increased risk for prostate cancer, cardiovascular diseases and polycythemia [31]. Vitamin D supplementation could be beneficial to men who had suboptimal testosterone level without the adverse effects of testosterone replacement therapy. In a clinical trial by Pilz et al. [15] involving 54 healthy overweight men undergoing weight reduction program, supplementation of 83 mg vitamin D for a year increased their 25(OH)D, total, bioavailable and free testosterone levels. The placebo arm did not experience similar increases [15]. Pooled data from randomized control trials in the Tromso

Study revealed a significant cross-sectional relationship between 25(OH)D and testosterone in men [14]. However, vitamin D supplementation did not increase testosterone level and testosterone supplementation did not increase vitamin D level in the subjects [14]. Thus, it is inconclusive as to whether supplementation program would benefit men in achieving optimal 25(OH)D or testosterone level and more studies are required. Several limitations should be considered when interpreting the results of the current study. Only Malay and Chinese men were recruited, hence the results might not be representative of the whole Malaysian population, which consist of other ethnic minorities. The testosterone and 25(OH)D levels were measured using the ELISA method. More accurate and sensitive methods of measurements, such as chromatographymass spectrometry are available [32,33]. As this was a crosssectional study, causality could not be inferred. A longitudinal study would be required to validate the relationship between 25(OH)D and testosterone levels. This was the first study that showed a significant relationship between 25(OH)D and testosterone and SHBG levels in the Asian population. It would serve as a basis for larger epidemiological studies and longitudinal studies to validate the link between 25(OH)D and androgen in Asian men. Possible confounding variables, such as age, ethnicity and BMI were adjusted in the regression models and univariate analyses. As a conclusion, there are significant positive relationships between 25(OH)D and testosterone, and between 25(OH)D and SHBG in Malaysian men. These relationships are dependent on BMI. The relationships warrant further studies as both vitamin D and testosterone are important determinants of health and mortality rate. Further, a longitudinal study would be needed to determine the causality of these relationships.

Declaration of interest The authors declared no conflict of interest. We thank Universiti Kebangsaan Malaysia for funding this study via Arus Perdana Grant (UKM-AP-TKP-09-2009).

Vitamin D and testosterone

DOI: 10.3109/13685538.2015.1034686

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Vitamin D is significantly associated with total testosterone and sex hormone-binding globulin in Malaysian men.

Cross-sectional studies in the Caucasian population have shown a significant relationship between vitamin D and testosterone levels, but data in the A...
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