Vitamin D, PCOS and androgens in men: a systematic review.

This review article was supported by funding from The Austrian Science Fund (FWF-KLIF project no.: 274, 2012).

We performed a systematic literature search in PubMed for relevant English language publications published from January 2012 until September 2017. We used the following search terms: ‘vitamin D’ and ‘polycystic ovary syndrome’, ‘vitamin D’ and ‘PCOS’, ‘vitamin D’ and ‘testosterone’, ‘vitamin D’ and ‘hypogonadism’. In addition, we also used the search terms ‘25-hydroxyvitamin D (25(OH)D)’, ‘1,25-dihydroxyvitamin D’ and ‘calcitriol’ instead of vitamin D. We also used listed references from selected articles to expand the search. We start with a short overview on the background and potential mechanisms explaining the relationship of vitamin D and PCOS. Next, we will discuss observational studies on vitamin D and PCOS, and we will then highlight results of intervention studies investigating vitamin D effects on PCOS. In the second part of the review, we will provide some information on possible mechanisms explaining the link of vitamin D with androgen metabolism in men. Further, we give an overview on observational studies on vitamin D and androgen levels. Finally, we will again focus on intervention studies analyzing vitamin D effects on androgen levels in men. The role of vitamin D in spermatogenesis and other aspects of female fertility (such as endometriosis or in vitro fertilization) as well as earlier articles on vitamin D and fertility have been comprehensively reviewed elsewhere ( 6 , 21 , 22 ) and are not included here.

The association of vitamin D and testosterone in men has been investigated in various studies including studies on molecular mechanisms, observational studies analyzing the relationship of vitamin D status and circulating testosterone levels in men and clinical intervention studies evaluating the effect of vitamin D treatment on testosterone levels in men. The following paragraph will provide an overview on possible molecular mechanisms regarding the association of vitamin D and testosterone. In addition to its important regulatory effect on spermatogenesis, testosterone is an anabolic hormone with a wide range of beneficial effects on men’s health, including important physiological effects on brain, muscle, bone and fat mass ( 66 ). There is accumulating evidence suggesting that androgen deficiency may contribute to the onset and progression of cardiovascular disease and play an important role in the development of the metabolic syndrome in men ( 67 ). Interestingly, men with combined vitamin D and androgen deficiencies are at high risk for all-cause and cardiovascular mortality, suggesting that a parallel deficiency of both hormones is a marker of poor overall health ( 68 ). Thus, a causal relationship between vitamin D and testosterone and in particular a potential increase of testosterone levels after vitamin D treatment is of high clinical interest. Testosterone is produced in the Leydig cells following pituitary pulsatile LH secretion, but its production is also modulated by paracrine and autocrine signals supplied by growth factors and cytokines secreted within the testis ( 69 , 70 ). The VDR is almost ubiquitously expressed in human cells, which underlines the clinical significance of the vitamin D endocrine system ( 1 , 2 , 71 ). VDR and vitamin D-metabolizing enzymes are concomitantly expressed in the entire reproductive male tract, including Leydig cells ( 72 ). This VDR expression suggests local autocrine as well as paracrine action of vitamin D and indicates that vitamin D is involved in regulation of testis function. Obviously, vitamin D metabolites are locally synthesized and degraded and vitamin D metabolism seems to be regulated by local as well as systemic factors ( 22 ). The negative effect of orchiectomy as well as testis dysfunction on circulating 25(OH)D levels, supports the hypothesis of vitamin D synthesis in the testis ( 73 , 74 , 75 ). Of note, it has been shown in an experimental study that mouse Leydig cells basally secrete 25(OH)D, which is also stimulated by human chorionic gonadotropin (hCG) ( 76 ). This notion is supported by the fact that hCG treatment in men with late-onset hypogonadism increased circulating 25(OH)D levels ( 76 ). Despite this hypothesis of a local 25(OH)D production in the testis driven by Leydig cells, the exact regulation of testis vitamin D metabolism is largely unknown. Some evidence suggests that regulatory mechanisms resembling renal vitamin D metabolism exist. These mechanisms include PTH-related molecules and fibroblast growth factor (FGF-23) pathways ( 22 ). Interestingly, it has been shown that androgens increase 1-a-hydroxylase, a key enzyme in vitamin D metabolism that converts 25(OH)D to 1,25(OH) 2 D ( 77 ). In addition, it has also been demonstrated that the regulation of gene expression by vitamin D metabolites is modified according to androgen levels ( 78 ). On the other hand, vitamin D significantly increased testosterone production in a human primary testicular cell culture model ( 79 ). After 1,25(OH) 2 D supplementation, 63 genes were significantly upregulated in human testicular cells, such as IGF-1, ALPL, DPP4 and other bone- and immune system-associated genes ( 79 ). In male VDR-knockout mice, high LH and FSH levels indicate the presence of hypergonadotropic hypogonadism ( 71 ). Vitamin D may be critical for testicular function because vitamin D treatment upregulates certain testis-specific genes in mice ( 35 ) including ABCA1 (ATP-binding cassette transporter 1). ABCA1-knockout mice have significantly reduced intratesticular testosterone levels as well as reduced sperm counts compared with wild-type animals ( 80 ). Experimental studies also indicate that testosterone secretion might be modulated by vitamin D-induced changes in intracellular calcium homeostasis in Leydig cells in animals ( 22 ) mediated via calbindin-D28k ( 81 ). Calbindin-D 28k is a cytosolic calcium-binding protein involved not only in the regulation of intracellular calcium homeostasis but also in testis hormone production ( 81 ). Vitamin D effects on testosterone production might also be mediated via osteocalcin, which is produced by osteoblasts and involved in bone metabolism. It has been postulated that vitamin D-induced stimulation of osteocalcin expression might have an indirect relevant role in modulating testosterone production by the testis ( 22 ). Further, in humans, a direct stimulatory genomic effect of vitamin D on steroidogenesis enzymes has been postulated ( 22 ). In the following paragraph, we will discuss observational studies on vitamin D status and circulating androgen levels in men (summarized in Table 3 ). The majority of studies found an independent association of vitamin D with circulating androgen levels or hypogonadism in men. In 2011, some of us demonstrated for the first time a significant association of 25(OH)D and TT levels in men ( 19 ). Similarly, Nimptsch and coworkers ( 82 ) reported an independent association of 25(OH)D with TT and FT levels in 1362 male participants of the Health Professionals Follow-up study. Lee and coworkers ( 83 ) observed no independent association of TT or FT with 25(OH)D in 3369 community-dwelling men aged 40–79 years from the European Male Aging study. There was, however, an independent association of 25(OH)D levels <50 nmol/L with compensated as well as with secondary hypogonadism ( 83 ). Similarly, Jorde and coworkers ( 84 ) found a significant positive association of vitamin D and TT levels (adjusted for age, BMI, season, presence of cardiovascular disease and DM and physical activity) in 893 men from the Tromsø Study. In that study, no significant association was found between 25(OH)D and FT, SHBG, FSH or LH ( 84 ). In 2854 Chinese men, 25(OH)D was positively associated with TT and estradiol after adjustments for age, residence area, economic status, smoking, BMI, HOMA-IR, DM and systolic pressure ( 85 ). Further, increasing quartiles of 25(OH)D were associated with significantly decreased odds ratios of hypogonadism ( 85 ). Heijboer and coworkers ( 86 ) observed a significant positive association of 25(OH)D and TT levels in 183 men (unadjusted). In addition, a significant positive association of TT and SHBG with 25(OH)D levels was reported in 382 Chinese and Malaysian men ( 87 ). The results lost, however, significance after adjustment for BMI ( 87 ). Tak and coworkers ( 88 ) found an independent association of 25(OH)D levels with TT (adjusted for body fat, WC, BMI, fasting plasma glucose, DM and dyslipidemia) and FT levels (adjusted for age, total muscle mass, smooth muscle mass, total cholesterol, DM, dyslipidemia and alcohol use) in 652 Korean men aged 56.7 ± 7.9 years. Further, vitamin D deficiency (<50 nmol/L) was associated with an increased risk of TT and FT deficiency (adjusting for age, season, BMI, body composition, chronic disease, smoking and alcohol use) ( 88 ). Data from the Longitudinal Aging Study Amsterdam, an ongoing population-based cohort study of older Dutch individuals ( n  = 643), documented an independent association of 25(OH)D levels with TT and bioavailable TT (adjusted for age, BMI, alcohol consumption, smoking status, season of blood collection, number of chronic diseases, serum creatinine and physical performance) ( 89 ). Others reported a significant positive association of 25(OH)D and TT as well as SHBG in 1315 men (NHANES III) and 318 men (NHANES 2001–2004), respectively (adjusted for age, race/ethnicity, body fat percentage and smoking) ( 90 ). Moreover, data from 1427 infertile men indicated lower SHBG and TT/estradiol ratios but higher FT and estradiol in men with 25(OH)D levels 75 nmol/L ( 91 ). The authors observed no independent association of 25(OH)D levels with hypogonadism, estradiol, SHBG, LH or FSH, respectively ( 91 ). In 3016 older men, lower 25(OH)D levels were associated with lower SHBG and higher FT levels after adjusting for demographic and lifestyle variables, whereas no independent association with TT was observed ( 92 ). Table 3 Summary of clinical observational studies investigating the association of vitamin D and androgen levels in men. Author/study Subjects Age Hypogonadism Androgens Other endocrine parameters Adjustment Wehr et al ./LURIC study ( 3 ) 2299 men at high cardiovascular risk 62 ± 11 years OR 2.47 (1.55–3.93) for men with 25(OH)D 75 nmol/L ↑TT, ↑FAI ↓SHBG Age, BMI, wine consumption, smoking, beta-blocker use, statin use and diabetes Heijboer et al . ( 86 ) 183 men (101 men with chronic heart failure; 76 male nursing home residents; 43 overweight non-Western immigrants) 20–86 years (range) na ↑TT Unadjusted Jorde et al . the Tromsø study ( 84 ) 893 men 60.6 ± 9.8 years na ↑TT, no association with FT Age, BMI, season, presence of cardiovascular disease and diabetes, and physical activity Chin et al . ( 87 ) 382 Chinese and Malay men ≥20 years na No independent association with TT ↑SHBG Age, ethnicity, BMI Wulaningsih et al . NHANES III ( 94 ) 1412 men ≥20 years na No independent association with TT or FT No independent association with SHBG or estradiol Age, race/ethnicity, % body fat, diabetes, cigarette smoking, alcohol intake, vigorous physical activity, and serum levels of 25(OH)D, calcium, and creatinine Anic et al. NHANES III and NHANES 2001–2004 ( 90 ) 1315 men (NHANES III) and 318 men (NHANES 2001–2004) ≥20 years na ↑TT ↑SHBG Adjusting for age, race/ethnicity, body fat percentage, and smoking Blomberg Jensen et al . the Copenhagen-Bone-Gonadal Study ( 91 ) 1427 infertile men 34.1 (31–38) years na Higher FT in men with 25(OH)D levels 75 nmol/L Lower SHBG and T/estradiol ratios and higher estradiol in men with 25(OH)D levels 75 nmol/L Age, BMI, smoking, season Lerchbaum et al . ( 95 ) 225 men 35 (30–41) years U-shaped association of vitamin D status and risk of hypogonadism. Significantly increased risk of hypogonadism in men within the highest 25(OH)D quintile (>102 nmol/L) compared to men in quintile 4 (reference, 82–102 nmol/L). (OR 9.21, 2.27–37.35, P  = 0.002) No independent association with TT and FT No independent association with SHBG Adjusted for age, BMI, ethnic background, study site Wang et al . ( 85 ) 2854 Chinese men 53.0 ± 13.5 years Increasing quartiles of 25(OH)D were associated with significantly decreased odds ratios of hypogonadism. OR 1.50 (95% CI, 1.14, 1.97) for men in the lowest compared to men in highest 25(OH)D quartile ↑TT ↑Estradiol Age, residence area, economic status, smoking, BMI, homeostasis model assessment-insulin resistance, DM and systolic pressure Tak et al . ( 88 ) 652 Korean men 56.7 ± 7.9 years Vitamin D deficiency (<50 nmol/L) was associated with an increased risk of TT (odds ratio (OR): 2.65; 95% confidence interval (CI): 1.21–5.78, P  = 0.014) and FT deficiency (OR: 1.44; 95% CI: 1.01–2.06 P  = 0.048) ↑TT, ↑FT TT: body fat, WC, BMI, FPG, DM and dyslipidemia FT: adjusted age, total muscle mass, smooth muscle mass, TC, DM, dyslipidemia and alcohol use Hypogonadism: adjusting for age, season, body mass index, body composition, chronic disease, smoking, and alcohol use) Rafiq et al . ( 89 ) Older Dutch individuals ( n  = 643) 65–89 years (range) No independent association of 25(OH)D levels with hypogonadism ↑TT and bioavailable testosterone Adjusted for age, BMI, alcohol consumption, smoking status, season of blood collection, number of chronic diseases, serum creatinine and physical performance Zhao et al . ( 92 ) 3016 older men 62.1 ± 10.2 years no independent association of 25(OH)D levels with hypogonadism ↑FT, no independent association with TT ↓SHBG Adjusting for age, race/ethnicity, and study site, BMI, smoking, education, intentional physical exercise, and self-reported health status, diabetes, systolic blood pressure, use of antihypertensive medications, eGFR, total cholesterol, HDL cholesterol, use of lipid lowering medication usage, and hsCRP Lee et al . the European Male Aging Study, ( 83 ) 3369 community-dwelling men Aged 40–79 years (range) Independent association of 25(OH)D 75 nmol/L) No independent association with TT or FT Adjusted for age, centre, BMI, smoking, alcohol consumption, physical activity, physical function, heart conditions, hypertension, DM, and depression Nimptsch et al . ( 82 ) 1362 male participants of the Health Professionals Follow-up Study 65.8 ± 7.4 years Comparing participants in the highest vs lowest quintile of 25(OH) vitamin D had a significantly decreased relative risk of hypogonadism of 0.50 (95% CI 0.31–0.93; P -trend = 0.01) Independent association with TT and FT Age (at blood collection), batch, time of blood collection, season, BMI at blood collection, smoking status, geographical region, physical activity Hammoud et al . ( 93 ) 170 healthy men 29.0 ± 8.5 years na No independent association with TT or FT Age, BMI, season, alcohol intake and smoking Data are given as mean ±  s.d. or median (IQR) unless otherwise stated. 25(OH)D, 25 hydroxyvitamin D; BMI, body mass index; DM, type 2 diabetes mellitus; eGFR, estimated glomerular filtration rate; FAI, free androgen index; FPG, fasting plasma glucose; FT, free testosterone; HDL, high density lipoprotein, hsCRP, high sensitive C-reactive protein; OR, odds ratio; SHBG, sex hormone binding globulin; TT, total testosterone; TC, total cholesterol; WC, waist circumference. Summary of clinical observational studies investigating the association of vitamin D and androgen levels in men. Data are given as mean ±  s.d. or median (IQR) unless otherwise stated. 25(OH)D, 25 hydroxyvitamin D; BMI, body mass index; DM, type 2 diabetes mellitus; eGFR, estimated glomerular filtration rate; FAI, free androgen index; FPG, fasting plasma glucose; FT, free testosterone; HDL, high density lipoprotein, hsCRP, high sensitive C-reactive protein; OR, odds ratio; SHBG, sex hormone binding globulin; TT, total testosterone; TC, total cholesterol; WC, waist circumference. Some authors failed, however, to demonstrate an independent association of vitamin D and serum androgens in men. Hammoud and coworkers ( 93 ) observed no independent association of 25(OH)D levels with TT or FT levels in 170 healthy men. Similarly, results from NHANES III suggested no significant association of 25(OH)D with TT, FT, SHBG or estradiol in 1412 middle-aged men ( 94 ). Of note, cross-sectional results from 225 middle-aged men suggest a U-shaped association of vitamin D status and risk of hypogonadism ( 95 ). In detail, we found a significantly increased risk of hypogonadism in men within the highest 25(OH)D quintile compared to men in quintile 4 (reference) as well as a trend towards increased risk of hypogonadism in men within the lowest 25(OH)D quintile. With respect to risk of male hypogonadism, these results suggest optimal serum 25(OH)D concentrations of 82–102 nmol/L. Those findings as well as previous studies showing no association of vitamin D and androgens in linear analyses might therefore be supported by previous inconsistent results with possible U-shaped or non-linear associations that have been suggested for vitamin D and cancer ( 5 ), cardiovascular disease ( 96 ) and mortality ( 97 , 98 ). Furthermore, inconsistent results reported in observational studies might be related to different study populations with respect to sample size, age, comorbidities, ethnicity as well as to various statistical methods used for data analyses. In addition to the above mentioned observational studies, there are some intervention studies evaluating vitamin D effects on androgen levels in men (summarized in Table 4 ). Table 4 Summary of clinical intervention studies investigating the effects of vitamin D treatment on androgen levels in men. Author/Study Study design Subjects Age 25(OH)D levels (baseline) TT levels (baseline) Primary outcome Study duration Study medication TT levels (study end) 25(OH)D levels (study end) vitamin D group Pilz et al . ( 20 ) RCT 54 obese men (vitamin D n  = 31, placebo n  = 23) 48.1 ± 11.1 years <50 nmol/L; 31.1 ± 21.9 nmol/L 11.4 nmol/L Weight loss 1 year 3332 IU/day vs placebo Significant increase in TT, bioactive testosterone, and FT levels 86.4 ± 68.8 nmol/L Jorde et al . the Tromsø study ( 84 ) RCT (pooled data from 3 independent RCTs) Study 1 (vitamin D and obesity): 129 men with BMI 28–47 kg/m², study 2 (insulin sensitivity): 53 men, study 3 (depression study): 100 men Study 1: 48.9 ± 10.6 years; study 2: 51.2 ± 10.0 years; study 3: 53.0 ± 11.1 years Study 1: 52.6 ± 17.8 nmol/L, study 2: 39.9 ± 14.0 nmol/L (25(OH)D <50 nmol/L), study 3: 45.8 ± 15.0 nmol/L (25(OH)D ≤ 55 nmol/L) Study 1: 13.5 ± 4.2 nmol/L, study 2: 16.9 ± 6.4 nmol/L, study 3: 14.2 ± 4.9 nmol/L Study 1: weight loss, study 2: change in insulin sensitivity as evaluated with a hyperglycemic glucose clamp, study 3: change in depression scores Study 1: 1 year, study 2: 6 months, study 3: 6 months Study 1: 40 000 IU/week vitamin D (~5714 IU/day), 20 000 IU/week vitamin D (~2857 IU/day), or placebo for 1 year (all subjects: 500 mg calcium/day); study 2 & 3: 40 000 IU vitamin D/week (~5714 IU/day) vs placebo for 6 months No significant effect 118.8 ± 52.2 nmol/L Heijboer et al . ( 86 ) RCT (pooled data from 3 independent RCTs) 92 male patients with heart failure (study 1), 49 male nursing home residents (study 2) and 42 male non-Western immigrants in the Netherlands (study 3) Study 1: 63 (range 42–86) years, study 2: 82 (range 71–97) years, study 3: 53 (range 20–70) years Study 1: 46.5 (38.5–62.5) nmol/L, study 2: 27.0 (23.0–31.5) nmol/L, study 3: (25OHD <50 nmol/L), 27.5 (18–33) nmol/L Study 1: 15 (11–19) nmol/L, study 2: 11 (8–15.8) nmol/L, study 3: 13 (11–17) nmol/L Vitamin D effects on the renin-angiotensin-aldosterone system (study 1), effects of different vitamin D doses (study 2), and vitamin D effects on insulin sensitivity (study 3) Study 1: 6 weeks, study 2: 16 weeks, study 3: 16 weeks Study 1: 2000 IU/day, study 2: 600 IU per day, 4200 IU per week or 18 000 IU/month, study 3: 1200/d vs placebo (+500 mg calcium carbonat: all subjects) No significant effect Study 1: 73.5 nmol/L, study 2: 57 nmol/L, study 3: 49 nmol/L Ferlin et al . ( 99 ) Uncontrolled intervention study 20 men with Klinefelter syndrome (substudy of a cross-sectional study of 127 Klinefelter men and 60 healthy controls); 12 men treated with testosterone + calcifediol (group 1), 8 men treated with calcifediol (group 2) 31.5 ± 8.5 years (all 127 men with Klinefelter syndrome) Baseline 25(OH)D <50 nmol/L; 31.3 ± 8.9 nmol/L (group 1: testosterone+calcifediol); 23.2 ± 18.9 nmol/L (group 2: calficediol) 10.5 ± 4.9 nmol/L (all 127 men with Klinefelter syndrome) Maintain 25(OH)D levels above 50 nmol/L 2 years Calcifediol treatment with Didrogyl, Calcifediol starting dose of 4000 IU/week, adjusting the dosage to maintain 25(OH)D levels >50 nmol/L, by determining the levels every 6 months No significant effect Group 1: 94.3 ± 12.9 nmol/L, group 2: 102.5 ± 28.7 nmol/L Foresta et al . ( 100 ) Uncontrolled intervention study 66 patients with hypogonadism (classic hypogonadism (TT<12 nmol/L, LH ≥ 8 IU/L) ( n  = 26) and subclinical hypogonadism (TT ≥ 12 nmol/L, LH ≥ 8 IU/L) ( n  = 40)) 34.5 ± 6.8 years Baseline 25(OH)D <50 nmol/L; cholecalciferol group : 33.8 ± 10.5 nmol/L ; calcidiol group: 33.4 ± 9.5 nmol/L Not given Effects of cholecalciferol vs calcidiol on 25(OH)D levels 3 months 5000 IU cholecalciferol per week (~714 IU/d; n  = 20) or 4000 IU calcidiol per week (~571 IU/d; n  = 36) No significant effect Cholecalficerol: 42.6 ± 11.6 nmol/L; calcidiol: 81.4 ± 25.0 nmol/L Canguven et al . ( 101 ) Uncontrolled intervention study 102 middle-aged men 53.2 ± 10.4 years Baseline 25(OH)D <75 nmol/L; 37.9 ± 11.6 nmol/L 12.46 ±  3.30 nmol/L Not specifically stated (vitamin D effects on biochemical and hormonal parameters as well as on erectile dysfunction) 1 year Men received an initial vitamin D dose (Ergocalciferol; oral solution 600 000 IU/1.5 ml), and followed a vitamin D treatment regime thereafte Significant increase in TT levels (12.46  ±  3.30 to 15.99 ±  1.84 nmol/L 121.4 ± 29.1 nmol/L Lerchbaum et al . Graz Vitamin D&TT-RCT ( 102 ) RCT 100 healthy men with TT levels ≥10.4 nmol/L (vitamin D n  = 50, placebo n  = 50) 37 (27–50) years <75 nmol/L; 52 (42–66) nmol/L 18.0 (15.8–21.5) nmol/L TT measured using mass spectrometry 12 weeks 20,000 IU/week (~2,857 IU/day) vs placebo No significant effect 107 (89–119) nmol/L Data are given as mean ±  s.d. or median (IQR) unless otherwise stated. 25(OH)D, 25 hydroxyvitamin D; BMI, body mass index; IU, international unit; LH, luteinizing hormone; RCT, randomized controlled trial; TT, total testosterone. Summary of clinical intervention studies investigating the effects of vitamin D treatment on androgen levels in men. Data are given as mean ±  s.d. or median (IQR) unless otherwise stated. 25(OH)D, 25 hydroxyvitamin D; BMI, body mass index; IU, international unit; LH, luteinizing hormone; RCT, randomized controlled trial; TT, total testosterone. A small study investigating men with Klinefelter syndrome found no significant effect of vitamin D supplementation (vitamin D treatment n  = 8, vitamin D + testosterone treatment n  = 12) on androgen levels in men with baseline 25(OH)D <50 nmol/L ( 99 ). Similarly, Foresta and coworkers ( 100 ) investigated the effect of cholecalciferol (5000 IU per week) ( n  = 20) or calcidiol (4000 IU per week) ( n  = 46) in 66 patients with hypogonadism and 25(OH)D <50 nmol/L and found no significant effect on TT levels. In contrast, Canguven and coworkers ( 101 ) observed a significant increase in TT levels (12.46 ± 3.30 to 15.99 ± 1.84 nmol/L) in 102 middle-aged men with 25(OH)D <75 nmol/L who received an initial vitamin D dose (Ergocalciferol; oral solution 600,000 IU/1.5 mL) and followed a vitamin D treatment regime thereafter. Interestingly, the authors observed an increase of erectile dysfunction scores as well as a decrease in estradiol levels after treatment ( 101 ). Evidence from RCTs on vitamin D and TT is sparse. Pilz and coworkers ( 20 ) investigated the effects of 1 year of vitamin D supplementation (3332 IU daily) on androgens in 54 men (vitamin D n  = 31, placebo n  = 23) undergoing a weight reduction program. The authors observed a significant increase in TT levels, bioactive testosterone levels, and FT levels compared to baseline levels, whereas no significant change was found in the placebo group. The study included men with vitamin D deficiency (25[OH]D <50 nmol/L) and relatively low baseline TT levels (11.4 nmol/L). Of note, no statistical analysis on treatment effect (between group differences) was performed. In contrast, Heijboer and coworkers ( 86 ) failed to find an effect of vitamin D supplementation on serum TT concentrations in 3 independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3). Those studies were designed to investigate vitamin D effects on the renin-angiotensin-aldosterone system (study 1), effects of different vitamin D doses (study 2) and vitamin D effects on insulin sensitivity (study 3). In study 1, 92 subjects received vitamin D (2000 IU daily) or placebo for 6 weeks. In study 2, 49 vitamin D-deficient subjects were randomized to vitamin D (600 IU daily) or placebo for 16 weeks. In study 3, 43 vitamin D-deficient subjects received 1200 IU vitamin D daily or placebo for 16 weeks. Similarly, Jorde and coworkers ( 84 ) failed to show a significant vitamin D effect on androgen concentrations (TT and FT) in pooled data from 3 vitamin D RCTs performed in Tromsø with weight reduction, insulin sensitivity and depression scores as endpoints. In that study, serum 25(OH)D and androgens were measured in 282 men at baseline and after 6–12 months of vitamin D supplementation (20,000–40,000 IU weekly vs placebo). Recently, we presented results of the first RCT (Graz Vitamin D&TT-RCT) designed for the evaluation of vitamin D effects on serum androgens in men ( 102 ). In detail, we randomly assigned 100 men with TT levels ≥10.4 nmol/L and 25(OH)D levels <75 nmol/L to receive 20,000 IU/week of vitamin D3 ( n  = 50) or placebo ( n  = 50) for 12 weeks. We found no significant effect on androgen levels in these healthy men with relatively high TT levels at baseline. These results are in line with the Jorde and coworkers ( 84 ) as well as with the Heijboer and coworkers study ( 86 ) but contradict previous promising findings from the Pilz and coworkers ( 20 ) study. Those differences might be related to different study designs and subjects. Although both studies used similar doses (2857 IU/day Lerchbaum and coworkers ( 102 ) vs 3332 IU/day Pilz and coworkers ( 20 ), respectively), the Graz Vitamin D&TT-RCT ( 102 ) investigated vitamin D effects after 12 weeks vs vitamin D effects after 1 year in the Pilz and coworkers study ( 20 ). Further, the Graz Vitamin D&TT-RCT ( 102 ) investigated men with 25(OH)D levels <75 nmol/L, whereas Pilz and coworkers ( 20 ) included subjects with 25(OH)D levels <50 nmol/L. Other differences are related to the study participants (healthy men vs significant weight loss in obese subjects), baseline TT levels (19.1 nmol/L vs 11.4 nmol/L) and the method used for TT measurements (mass spectrometry vs immunoassay) for the Graz Vitamin D&TT-RCT report and the Pilz and coworkers study, respectively. In summary, to date, there is only 1 RCT showing increased androgen levels after vitamin D supplementation ( 20 ); however, vitamin D effects on androgen levels have not been the primary outcome of this study. It should, therefore, be noted that only 1 RCT was specifically designed for the investigation of vitamin D effects on TT levels ( 102 ). As this RCT investigated men with relatively high baseline TT levels, a vitamin D effect on TT levels in hypogonadal men or men with low normal TT levels cannot be excluded. This issue is addressed in the second arm of the Graz Vitamin D&TT-RCT (ClinicalTrials.gov Identifier Nbib1748370), results are expected in 2018. Further, the Graz Vitamin D&TT-RCT investigated a cohort of men with relatively high baseline 25(OH)D levels. Thus, vitamin D effects in men with severe vitamin D deficiency cannot be excluded. Given the fact that in healthy middle-aged men a U-shaped association of vitamin D levels with hypogonadism has been observed ( 95 ), one might speculate that a RCT aiming at target 25(OH)D levels between 75 and 100 nmol/L would provide different results. In summary, evidence from RCTs on vitamin D and TT is sparse and revealed conflicting results. We therefore recommend further investigation of potential vitamin D effects on androgen levels in various cohorts including hypogonadal men with severe vitamin D deficiency.

As outlined above, vitamin D might play an important role in androgen metabolism as well as in metabolic and reproductive processes in PCOS women. Indeed, in PCOS women some RCTs revealed promising results regarding vitamin D effects on metabolic as well as on fertility aspects. Nevertheless, considering previous inconsistent results as well as the large differences in study design and PCOS populations (i.e. PCOS phenotypes), large-scale RCTs in well-defined PCOS populations with clearly defined end points are needed before a general recommendation regarding 25(OH)D measurement and vitamin D supplementation in PCOS can be made. Similarly, existing evidence from available RCTs evaluating the effect of vitamin D supplementation on androgen levels in men is insufficient to recommend measurement of 25(OH)D levels or vitamin D supplementation in hypogonadal men. Still, we cannot exclude vitamin D effects on androgen levels in men with low TT levels or in men with severe vitamin D deficiency. This question remains to be answered in future RCTs.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Considering the high prevalence of an insufficient vitamin D status in many populations as well as the potential link between low vitamin D status and adverse health outcomes ( 1 ), vitamin D deficiency is classified as an important public health problem ( 2 ). Vitamin D has been well known for its role in maintaining calcium homeostasis and promoting bone mineralization ( 2 ). Beyond the established relationship between vitamin D deficiency and musculoskeletal diseases, evidence is accumulating that vitamin D deficiency is also a risk marker for insulin resistance ( 3 ), cardiovascular disease ( 4 ), infectious and autoimmune diseases ( 1 ), cancer ( 5 ), increased mortality ( 2 ) as well as decreased fertility ( 6 ). Infertility is a complex disorder with significant medical, psychosocial and economic aspects ( 7 ), which affects about 15% of couples ( 8 ). One major cause of female infertility is polycystic ovary syndrome (PCOS). Women affected by PCOS frequently suffer from oligo- or anovulation as well as from obesity and insulin resistance ( 9 , 10 ). Thus, PCOS women are considered to be at high risk for metabolic diseases such as type 2 diabetes mellitus (DM) and metabolic syndrome as well as for cardiovascular diseases ( 11 ). Interestingly, there is accumulating evidence showing an association of vitamin D status with pathogenesis, signs and symptoms of PCOS ( 3 , 12 ). Besides the above mentioned important causes of female infertility, population-based studies found that in 30–40% of infertile couples, the underlying cause is the male factor ( 13 ). One major aspect regarding male fertility is the complex interaction between pituitary gland and testis. Of note, testosterone is not only an important regulator of spermatogenesis, but decreasing testosterone levels might also contribute to many adverse aspects of male aging ( 14 ). It is therefore worth mentioning that similar to the above stated association of low vitamin D status with adverse health outcomes, several lines of evidence suggest that low testosterone levels are associated with adverse events including higher cardiovascular and all-cause mortality ( 15 , 16 , 17 , 18 ). In this context, it should be noted that androgen and vitamin D metabolism seem to be associated ( 19 , 20 ). Considering the potential link between vitamin D and human fertility, we performed this systematic review summarizing current literature on vitamin D, PCOS and androgen metabolism in men.