LISBON, Portugal — Vitamin D supplementation leads to a significant increase of estradiol levels and a significant decrease of sex-steroid-hormone–binding globulin (SHBG) in middle-aged men with normal testosterone levels, according to the results of a randomized controlled trial presented here at the European Congress of Endocrinology (ECE) 2017. Results in men with low testosterone levels, who formed the other arm of the double-blind, placebo-controlled trial, are expected later this year. Presenting the initial results of the first study of its kind, lead investigator Elisabeth Lerchbaum, MD, from the Medical University of Graz, Austria, remarked that looking at the metabolism of vitamin D could open up new avenues of treatment. "Vitamin D supplementation might be a safe and affordable treatment option in polycystic ovary syndrome (PCOS) or might support couples who want to have children." Men with normal testosterone levels showed an SHBG decrease from 43.2 nmol/L to 40.9 nmol/L (P < .05) in group randomized to receive vitamin D vs 44.0 nmol/L to 41.9 nmol/L in the placebo group; the latter difference wasn't significant. Regarding the increase in estradiol and decrease in SHBG levels, she added that it was important to explore in more detail the changes seen in levels of estradiol and SHBG in healthy men. "We have observed this for the first time with these results, and we expect to see a more pronounced effect in hypogonadal men when these results become available." In explaining the rationale for the trial, Dr Lerchbaum said that prior studies show that vitamin D receptors and vitamin D–metabolizing enzymes are expressed in reproductive tissues and that vitamin D is involved in the production and maturation of sperm cells, the maturation of egg cells, and of the uterine lining in preparation for pregnancy, as well as the production of estrogen and testosterone in women and men. She added that in vitro fertilization (IVF) is less effective in vitamin D–deficient couples than in couples with sufficient vitamin D levels and that low vitamin D levels are linked with a poor semen quality in men. As a reflection of this, "IVF is more successful in the summer and autumn (vitamin D levels are higher) than in winter and spring," she said. Vitamin D Supplementation for Low Vitamin D The trial discussed at this year's ECE meeting evaluated the effect of vitamin D supplementation on sex steroid levels in men with normal testosterone levels. Of the participating men, 100 had total testosterone levels <3.0 ng/mL (defined as low testosterone) and 25(OH)D <30 ng/mL and 100 had testosterone levels ≥3.0 ng/mL (controls defined as having normal testosterone) and 25(OH)D <30 ng/mL. "All participants were required to have low vitamin D levels." Participants in the normal-testosterone group had an average age of 39 years, and body mass index 25.3 kg/m2, level of 25(OH)D 21.3 ng/mL, and total testosterone level 5.5 ng/mL. They were randomized to receive either 20,000 IU cholecalciferol (vitamin D3) weekly or placebo for 12 weeks. At that point, participants were evaluated for the primary end point of total testosterone level and secondary end points of levels of free testosterone, SHBG, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Metabolic indicators including insulin resistance, insulin sensitivity, and lipids were measured, as were fat and lean mass, as well as physical and psychological symptoms, the analyses of which are ongoing. Dr Lerchbaum reported the results in men with normal levels of testosterone: "We found no significant effect on testosterone levels in the healthy men (P > .05), which surprised us; likewise that there was an increase in estradiol. When we obtain the results in the low-testosterone men we hope we will see an effect. However, in our men with normal testosterone levels we did see a decrease in SHBG levels and an increase in estradiol levels." Testosterone is converted to estradiol, and SHBG binds testosterone and estradiol, Dr Lerchbaum observed, but only the unbound fraction of hormones is biologically active. Effectively, the lower SHBG levels result in more bioavailable testosterone. "We think that low SHBG levels should be an advantage for these men because they have more biologically active hormone." A literature search showed us that men with low estradiol also have low vitamin D levels, so this fits," added Dr Lerchbaum. "However, we need to ask, are these relationships clinically relevant?" "Maybe. Sufficient estradiol levels are important for the feedback mechanism with hypothalamus and the pituitary gland (LH and FSH levels)," she said. The exact mechanisms remain to be determined and are subject of further studies. Alper Gurlek, MD, from Hacettepe University Hospital, Ankara, Turkey, commented on the findings as session moderator. "It may be speculated that the decrease in SHBG and the resultant increases in free testosterone levels might help improve the hypogonadism problem and fertility in these hypogonadal men." Dr Gurlek also noted that there might be benefits for bones. "The increase in free estradiol levels might also be beneficial for the bones of these men, because estradiol is useful in the maintenance of bone mass not only in women, but also in men." Mary Ann McLaughlin, MD, from Mount Sinai Hospital, New York, NY, is a cardiologist with an interest in research in the field of vitamin D supplementation and testosterone levels. She pointed out that clinical investigations have also demonstrated a link between low serum 25-hydroxyvitamin D and erectile dysfunction. "In the current study, interestingly, supplementation with oral vitamin D had a positive effect on vitamin D and estradiol levels and decreased SHBG," she said. "Although this study did not include enough subjects to give definitive conclusions, it generates hypotheses that would benefit from further investigation." Drs Lerchbaum, Gurlek, and McLaughlin have declared no relevant financial relationships. Source
