Effects of Vitamin D Supplementation on Semen Quality, Reproductive Hormones, and Live Birth Rate

A Randomized Clinical Trial

Martin Blomberg Jensen; Jacob Gerner Lawaetz; Jørgen Holm Petersen; Anders Juul; Niels Jørgensen

Disclosures

J Clin Endocrinol Metab. 2018;103(3):870-881. 

In This Article

Abstract and Introduction

Abstract

Context: Results of animal models and cross-sectional cohort studies have suggested a beneficial role for vitamin D in male reproduction.

Objective: Determine the effect of vitamin D and calcium supplementation on semen quality in infertile men with serum 25-hydroxyvitamin-D (25OHD) levels ≤50 nmol/L.

Design: A single-center, triple-blinded, randomized clinical trial.

Participants: A total of 1427 infertile men were screened to include 330; 1002 men did not meet inclusion criteria and 95 did not wish to participate.

Intervention: The active group received cholecalciferol 300,000 IU initially, then 1400 IU cholecalciferol and 500 mg of calcium daily for 150 days; the other group received placebo.

Results: Serum concentrations of 25OHD and 1,25-dihydroxyvitamin D3 were significantly higher in men in the treatment group compared with the placebo group. Vitamin D supplementation was not associated with changes in semen parameters, although spontaneous pregnancies tended to be higher in couples in which the man was in the treatment group [7.3% vs 2.4%, D5.0% (-0.6%; 10.5%)]. Vitamin D treatment in a subgroup of oligozoospermic men increased the chance for a live birth compared with placebo [35.6% vs 18.3%, D17.3% (1.6%; 32.9%)]. Moreover, serum inhibin B levels were higher in men deficient in vitamin D who were randomly assigned to receive high-dose vitamin D [193 pg/mL vs 143 pg/mL, D49 pg/mL (8; 91 pg/mL)]; however, the increase in sperm concentration was not significantly higher than in the placebo group (P = 0.07).

Conclusion: High-dose vitamin D supplementation did not improve semen quality in vitamin D–insufficient infertile men. The positive impact of vitamin D supplementation on live birth rate and serum inhibin B in oligozoospermic and vitamin D–deficient men may be of clinical importance and warrant verification by others.

Introduction

Infertility, defined as the inability to achieve a clinical pregnancy within 12 months of regular unprotected intercourse, is estimated to affect 15% of all couples globally.[1] Most couples are treated with assisted reproductive techniques (ARTs) such as intrauterine inseminations, in vitro fertilization (IVF), or intracytoplasmic sperm injection (ICSI) irrespective of the etiology.[2] ART ensures a live birth for 70% of couples after three attempts.[2,3] However, ART is very costly and a burden, particularly for the woman, owing to the invasive procedures and lengthy hormonal stimulation. Infertility attributable to the male partner accounts for ~50% of all cases of infertility; semen analysis is the most commonly used test for assessing male fertility.[1] According to the World Health Organization (WHO), men are classified as having impaired semen quality when sperm concentration is <15 million/mL (oligozoospermia), the number of motile spermatozoa is <40% (asthenozoospermia), or the percentage of morphologically normal spermatozoa is <4% (teratozoospermia).[4] Unfortunately, there exists no available treatment option to improve semen quality in most men.[5] However, an intensive search to identify endocrine and lifestyle factors influencing semen quality in adulthood provides some hope that male fertility potential and semen quality may be improved in some infertile men.[1,6,7]

The vitamin D receptor (VDR) is expressed in most organs, which suggests a broader role of vitamin D than only as a regulator of calcium homeostasis and bone health.[6,8] Vitamin D (cholecalciferol) is not biologically active; it has to be activated by hepatic 25-hydroxylation that converts cholecalciferol into the main circulating metabolite 25-hydroxyvitamin D (25OHD). Renal 1a-hydroxylase converts 25OHD into the active metabolite 1,25(OH)2D3 that binds and activates VDR.[6,8] Clinically, vitamin D status is determined by serum 25OHD concentrations that are associated with rickets, calcium absorption, and serum parathyroid hormone (PTH).[9,10]

Optimal vitamin D status has been discussed intensely for several years, but most clinicians recognize vitamin D deficiency defined by a threshold set at 25 nmol/L (10 ng/mL) and insufficiency at 50 nmol/L.[11] Study results in rodents with vitamin D deficiency or global genetic deletion of VDR/1a-hydroxylase[6,8] have shown impaired male fertility, which suggests a role for vitamin D in male reproduction. However, it has been suggested that impaired fertility in these animal models, at least in part, is caused by hypocalcemia, which often develops as a result of vitamin D deficiency. The role of calcium was best illustrated by the partial rescue of the reproductive phenotype in rodent models after supplementation with a high calcium diet.[12–15] Low vitamin D status has also been associated with impaired semen quality in humans.[16,17] Infertile men with vitamin D deficiency had significantly lower sperm production and motility compared with men having normal vitamin D status.[18,19] Interestingly, the serum inhibin B level was also lower in men with vitamin D deficiency, which may be important because serum inhibin B also serves clinically as a quantitative marker of spermatogenesis.[19,20]

Combined, these data suggest that vitamin D supplementation may improve sperm production and sperm motility. In this study, we randomly assigned 330 infertile men with vitamin D insufficiency to receive either placebo or a high dose of vitamin D for two full lengths of spermatogenesis to compare the effects on semen quality, reproductive hormones, and live birth rate.

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