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

Discussion

In this study, we demonstrated that a single dose of 300,000 IU of vitamin D followed by 1400 IU of vitamin D and 500 mg of calcium daily for 150 days had no effect on semen quality and serum FSH or inhibin B levels in infertile men compared with placebo. The treatment regimen proved to be a safe way to correct vitamin D insufficiency in young infertile men having a low risk of fractures and falls. Men in the treatment group reached, on average, serum 25OHD concentrations of 89 nmol/L, which, for most purposes, can be considered optimal.[26] By the end of the study, the placebo group had a mean 25OHD concentration of 51 nmol/L, which was significantly lower than in the treatment group. The observed difference in vitamin D status between the study arms was also reflected in serum concentrations of total and ionized calcium, 1,25(OH)2D3, and PTH, which demonstrated that the intervention was efficient. However, it also illustrates that 50% of the men in the placebo group reached vitamin D sufficiency during the study period. The best explanation for the increase in vitamin D status in the placebo group is seasonal variation, because most men were included during winter and spring, and endogenous vitamin D synthesis after ultraviolet-B light exposure increased during the study period.

Semen quality was a soft end point[27] and not an optimal predictor of male fertility potential.[27,28] However, it is still in clinical use because no better alternatives exist. Particularly, total sperm count and sperm concentration are prone to interindividual and intraindividual variation, which could compromise the conclusion made from this study.[29] To counteract this intraindividual variability, two semen samples from each participant were analyzed before and after intervention.

Moreover, live-birth rate was used as a hard secondary end point for male fertility because we had no influence on the ART treatment of the women and, therefore, assumed that the proportion of female fertility problems by chance would be comparable in the two study arms. The live-birth rate in couples that included men in the treatment arm was not higher than in couples that included men in the placebo arm. Although the number of spontaneous pregnancies was almost threefold, it was not statistically significantly higher in vitamin D–treated men. The high number of spontaneous pregnancies is remarkable because the couples attempted to conceive naturally for >26 months before inclusion.[30,31] Moreover, men in the treatment group had fewer spermatozoa with normal morphology and had lower sperm motility compared with men in the placebo group before the start of the intervention, which theoretically would augment their fertility problem compared with the placebo group. This prompted us to investigate the live-birth rate in subgroups of men with oligozoospermia, because this would allow comparison of men with comparable semen quality from the two study arms. The live-birth rate was almost twice as high in the treatment group compared with men in the placebo arm in this subgroup. Still, the observed effects of vitamin D and calcium supplementation on spontaneous pregnancies and live-birth rates cannot be explained by improved semen quality. This implies that the positive effect on live-birth rate either could be a chance finding or that activated vitamin D is able to improve gamete function in a yet-unidentified manner. The last suggestion is supported by the presence of VDR and vitamin D metabolizing enzymes preferentially in good-quality spermatozoa.[32–34] One of the beneficial effects of 1,25(OH)2D3 on sperm function could be by lowering DNA fragmentation, although our small pilot study showed no striking differences between the vitamin D and placebo groups.

It is reasonable to assume that vitamin D and calcium supplementation may have a more pronounced effect on semen quality in men with vitamin D deficiency rather than in men with mild vitamin D insufficiency. This suggestion is corroborated by the baseline characteristics of the 1427 men screened, of whom 330 were included in this study. The baseline characteristics showed that only men with severe vitamin D deficiency had lower semen quality and inhibin B levels than men with normal vitamin D status.[19] These findings are in accordance with those of previous studies in both men and animals that have linked impaired male fertility with severe vitamin D deficiency.[6,12,19] Our analyses of the prespecified subgroup of vitamin D deficiency found that men in the treatment group, as expected, had an increase in serum concentrations of 25OHD and 1,25(OH)2D3 compared with men in the placebo group. It is noteworthy that men in the placebo arm actually augmented their vitamin D deficiency, as illustrated by their serum 25OHD and 1,25(OH)2D3 levels, which remained low and resulted in a compensatory increase in PTH levels at day 150 to maintain serum calcium levels.

Despite these changes in calcium and vitamin D homeostasis, no statistically significant differences in total sperm count or sperm concentration were found between the two study arms at day 150. However, the confidence intervals were large and revealed a clinically important effect, indicated by the two- to threefold higher median total sperm count and sperm concentration in vitamin D–deficient men treated with vitamin D and calcium compared with those in the placebo group.

The putative beneficial effect of vitamin D on sperm production was supported by a significantly higher serum inhibin B concentration at day 150 in men in the treatment group compared with the placebo group. Moreover, the inhibin B-to-FSH ratio was borderline statistically significantly higher, and men fathering a live birth in the treatment group had higher vitamin D status from the start of the study than men who did not father a live birth.

A fundamental role of vitamin D for male reproductive function has been indicated by previous studies showing direct effects of 1,25(OH)2D3 on germ cells, spermatozoa, epididymis, and prostate,[6] and the impaired fertility in vitamin D–deficient animals, which only can be fully rescued by supplementation of vitamin D rather than 1,25(OH)2D3 or calcium.[12,35] The observed effect on serum inhibin B concentration and putative impact on sperm production in vitamin D–deficient infertile men indicates the main target of 25OHD and 1,25(OH)2D3 may be the gonad rather than the epididymis, because there was no effect on sperm motility. This suggestion is in line with a recent study showing that vitamin D metabolites could not be detected in the seminal fluid,[33] which highlights that male gametes are exposed to vitamin D metabolites mainly in the testis and then are not exposed again until reaching the female reproductive tract. Moreover, the suggested increase in sperm production in vitamin D–deficient men may provide some explanation for the higher number of live births and spontaneous pregnancies after treatment with vitamin D plus calcium. The observed impact on live-birth rate and inhibin B is of potential clinical interest but cannot be regarded as hard evidence because the results are based on findings in a prespecified subgroup and not the primary end point.

Other limitations of this study include the 80% completion rate of telephone interviews, insufficient power to investigate the impact of vitamin D deficiency on sperm production, and the high number of men excluded because they had comorbidities, which limit generalizability to most cohorts of infertile men. The main strengths of this study are the single-center design, use of a single laboratory, efficient intervention, two semen samples analyzed before and after intervention, good compliance, high completion rate, and a long follow-up after completion of the intervention to validate the live-birth rate.

In conclusion, this study shows that for men with vitamin D insufficiency, supplementation with vitamin D and calcium had no effect on semen quality or on live-birth rate. However, vitamin D treatment increased serum inhibin B concentration and resulted in an insignificant increase in sperm production in infertile men with vitamin D deficiency. Vitamin D treatment was also associated with higher live-birth rate in couples in which the man had oligozoospermia compared with those men in the placebo arm, which may be of clinical importance if this observation can be validated by others. Before vitamin D supplementation can be recommended routinely as part of the treatment of male infertility, new clinical studies are required to investigate whether daily highdose vitamin D supplementation to the man and/or woman influences the function of the male gamete and, thereby, increases the chance of spontaneous pregnancies and increases live-birth rates.

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