Fig 1. Vitamin D supplement (Image from freepik <a href=”https://www.freepik.com/free-photos-vectors/food”>Food photo created by whatwolf – www.freepik.com</a>)

Infertility has a range of causes, which include lifestyle, eating habits or environmental factors (1). One current avenue of interest for environmental cause for infertility is vitamin D, with an estimated 20-52% of women of reproductive age being vitamin D-deficient (2).

Vitamin D is a fat-soluble steroid hormone with important roles when acting as either a vitamin or a hormone, and so it is required for a healthy life. Its main source, which constitutes to approximately 80-90% of the total, is derived from sunlight-induced production in the skin, however small amounts are also obtained from dietary sources and/or supplements (2). This may derive from plants, fungi, fatty fish or cod-liver oil (2). Vitamin D is metabolized to 25(OH)D, which can be used to assess blood levels: 30 ng/mL and above is considered to be sufficient, 20-29 ng/mL insufficient, and 20 ng/mL indicates a deficiency (2). People with vitamin D deficiency can take supplements in order to reach normal levels; adults need 600 international units (IU) of vitamin D each day, and yet there is evidence that the majority of people present deficient levels (3). Hypervitaminosis D (vitamin D toxicity) could be caused by excessive vitamin D supplementation, which may result in physical damage (bone pain, abdominal pain, tiredness, constipation or diarrhea…etc). Nevertheless, if the appropriate dose is taken, no harm is expected and no such symptoms should appear (4).

The main function of vitamin D is to keep bones strong and healthy. It helps to absorb calcium and phosphate, minerals that are necessary for the proper functioning of cells (1, 2). In addition, they also promote bone mineralization and increase the activity of osteoclasts (bone cells) (5). Vitamin D regulates levels of parathyroid hormone, involved in reabsorption of bone tissue (1) (Fig. 2). 

Vitamin D also displays additional functions in the intestine, kidney, pancreas, the pituitary gland and the immune system. It has a known an effect on female reproductive tissues such as the ovary, endometrium, granulosa cells, Fallopian tube cells and placenta cells (5). Additionally, it has been related with the production of female sex hormones (oestrogen, progesterone and hCG) and it is involved in the fertilisation process (1, 5) (Fig.1).

In male tissues, vitamin D is detected in testicular tissue, sperm, epididymis, seminal vesicle and prostate. However, its effects on male reproductive tissues are not yet well understood (5) (Fig.2).

 

Fig. 2. Vitamin D effects on different tissues. (a) Classical vitamin D effects. (b) Non-classical vitamin D effects (5).

VITAMIN D IN ANIMAL STUDIES IN REPRODUCTION

A popular model for human reproduction are rats, reason why several studies on vitamin D-deficient diet are currently performed on rats. These studies have shown a decrease in fertility with incomplete spermatogenesis in male rats (5).

In addition, female rats with a vitamin D-deficient diet have been observed to have an abnormal development of the uterus (hypoplasia), presenting an increased risk of pregnancy complications (5) and problems of the menstrual cycle, such as anovulation or deficiency of follicular development (6, 7).

CLINICAL OUTCOME: VITAMIN D AND HUMAN REPRODUCTION

Vitamin D is related with calcium metabolism, and calcium has been reported to play roles in oocyte activation and maturation (5). Moreover, the effect of calcium in endometrial cell differentiation, essential for blastocyst process, has also been described (5). 

Vitamin D also could have an effect on human reproduction, hypothesis supported by a relationship between fertility and the difference in exposure time to sunlight between seasons (2). Conception rate, ovulation rates and endometrial receptivity have all been shown to be higher in the summer and autumn compared to winter and spring (2, 5). In fact, higher birth rates are observed during the spring and summer months in Northern countries, which is thought to be associated with increased serum levels of vitamin D (2,5).

If vitamin D has an effect on human reproduction, it may impact on assisted reproductive technology (ART) outcomes.

VITAMIN D IN ART TREATMENTS

Some authors have suggested that vitamin D supplementation could become routine practice in ART, due to the improvements noted. Positive effects of vitamin D supplementation have been reported on endometrial quality and receptivity (1), as well as on both chemical and clinical pregnancy rates, which were found to be almost four times higher (2, 8). Nevertheless, Abedi and coauthors reported no difference regarding other assessed parameters, including number of oocytes and percentage of mature oocytes  (1).

One such study looked at the impact of vitamin D supplementation on chemical and clinical pregnancy rates in patients undergoing intracytoplasmic sperm injection (ICSI) (1). Rates of chemical and clinical pregnancy rates were improved by 10.7% and 82%, respectively (1). These and similar results suggest that vitamin D improves ICSI and could increase rates of live births and both chemical and clinical pregnancy rates (1, 7). On the contrary, other authors found no effect of vitamin D on ART outcomes (7), or they even found a negative association (8). Therefore, more studies are needed before routine recommendation or application of vitamin D is decided.

VITAMIN D AND EMBRYO QUALITY 

Women with normal or sufficient levels of vitamin D have been observed to present reduced embryo quality and lower pregnancy rate, when compared to patients with insufficient or deficient vitamin D status (although the authors urged further research before making any conclusions) (9). This finding could be due to high concentrations of vitamin D level decreasing glucose concentrations supplied to the cumulus-oocyte complex (COC), which could have a negative impact on embryo quality (9). In addition, an independent line of research was unable to find effects of vitamin D on neither fertilisation rate nor embryo quality on day 3 of development (1). Consequently, it is reasonable to expect more studies before conclusions on associations between embryo quality and vitamin D concentrations are stated.

VITAMIN D AND PREGNANCY AND MISCARRIAGE

Several studies found no associations between serum vitamin D levels and pregnancy rates or risk of miscarriage (2, 6), or a relation between vitamin D levels and time to conception (10). However, one of these studies did observe that lower concentration of vitamin D in plasma during the first trimester was related to miscarriage after gestational week 10 (10). Additionally, vitamin D supplementation could reduce the risk of obstetric complications such as gestational diabetes, pre-eclampsia, bacterial vaginosis and foetal growth restriction, and in the offspring reduction chance of rickets, asthma, reduced bone density and schizophrenia (2, 5, 7). 

Vitamin D deficiency has been shown to be associated with a decreased chance of live birth, without being related to clinical pregnancy and ongoing pregnancy (11). Moreover, vitamin D deficiency has been related to poor placentation, hypertensive disorders of pregnancy and foetal growth restriction (2). It has also been proposed to regulate embryo implantation (7), however, certain studies have found no relationship between pregnancy rate or risk of abortion (10). 

MALE FERTILITY AND VITAMIN D

There is evidence that vitamin D may be important for spermatogenesis, semen quality, sperm progressive motility (5, 7, 12), hyperactivation, testiculophaties and acrosome reaction (5, 7). Furthermore, men with poor vitamin D status (<10ng/mL) produce a lower proportion of motile, progressively motile and morphological normal spermatozoa when compared to men with normal vitamin D levels (>30ng/mL) (13).

CONCLUSION

Results about vitamin D and fertility are still inconclusive and further high-quality research is needed, since contradictory findings have been reported. Notably, the sample size of some studies carried out has been too small so far (9, 11).

Nevertheless, there is evidence that vitamin D may influence sperm quality as well as pregnancy rates, and so, further research on its effects on reproduction will be likely needed to improve the chances of achieving pregnancy. 

BIBLIOGRAPHY

  1. Abedi S, Taebi M, Nasr Esfahani MH. Effect of Vitamin D Supplementation on Intracytoplasmic Sperm Injection Outcomes: A Randomized Double-Blind Placebo-Controlled Trial. Int J Fertil Steril. 2019 Apr;13(1):18–23.
  2. Chu J, Gallos I, Tobias A, Tan B, Eapen A, Coomarasamy A. Vitamin D and assisted reproductive treatment outcome: a systematic review and meta-analysis. Hum Reprod. 2018 01;33(1):65–80.
  3. Office of Dietary Supplements – Vitamin D [Internet]. [cited 2019 Sep 29]. Available from: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
  4. Am I getting too much vitamin D? [Internet]. Vitamin D Council. [cited 2019 Sep 29]. Available from: https://www.vitamindcouncil.org/about-vitamin-d/am-i-getting-too-much-vitamin-d/
  5. Lerchbaum E, Obermayer-Pietsch B. Vitamin D and fertility: a systematic review. Eur J Endocrinol. 2012 May;166(5):765–78.
  6. De-Regil L, Palacios C, Lombardo LK, Peña-Rosas J. Vitamin D supplementation for women during pregnancy. Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD008873. 
  7. Pacis MM, Fortin CN, Zarek SM, Mumford SL, Segars JH. Vitamin D and assisted reproduction: should vitamin D be routinely screened and repleted prior to ART? A systematic review. J Assist Reprod Genet. 2015 Mar;32(3):323–35.
  8. Aleyasin A, Hosseini MA, Mahdavi A, Safdarian L, Fallahi P, Mohajeri MR, et al. Predictive value of the level of vitamin D in follicular fluid on the outcome of assisted reproductive technology. Eur J Obstet Gynecol Reprod Biol. 2011 Nov;159(1):132–7.
  9. Anifandis GM, Dafopoulos K, Messini CI, Chalvatzas N, Liakos N, Pournaras S, et al. Prognostic value of follicular fluid 25-OH Vitamin D and glucose levels in the IVF outcome. Reprod Biol Endocrinol. 2010; 8: 91
  10. Gaskins AJ, Chavarro JE. Diet and fertility: a review. American Journal of Obstetrics & Gynecology. 2018 Apr 1;218(4):379–89.
  11. Zhao J, Huang X, Xu B, Yan Y, Zhang Q, Li Y. Whether vitamin D was associated with clinical outcome after IVF/ICSI: a systematic review and meta-analysis. Reprod Biol Endocrinol [Internet]. 2018 Feb 9;16. 
  12. Yoshida M, Kawano N, Yoshida K. Control of sperm motility and fertility: diverse factors and common mechanisms. Cell Mol Life Sci. 2008 Nov;65(21):3446–57.
  13. Blomberg Jensen M, Bjerrum PJ, Jessen TE, Nielsen JE, Joensen UN, Olesen IA, et al. Vitamin D is positively associated with sperm motility and increases intracellular calcium in human spermatozoa. Hum Reprod. 2011 Jun;26(6):1307–17.