Clinical Trial: Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Vitamin D Supplementation and Male Infertility: The Copenhagen Bone-Gonadal Study a Double Blinded Randomized Clinical Trial

Brief Summary: Today, it is evident that vitamin D (VD) has more widespread effects than the classical actions related to bone mineralization and calcium homeostasis1. VD deficiency results in impaired reproductive performance in various species of animals, and recently the investigators have shown that the VD receptor (VDR), activating (CYP2R1, CYP27A1, CYP27B1) and inactivating (CYP24A1) enzymes are expressed in the human testis, epididymis, seminal vesicle, prostate and spermatozoa. Our following functional studies showed that VD increases intracellular calcium in mature spermatozoa, and hence may be important not only for spermatogenesis but also for sperm maturation. A new, and yet unpublished cross sectional study of 300 young healthy Danish men showed that men with lower levels of serum VD have significantly lower number of normally developed and motile spermatozoa. Hitherto, most cases of male infertility have been classified as "idiopathic", and infertile couples have been referred to symptomatic treatment at infertility clinics. These fertility treatments are often physically demanding for the female partner as well as expensive for the health care system. Any treatment that might improve semen quality of involuntary infertile men would be beneficial both for the infertile couples and the society in general. Our findings that VD may play a role for human semen quality have not yet been tested clinically. However, if VD supplementation proves efficient this opens for the first time for a causal, safe and cheap treatment of at least some cases of "idiopathic" impaired semen quality. The investigators believe our new human data supported by the results from the VD deficient and VDR KO animal studies and the high proportion of VD deficient Danish men provide sufficient evidence to initiate a randomized clinical trial of VD supplementation to infertile men. Infertile men have also have unfavorable altered levels of sex hormones and higher mortality than fe

Detailed Summary:

Background In 2008, approximately 8% of all newborn children were conceived by assisted reproduction. Intracytoplasmatic sperm injection (ICSI) accounts for ~50% of all treatments and is mainly used in cases of severely reduced semen quality. This is in many cases most likely caused by prenatal factors adversely affecting the developing testicles, and it is therefore unlikely that any treatment of adult men will be able to completely normalize their semen quality. However, less would also be clinically relevant. If reduced semen quality could be improved prior to any assisted reproduction a less invasive treatment would be needed. Eg. classical in vitro fertilization (IVF) rather than ICSI, simple intrauterine insemination (IUI) rather than IVF or natural conception rather than IUI.

Several endocrine factors have been implicated in sperm production and maturation, but little is known about the potential role of VD. VD is a key regulator of calcium homeostasis and bone mineralization, although expression of the vitamin D receptor (VDR) in various tissues has been related to several diverse actions. VD affects reproduction in several animal species, convincingly shown in rodents, where VD deficiency in male rats resulted in reduced sperm counts, and female rats inseminated with semen from VD deficient male rats had lower fertility rates. The impaired reproductive performance is reversible and can be corrected either by supplying VD or by normalizing calcium levels. Supported by VDR knockout mice, which showed decreased sperm counts, reduced sperm motility and histological abnormalities of the testis, which unlike the VD deficient male rats only partly can be restored by calcium supplements.

The investigators have recently shown expression of VDR and the VD metabolizing enzymes in the human testis, ejaculatory tract and in ma
Sponsor: Rigshospitalet, Denmark

Current Primary Outcome:

  • semen quality [ Time Frame: 150 days ]
    difference in semen quality (semen variables total sperm count, sperm concentration, sperm motility, sperm morphology and semen volume) between VD and placebo treated men after 150 days of treatment.
  • sperm motility [ Time Frame: 150 days ]
    Differences in Sperm motility (ABC) and progressive sperm motility (AB) between placebo and VD group, supported by other motility measures such as length of penetration in egg media and difference in motility over time (3-5 hours from ejaculation)between VD and placebo treated men
  • sperm morphology [ Time Frame: 150 days ]
    Differences in percentage of spermatozoa with normal morphology assessed according to strict criteria between placebo and VD group.
  • sperm concentration [ Time Frame: 150 days ]
    Differences in sperm concentration between placebo and VD group.
  • total sperm count [ Time Frame: 150 days ]
    Differences in total sperm count between placebo and VD group.
  • semen volume [ Time Frame: 150 days ]
    Differences in semen volume between placebo and VD group.


Original Primary Outcome:

  • semen quality [ Time Frame: 150 days ]
    difference in semen quality (semen variables total sperm count, sperm concentration, sperm motility, sperm morphology and semen volume) between VD and placebo treated men after 150 days of treatment.
  • sperm motility [ Time Frame: 150 days ]
    Differences in Sperm motility (ABC) and progressive sperm motility (AB) between placebo and VD group, supported by other motility measures such as length of penetration in egg media and difference in motility over time (3-5 hours from ejaculation)between VD and placebo treated men
  • sperm morphology [ Time Frame: 150 days ]
    Differences in percentage of spermatozoa with normal morphology assesed according to strict criteria between placebo and VD group.
  • sperm concentration [ Time Frame: 150 days ]
    Differences in sperm concentration between placebo and VD group.
  • total sperm count [ Time Frame: 150 days ]
    Differences in total sperm count between placebo and VD group.
  • semen volume [ Time Frame: 150 days ]
    Differences in semen volume between placebo and VD group.


Current Secondary Outcome:

  • Inhibin-B [ Time Frame: 90 and 150 days ]
    Difference in serum levels of Inhibin B between placebo and VD group after 90 and/or 150 days
  • Testosterone [ Time Frame: 90 and 150 days ]
    Difference in serum levels of total and free testosterone between placebo and VD group after 90 and/or 150 days
  • AMH [ Time Frame: 90 and 150 ]
    Difference in serum levels of anti-müellerian hormone (AMH) between placebo and VD group after 90 and/or 150 days
  • estrogen [ Time Frame: 90 and 150 ]
    Difference in serum levels of estrogen (estradiol) between placebo and VD group after 90 and/or 150 days
  • LH [ Time Frame: 90 and 150 days ]
    Difference in serum levels of lh (luteinizing hormone) between placebo and VD group after 90 and/or 150 days
  • FSH [ Time Frame: 90 and 150 days ]
    difference in FSH (follicle stimulating hormone) between placebo and VD group after 90 and/or 150 days
  • SHBG [ Time Frame: 90 and 150 days ]
    difference in SHBG (sex hormone binding hormone) between placebo and VD group after 90 and/or 150 days
  • DXA scan [ Time Frame: 150 days ]
    difference in fat mass, fat free mass, muscle mass and bone mineral density evaluated by full body DXA scan between placebo and VD group after 150 days
  • Circulating metabolites of Vitamin D [ Time Frame: 90 and 150 days ]
    difference in the following VD metabolites inactive VD2 and VD3,25-hydroxy-VD2, 25-hydroxy-VD3, 1,25(OH)2D3, 24,25(OH)2D3, and 1,24,25(OH)2D3 between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • PTH [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of PTH (parathyroid hormone between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • alkaline phosphatase [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of alkaline phosphatase (also bone specific subtype) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • calcium [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of calcium ( meaning total calcium, calcium ion and albumin corrected calcium) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • phosphate [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of phosphate between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • FGF23 [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of FGF23 (both intact and fragmented) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • Klotho [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of klotho (also subtypes) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • osteocalcin [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of osteocalcin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • osteopontin [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of osteopontin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • Rank-L [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of Rank-L between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • calcitonin [ Time Frame: 90 and 150 days ]
    difference in the following serum levels of calcitonin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
  • bone markers [ Time Frame: 

    Original Secondary Outcome:

    • Inhibin-B [ Time Frame: 90 and 150 days ]
      Difference in serum levels of Inhibin B between placebo and VD group after 90 and/or 150 days
    • Testosterone [ Time Frame: 90 and 150 days ]
      Difference in serum levels of total and free testosterone between placebo and VD group after 90 and/or 150 days
    • AMH [ Time Frame: 90 and 150 ]
      Difference in serum levels of anti-müellerian hormone (AMH) between placebo and VD group after 90 and/or 150 days
    • estrogen [ Time Frame: 90 and 150 ]
      Difference in serum levels of estrogen (estradiol) between placebo and VD group after 90 and/or 150 days
    • LH [ Time Frame: 90 and 150 days ]
      Difference in serum levels of lh (luteinizing hormone) between placebo and VD group after 90 and/or 150 days
    • FSH [ Time Frame: 90 and 150 days ]
      difference in FSH (follicle stimulating hormone) between placebo and VD group after 90 and/or 150 days
    • SHBG [ Time Frame: 90 and 150 days ]
      difference in SHBG (sex hormone binding hormone) between placebo and VD group after 90 and/or 150 days
    • DXA scan [ Time Frame: 150 days ]
      difference in fat mass, fat free mass, muscle mass and bone mineral density evaluated by full body DXA scan between placebo and VD group after 150 days
    • Circulating metabolites of Vitamin D [ Time Frame: 90 and 150 days ]
      difference in the following VD metabolites inactive VD2 and VD3,25-hydroxy-VD2, 25-hydroxy-VD3, 1,25(OH)2D3, 24,25(OH)2D3, and 1,24,25(OH)2D3 between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • PTH [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of PTH (parathyroid hormone between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • alkaline phosphatase [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of alkaline phosphatase (also bone specific subtype) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • calcium [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of calcium ( meaning total calcium, calcium ion and albumin corrected calcium) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • phosphate [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of phosphate between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • FGF23 [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of FGF23 (both intact and fragmented) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • Klotho [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of klotho (also subtypes) between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • osteocalcin [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of osteocalcin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • osteopontin [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of osteopontin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • Rank-L [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of Rank-L between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • calcitonin [ Time Frame: 90 and 150 days ]
      difference in the following serum levels of calcitonin between placebo and VD group after 90 and/or 150 days and between the initial level (day 0) and 90 and 150 days in both arms.
    • bone markers [ Time Frame: 

      Information By: Rigshospitalet, Denmark

      Dates:
      Date Received: February 25, 2011
      Date Started: February 2011
      Date Completion:
      Last Updated: June 6, 2016
      Last Verified: June 2016