NCT01304927

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 A new, and yet unpublished cross sectional study of 300 young healthy Danish men showed that men with lower levels of serum VD have significantly lower number of normally developed and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 fertile men. Since VD deficiency is associated with increased mortality, regulation of aromatase, immune system, bone metabolism, glucose metabolism, cardiovascular system etc. our suggested clinical trial may also be able to evaluate several secondary endpoints in addition to the potential effect on semen quality.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
307

participants targeted

Target at P75+ for phase_2

Timeline
Completed

Started Feb 2011

Longer than P75 for phase_2

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

February 1, 2011

Completed
24 days until next milestone

First Submitted

Initial submission to the registry

February 25, 2011

Completed
3 days until next milestone

First Posted

Study publicly available on registry

February 28, 2011

Completed
3.8 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2014

Completed
1.4 years until next milestone

Study Completion

Last participant's last visit for all outcomes

May 1, 2016

Completed
Last Updated

June 8, 2016

Status Verified

June 1, 2016

Enrollment Period

3.8 years

First QC Date

February 25, 2011

Last Update Submit

June 6, 2016

Conditions

Male Infertility

Keywords

ReproductionSex hormonesGlucose metabolismBone metabolismCalciumSpermtestisboneendocrinology

Outcome Measures

Primary Outcomes (6)

  • semen quality

    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.

    150 days

  • sperm motility

    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

    150 days

  • sperm morphology

    Differences in percentage of spermatozoa with normal morphology assessed according to strict criteria between placebo and VD group.

    150 days

  • sperm concentration

    Differences in sperm concentration between placebo and VD group.

    150 days

  • total sperm count

    Differences in total sperm count between placebo and VD group.

    150 days

  • semen volume

    Differences in semen volume between placebo and VD group.

    150 days

Secondary Outcomes (39)

  • Inhibin-B

    90 and 150 days

  • Testosterone

    90 and 150 days

  • AMH

    90 and 150

  • estrogen

    90 and 150

  • LH

    90 and 150 days

  • +34 more secondary outcomes

Study Arms (2)

Cholecalciferol + calcium

ACTIVE COMPARATOR

Group of intervention: Each man will receive 300,000 IU (7500 ug) Cholecalciferol (VD3) orally once after blood and semen sampling and performed DXA scan. Thereafter they will receive VD tablets of 1,400 IU (35 ug) + 500 mg calcium daily for 3 months. At 3 months a clinical control and blood sampling will be performed, followed by continued daily intake of 1400 IU VD3 + 500 mg calcium. At end of treatment at five months after inclusion the men deliver two semen samples, have a blood sample drawn and a DEXA scan performed.

Drug: Cholecalciferol and calcium

placebo

PLACEBO COMPARATOR

Group receiving placebo: Each man will receive placebo oral mixture once after blood- and semen sampling and performed DXA scan. Thereafter they will receive placebo tablets daily for 3 months. At 3 months a clinical control and blood sampling will be performed, followed by continued daily intake of placebo. At end of treatment at five months after inclusion the men deliver two semen samples, have a blood sample drawn and a DEXA scan performed.

Other: Placebo

Interventions

Cholecalciferol and calciumDRUG

Initial one dose oral mixture of 300.000 IU Cholecalciferol followed by 5 months treatment with one tablet daily containing 35 ug Cholecalciferol and 500 mg calcium

Also known as: Inactive vitamin D
Cholecalciferol + calcium
PlaceboOTHER

microcrystalline cellulose maltodextrin Arachidis oil

placebo

Eligibility Criteria

Age18 Years+
Sexmale
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Male with an age \> 18 years old
  • Referred for male infertility with sperm concentration \>= 0.01 million/ml. Additionally, all men must have either sperm concentration \< 20 million/ml or \< 50% progressive motile spermatozoa or \< 12% morphological normal spermatozoa using strict criteria

You may not qualify if:

  • Men with chronic diseases (such as diabetes mellitus, Thyroid disease, endocrine disturbances in need of treatment, malignant disease, or diseases known to interfere with VD intake or very sensitive to VD intake (such as inflammatory disease with granuloma: sarcoidoses, tuberculosis, Wegeners, vasculitis, inflammatory bowel disease (Crohn's and colitis ulcerosa etc).
  • Men with present or previous malignant disease
  • If there is an indication for testis biopsy and it is planned or conducted within the next 6 months
  • Serum Calcium ion \> 1,35 mmol/l
  • Inhibin-B \< 30 pg/ml
  • Intake of vitamin D above 15 ug daily
  • Allergy towards vitamin D or arachidis oil (peanuts)
  • Men with total or partly obstructive oligospermia and men who had vasectomy performed
  • Criteria for drop out:
  • Abrogation of the treatment
  • Newly diagnosed endocrine, calcium metabolic disease, parathyroid, thyroid, diabetes or other endocrine disease in need of treatment
  • New malignant disease
  • Treatment with chemotherapy, immunomodulating therapy, salazopyrin
  • Oral or iv treatment with steroid hormones
  • Treatment with diuretics, antihypertensive treatment, treatment the heart, calcium channel blockers
  • +2 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (8)

  • Yahyavi SK, Toft FB, Probst-Drejer B, Boisen IM, Priskorn L, Jorgensen N, Juul A, Blomberg Jensen M. High Seminal Fluid Calcium Is Associated With Higher Sperm Concentration in Infertile Men and Men From the General Population. Andrology. 2026 Jan 14:e70172. doi: 10.1111/andr.70172. Online ahead of print.

    PMID: 41531256DERIVED

  • Wall-Gremstrup G, Holt R, Yahyavi SK, Jorsal MJ, Juul A, Jorgensen N, Blomberg Jensen M. High-dose vitamin D3 supplementation shows no beneficial effects on white blood cell counts, acute phase reactants, or frequency of respiratory infections. Respir Res. 2024 Jan 4;25(1):11. doi: 10.1186/s12931-023-02642-9.

    PMID: 38178229DERIVED

  • de Ligny W, Smits RM, Mackenzie-Proctor R, Jordan V, Fleischer K, de Bruin JP, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2022 May 4;5(5):CD007411. doi: 10.1002/14651858.CD007411.pub5.

    PMID: 35506389DERIVED

  • Holt R, Petersen JH, Dinsdale E, Knop FK, Juul A, Jorgensen N, Blomberg Jensen M. Vitamin D Supplementation Improves Fasting Insulin Levels and HDL Cholesterol in Infertile Men. J Clin Endocrinol Metab. 2022 Jan 1;107(1):98-108. doi: 10.1210/clinem/dgab667.

    PMID: 34508607DERIVED

  • Juel Mortensen L, Lorenzen M, Jorgensen A, Albrethsen J, Jorgensen N, Moller S, Andersson AM, Juul A, Blomberg Jensen M. Possible Relevance of Soluble Luteinizing Hormone Receptor during Development and Adulthood in Boys and Men. Cancers (Basel). 2021 Mar 16;13(6):1329. doi: 10.3390/cancers13061329.

    PMID: 33809538DERIVED

  • Juel Mortensen L, Lorenzen M, Jorgensen N, Andersson AM, Nielsen JE, Petersen LI, Lanske B, Juul A, Hansen JB, Blomberg Jensen M. Possible link between FSH and RANKL release from adipocytes in men with impaired gonadal function including Klinefelter syndrome. Bone. 2019 Jun;123:103-114. doi: 10.1016/j.bone.2019.03.022. Epub 2019 Mar 23.

    PMID: 30914274DERIVED

  • Blomberg Jensen M, Lawaetz JG, Petersen JH, Juul A, Jorgensen N. Effects of Vitamin D Supplementation on Semen Quality, Reproductive Hormones, and Live Birth Rate: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2018 Mar 1;103(3):870-881. doi: 10.1210/jc.2017-01656.

    PMID: 29126319DERIVED

  • Blomberg Jensen M, Gerner Lawaetz J, Andersson AM, Petersen JH, Nordkap L, Bang AK, Ekbom P, Joensen UN, Praetorius L, Lundstrom P, Boujida VH, Lanske B, Juul A, Jorgensen N. Vitamin D deficiency and low ionized calcium are linked with semen quality and sex steroid levels in infertile men. Hum Reprod. 2016 Aug;31(8):1875-85. doi: 10.1093/humrep/dew152. Epub 2016 Jun 19.

    PMID: 27496946DERIVED

MeSH Terms

Conditions

Infertility, Male

Interventions

CholecalciferolCalciumCalcifediol

Condition Hierarchy (Ancestors)

Genital Diseases, MaleGenital DiseasesUrogenital DiseasesInfertilityMale Urogenital Diseases

Intervention Hierarchy (Ancestors)

CholestenesCholestanesSteroidsFused-Ring CompoundsPolycyclic CompoundsSterolsVitamin DSecosteroidsMembrane LipidsLipidsMetals, Alkaline EarthElementsInorganic ChemicalsMetalsBlood Coagulation FactorsBiological FactorsHydroxycholecalciferols

Study Officials

  • Martin Blomberg Jensen, MD

    Department of growth and reproduction, Rigshospitalet

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
MD

Study Record Dates

First Submitted

February 25, 2011

First Posted

February 28, 2011

Study Start

February 1, 2011

Primary Completion

December 1, 2014

Study Completion

May 1, 2016

Last Updated

June 8, 2016

Record last verified: 2016-06

Locations

DK(1)