Vitamin D Supplementation and Male Infertility: The Copenhagen Bone-Gonadal Study a Double Blinded Randomized Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 307
- 试验地点
- 1
- 主要终点
- semen quality
研究概览
简要总结
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 A new, and yet unpublished cross sectional study of 300 young healthy Danish men showed that men with lower levels of serum VD have significantly lower number of normally developed and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.
详细描述
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 mature spermatozoa. The investigators subsequently showed that VD in physiological concentrations increased intracellular calcium in spermatozoa. VD acts through a rapid non-genomic response and the VD induced increase in calcium may be crucial for the spermatozoa, because VD induced sperm motility and the acrosome reaction. Expression analysis of spermatozoa from fertile and infertile men showed that men with impaired semen quality have fewer that can metabolize VD than normal men(p < 0.0005) making presence of one of the proteins a potential marker of semen quality. Furthermore, the investigators have just completed a cross sectional study of 300 young men from the general population and found that low serum VD was associated with reduced sperm motility and morphology.
SETTING, SCIENTIFIC PLAN AND RECRUITMENT Participants will be included among men referred to the Department of Growth and Reproduction (dept. of GR), Rigshospitalet (RH) for evaluation of male infertility
DESIGN This is a prospective, double blinded, two-arm randomized controlled trial
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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 25-hydroxy-D3 > 50 nmol/l at the time of inclusion
- •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
- •Development of vitamin d intoxication
- •If testis biopsy is performed or other surgery in the genital region during the trial
研究组 & 干预措施
Cholecalciferol + calcium
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.
干预措施: Cholecalciferol and calcium (Drug)
placebo
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.
干预措施: Placebo (Other)
结局指标
主要结局
semen quality
时间窗: 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
时间窗: 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
时间窗: 150 days
Differences in percentage of spermatozoa with normal morphology assessed according to strict criteria between placebo and VD group.
sperm concentration
时间窗: 150 days
Differences in sperm concentration between placebo and VD group.
total sperm count
时间窗: 150 days
Differences in total sperm count between placebo and VD group.
semen volume
时间窗: 150 days
Differences in semen volume between placebo and VD group.
次要结局
- Predefined Subgroup analyses(day 90 and 150)
- FSH(90 and 150 days)
- SHBG(90 and 150 days)
- DXA scan(150 days)
- Circulating metabolites of Vitamin D(90 and 150 days)
- PTH(90 and 150 days)
- alkaline phosphatase(90 and 150 days)
- calcium(90 and 150 days)
- phosphate(90 and 150 days)
- estrogen(90 and 150)
- LH(90 and 150 days)
- Inhibin-B(90 and 150 days)
- Testosterone(90 and 150 days)
- AMH(90 and 150)
- FGF23(90 and 150 days)
- Klotho(90 and 150 days)
- osteocalcin(90 and 150 days)
- osteopontin(90 and 150 days)
- Rank-L(90 and 150 days)
- calcitonin(90 and 150 days)
- bone markers(90 and 150 days)
- change in the method of assisted reproductive technique or number of pregnancies(90 and 150 days)
- change in the number of spontaneous pregnancies(90 and 150 days)
- blood pressure(90 and 150 days)
- CYP24A1 expression at the annulus(150 days)
- Growth and IGF axis(90 and 150 days)
- weight and BMI(90 and 150 days)
- Bone and calcium regulators in seminal fluid(150 days)
- Glucose metabolism(90 and 150 days)
- tumor markers(90 and 150 days)
- stress hormones(90 and 150 days)
- prolactin(90 and 150 days)
- kidney and cardiovascular markers(90 and 150 days)
- liver markers(90 and 150 days)
- infectious disease(28, 90 and 150 days)
- fever(28, 90 and 150 days)
- inflammatory markers(90 and 150 days)
- natriuretic peptides(90 and 150 days)
- DNA Fragmentation(0-150)
研究者
Martin Blomberg Jensen
MD
Rigshospitalet, Denmark