Choline Dehydrogenase and Sperm Function: Effects of Betaine

Study Overview
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Brief Summary
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The ability of sperm to swim is important for normal fertility. Men with a genetic variation in the gene coding for Choline Dehydrogenase (CHDH) have decreased energy production by sperm, and their sperm do not swim normally. The metabolic product of this gene is a nutrient called betaine (found normally in the diet as a part of many foods such as spinach, beets and grain products). This study tests whether treatment with betaine is safe and whether it can normalize energy production in sperm of these men and restore normal swimming ability.

Detailed Description
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Unidentified genetic aberrations such as single nucleotide polymorphisms (SNPs) may be the underlying cause of many cases of idiopathic infertility in men. Choline dehydrogenase (encoded by CHDH) converts choline to betaine in the mitochondria. 5-9% of men have 2 alleles for a functional SNP in CHDH (rs12676), and they have low sperm adenosine triphosphate (ATP) concentrations with impaired sperm motility (asthenospermia) that should decrease fertility. Male mice in which CHDH is deleted also have very low sperm ATP, asthenospermia and are infertile. Supplementation of these mice with dietary betaine increases sperm motility and ATP concentrations. This purpose of this study is to conduct a phase I study of betaine treatment in men with 2 minor alleles for CHDH rs12676 to determine whether betaine supplementation is safe and to obtain preliminary data on the effects of betaine on sperm mitochondrial ATP concentrations and sperm motility in these men.

Official Title
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Choline Dehydrogenase and Sperm Function: Effects of Betaine

Conditions
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Men Carrying 2 Minor Alleles for Choline Dehydrogenase rs12676, Male Infertility

Intervention / Treatment
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* Drug: Betaine supplement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 - 60 year old men of multiple races and ethnicities Estimated dietary intake of betaine of <150 mg/day Carrying two alleles of the rs 12676 single nucleotide polymorphism Exclusion Criteria: Cystathionine-beta-synthase (CBS) deficiency Currently taking betaine supplements Currently receiving chemotherapy, radiation or any gonadotoxic drug Female gender

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Betaine supplement<br>Will use powdered betaine (BetaPower, Dupont Nutrition) that is commercially available for food uses. This powder will be delivered as capsules containing 0.5 gram of powdered betaine which will be administered as eleven capsules twice per day (6 in the morning, 5 in the evening) for a daily total of 6 grams of betaine. | Drug: Betaine supplement<br> <br> * Other names: BetaPower (Dupont Nutrition);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sperm motility from baseline | Assessed using Computer-Aided Sperm Analysis methodology | On day zero, day 10, day 30, day 50 and at the end of the 75 day treatment period | 
| Change in sperm count from baseline |  | On day zero, day 10, day 30, day 50 and at the end of the 75 day treatment period | 
| Change in sperm mitochondrial function from baseline | Using Seahorse biochemical function assessment | On day zero, day 10, day 30, day 50 and at the end of the 75 day treatment period | 
| Change in sperm ultrastructure from baseline | Using light and transmission electron microscopy | On day zero, day 10, day 30, day 50 and at the end of the 75 day treatment period | 
| Change in sperm choline dehydrogenase concentration from baseline | Assessed by Western Blot analysis | On day zero, day 10, day 30, day 50 and at the end of the 75 day treatment period | 
| Change in sperm betaine concentration from baseline |  | On day zero, day 10, day 30, day 50 and at the end of the 75 day treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Betaine intake | Assessed using 3-day food records | At screening and every 21 days during the study | 
| Change in complete blood count from baseline |  | At 0, 10, 30, 50, and 75 days on treatment | 
| Change in uric acid concentration from baseline |  | At 0, 10, 30, 50, and 75 days on treatment | 
| Change in alkaline phosphatase concentration from baseline |  | At 0, 10, 30, 50, and 75 days on treatment | 
| Change in aspartate transaminase concentration from baseline |  | At 0,10, 30, 50, and 75 days on treatment | 
| Change in lactic dehydrogenase concentration from baseline |  | At 0, 10, 30, 50, and 75 days on treatment | 
| Change in bilirubin concentration from baseline |  | At 0, 10, 30, 50, and 75 days on treatment | 
| Change in blood urea nitrogen concentration from baseline |  | At 0, 10, 30, 50, and 75 days on treatment | 
| Change in creatinine concentration from baseline |  | At 0, 10, 30, 50, and 75 days on treatment | 
| Change in urinalysis parameters from baseline |  | At 0, 10, 30, 50, and 75 days on treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sperm motility