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Efficacy Study of a Food Supplement With Myo-inositol, N-Acetyl-Cystein, Zinc and Vitamins on Sperm DNA Fragmentation

Primary Purpose

Male Infertility

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Isitol®
Placebo
Sponsored by
GYNOV
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Male Infertility focused on measuring Spermatozoa, DNA Fragmentation, Chromatin Condensation, Food supplement, TUNEL

Eligibility Criteria

20 Years - 45 Years (Adult)MaleAccepts Healthy Volunteers

Selection Criteria:

  • Male patient volunteers aged 20 to 45 years (limits included);
  • Socially insured patient receiving benefits from the French Social Security's health branch

Non-Selection Criteria:

  • Patients suffering from infertility of infectious or genetic origin, or from a pathology requiring concomitant medical treatment;
  • Consumption of dietary supplements during the previous 3 months and during the course of the study;
  • Smoking ≥ 5 cigarettes/day;
  • Alcoholism ≥ 10 drinks (alcohol standard)/week ;
  • Body Mass Index (BMI) not between [19 and 29] (inclusive).
  • Occupation at risk of exposure to carcinogenic, mutagenic and toxic agents for reproduction defined according to articles R.4412-2 2°, R.4412-3 and R.4412-60 of the French Labour Code;
  • Patient unable to give consent;
  • Minors and protected adults, vulnerable persons;
  • Patient participating in another clinical research study

Inclusion Criteria:

  • Sperm DNA fragmentation rate ≥ 30 %

Exclusion Criteria:

  • Positive semen culture

Sites / Locations

  • Laboratoire DrouotRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Isitol® (Food supplement treated group)

Placebo treated group

Arm Description

36 eligible males between 20 and 45 yo. (included limits) will take 1 sachet of Isitol® per day during 16 (± 2) weeks. The sachet of powder is to dissolve in a glass of water or directly in mouth. 1 sachet of Isitol® (2,1g) contains 1000 mg of myo-inositol, 300 mg of N-acetyl-cysteine, 150 % of the Nutritional Reference Values (NRV) in zinc and 100 % of the NRV: in vitamins B2, B3, B6, B9 and E.

36 eligible males between 20 and 45 yo. (included limits) will take 1 sachet of placebo per day during 16 (± 2) weeks. The sachet of powder is to dissolve in a glass of water or directly in mouth. 1 sachet of placebo (2,1g) contains only excipients used in Isitol® and excipients to get similar organoleptic aspect (maltodextrin, sucralose, silicon dioxide, magnesium carbonate, citric acid and beta-carotene).

Outcomes

Primary Outcome Measures

Change from baseline sperm DNA fragmentation rate at 4 months
Sperm DNA fragmentation rate is assessed by the TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) method. This method is based on the attachment of fluorochrome-coupled biotin-deoxyuridine (dUDP) complexes to the 3'OH ends of possible DNA fragments. The binding of the complexes to the DNA is catalysed by the enzyme Terminal-deoxynucleotidyltransferase. Spermatozoa with fragmented DNA are detected and their percentage measured directly by in-situ confocal fluorescence microscopy.

Secondary Outcome Measures

Change from baseline nuclear chromatin decondensation of spermatozoa at 4 months
Nuclear chromatin decondensation is assessed by the aniline blue method and expressed in percentage (%).
Change from baseline semen volume at 4 months
Semen volume is expressed in mL.
Change from baseline semen pH at 4 months
Semen pH is expressed without unit, the values ranging from 1 to 14.
Change from baseline semen liquefaction time at 4 months
When the sample is collected it presents a state of coagulation, and must be liquefied to proceed to its study. Semen liquefaction time is expressed in minutes.
Change from baseline spermiogram total spermatozoa, round cells and polynuclear cells count at 4 months
The total number of each cell type is counted and expressed in millions (10^6)/ejaculate. The relative concentrations in spermatozoa, round cells and polynuclear cells are obtained after weighting by sample volume and expressed in millions (10^6)/mL.
Change from baseline spermiogram viability and mobility count at 4 months
Viability and mobility of spermatozoa is evaluated and expressed in percentage (%).
Change from baseline spermocytogram abnormalities count at 4 months
Spermocytogram is a microscopic analysis of the ejaculate in order to evaluate the number of sperm morphological abnormalities on each part of the spermatozoon (head, middle piece, flagellum).
Change from baseline spermocytogram isolated flagella and of spermatozoa in cell lysis phase numbers at 4 months
Isolated flagella and spermatozoa in cell lysis phase are counted and expressed in percentage (%).
Change from baseline sperm morphology scoring at 4 months
The score of sperm morphology is assessed according to Cassuto-Barak classification. Spermatozoa are classified into 3 categories (I,II,III) according to the number and/or localisation of morphological abnormalities. The results are expressed in percentage (%) of each class I, II and III.
Change from baseline semen Red/ox potential at 4 months
The measurement of the semen Red/Ox potential is performed using the MiOXSYS measuring device (Aytu Bioscience 373 Inverness Parkway - Englewood, CO 80112 USA). This device measures the static oxidation reduction potential (sORP) of a biological sample, in this case human semen. The sORP has been described as an integrated measure of the balance between total oxidative activity (including reactive oxygen species) and total reducing activity. Therefore, the level of oxidative stress (increase in oxidative species and/or decrease in antioxidant activity) can be quantified electrically using an sORP sensor. The result is indicated in mV and the increase in sORP is correlated with an increase in the level of oxidative stress. The relative sORP is obtained after weighting by concentration in spermatozoa and expressed in mV/millions (10^6)/mL.
Change from baseline genes expression (AURKA, CCDC60, CCDC88B, CFAP46, HDAC4, CACNA1C, CACNA1H, CARHSP1, DNAH2, HMGB4, SPATA18) at 4 months
The expression level of the AURKA, CCDC60, CCDC88B, CFAP46, HDAC4, CACNA1C, CACNA1H, CARHSP1, DNAH2, HMGB4 and SPATA18 genes in spermatozoa will be measured using an RT-qPCR (Reverse transcriptase quantitative polymerase chain reaction) technique with specific primer pairs. The different mRNAs will be extracted from spermatozoa using an extraction kit (miRNeasy Kit (QIAGEN)). Using primers specific to each of the genes studied, the mRNAs of these genes of interest will be back-transcribed into complementary DNA and then amplified according to a determined number of replication cycles (45 cycles). By measuring the fluorescence intensity in each of the cells, the concentration of complementary DNA is calculated. The relative expression of these different genes is obtained after normalisation using two ubiquitous and constant expression genes.

Full Information

First Posted
June 23, 2021
Last Updated
August 2, 2022
Sponsor
GYNOV
Collaborators
Laboratoire Drouot
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1. Study Identification

Unique Protocol Identification Number
NCT04959864
Brief Title
Efficacy Study of a Food Supplement With Myo-inositol, N-Acetyl-Cystein, Zinc and Vitamins on Sperm DNA Fragmentation
Official Title
Double-Blind Randomized Controlled Trial Evaluating the Efficacy of the Food Supplement Isitol® Versus Placebo on the Rate of Abnormal Sperm DNA Fragmentation
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
July 7, 2021 (Actual)
Primary Completion Date
July 2023 (Anticipated)
Study Completion Date
July 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
GYNOV
Collaborators
Laboratoire Drouot

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
In industrialised countries, it is estimated that about 15% of couples who wish to have a child are currently facing infertility problems, of which, in half of the cases, an anomaly in sperm quality or at least a factor of male origin is identified. The evaluation of sperm quality in males is based, for the most part, on the micro and macroscopic examination of various parameters (concentration, motility, physical abnormalities of the spermatozoa, etc.). Nevertheless, an increasing number of scientific studies have shown that the quality of sperm DNA, and in particular its fragmentation rate, is also associated with a lower fertilisation rate. The integrity of sperm DNA may be affected by an imbalance in the Red/Ox balance leading to uncompensated oxidative stress, and could be restored or improved by dietary hygiene measures and the consumption of specific dietary products. The ISITOL clinical study aims to evaluate the efficacy of a dietary supplement specifically formulated to target the various issues associated with male infertility, and in particular to contribute to the improvement of the sperm DNA fragmentation rate. The efficacy of the dietary supplement Isitol® (GYNOV SAS) on sperm DNA fragmentation rate and other secondary parameters is being evaluated through a single-centre, prospective, randomised, double-blind, interventional vs. placebo clinical study being conducted in France at Laboratoire Drouot (21 Rue Drouot - 75009 Paris - France) and led by Dr. Nino-Guy Cassuto. A total of 72 men aged between 20 and 45 years, with sperm DNA fragmentation rate ≥ 30% and with negative semen culture are recruited. The recruited patients were randomized in a 1:1 scheme into 2 groups (Isitol® treated vs placebo treated). [Results to be reported later]
Detailed Description
Infertility is generally defined as a partner's failure to conceive after at least 12 months off contraception and is steadily increasing worldwide. In industrialised countries, it is estimated that around 15% of couples who wish to have a child are now facing it, and in half of the cases, an abnormality in sperm quality or at least a male factor is identified. In males, the measurement of male fertility is mainly based on analyses that assess sperm quality macroscopically (spermiogram, spermocytogram) by evaluating the number, morphology, motility, presence of abnormalities, etc. These indicators are still considered to be the preferred indicators for assessing male fertility. Nevertheless, since the mid-2000s, numerous in vitro and in vivo studies in humans and animals have shown that the integrity of sperm DNA, assessed by measuring the rate of DNA fragmentation and chromatin decondensation in spermatozoa, could be a relevant parameter in the etiology of male infertility. Furthermore, it has been observed that the rate of sperm DNA fragmentation is inversely correlated with pregnancy rate, success rate of assisted reproductive techniques and embryo quality. The major identified cause of direct damage to DNA molecules and their possible fragmentation, but also to proteins and cell membranes in spermatozoa is oxidative stress. Unreduced Reactive oxygen species produced in the mitochondria-rich midpiece in excess are susceptible to damage the DNA in the sperm head. Several exogenous factors such as exposure to toxins, smoking, alcohol or unbalanced diet are also associated with promoting oxidative stress. A fragmentation rate higher than 30% is considered high, it is indicative of altered chromatin and especially associated with a low probability of conceiving naturally or through in vitro techniques. To resolve this problem and improve the process of spermatogenesis and fertilisation, it is relevant to evaluate the effectiveness of a food supplement (Isitol®), manufactured and marketed by the company Gynov SAS (2B Rue Sauteyron - 33000 Bordeaux - France), which provides myo-inositol and a complex with antioxidant properties based on N-acetyl-cysteine, group B vitamins (B2, B3, B6, B9), vitamin E and zinc. In addition to providing the nutrients that contribute to a better management of the reactive oxygen species, the food supplement provides myo-inositol, which is essential for the functioning of a wide range of cellular functions. This molecule, related to glucose, is produced in the testis, mainly by Sertoli cells, and is excreted into the seminiferous tubules as a gradient. This gradient contributes to sperm maturation by reducing sperm viscosity and increasing sperm motility. Numerous studies evaluating the impact of myo-inositol have shown a significant improvement in sperm parameters (concentration, motility, morphology) and in particular in the rate of sperm DNA fragmentation. In order to evaluate the efficacy of this dietary supplement, a single-centre, prospective, randomised, double-blind, interventional vs. placebo clinical study was set up in France at Laboratoire Drouot (21 Rue Drouot - 75009 Paris - France) and directed by Dr. Nino-Guy Cassuto. A total of 72 men aged between 20 and 45 years, with sperm DNA fragmentation rate ≥ 30% and with negative semen culture are recruited. The recruited patients were randomised in a 1:1 design into 2 groups (Isitol® treated vs placebo treated). The primary hypothesis is that after 16 (± 2) weeks of treatment with the dietary supplement, the expected decrease in sperm DNA fragmentation rate will be ≥ 23% compared to the placebo treated group to validate the efficacy hypothesis. The measurement of the sperm DNA fragmentation rate is performed by TUNEL (Terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling) method. The secondary objectives are the evaluation of classical sperm parameters (spermiogram, spermocytogram), sperm morphology score, chromatin decondensation rate, sperm red/ox potential, differential expression of 11 specific genes involved in spermatogenesis and/or at different stages of the fertilisation process (AURKA, CCDC60, CCDC88B, etc.)). [Results to be reported later]

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Male Infertility
Keywords
Spermatozoa, DNA Fragmentation, Chromatin Condensation, Food supplement, TUNEL

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
The randomization scheme is 1 : 1 (treated with food supplement vs placebo). The different treatments (2) have been anonymized, a randomization list is used to assign an anonymous box number (5 random numbers) according to the patient's order of inclusion. Only the promoter is aware of the assignment of the randomization number with which treatment it corresponds.
Masking
ParticipantCare Provider
Masking Description
The randomization scheme is 1 : 1 (treated with food supplement vs placebo). The different treatments (2) have been anonymized, a randomization list is used to assign an anonymous box number (5 random numbers) according to the patient's order of inclusion. Only the promoter is aware of the assignment of the randomization number with which treatment it corresponds.
Allocation
Randomized
Enrollment
72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Isitol® (Food supplement treated group)
Arm Type
Experimental
Arm Description
36 eligible males between 20 and 45 yo. (included limits) will take 1 sachet of Isitol® per day during 16 (± 2) weeks. The sachet of powder is to dissolve in a glass of water or directly in mouth. 1 sachet of Isitol® (2,1g) contains 1000 mg of myo-inositol, 300 mg of N-acetyl-cysteine, 150 % of the Nutritional Reference Values (NRV) in zinc and 100 % of the NRV: in vitamins B2, B3, B6, B9 and E.
Arm Title
Placebo treated group
Arm Type
Placebo Comparator
Arm Description
36 eligible males between 20 and 45 yo. (included limits) will take 1 sachet of placebo per day during 16 (± 2) weeks. The sachet of powder is to dissolve in a glass of water or directly in mouth. 1 sachet of placebo (2,1g) contains only excipients used in Isitol® and excipients to get similar organoleptic aspect (maltodextrin, sucralose, silicon dioxide, magnesium carbonate, citric acid and beta-carotene).
Intervention Type
Dietary Supplement
Intervention Name(s)
Isitol®
Intervention Description
1 sachet of Isitol® (2,1g) contains : 1000 mg of myo-inositol ; 300 mg of N-acetyl-cystein ; 48.5 mg of zinc citrate (equivalent zinc pure element : 15 mg) ; 35 mg of D-a-tocopherol (equivalent vitamin E pure element : 12 mg) ; 16 mg of vitamin B3 ; 1.8 mg of pyridoxin hydrochloride (equivalent vitamin B6 pure element : 1.4 mg) ; 1.4 mg of vitamin B2 ; 0.37 mg of (6S)-5-methyltetrahydrofolic acid, glucosamine salt (equivalent vitamin B9 pure element : 0.2 mg). Sachets are packaged in box of 30.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
1 sachet of placebo (2,1g) contains : 1765.1 of maltodextrin ; 300 mg of magnesium carbonate ; 40 mg of citric acid ; 5.3 mg of beta-carotene ; 2.16 mg of silicon dioxide ; 1.44 mg of sucralose. Sachets are packaged in box of 30.
Primary Outcome Measure Information:
Title
Change from baseline sperm DNA fragmentation rate at 4 months
Description
Sperm DNA fragmentation rate is assessed by the TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) method. This method is based on the attachment of fluorochrome-coupled biotin-deoxyuridine (dUDP) complexes to the 3'OH ends of possible DNA fragments. The binding of the complexes to the DNA is catalysed by the enzyme Terminal-deoxynucleotidyltransferase. Spermatozoa with fragmented DNA are detected and their percentage measured directly by in-situ confocal fluorescence microscopy.
Time Frame
Sperm DNA fragmentation rate is measured at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Secondary Outcome Measure Information:
Title
Change from baseline nuclear chromatin decondensation of spermatozoa at 4 months
Description
Nuclear chromatin decondensation is assessed by the aniline blue method and expressed in percentage (%).
Time Frame
Nuclear chromatin decondensation is measured at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline semen volume at 4 months
Description
Semen volume is expressed in mL.
Time Frame
Semen volume is mesured at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline semen pH at 4 months
Description
Semen pH is expressed without unit, the values ranging from 1 to 14.
Time Frame
Semen pH is measured at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline semen liquefaction time at 4 months
Description
When the sample is collected it presents a state of coagulation, and must be liquefied to proceed to its study. Semen liquefaction time is expressed in minutes.
Time Frame
Semen liquefaction time is mesured at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline spermiogram total spermatozoa, round cells and polynuclear cells count at 4 months
Description
The total number of each cell type is counted and expressed in millions (10^6)/ejaculate. The relative concentrations in spermatozoa, round cells and polynuclear cells are obtained after weighting by sample volume and expressed in millions (10^6)/mL.
Time Frame
Cells counts are realised at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline spermiogram viability and mobility count at 4 months
Description
Viability and mobility of spermatozoa is evaluated and expressed in percentage (%).
Time Frame
Viability and mobility are are evaluated at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline spermocytogram abnormalities count at 4 months
Description
Spermocytogram is a microscopic analysis of the ejaculate in order to evaluate the number of sperm morphological abnormalities on each part of the spermatozoon (head, middle piece, flagellum).
Time Frame
Spermocytogram abnormalities count is realised at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline spermocytogram isolated flagella and of spermatozoa in cell lysis phase numbers at 4 months
Description
Isolated flagella and spermatozoa in cell lysis phase are counted and expressed in percentage (%).
Time Frame
Spermocytogram isolated flagella and of spermatozoa in cell lysis phase count is realised at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline sperm morphology scoring at 4 months
Description
The score of sperm morphology is assessed according to Cassuto-Barak classification. Spermatozoa are classified into 3 categories (I,II,III) according to the number and/or localisation of morphological abnormalities. The results are expressed in percentage (%) of each class I, II and III.
Time Frame
Sperm morphology scoring is realised at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline semen Red/ox potential at 4 months
Description
The measurement of the semen Red/Ox potential is performed using the MiOXSYS measuring device (Aytu Bioscience 373 Inverness Parkway - Englewood, CO 80112 USA). This device measures the static oxidation reduction potential (sORP) of a biological sample, in this case human semen. The sORP has been described as an integrated measure of the balance between total oxidative activity (including reactive oxygen species) and total reducing activity. Therefore, the level of oxidative stress (increase in oxidative species and/or decrease in antioxidant activity) can be quantified electrically using an sORP sensor. The result is indicated in mV and the increase in sORP is correlated with an increase in the level of oxidative stress. The relative sORP is obtained after weighting by concentration in spermatozoa and expressed in mV/millions (10^6)/mL.
Time Frame
Red/ox potential measurement is realised at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo
Title
Change from baseline genes expression (AURKA, CCDC60, CCDC88B, CFAP46, HDAC4, CACNA1C, CACNA1H, CARHSP1, DNAH2, HMGB4, SPATA18) at 4 months
Description
The expression level of the AURKA, CCDC60, CCDC88B, CFAP46, HDAC4, CACNA1C, CACNA1H, CARHSP1, DNAH2, HMGB4 and SPATA18 genes in spermatozoa will be measured using an RT-qPCR (Reverse transcriptase quantitative polymerase chain reaction) technique with specific primer pairs. The different mRNAs will be extracted from spermatozoa using an extraction kit (miRNeasy Kit (QIAGEN)). Using primers specific to each of the genes studied, the mRNAs of these genes of interest will be back-transcribed into complementary DNA and then amplified according to a determined number of replication cycles (45 cycles). By measuring the fluorescence intensity in each of the cells, the concentration of complementary DNA is calculated. The relative expression of these different genes is obtained after normalisation using two ubiquitous and constant expression genes.
Time Frame
Genes expression measurement is realised at first Visit (V0) and at the last Visit (V2) after 16 +/- 2 weeks of treatment with Isitol or placebo

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Selection Criteria: Male patient volunteers aged 20 to 45 years (limits included); Socially insured patient receiving benefits from the French Social Security's health branch Non-Selection Criteria: Patients suffering from infertility of infectious or genetic origin, or from a pathology requiring concomitant medical treatment; Consumption of dietary supplements during the previous 3 months and during the course of the study; Smoking ≥ 5 cigarettes/day; Alcoholism ≥ 10 drinks (alcohol standard)/week ; Body Mass Index (BMI) not between [19 and 29] (inclusive). Occupation at risk of exposure to carcinogenic, mutagenic and toxic agents for reproduction defined according to articles R.4412-2 2°, R.4412-3 and R.4412-60 of the French Labour Code; Patient unable to give consent; Minors and protected adults, vulnerable persons; Patient participating in another clinical research study Inclusion Criteria: Sperm DNA fragmentation rate ≥ 30 % Exclusion Criteria: Positive semen culture
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Pierre-Yves Mousset, MD
Phone
616310400
Ext
+33
Email
py.mousset@gynov.com
First Name & Middle Initial & Last Name or Official Title & Degree
Axel Dries, Master
Phone
636630660
Ext
+33
Email
a.dries@gynov.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nino-Guy Cassuto, PharmD
Organizational Affiliation
Laboratoire Drouot
Official's Role
Principal Investigator
Facility Information:
Facility Name
Laboratoire Drouot
City
Paris
ZIP/Postal Code
75009
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Axel Dries, Master
Phone
+33636630660
Ext
+33547742633
Email
a.dries@gynov.com
First Name & Middle Initial & Last Name & Degree
Pierre-Yves Mousset, MD
Phone
+33616310400
Ext
+33547742633
Email
py.mousset@gynov.com

12. IPD Sharing Statement

Plan to Share IPD
No

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Efficacy Study of a Food Supplement With Myo-inositol, N-Acetyl-Cystein, Zinc and Vitamins on Sperm DNA Fragmentation

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