Administration of Antioxidants to Infertile Men and Sperm Quality

Sponsor

Aristotle University Of Thessaloniki (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04256278

Collaborator

Andrology lab Zeginiadou (Other), Armatura (Other)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The purpose of this randomized clinical trial is to assess the effect of oral antioxidant administration to infertile men, by evaluating semen variables, sperm DFI and levels of ROS. Oral antioxidants or placebo will be given for 3 consecutive months.

Condition or Disease	Intervention/Treatment	Phase
Male Infertility	Other: Spermotrend	N/A

Detailed Description

Infertility affects up to 15% of couples trying to conceive with the male factor contributing in about 50% of cases. Oxidative stress (OS) has been found as one of the many factors causing male infertility, by inducing sperm damage. OS causes cell damage due to the raised production of reactive oxygen species (ROS), that overcome the antioxidant mechanisms of the human body. ROS are oxidizing agents that are produced as a by-product of oxygen metabolism, having at least one free electron. Due to this free electrone in their outer layer, the form very active or unstable substances. While small amounts of ROS are necessary for the proper function of sperm, increased amounts have a negative effect on sperm quality and can harm its fertility potential, thus inducing male infertility.

Spermatozoa were the first cells found to be sensitive to OS, as they lack the necessary repair cytoplasmic enzyme systems, thus being unable to repair damage. In addition, their cytoplasmic membranes are rich in polyunsaturated fatty acids (PUFAs), making them highly susceptible to oxygen-induced damage, such as lipid peroxidation (LPO). Rapid loss of intracellular adenosine triphosphate (ATP) by LPO, is responsible for axial damage, morphological damage to the sperm neck and reduced sperm motility; these events contribute to reduced sperm motility.

OS has also been associated with reduced fertilization, delayed intrauterine growth, miscarriages, birth defects (including autism) and childhood cancer. ROS found in semen come from a variety of endogenous and exogenous factors. Human sperm includes mature and immature sperm cells, leukocytes, and white blood cells. The leukocytes (mainly neutrophils and macrophages) and the immature spermatozoa are considered the major endogenous sources of ROS, whereas lifestyle, such as smoking, excessive alcohol consumption and other environmental factors such as radiation and toxins may contribute to the production of exogenous ROS.

As oxidative stress (OS) results from the imbalance of ROS overproduction and the reduced capacity of sperm antioxidant systems, many studies have aimed to improve sperm quality by administering antioxidant therapeutic regimens. In general, antioxidant therapy involves the administration of oral antioxidants, and the in vitro addition of antioxidants to culture media that are used for sample preparation in assisted reproduction techniques (ART). Many different antioxidants combinations have been studied. More and more studies have shown the beneficial effect of antioxidants on reducing sperm fragmentation and improving sperm quality. Agarwal & Sekhon's study showed a positive correlation between antioxidant therapy and various semen parameters. However, no firm conclusion regarding the beneficial effect of oral antioxidants can be made, as the majority of available studies had small sample size, used different antioxidant combinations, and the techniques that were used for the detection of ROS and DNA fragmentation index (DFI) were not standardized.

AIM OF THE STUDY The purpose of this randomized clinical trial is to assess the effect of oral antioxidant administration to infertile men, by evaluating semen variables, sperm DFI and levels of ROS.Oral antioxidants or placebo will be given for 3 consecutive months.

This study will take place at the Unit of Reproductive Endocrinology at the 1st Ob/Gyn Dept, Medical School, Aristotle University of Thessaloniki in collaboration with the private andrology diagnostic center of Mr Th. Zeginiadou.

PATIENTS The study will recruit infertile men, who have one previous abnormal spermiogram, with at least one pathological variable (concentration, motility, morphology), according to WHO 2010 criteria.

OUTCOMES

Main Outcome:

WHO Sperm analysis variables: concentration, motility, morphology.

Secondary outcomes:

Concentration of ROS in sperm and sperm DFI

STUDY DESIGN

Type of study:

Randomized clinical trial

The study will recruit infertile men, who have one previous abnormal spermiogram, with at least one pathological variable (concentration, motility, morphology), according to WHO 2010 criteria. Participants will be recruited in the outpatient clinic of the Unit of Human Reproduction and of the Unit of Reproductive Endocrinology at the 1st Ob/Gyn Dept. Selected participants will sign the consent form and will be asked to sample sperm at the private andrology diagnostic center of Mr Th. Zeginiadou. The sperm samples will be evaluated regarding the concentration, motility, morphology and vitality of spermatozoa, as well as the concentration of ROS, and DFI. Oral antioxidants or placebo will be given for 3 consecutive months. At the end of the 3 months period participants will be asked to re-sample their sperm in order to evaluate the same variables.

Sample size calculation Estimated sample size for two-sample means test, assuming and common standard deviation of 15 and a mean motility of 20 in the control group and 30 in the antioxidant group results in calculated sample size of 74. To allow for dropouts 80 patients will be recruited.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

quadruple-blind studyquadruple-blind study

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

use of placebo, masked randomization list

Primary Purpose:

Treatment

Official Title:

Does Antioxidant Administration Improve Sperm Quality in Infertile Men

Anticipated Study Start Date :

Mar 30, 2020

Anticipated Primary Completion Date :

Jan 30, 2021

Anticipated Study Completion Date :

Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intervention Group	Other: Spermotrend oral administration of antioxidants for three months
Placebo Comparator: Control Group	Other: Spermotrend oral administration of antioxidants for three months

Arm

Intervention/Treatment

Experimental: Intervention Group

Other: Spermotrend

oral administration of antioxidants for three months

Placebo Comparator: Control Group

Other: Spermotrend

oral administration of antioxidants for three months

Outcome Measures

Primary Outcome Measures

Sperm parameters [immediately before treatment initiation]
Sperm motility(Sperm motility was classified using a four-category scheme: A:rapid progressive, B:slow progressive, C:non-progressive, and D:immotile , %A+B, normal values >32% A+B)
Sperm parameters [immediately after the end of a 3 month treatment]
Sperm motility(Sperm motility was classified using a four-category scheme: A:rapid progressive, B:slow progressive, C:non-progressive, and D:immotile , %A+B, normal values >32% A+B)
Sperm parameters [immediately before treatment initiation]
Sperm concentration (ml, normal values > 1.5 ml)
Sperm parameters [immediately after the end of a 3 month treatment]
Sperm concentration (ml, normal values > 1.5 ml)
Sperm parameters [immediately before treatment initiation]
Sperm vitality (%, normal values > 58%)
Sperm parameters [immediately after the end of a 3 month treatment]
Sperm vitality (%, normal values > 58%)
Sperm parameters [immediately before treatment initiation]
Sperm morphology(Tygerberg Strict Criteria were used for the evaluation of human sperm morphology, normal form per 100 sperm, normal values >4%)
Sperm parameters [immediately after the end of a 3 month treatment]
Sperm morphology(Tygerberg Strict Criteria were used for the evaluation of human sperm morphology, normal form per 100 sperm, normal values >4%)

Secondary Outcome Measures

Reactive Oxygen Species (ROS) [immediately before treatment initiation]
ROS (8-hydroxy-2-deoxy-quanosine%, normal values < 3% on sperm)
Reactive Oxygen Species (ROS) [immediately after the end of a 3 month treatment]
ROS (8-hydroxy-2-deoxy-quanosine%, normal values < 3% on sperm)
DNA fragmentation Index (DFI) [immediately before treatment initiation]
DFI (%DFI: % sperm cells containing damaged DNA)
DNA fragmentation Index (DFI) [immediately after the end of a 3 month treatment]
DFI (%DFI: % sperm cells containing damaged DNA)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion criteria

Men, 18-50 years old
Infertility defined as follows:

Failure to obtain a pregnancy after at least twelve (12) months of regular sexual intercourse without the use of contraceptives or six (6) months if the woman is> 35 years old AND
At least one previous abnormal spermiogram, with at least one pathological parameter (concentration, motility, morphology), according to the WHO 2010 criteria.

No treatment for infertility in the last three (3) months
Normal hormone profile (TSH, FSH, LH, total testosterone, prolactin)
Negative culture for mycoplasma or ureaplasma
Physiological scrotal ultrasound

Exclusion criteria

Genetic cause of infertility
History of cryptorchidism
History of orchectomy
History of testicular cancer
History of severe heart, liver or kidney disease
History of endocrine disease (primary or secondary hypogonadism, hyperprolactinemia, thyroid, pituitary or adrenal disease)
History of systemic disease or treatment in the last three (3) months
BMI > 30 kg/m2
Participation in another study and the possibility of the patient not being available for follow-up