DNA Damage, Infertility, Male, Infertility Unexplained
Conditions
Keywords
Unexplained Infertility, Idiopathic Infertility, DNA damage, DNA fragmentation, Insemination
Brief summary
Infertility affects about 10% of all couples and is defined by a failure to achieve a clinical pregnancy within a year of regular unprotected sexual intercourse. Up to one third of these couples will not have an identifiable cause after routine investigation, id est idiopathic infertility. The current diagnosis of male infertility relies on the World Health Organization (WHO) 2010 criteria which focus on concentration, motility and morphology in comparison to cut-off values of a fertile population. Alas, the relevance of the conventional semen analysis for the choice of treatment and the predictive value for an infertile couple with idiopathic or mild male infertility embarking on medically assisted reproduction (MAR) remains questionable. In other words, there is a strong clinical need to distinguish fertile from infertile men through new sperm function testing and to be able to select both the patient population who will benefit from MAR as well as the type of treatment. Numerous studies utilizing different techniques for assessing sperm DNA fragmentation support the existence of a significant association between sperm DNA damage and pregnancy outcomes. In this prospective cohort study the investigators aim to study the role of sperm DNA fragmentation analysis in selecting the patient who will benefit from intra-uterine insemination (IUI) therapy since IUI is still considered the first step in MAR and is performed at a large scale in Belgium and worldwide.
Interventions
DIAGNOSTIC_TESTDNA fragmentation by TUNEL assay
Direct DNA fragmentation testing with terminal deoxyuridine nick end labeling (TUNEL) assay.
Sponsors
Universiteit Antwerpen
University Hospital, Antwerp
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
Single center, university setting, no commercial affiliation
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Couples seeking fertility treatment after at least 12 months of unprotected intercourse are eligible. All couples underwent basic fertility investigations which included semen analysis, evaluation of menstrual cycle, and tubal patency testing.
Exclusion criteria
Double sided tubal disease, severe endometriosis (classified as revised American Society for Reproductive Medicine stage III or IV), premature ovarian failure, and known endocrine disorders (such as Cushing's syndrome or adrenal hyperplasia), azoö- or necrozoospermia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DNA Fragmentation as a Predictor of Live Birth Rate | up to 36 months | The odds ratio on live birth per unit increase in % total Sperm DNA Fragmentation of the diagnostic sample. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| % SDF in the Vital Fraction After Density Gradient in the Diagnostic Sample (Pre-IUI) | up to 3 months | % of spermatozoa with DNA fragmentation in the vital fraction after density gradient in the diagnostic sample (pre-IUI) |
| % SDF in the Total Fraction in the Ejaculate of the IUI- Sample | 36 months | % of spermatozoa with DNA fragmentation in the total fraction in the ejaculate (before density gradient) of the IUI-sample |
| % SDF in the Total Fraction After Density Gradient in the Diagnostic Sample (Pre-IUI) | up to 3 months | % of spermatozoa with DNA fragmentation in the total fraction after density gradient in the diagnostic sample (pre-IUI) |
| % SDF in the Total Fraction After Density Gradient in the IUI Sample | 36 months | % of spermatozoa with DNA fragmentation in the total fraction after density gradient in the IUI sample |
| % SDF in the Vital Fraction After Density Gradient in the IUI Sample | 36 months | % of spermatozoa with DNA fragmentation in the vital fraction after density gradient in the IUI sample |
| % SDF in the Vital Fraction in the Ejaculate of the IUI- Sample | 36 months | % of spermatozoa with DNA fragmentation in the vital fraction in the ejaculate (before density gradient) of the IUI-sample |
Countries
Belgium
Participant flow
Recruitment details
Centre for Reproductive Medicine of the Antwerp University Hospital, Belgium
Pre-assignment details
6 included patients did not proceed to treatment; 1 due to spontaneous pregnancy - 5 loss to follow-up
Participants by arm
| Arm | Count |
|---|---|
| Spontaneous Cycle IUI The couples underwent natural cycle IUI with or without ovulation trigger until pregnancy was achieved for a maximum of four cycles.
DNA fragmentation was measured by TUNEL assay. | 228 |
| Total | 228 |
Baseline characteristics
| Characteristic | Spontaneous Cycle IUI | — |
|---|---|---|
| Abstinence period | 4 days STANDARD_DEVIATION 2 | — |
| Age, Continuous Men | 32.8 years STANDARD_DEVIATION 5.3 | — |
| Age, Continuous Women | 30.3 years STANDARD_DEVIATION 3.7 | — |
| Infertility Duration | 23.3 months STANDARD_DEVIATION 12.4 | — |
| Mean menstrual cycle length | 29 days STANDARD_DEVIATION 2 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| % SDF total in ejaculate | 9 % of spermatozoa with SDF in ejaculate STANDARD_DEVIATION 7.2 | — |
| % SDF vital in ejaculate | 1 % of vital sperm with SDF in ejaculate STANDARD_DEVIATION 0.9 | — |
| Semen volume | 3.7 ml ejaculate STANDARD_DEVIATION 2.3 | — |
| Sex: Female, Male Female | 114 Participants | — |
| Sex: Female, Male Male | 114 Participants | — |
| Sperm concentration | 48 Million spermatozoa /ml ejaculate STANDARD_DEVIATION 63.7 | — |
| Sperm ideal morphology | 5 % of total sperm count STANDARD_DEVIATION 5 | — |
| Sperm progressive motility | 55 % progessively motile spermatozoa STANDARD_DEVIATION 16 | — |
| Total sperm count | 165.2 Million spermatozoa STANDARD_DEVIATION 199 | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 228 |
| other Total, other adverse events | 0 / 228 |
| serious Total, serious adverse events | 0 / 228 |
Outcome results
Primary
DNA Fragmentation as a Predictor of Live Birth Rate
The odds ratio on live birth per unit increase in % total Sperm DNA Fragmentation of the diagnostic sample.
Time frame: up to 36 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Spontaneous Cycle IUI - Sperm DNA Fragmentation Analysis | DNA Fragmentation as a Predictor of Live Birth Rate | 32 Participants |
Comparison: The null hypothesis is: there is no association between % total Sperm DNA Fragmentation and live birth.p-value: 0.0495% CI: [0.9, 0.9985]GEE-model
p-value: >0.05Receiver Operating Characteristics curve
Secondary
% SDF in the Total Fraction After Density Gradient in the Diagnostic Sample (Pre-IUI)
% of spermatozoa with DNA fragmentation in the total fraction after density gradient in the diagnostic sample (pre-IUI)
Time frame: up to 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spontaneous Cycle IUI - Sperm DNA Fragmentation Analysis | % SDF in the Total Fraction After Density Gradient in the Diagnostic Sample (Pre-IUI) | 9.6 % of spermatozoa with SDF |
Secondary
% SDF in the Total Fraction After Density Gradient in the IUI Sample
% of spermatozoa with DNA fragmentation in the total fraction after density gradient in the IUI sample
Time frame: 36 months
Population: number of semen samples for IUI analyzed for SDF after density gradient
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spontaneous Cycle IUI - Sperm DNA Fragmentation Analysis | % SDF in the Total Fraction After Density Gradient in the IUI Sample | 8.3 % of spermatozoa with SDF |
Secondary
% SDF in the Total Fraction in the Ejaculate of the IUI- Sample
% of spermatozoa with DNA fragmentation in the total fraction in the ejaculate (before density gradient) of the IUI-sample
Time frame: 36 months
Population: number of semen samples for IUI analyzed for sperm DNA fragmentation before density gradient
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spontaneous Cycle IUI - Sperm DNA Fragmentation Analysis | % SDF in the Total Fraction in the Ejaculate of the IUI- Sample | 8 % of spermatozoa with SDF |
Secondary
% SDF in the Vital Fraction After Density Gradient in the Diagnostic Sample (Pre-IUI)
% of spermatozoa with DNA fragmentation in the vital fraction after density gradient in the diagnostic sample (pre-IUI)
Time frame: up to 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spontaneous Cycle IUI - Sperm DNA Fragmentation Analysis | % SDF in the Vital Fraction After Density Gradient in the Diagnostic Sample (Pre-IUI) | 0.6 % of spermatozoa with SDF |
Secondary
% SDF in the Vital Fraction After Density Gradient in the IUI Sample
% of spermatozoa with DNA fragmentation in the vital fraction after density gradient in the IUI sample
Time frame: 36 months
Population: number of semen samples for IUI analyzed for SDF after density gradient
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spontaneous Cycle IUI - Sperm DNA Fragmentation Analysis | % SDF in the Vital Fraction After Density Gradient in the IUI Sample | 0.4 % of spermatozoa with SDF |
Secondary
% SDF in the Vital Fraction in the Ejaculate of the IUI- Sample
% of spermatozoa with DNA fragmentation in the vital fraction in the ejaculate (before density gradient) of the IUI-sample
Time frame: 36 months
Population: number of semen samples for IUI analyzed for sperm DNA fragmentation before density gradient
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spontaneous Cycle IUI - Sperm DNA Fragmentation Analysis | % SDF in the Vital Fraction in the Ejaculate of the IUI- Sample | 1 % of spermatozoa with SDF |