Semen parameter thresholds and time-to-conception in subfertile couples: how high is high enough?

Abstract

STUDY QUESTION What thresholds for total sperm count, sperm concentration, progressive motility, and total progressive motile sperm count (TPMC) are associated with earlier time-to-conception in couples undergoing fertility evaluation? SUMMARY ANSWER Values well above the World Health Organization (WHO) references for total sperm count, concentration, and progressive motility, and values up to 100 million for TPMC were consistently associated with earlier time-to-conception and higher conception rates. WHAT IS KNOWN ALREADY Although individual semen parameters are generally not able to distinguish between fertile and infertile men, they can provide clinically useful information on time-to-pregnancy for counseling patients seeking fertility treatment. Compared to the conventional semen parameters, TPMC might be a better index for evaluating the severity of male infertility. STUDY DESIGN, SIZE, DURATION We used data from a longitudinal cohort study on subfertile men from 2002 to 2017 and included 6061 men with initial semen analysis (SA) in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS Men from subfertile couples who underwent a SA within the study period were included, and 5-year follow-up data were collected to capture conception data. Couples were further categorized into two subgroups: natural conception (n = 5126), after separating those who achieved conception using ART or IUI; natural conception without major female factor (n = 3753), after separating those with severe female factor infertility diagnoses. TPMC was calculated by multiplying the semen volume (ml) by sperm concentration (million/ml) and the percentage of progressively motile sperm (%). Cox proportional hazard models were used to report hazard ratios (HRs) with 95% CIs before and after adjusting for male age, the number of previous children before the first SA, and income. Using the regression tree method, we calculated thresholds for total sperm count, sperm concentration, progressive motility, and TPMC to best differentiate those who were more likely to conceive within 5 years after first SA from those less likely to conceive. We also plotted continuous values of semen parameters in predicting 5-year conception rates and time-to-conception. MAIN RESULTS AND THE ROLE OF CHANCE Overall, the median time to conception was 22 months (95% CI: 21–23). A total of 3957 (65%) couples were known to have achieved conception within 5 years of the first SA. These patients were younger and had higher values of sperm concentration, progressive motility, and TPMC. In the overall cohort, a TPMC of 50 million best differentiated men who were more likely to father a child within 5 years. Partners of men with TPMC ≥50 million had a 45% greater chance of conception within 5 years in the adjusted model (HR: 1.45; 95% CI: 1.34–1.58) and achieved pregnancy earlier compared to those men with TPMC < 50 million (median 19 months (95% CI: 18–20) versus 36 months (95% CI: 32–41)). Similar results were observed in the natural conception cohort. For the natural conception cohort without major female factor, the TPMC cut-off was 20 million. In the visual assessment of the graphs for the continuous semen parameter values, 5-year conception rates and time-to-conception consistently plateaued at higher values of sperm concentration, total sperm count, progressive motility, and TPMC compared to the WHO reference levels and our calculated thresholds. For TPMC, values up to 100–150 million were still associated with a better conception rate and time-to-conception in the visual assessment of the curves. LIMITATIONS, REASONS FOR CAUTION There was limited information on female partners and potential for inaccuracies in capturing less severe female infertility diagnoses. Also we lacked details on assisted pregnancies achieved outside of our healthcare network (with possible miscoding as ‘natural conception’ in our cohort). We only used the initial SA and sperm morphology, another potentially important parameter, was not included in the analyses. We had no information on continuity of pregnancy attempts/intention, which could affect the time-to-conception data. Finally, most couples had been attempting conception for >12 months prior to initiating fertility treatment, so it is likely that we are underestimating time to conception. Importantly, our data might lack the generalizability to other populations. WIDER IMPLICATIONS OF THE FINDINGS Our results suggest that a TPMC threshold of 50 million sperm provided the best predictive power to estimate earlier time-to-conception in couples evaluated for male factor infertility. Higher values of sperm count, concentration and progressive motility beyond the WHO references were still associated with better conception rates and time-to-conception. This provides an opportunity to optimize semen parameters in those with semen values that are low but not abnormal according to the WHO reference values. These data can be used to better inform patients regarding their chances of conception per year when SA results are used for patient counseling. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER N/A.

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“…The probability of conception depends on the quality of semen, which is reduced as one of the leading causes of male infertility ( 6 ), including reduced sperm concentration (oligospermia), decreased percentage of forward-moving sperm (weak sperm), a lower percentage of morphologically normal sperm (teratozoospermia), and complete absence of sperm in the semen (azoospermia) ( 7 ). However, basic diagnostic procedures using semen parameters are often inadequate to differentiate between fertile and infertile men ( 8 ). Among the approximately 30-40% of men with idiopathic infertility, standard semen parameters are often assessed in the ‘normal’ range ( 1 , 9 ), and even when the semen analysis is below typical average values, it is not a direct indicator or predictor of fertility outcome ( 10 ).…”

Effect of Malignancy on Semen Parameters

“…For example, a large European study showed that a sperm concentration up to 55 million and a total sperm count of up to 145 million, which are well beyond the WHO reference levels, are associated with an earlier time to pregnancy in fertile couples [40]. Another study showed that a higher sperm count, concentration, and progressive motility beyond the WHO references are associated with better conception rates and time to conception [42].…”

A paradigmatic shift in the care of male factor infertility: how can the recommendations for basic semen examination in the sixth edition of the WHO manual and the ISO 23162:2021 standard help?

“…Also in this population, a huge majority was successful within 3-4 months. In a recent study among men with semen examination results much higher than the lower 5 th percentile of results from men in couples with TTP ≤12 months (TTP timeto-pregnancy -or -conception), the time to conception was much shorter than 12 months (Keihani, Verrilli et al 2021). This altogether indicates that a population based on TTP ≤12 months is a rather mixed population.…”

“…TTP ≤4 months) would encourage in-depth investigations of more men with probable male factor abnormalities. It may sound challenging but is not at all impossible (Tietze 1968, Keihani, Verrilli et al 2021).…”