Reduced Testicular Steroidogenesis and Increased Semen Oxidative Stress in Male Partners as Novel Markers of Recurrent Miscarriage

Authors Jayasena CN., Radia UK., Figueiredo M. et al.

Review Date February 2019

Citation Clinical Chemistry 2019;65(1):161-169

Background

Men’s preconception health, in particular the health of their sperm, is known to contribute to reproductive outcomes, including time to conception, pregnancy success and childhood health. Sperm quality can be affected by many factors including smoking, infections, obesity, medications and age. Poor sperm quality, including sperm DNA damage, and recurrent miscarriage have been linked, but the physiological factors that cause this are not clear. For example, it is not known if men’s reproductive hormones, such as testosterone levels, are associated with risk of recurrent miscarriage.

Aim

To study whether reproductive hormones, sperm quality and sperm function are different for men for whom their partners have had recurrent miscarriages, compared to unaffected couples.

Methods

Between September 2016 and May 2017, men were recruited to the study if their partners had experienced recurrent miscarriages, with no known female cause (n=50). Recurrent miscarriage was defined as 3 or more consecutive miscarriages before 20 weeks gestation. Healthy male controls without history of infertility, were recruited to the study as a reference group (n=63). Study participants filled in a questionnaire and provided blood and semen samples.

Semen samples were analysed according to WHO standards to obtain semen parameters, including volume, and sperm concentration, motility and shape. Sperm function was also assessed by measuring levels of reactive oxygen species (ROS), a marker of cell damage, and sperm DNA fragmentation in each semen sample.

Endocrine hormones testosterone, estradiol, sex hormone binding globulin (SHBG),  luteinising hormone (LH), follicle stimulating hormone (FSH) were measured in blood samples collected in the morning.

Results

Clinical characteristics were similar between the two groups of men, but the recurrent miscarriage group did have slightly higher BMIs (Mean [SE], 27.6 [0.6] vs 24.8 [0.4]) and were older (Mean [SE], 37.3 [0.7] vs 30.8 [1.0]), compared to the reference group.

Serum testosterone and estradiol levels were 15-16% lower in the recurrent miscarriage group compared to the control group, albeit still within normal reference ranges. However, when the analysis was restricted to age-matched controls the difference was no longer significant. Serum LH was not significantly reduced in men in the recurrent miscarriage group, and FSH and SHBG were not different, compared to controls.

Semen volume, sperm counts and sperm motility were not different between the two groups, after controlling for age. In men whose partners had had recurrent miscarriage, semen ROS levels were four-fold higher (mean [SE], 9.1 [4.1] vs 2.0 [0.8]; P<0.05), and sperm DNA fragmentation was two-fold higher (mean [SE], 16.4 [1.5] vs 7.7 [7.0]; P<0.0001), compared with age-matched controls. These men also had a higher percentage of sperm with an abnormal morphology (mean [SE], 5.0 [0.4] vs 3.0 [0.3]; P<0.001), compared with controls.

Conclusion

Sperm DNA fragmentation, semen ROS levels and sperm morphology significantly discriminated between control men and men whose partners had had recurrent miscarriage. The findings suggest that male partners should be included in investigations when diagnosing the cause of recurrent miscarriage. Studies like these provide further evidence of the importance of male factors in achieving a successful pregnancy.

Points to Note

1. Paternal age has previously been linked with miscarriage (Yatsenko AN and Turek PJ. J Assist Reprod Genet. 2018;35(6):933-941). In this study, certain differences in measured parameters (such as lower testosterone and estradiol levels) were lost when controlling for paternal age although this was not accounted for in the abstract.

2. However, deficits in aspects of sperm quality were still significant compared to age-matched controls, including abnormal sperm morphology, sperm DNA fragmentation and semen ROS levels, suggesting that it is these parameters that could contribute to idiopathic recurrent miscarriage.
3. Levels of semen leukocytes, which can also generate ROS in the semen, were not different between healthy control and recurrent miscarriage males, but it is not clear if the high levels found in the recurrent miscarriage group of men were derived from the sperm or the leukocytes within the semen sample.

Website: https://www.ncbi.nlm.nih.gov/pubmed/30602480