There is strong evidence of a fetal and even preconceptional origin to male reproductive and general health. A Campus meeting in March reviewed the evidence and underlined the importance of male infertility as a marker of future health.
One recurring theme running through a SIG Andrology Campus meeting in March was the relevance of inheritance to the risk of infertility and other testicular abnormalities in men. This involves exposure in utero to environmental pollutants, smoking and dietary patterns, and even a genetic effect of paternal programming - possibly with origins in the grandfather's diet, which may also influence embryonic and fetal development in the (grand) child, and even its general health.
Indeed, many clinical phenotypes in later life, such as testicular cancer, cryptorchidism and hypospadias, have a common fetal origin, said Anders Juul from the Rigshospital in Copenhagen. Testicular cancer, for example, is a genetic aberration whose prevalence can't easily explained. However, it has to be lifestyle or environment, said Juul, acting in some way through the genome, and having their greatest impact on fetal life and fetal development. Indeed, a recent study of sperm quality in around 300 Copenhagen men (per year) followed-up for 21 years showed that a declining pattern of smoking in Danish women (and therefore in utero exposure) had no overall effect on sperm counts, although they did remain consistently low in 35% of the study group.(1) 'Results suggest that other unknown adverse factors may maintain the low semen quality among Danish men,' said Juul.
Declining sperm counts
Juul's work with his Copenhagen colleague Niels Skakkebaek has already established a link between environmental pollutants and increasing rates of testicular dysgenesis syndrome, testicular germ cell cancer and declining sperm counts. These links were reaffirmed - with a 'canary in the coalmine' warning - in a meta-analysis of 2017 in which Levine and colleagues found significant declines in sperm count between 1973 and 2011 of around -70 million ml/year, and an overall decline of 52.4%.(2) 'Because of the significant public health implications of these results,' wrote the authors, 'research on the causes of this continuing decline is urgently needed.' This call to arms echoed an op-ed piece from Skakkebaek in 2001 concluding that testicular dysgenesis syndrome 'is a result of disruption of embryonal programming and gonadal development during fetal life'.
The genetic connection was taken even further by Adam Watkins from Nottingham, who proposed that paternal dietary patterns affect sperm DNA methylation with an effect on offspring growth and skeletal formation. Moreover, the widely accepted Barker hypothesis on the developmental origins of disease now dictates that fetal growth as seen in smaller or larger babies is linked to the risks of hypertension, cardiovascular disease and diabetes. Such a pattern was seen in a rodent study reported by Watkins in which the offspring of males with a low protein diet had increased weight at birth and higher rates of vascular dysfunction.
General health and mortality
Similarly, while in utero exposures may determine reproductive status in life, Tina Kold Jensen - speaking via Skype from Denmark - further proposed that semen quality may also be linked to mortality. The association of birth weight with, for example, cardiovascular diseases would imply a link to life expectancy, but Jensen proposed a multifactorial association which was mediated through genetic inheritance, hormonal levels, in utero exposures, lifestyle and general health. Indeed, she added, 'semen quality could be a marker for general health'. Testicular cancer, for example, is associated with reduced semen quality, and decreased fertility before the cancer is diagnosed.
A 2009 registry study from Jensen and colleagues, which followed around 50,000 Danish men, linked individual sperm counts to central registry records to plot health outcomes with trends in semen characteristics over a long follow-up period.(3) Results showed that in men without azoospermia mortality decreased as the sperm concentration increased up to a threshold of 40 million/ml. Similarly, as the percentages of motile and morphologically normal sperm and semen volume increased, mortality rate decreased in a dose-response manner. This decrease in mortality was attributed to a decrease in a range of diseases and not solely to lifestyle and/or social factors. This latter conclusion was confirmed in a 2018 study which adjusted for occupation, marital status, fertility, cryptorchidism, BMI and smoking and ruled out their confounding effect in the association of semen quality with hospitalisation.
These were population studies linking sperm counts in a fixed group of men with health outcomes. However, to extend the significance of such findings to implications for public health requires the certainty of a decline in semen quality across a broad population, and that remains a matter of continuing controversy. Indeed, even Levine et al in their canary-in-the-coalmine report of 2017 began by asking: 'Have sperm counts declined?' And they went on to note that the question remains as controversial today as it was in 1992 when Carlsen et al dropped their bombshell of a 'genuine decline' in sperm count over the previous 50 years.(4) It is, as Levine et al acknowledged, a question of huge public importance which a single study is unlikely to resolve, especially when the methods and accuracy of semen analysis have been and continue to be challenged. But, as this Campus meeting confirmed yet again, semen quality and its association with endocrine disrupting chemicals, pesticides, maternal smoking and diet may well reflect the effects of living in a 'developed' modern environment on reproductive and general health in the male. And few seem ready to draw any unequivocal conclusions on lifestyle and environment until the sperm-count evidence is water-tight. What this Campus meeting did emphasise, however, was that a decrease in sperm count, whatever its magnitude, should not detract from the emerging evidence of a relationship with future health.
1. Priskorn L, Nordkap L, Bang AK, et al. Average sperm count remains unchanged despite reduction in maternal smoking: results from a large cross-sectional study with annual investigations over 21 years.
Hum Reprod 2018; 33: 998-1008.
2. Levine H, Jørgensen N, Martino-Andrade A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis.
Hum Reprod Update 2017; 23: 646-659.
3. Jensen TK, Jacobsen R, Christensen K, et al. Good semen quality and life expectancy: A cohort study of 43,277 men.
Am J Epidemiol 2009; 170: 559-565.
4. Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years.
Br Med J 1992; 305: 609–613.