Male Subfertility and Prostate Cancer Risk: Epidemiological and Genetic Studies

Abstract: Androgen action plays a pivotal role in male reproductive tract physiology and pathology. The androgen receptor (AR) gene harbors two codon repeat tracts: the CAG and GGN repeats, encoding corresponding amino acid sequences of variable length; the polyglutamine and polyglycine stretches, respectively. Variation in CAG repeat length had been associated with a number of andrological disorders, whereas very little was known about the GGN repeat when the work for this thesis was started. We hypothesized that variation in GGN length may modulate AR activity, and hence the individual susceptibility to male reproductive tract disorders. We also assessed the relationship between male subfertility-dependent childlessness and prostate cancer (PCa) risk in a nested case-control study to test the hypothesis that subfertile men are at lower risk of developing PCa than fertile men, since they are frequently hypogonadal secondary to testicular dysfunction. Our specific aims were to investigate: 1) whether the AR codon repeats are associated with clinical reproductive parameters, subfertility, hypospadias, or cryptorchidism; 2) whether childlessness secondary to male subfertility is associated with reduced PCa risk; and 3) the possible involvement of genetic variants in reducing PCa risk in subfertile men, including in the sex steroid signaling pathway and aryl hydrocarbon receptor (AHR) pathway, which mediates some of the effects of endocrine disrupting chemicals, and also in PCa risk genes implicated in previous genome-wide association studies. Our main findings were that: 1) GGN repeat lengths were significantly longer in men with penile hypospadias or cryptorchidism than in controls (median 24 vs. 23) and that the longer allele may be associated with superior AR function; 2) subfertile men were at reduced PCa risk compared with fertile men, OR: 0.45 (95% CI: 0.25-0.83); and 3) genes harboring variants that may play a role in reducing PCa risk in subfertile men include AHR, its partner molecule AHR nuclear translocator (ARNT), and estrogen receptor beta (ESR2), as well as a number of other genes, of which poly (ADP-ribose) polymerase 2 (PARP2) showed the most robust association. We conclude that: 1) longer GGN repeat lengths may be associated with cryptorchidism and hypospadias; 2) subfertile involuntarily childless men are at an approximately 50% lower risk of being diagnosed with PCa than are fathers of at least one biological child; 3) variants in a number of genes may play a role in linking male subfertility with reduced PCa risk through their associations with impaired reproductive function. The findings support the hypothesis that alterations in sex steroid action, potentially via interaction with the AHR-ARNT signaling pathway, may contribute to the overall reduction in PCa risk in subfertile men.