Melatonin in testes of infertile men: evidence for anti‐proliferative and anti‐oxidant effects on local macrophage and mast cell populations

Abstract

SUMMARYMelatonin acting through the hypothalamus and pituitary regulates testicular function. In addition, direct actions of melatonin at the testicular level have been recently suggested. We have described that melatonin inhibits androgen production in hamster Leydig cells via melatonin subtype 1a (mel1a) receptors and the local corticotrophin-releasing hormone (CRH) system. The initial events of the melatonin/CRH signalling pathway have also been established. Melatonin and all components of the melatonergic/CRH system were also detected in Leydig cells of infertile men. This study attempted to search for additional targets of melatonin in the human testis, and to investigate the effects of melatonin on proliferation and the oxidative state in these novel target cells. To this aim, evaluation of human testicular biopsies of patients suffering from hypospermatogenesis or Sertoli cell only syndrome and cell culture studies were performed. Melatonergic receptors were found in macrophages (MACs) and mast cells (MCs) of the human testis. In biopsies of patients suffering idiopathic infertility, melatonin testicular concentrations were negatively correlated with MAC number per mm 2 and TNFa, IL1b and COX2 expression, but positively correlated with the expression of the anti-oxidant enzymes SOD1, peroxiredoxin 1 and catalase. Melatonin inhibited proliferation and the expression of pro-inflammatory cytokines and cyclooxygenase 2 (COX2) in both the human non-testicular THP-1 MAC cell line and primary cell cultures of hamster testicular MACs. In the human HMC-1 MC line, melatonin increased the expression of anti-oxidant enzymes and decreased reactive oxygen species (ROS) generation. The results reveal new testicular targets of melatonin and describe anti-proliferative and anti-inflammatory effects of this hormone on testicular MACs. Furthermore, melatonin might provide protective effects against oxidative stress in testicular MCs.

Local Actions of Melatonin in Somatic Cells of the Testis

“…In addition to its anti-proliferative role on testicular macrophages, melatonin also inhibited the expression of the pro-inflammatory cytokines TNFα and IL1β, as well as the expression of COX2 in human non-testicular and testicular non-human macrophages [80]. Therefore, melatonin targeting testicular macrophages plays local anti-inflammatory effects.…”

“…The human testis contains melatonin as well as macrophages and mast cells expressing melatonergic receptors [80]. Data from our group described that the number of macrophages is significantly higher in testes of patients with hypospermatogenesis or Sertoli cell only (SCO) syndrome than in gonads of healthy men [76].…”

“…Moreover, testicular melatonin concentrations inversely correlate with the number of macrophages in biopsies from infertile patients. Subsequent studies established that melatonin decreases cell density and the expression of the proliferating cell nuclear antigen (PCNA) without affecting cell viability in both nonhuman testicular macrophages and human non-testicular macrophages [80].…”

“…Although the number of testicular mast cells is significantly higher in infertile patients than in healthy men [74], no correlation was found between testicular melatonin concentrations and the number of mast cells in testes of patients suffering from hypospermatogenesis or SCO syndrome [80]. However, in the frog Rana esculenta, Izzo et al [86] described that melatonin decreases testicular mast cell number.…”

“…Therefore, the serine protease tryptase is of special interest because it is expressed in almost all populations of mast cells. The expression of tryptase and chymase was described in testicular mast cells of infertile patients [80]. The mast cells product tryptase decreased motility in human spermatozoa while chymase showed no such effect [88].…”