Disturbed testicular expression of the estrogen‐metabolizing enzymes CYP1A1 and COMT in infertile men with primary spermatogenic failure: possible negative implications on Sertoli cells

Abstract

Estradiol (E ) is normally metabolized to hydroxyestradiols and methoxyestradiols by CYP1A1, CYP1B1 and COMT. However, an altered production of these metabolites by a disturbed expression of these enzymes is associated with reproductive and non-reproductive pathologies. In vitro studies suggest that increased hydroxyestradiols and methoxyestradiols intratesticular generation is related to male infertility, but no studies have explored whether infertile men have a disturbed testicular expression of the enzymes that generate these E metabolites. The aim of this study was to assess CYP1A1, CYP1B1 and COMT testicular expression at mRNA and protein level in men with spermatogenic impairment. Seventeen men with primary spermatogenic failure (13 with Sertoli cell-only syndrome and four with maturation arrest) and nine controls with normal spermatogenesis were subjected to testicular biopsy. mRNA was quantified using real-time RT-PCR and protein expression was evaluated using western blot and immunohistochemistry followed by integrated optic density analysis. Besides, the effects of hydroxyestradiols and methoxyestradiols on testosterone-induced transcriptional activity were evaluated in TM4 cells using a luciferase reporter assay system. Our results show that patients with Sertoli cell-only syndrome had significantly elevated COMT expression at the mRNA level, higher COMT immunoreactivity in their seminiferous tubules and increased protein expression of the soluble COMT isoform (S-COMT), whereas patients with maturation arrest had significantly elevated CYP1A1 mRNA levels and higher CYP1A1 immunoreactivity in interstitial space. Finally, 2-hydroxyestradiol decreased testosterone-induced transcriptional activity in Sertoli cells in vitro. In conclusion, male infertility is related to disturbed testicular expression of the enzymes responsible for producing hydroxyestradiols and/or methoxyestradiols. If these changes are related with increased intratesticular hydroxyestradiols and methoxyestradiols concentrations, they could elicit an impaired Sertoli cell function. Our results suggest CYP1A1 and COMT as new potential targets in treating male infertility.

Features of gonadal dysgenesis and Leydig cell impairment in testes with Sertoli cell-only syndrome

“…Some earlier studies reported decreased serum levels of T in men with infertility; however, in most of those studies the patients were recruited by their seminal parameters or fertility status [14,24,25]. Similarly to our results, the decrease in T levels was not found in some other studies, where the subjects were selected and grouped according to histological pattern of testicular biopsy [7,12,16,26]. The observed discrepancies may be explained by the fact that there is an extensive overlap between fertile and infertile men hormones' levels which may mask, to some extent, the differences between studied groups depending on selection criteria.…”

Association between CYP1A1 rs4646903 T > C genetic variations and male infertility risk

“…Subsequently, two meta-analysis, included 6 studies involving 1060 cases and 1225 controls, comprehensively evaluated the associations between CYP1A1 rs4646903 polymorphism and male infertility risk, but there results were still inconsistent. [14,15] This inconsistent result may arise from different search strategies, and the 2 meta-analyses do not include all relevant studies.…”

“…[13] The disturbed testicular expression of CYP1A1 is responsible for producing hydroxyestradiols and/or methoxyestradiols, and the increased intratesticular hydroxyestradiols and methoxyestradiols concentrations could elicit an impaired Sertoli cell function, this could ultimately lead to male infertility. [14] Several single-nucleotide polymorphisms (SNPs) of Cytochrome P4501A1 gene have been identified, including T3801C, T3205C, A2455G. [13] Among them, P4501A1 MspI (3798 T > C; CYP1A1 ∗2A; rs4646903) polymorphism is one of the most-studied single-nucleotide polymorphism (SNP).…”

A decrease of docosahexaenoic acid in testes of mice fed a high-fat diet is associated with impaired sperm acrosome reaction and fertility

“… 54 55 A recent report showed elevated levels of cytochrome P450, family 1, subfamily A, member 1 (CYP1A1) and Catechol-O-methyltransferase (COMT), which produce hydroxyl-estradiol and methoxy-estradiol, respectively, in testicular biopsies of overweight patients with spermatogenic failure. 56 In addition, these E2 metabolites induce DNA fragmentation in Sertoli cells. 57 Thus, an increase in E2 metabolism rather than decreased E2 production could explain E2 decline without altered testosterone levels.…”