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- Sexual steroid regulation of spermatogenesis: new actors enter the stagePublication . Laurentino, Sandra Filipa Tomás Sequeira; Cavaco, José Eduardo Brites; Socorro, Sílvia Cristina da Cruz Marques; Sousa, Mário Manuel da Silva LeiteSpermatogenesis, the process of male gamete (i.e. spermatozoa) production, requires tight hormonal regulation in order to proceed successfully. The importance of androgens (like testosterone and 5α-dihydrotestosterone) to the regulation of spermatogenesis is well recognized. However, more recently, the importance of estrogens (like 17β-estradiol), has also been demonstrated. These sexual steroids act through ligand-activated transcription factors, estrogen receptors α and β (ERα and ERβ) and androgen receptor (AR), respectively. Most actions of these hormones are achieved through the regulation of target genes. The two ERs have different and sometimes opposing effects on the regulation of target genes, and estrogenic action will ultimately depend on interplay between them, when co-expressed in the same cell. The expression of ERα and ERβ in human testis has been strongly debated and a definite answer to whether only ERβ or both ERs are expressed is pivotal to understanding the estrogenic actions in human spermatogenesis. Several splice variants for ERα and ERβ have been described in testis, playing important roles in the regulation of their prototype receptors. In contrast, only one AR variant has been described so far in human testis, although the existence of more variants responsible for regulatory and non-classical actions is highly expected. The definition of the estrogen and androgen regulated transcriptome is of pivotal importance to understand the precise roles of sexual steroid hormones in testis. The main objectives of this thesis were to clarify the expression of ERα and ERβ in human testis, search for alternatively spliced AR variants, and to identify and characterize novel estrogen and androgen regulated genes with a potential importance in the control of spermatogenesis. The results presented herein demonstrate unequivocally that both ERα and ERβ are expressed in human testis, and clarify their cellular distribution. The existence of alternatively spliced testicular AR variants was confirmed with detection of four new AR forms in human testis, two of them conserved along the vertebrate evolutive line indicating a relevant functional importance. Conserning the sex steroid regulated transcriptome, two novel genes were identified, one regulated by estrogens and the other by androgens. Apoptosis inhibitor and modulator of DNA-damage response Aven was identified as a novel estrogen target gene in testis. Its expression was for the first time characterized in human and rat testis, as well as its cellular distribution to Sertoli and germ cells. Perhaps more importantly, it was shown that the expression levels of Aven in human testis are positively correlated with quality of spermatogenesis. Concerning androgen regulated gene, the expression of Regucalcin (RGN) in response to 5α-dihydrotestosterone was characterized, and RGN shown to be expressed by all cells in rat and human testis. Regucalcin is involved in the control of intracellular calcium concentration and regulation of cell proliferation and apoptosis, processes whose regulation is of pivotal importance in the control of spermatogenesis. Estrogens and androgens are well recognized as germ cell survival factors and are known to regulate control mechanisms for testicular apoptosis. Therefore, we believe that both Aven and RGN are involved in mechanisms of germ cell survival, which are controlled by androgens and estrogens. In conclusion, this thesis has contributed to increase the knowledge about estrogenic and androgenic action in testis. The “new actors cast” to the drama that is the hormonal control of spermatogenesis open new storylines in the research of mammalian spermatogenesis and perheaps male fertility.