CYCLIC ADENOSINE 3',5'-MONOPHOSPHATE-RESPONSIVE ELEMENT MODULATOR GENE-EXPRESSION IN GERM-CELLS OF NORMOAZOOSPERMIC AND OLIGOAZOOSPERMIC MEN

In about one third of infertile men the cause of impaired spermatogene sis is not known. Spermatogenesis appears to be mediated at least in p art by the pituitary gonadotropins, which activate the cAMP-dependent signaling pathway. The end point of this pathway is the activation of nuclear transcription Factors, such as cAMP-responsive element-binding protein and cAMP-responsive element modulator (CREM). These factors, upon binding to gene sequences identified as cAMP response elements, m odulate the expression of germ cell-specific genes that, in turn, prom ote the completion of spermatogenesis. The expressions of the cAMP-res ponsive element-binding protein and CREM genes create different isofor ms, which can be divided into two groups: activators or repressors of gene regulation. Only CREM repressors are expressed in premeiotic germ cells in mice, whereas a switch to the expression of the CREM activat or tau is observed from postmeiotic germ cells onward. Completion of g erm cell maturation appears to be dependent on this phenomenon. Recent ly, mice lacking CREM gene expression have been generated. These anima ls were infertile and presented a developmental arrest of germ cell ma turation at the stage of early spermatid. In this report we demonstrat e that CREM gene expression also occurs in human germ cells. In partic ular, we determined by RT-PCR that a switch from the expression of CRE M repressors to CREM activators is present in postmeiotic germ cells i n normospermic men. Conversely, in oligoazoospermic patients only the expression of CREM repressors was detected. These data were confirmed by in situ hybridization studies in which transcripts for CREM activat ors were detected in postmeiotic germ cells in testis specimens showin g conserved spermatogenesis, but not in specimens showing maturation a rrest at the spermatid stage. Thus, our results indicate that the lack of a switch in the expression of CREM gene isoforms may be related to impaired spermatogenesis in humans.