Genomic and nongenomic effects of estrogens: molecular mechanisms of action and clinical implications for male reproduction.

Although estrogens have been always referred as female hormones, the deep involvement of these steroids in the development and control of male reproductive functions is only recently emerging. After a brief overview of estrogen effects on male different systems and organs, the present review will focus on estrogens as potential hormones in male reproduction. The present knowledge on the structure and regulation of estrogen receptor (ER) genes will be summarized and the expression pattern of the different isoforms of ERs in male reproductive system and of aromatase (Ar), the enzyme responsible for conversion of androgens into estrogens, will be reported, paying particular attention to distribution in human tissue. In addition to the description of the well-known genomic action exerted by estrogens through the classical nuclear receptors, alternative intracellular mechanisms of action of these hormones will be reviewed, with particular attention to the recently described so called nongenomic ones. In particular, recent data supporting evidences of nongenomic action of estrogens on human spermatozoa will be discussed. Possible cross-talks between the different signaling pathways will be taken into account. Comparison between phenotype in knockout mice for the genes encoding ERs and Ar and patients carrying congenital estrogen deficiency due to inactivating mutations of Ar gene or to estrogen resistance has been of fundamental importance in our understanding of the role of estrogens in male fertility. Finally, the requirement of estrogens in physiological development of male reproductive system will be described pointing out the possible deleterious effects on male reproductive structures exerted by abnormal exposure of male fetuses and adults to these hormones.