Normal men produce approx 40 ^g of estradiol and 60 ^g of estrone per day. Estra-diol is produced from testosterone and estrone from androstenedione, by aromatase P450, the product of the CYP19 gene (46). This microsomal enzyme oxidizes the C19 angular methyl group to produce a phenolic A ring. Aromatase mRNA is expressed in adult Leydig cells, where it is activated by LH/hCG (47). However, most of the estrogen in men is derived from aromatase in adipose and skin stromal cells, aortic smooth muscle cells, kidney, skeletal cells, and the brain. The promoter sequences of the extragonadal and testicular and P450 aromatase genes are distinct and tissue specific, resulting from differential splicing, but the translated protein is the same in all tissues. The factors that regulate extratesticular aromatase are not well understood.
Exogenous estrogens suppress testosterone production and disrupt spermatogenesis by reducing GnRH secretion and decreasing responsiveness to GnRH (48). It is now known that there are two forms of the ER that are encoded by separate genes and play a role in reproduction (49). These genes have been designated ER-a and ER-p. ER-a is the dominant form in the pituitary and hypothalamus, whereas ER-a and ER-P are both found in the testis, prostate, and epididymis (50). Clinical findings in an adult man with an inactivating mutation of the ER-a and in two men with mutations of the CYP19 aromatase gene (reviewed 51), together with results from mice in which estrogen receptors (49) or aromatase (52) have been "knocked-out," have enhanced understanding of the importance of estradiol in the neuroendocrine control of testicular function, as described
in the section on testicular control of gonadotropin secretion. Dilatation and atrophy of the seminiferous tubules are also found in ER-a-deficient mice, implying an effect of estrogen to regulate the efferent ductules of the testis. Aromatase-deficient mice although fertile in early life, develop infertility. Thus, estradiol is essential for male fertility.
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