Genetic mutations resulting in estrogen insufficiency in the male

The biosynthesis of estrogens is catalyzed by an enzyme known as aromatase (aromatase cytochrome P450; P350 arom; the product of the CYP19 gene). In r ecent years a number of patients have been described suffering from aromata se deficiency due to mutations in the CYP19 gene, resulting in the synthesi s of a non-functional gene product and a resulting failure to synthesize es trogens. Males with this condition have sustained linear growth into adulth ood resulting from failure of epiphyseal closure. Osteopenia and reduced bo ne mineral density and bone age are also characteristic. Lack of circulatin g estrogens is accompanied by elevated testosterone and gonadotropins. One of the men had macroorchidism with testicular volumes in excess of 25 ml (M orishima et al. J. Clin. Endocrinol. Metab. 80, 3689, 1995). Semen analysis was not performed on this patient, but it is of note that the one patient described with estrogen insensitivity due to a mutation in the estrogen rec eptor had a normal sperm count, although motility was decreased (Smith et a l., New England J. Med. 331. 1056, 1994). By contrast, the other man with a romatase deficiency had testicular volumes of only 8 ml per testes, and was infertile. Sperm analysis revealed a count of 1 million/ml with 100% immot ile sperm (Carani et al. New England J. Med. 337, 91, 1997). However, his c linical picture is confused by the fact that another male sibling has azoos permia, but has no CYP19 mutation, suggesting that the infertility problem may be due to a second genetic condition in this consanguineous family. Rec ently mice have been generated in which the aromatase (CYP19) gene and the gene encoding the estrogen receptor-cc have been inactivated by targeted di sruption (ArKO and ERKO mice, respectively). Male ERKO mice are infertile w ith atrophy of the testes and seminiferous tubule dysmorphogenesis resultin g in decreased spermatogenesis and inacive sperm. By contrast the ArKO mice are initially fertile and sire litters of normal size ad frequency, howeve r with advancing age the number of litters sired decreases relative to thos e of wild type litter ates. In contrast to the ERKO mice, light microscopic analysis of the testes of the ArKO mice reveals no gross morphological abn ormalties and the testes are of normal size. Following recent observations that the estrogen receptor-beta isoform is highly expressed in seminiferous epthelium, spermatids and spermatocytes, it is conceivable that the relati vely high levels of estrogens present in the ERKO mice can act through the ER-B to cause infertility by a direct action on the testes. In this context it is well known that administration of high levels of estrogen to men res ults in infertility. It is apparent that studies of human and mouse models with disruptions of aromatase and the estrogen receptor have as yet failed to clarify the role of estrogens in male fertility and testicular function. Development of an ER-B knockout mouse, or else a double, or even triple, k nockout model, may be required in order to resolve these issues. (C) 1998 P ublished by Elsevier Science Ireland Ltd. All rights reserved.