by Kenneth S. Korach, USA

Much new information on the role of estrogen in the male has been obtained from the estrogen receptor (ER) knock-out (ERKO) mouse model as reviewed by Dr. Korach. Estrogen seems to have prominent effects on the male cardiovascular system and skeleton, in addition to reproductive effects. These effects seem to be mainly mediated by the classical ERa, which is disrupted in the ERKO model. The role of the newly discovered other estrogen receptor, ERb, still remains unclear, as well as the potential non-ER mediated membrane effects of estrogens.

The male ERKO mice are infertile and upon histological examination they show seminiferous tubular swelling and loss of spermatogenesis. The sperm made in the testes of these animals are non-functional. The testicular LH and FSH receptors are up-regulated, but gonadotropin levels are normal. ERb persists in the ERKO mice, showing that there is no interrelationship between expression of the two ER types.
Seminal vesicle and epididymis weights of the mice are normal, indicating that androgen action is not compromised. The hypothalamic-pituitary level appears to adapt to the lack of estrogen action by maintaining or developing responsiveness to negative feedback effect to DHT, which is not seen in normal male mice. Hence the neuroendocrine regulation of gonadotropin secretion in the ERKO mice is reprogrammed.

As regards sexual behavior, the ERKO mice have normal amount of mountings but lower number of intromissions and ejaculations. The level of aggression of the ERKO males is also suppressed. Moreover, the bone density of the ERKO mice is suppressed.

Dr. Korach also reviewed the current knowledge on the single case of a human male with ER inactivation. As with the ERKO mouse, ER deficiency does not seem to be lethal in the human. The patient had delayed bone age and kept growing past the 20th year of age. He displayed incomplete closure of the epiphyses, had osteoporosis and was resistant to estrogen therapy. A similar phenotype has very recently been demonstrated in inactivating mutation of aromatase.

This very interesting mouse model and its human equivalents present the future direction of endocrinological research. In search of the physiological role of the various hormone and receptor genes, the transgenic and knock-out models will play a key role. The new question in the ER field is the phenotype caused by the ERb (or combined ERa and ERb) knock-out, as well as the tissue-specific and inducible time-dependent ER gene mutations, which are now technically feasible.

Ilpo Huhtaniemi, Finland



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