Review
Role of 17β-Hydroxysteroid Dehydrogenases in Sex Steroid Formation in Peripheral Intracrine Tissues

https://doi.org/10.1016/S1043-2760(00)00342-8Get rights and content

Abstract

In postmenopausal women, almost 100% of active sex steroids are synthesized in peripheral target tissues from inactive steroid precursors and, in adult men, approximately 50% of androgens are made locally in target tissues. This new field of endocrinology has been called intracrinology. The last and key step in the formation of all estrogens and androgens is catalyzed by a series of substrate-specific, cell-specific and unidirectional 17β -hydroxysteroid dehydrogenases (17β -HSDs). To date, seven human 17β -HSDs have been cloned, sequenced and characterized. The 17β -HSDs provide each cell with the means of precisely controlling the intracellular concentration of each sex steroid according to local needs.

Section snippets

•17β-Hydroxysteroid Dehydrogenases, Key Enzymes in Androgen and Estrogen Formation

The synthesis from DHEA of the most potent natural androgen, dihydrotestosterone (DHT), and of the most potent natural estrogen, 17β-estradiol (E2) involves several enzymes; namely, 3β-hydroxysteroid dehydrogenase/Δ54 isomerase (3β-HSD), 17β-HSD, 5α-reductase and/or aromatase (Fig. 3).

Because the molecular structure of the key, non-P-450-dependent, enzymes involved in sex steroid formation had not been elucidated and because local formation of sex steroids plays a major role in both normal

•Unidirectional Activity of 17β-HSDs

It is important to know that in intact cells the activity catalyzed by each type of 17β-HSD is almost exclusively unidirectional: for example, types 1, 3, 5 and 7 17β-HSDs catalyze the reaction in a reductive way or towards the formation of active estrogens or androgens, whereas types 2 and 4 17β-HSDs catalyze the oxidative reaction or the inactivation of sex steroids. In estrogen target tissues, such as in the placenta and breast, the presence of type 1 17β-HSD ensures a high level of E2

•Implications of 17β-HSDs in Physiology and Disease

In humans, the continuous formation of sex steroids from DHEA in peripheral target tissues is likely to play a major role in maintaining the adequate functioning of most tissues. Knowledge of this important role of intracrinology should be helpful in the design of better adapted therapies for the prevention and treatment of sex steroid-sensitive cancers, especially prostate and breast cancer, which are the two most common cancers in men and women and the second most frequent causes of death

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