17β-Hydroxysteroid dehydrogenase

Steroidogenesis

17β-Hydroxysteroid dehydrogenase (17β-HSD) is an enzyme that plays a crucial role in the metabolism of steroids, specifically in the biosynthesis and degradation of estrogens and androgens. This enzyme is part of the hydroxysteroid dehydrogenase family and is involved in the conversion of estrone to estradiol and androstenedione to testosterone, which are critical processes in the regulation of sex hormones.

Function

17β-HSD catalyzes the oxidation and reduction reactions of steroid hormones, converting ketones to alcohols (reduction) and vice versa (oxidation). There are several isozymes of 17β-HSD, each with specific tissue distributions and functions, influencing the local availability of active sex steroids. For example, 17β-HSD type 1 primarily converts estrone to the more potent estradiol in ovarian and placental tissues, while 17β-HSD type 2 plays a key role in the inactivation of estradiol to estrone in liver and uterine tissues.

Clinical Significance

Alterations in the activity or expression of 17β-HSD enzymes can lead to disorders of sex development (DSD), such as androgen insensitivity syndrome and polycystic ovary syndrome (PCOS). Additionally, because these enzymes are involved in the synthesis of sex hormones, they have been targets for the development of drugs for hormone-dependent cancers, such as breast cancer and prostate cancer.

Isozymes

There are at least 14 known isozymes of 17β-HSD, each encoded by a separate gene. These isozymes differ in their substrate specificities, tissue distribution, and role in steroid hormone metabolism. For instance:

• 17β-HSD type 1 is involved in the synthesis of estradiol and is a target for breast cancer therapy.
• 17β-HSD type 3 is critical for the synthesis of testosterone in the testes and is associated with male puberty and fertility.
• 17β-HSD type 5 is implicated in the production of androgens in peripheral tissues and is studied in the context of PCOS and acne.

Research Directions

Research on 17β-HSD is focused on understanding the specific roles of its different isozymes in health and disease, developing selective inhibitors or activators as therapeutic agents, and exploring their potential in treating hormone-dependent conditions.