Formation of 5Androstene317Diol and Testosterone

5-Androstene-3j6,17jS-diol and testosterone are formed from DHEA and androstenedione, respectively, through the action of 17^-hydroxys-teroid oxidoreductase, which is commonly referred to as 17j6-hydroxysteroid dehydrogenase (17jS-HSD); the reactions are reversible. Five isoforms of the enzyme, encoded by the 17fi-HSD gene, have been described in humans, each having cell-specific expression, substrate specificity, regulatory mechanisms, and reductase or oxidative catalytic activities. They are designated types 1-5 in the chronological order of their isolation. Chromosomal locations, enzymatic activities, and cellular distributions of the human 17fi-HSD isoenzymes vary (see review by An-dersson and Moghrabi38).

The 17fi-HSD type 1 isoenzyme, originally referred to as placental estradiol-17fi-dehydroge-nase, was the first 17fi-HSD to be purified to homogeneity and cloned.23,39,40 The gene encoding 17fi-HSD type 1 is located at chromosome 17q21, which is in close proximity to the BRCA1 locus. The enzyme is a soluble protein with substrate preference for estrogens.41 Its affinity for C18 steroids is approximately 100 times higher than for C19 steroids.41 Although 17fi-HSD type 1 is localized predominantly in the ovary (granulosa cells)42 and placenta (syn-cytiotrophoblasts),43 it is also expressed in some malignant epithelial cells of the breast44 and en-dometrium.45 The enzyme utilizes NADPH as cofactor,40 and its catalytic preference is reduc-tion.46,47

17fi-HSD type 2, which is encoded by the gene located at chromosome 16q24,48,49 is a mi-crosomal enzyme50 that preferentially utilizes NAD+ as cofactor and catalyzes the oxidation of steroids with a hydroxyl group at carbon 17 (e.g., testosterone, estradiol) or carbon 20 (e.g., 20a-dihydroprogesterone).50 The enzyme is distributed among many extraglandular tissues, e.g., endometrium, placenta, and liver; however, it is primarily expressed in the endometrium.48 The level and specific activity of 17fi-HSD type 2 are increased during the luteal phase of the menstrual cycle in a manner that parallels circulating progesterone levels during this period.48

The 17fi-HSD type 3 isoenzyme is predomi nantly expressed in the testis.51 It is encoded by the gene located at chromosome 9q22 and localized in the microsomal fraction of testicular homogenates.38 The preferred cofactor for this isozyme is NADPH, which preferentially catalyzes the reduction of androstenedione to testosterone at carbon 17.52

Deficiency of 17fi-HSD type 3 causes a form of male pseudohermaphroditism referred to as 17fi-HSD deficiency,53 in which there is a deficiency in the biosynthesis of testosterone from androstenedione. The deficiency is confined to individuals with a 46 XY karyotype; these individuals have testes, wolffian duct-derived male internal genitalia (with the exception of a prostate), female external genitalia, and gynecomastia.54,55

Considerably less is known about the more recently characterized isozymes, 17fi-HSD type 456 and 17fi-HSD type 5.57 The type 4 isozyme appears to be distributed in many different tissues and localized in peroxisomes. It catalyzes the oxidation of C18 steroids, utilizing NAD+ as cofactor. In contrast, the type 5 isozyme is located in cytosol liver and skeletal muscle and catalyzes the reduction of C19 and C21 steroids, utilizing NADPH as cofactor. The isozyme is encoded by a gene located at chromosome 10p14,15.

Studies show that 17fi-HSDs are important in the regulation of estrogen action and preservation of tissue levels of progesterone. In the human endometrium, this is accomplished by oxidation of estradiol to estrone and of 20a-dihydroprogesterone to progesterone, respectively. The NAD +-dependent oxidation of estradiol to estrone and conversion of 20a-di-hydroprogesterone to progesterone are much greater in human endometrium during the luteal phase of the ovarian cycle, when progesterone production is high, compared to the follicular phase, which is characterized by low progesterone production.58 Addition of progesterone 20a-dihydroprogesterone, 5a-androstene-3fi,17fi-diol, testosterone, or estra-diol to human endometrial explants causes an increase in the oxidative activity of both the 17fi-HSD and 20a-HSD enzymes.59,60 Because of the tissue-specific expression and substrate specificity of 17fi-HSDs, cells in peripheral (nonendocrine gland) tissues are provided with the necessary mechanisms to control levels of intracellular androgens and/or estrogens. This hormonal control has been termed "intracrinol-ogy" by Labrie and coworkers.61 Through in-tracrine activity, androgens and/or estrogens that are produced locally exert their action inside the same cells where they are synthesized. Therefore, due to their pivotal role in the formation of active steroid hormones, 17^-HSDs allow each peripheral cell to regulate its own development, growth, and function.

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