Androgens precursors

The major androgen or androgen precursor produced by the adrenal cortex is dehydroepiandrosterone (DHEA). Most 17-hydroxypregnenolone follows the glucocorticoid pathway, but a small fraction is subjected to oxidative fission and removal of the two-carbon side chain through the action of 17,20-lyase. The lyase activity is actually part of the same enzyme (P450cl7) that catalyzes 17tt-hydroxylation. This is therefore a dual function protein. The lyase activity is important in both the adrenals and... 

The short-term action of ACTH on the adrenocortical cell is the stimulation of the conversion of cholesterol to glucocorticoid, mineralocorticoid or androgen-precursor steroids (Fig. 2). The conversion of cholesterol to the end-product steroids involves two mitochondrial cytochrome P-450 enzymes, cytochrome P-450scc (cho-... 

Androgen biosynthesis (secretory capacity for androgen precursors and testosterone) is assessed by incubation of the testis in vitro with hCG 250 mU for 3 hours. 

The primary estrogen in premenopausal women is 17-P-estradiol (E2), which is synthesized by developing ovarian follicles. Estradiol is oxidized to estrone (El) and then to estriol (E3). Estrone is also produced in peripheral tissues by aromatization of androstenedione, an androgen precursor that is produced by both the ovaries and the adrenal glands after the menopause, estrone produced in this way becomes the predominant estrogen. All of the estrogens are sulfated and glucuronidated before excretion. 

In most mammals, estrogens (female sex steroid hormones) are synthesized from cholesterol using the parent ring structure, cyclopentanoperhydrophenan-threne of the estrane series. The steroidogenic pathway includes the production of the androgenic precursors dehydroepiandrosterone and androstenedione, the latter of which is converted to testosterone, then to estradiol-17/i. This requires aromatization of these andogenic precursors by an aromatase enzyme complex. The major source of estrogen in postmenopausal women is the conversion of androstenedione to estrone by aromatase activity... 

At the distal end of the hormone skeleton, it has been suggested as a result of studies on model systems that ring a may be aromatized in vivo by epoxidation rather than by simple hydroxylation (Scheme 16). This work may stimulate biochemical studies on the role of unsaturation in ring a of androgen precursors. ... 

Placental synthesis of estrogens. The placenta lacks the key enzyme necessary for formation of estrogens from cholesterol (CYP 17) and relies on androgenic precursors from the maternal and fetal compartments. The major androgen used comes from the fetal zone of the fetal adrenal this is DHEAS, which is also taken up and metabolized by fetal liver into Iba-hydroxy-DHEAS. The placenta converts DHEAS into estrone (E ) and estradiol (E2) and proces.ses 16a-hydroxy-DHEAS into estriol (Ej). Estrogens enter the maternal circulation and appear in maternal urine as conjugated estrogens. 

Only 2% of total plasma testosterone is present in the physiologically active unbound state. The remaining testosterone is reversibly bound to a steroid hormone-binding globulin. The unbound testosterone or androgen precursors penetrate the prostatic cell by passive diffusion and are converted to DHT by 5-o -reductase. DHT subsequently binds with a specific cytoplasmic receptor. This DHT-receptor complex is then transported to the nucleus of the cell, where transcription and ultimately translation of stored genetic material occur. 

It is important to remember that brain androgen and oestrogen pathways are coupled together, because androgen precursors (androstenedione and testosterone) are converted into oestrogens (oestrone and estradiol respectively) in the brain, by... 

Here the follicle-stimulating hormone (FSH) is definitely more increased than the luteinising hormone (LH), which leads to an inverse relation between the two gonadotrophic hormones. Furthermore, there is extraglandular synthesis of oestrogens from androgenous precursors in the ovaries and adrenal glands. 

Dehydroepiandrosterone (DHEA) Androgen precursor advocated for treatment of AIDs (t CD4 in females), Alzheimer disease and aging , diabetes, hypercholesterolemia and SLE (1 in symptoms and flare-ups in females). Females androgenization and concern regarding CV disease 1 and breast cancer Males feminization in young and concern in elderly regarding BPH and cancer... 

The supply of oestrogen produced endogenously for the continued maintenance of tumour growth may be supplemented by the cancerous tissue itself (see review by Miller [30]). Over half [31] of human breast cancer cells synthesize oestrogen from androgen precursors in vitro [32-35]. Studies [35] on the synthesis in situ of oestrogens from human breast tumours by either the aromatase enzyme (from androstenedione) or a sulphatase enzyme (from oestrone sulphate) have shown that the latter pathway predominates. The sulphatase laromatase activity ratio is about 10 at normal in vivo concen-... 

Cells of the zona fasciculata have fewer receptors for Angll and express two enzymes, steroid 17a-hydroxylase (CYP17) and 11/3-hydroxylase (CYPllBl), which catalyze the production of glucocorticoids. In the zona reticularis, CYP17 carries out a second C17-20 lyase reaction that converts C21 corticosteroids to C19 androgen precursors. 

E. Aromatase Inhibitors Anastrozole and letrozole inhibit aromatase, the enzyme that catalyzes the conversion of androstenedione (an androgenic precursor) to estrone (an estrogenic hormone). Both drugs are used in advanced breast cancer. Toxicity includes nausea, diarrhea, hot flushes, bone and back pain, dyspnea, and peripheral edema. 

Nature Dehydroepiandrosterone (DHEA), derived mainly from the adrenal cortex, is an androgen precursor and in peripheral tissues is converted by aromatase to estradiol, fit the plasma, DHEA is converted to DHEA sulfate (DHEAS). No specific physiologic function has been defined for DHEA or DHEAS. However, DHEA levels decrease during aging and possibly in some disease states, including advanced AIDS, diabetes, and systemic lupus erythematosus (in women). 

---