Androgen conversion

Fig. 9.28 Unified mechanism of CMi cleavage in the 19-carboxylic acids. The mechanism is based on labeling third oxidation step of androgen conversion to estro- studies with 02 [2295] gens by P450 19A1, including the formation of androgen...

The alkynyl steroid (96) inactivates aromatase, an enzyme which catalyzes the conversion of androgen to estrogen. It has been suggested (81JA3221) that the inactivation process involves the oxidation of (96) to an oxirene which rearranges to an oxocarbene which then binds to the enzyme prosthetic group, thus inactivating it. 

Testiculat androgens are synthesized in the interstitial tissue by the Leydig cells. The immediate precursor of the gonadal steroids, as for the adrenal steroids, is cholesterol. The rate-limiting step, as in the adrenal, is delivery of cholesterol to the inner membrane of the mitochondria by the transport protein StAR. Once in the proper location, cholesterol is acted upon by the side chain cleavage enzyme P450scc. The conversion of cholesterol to pregnenolone is identical in adrenal, ovary, and testis. In the latter two tissues, however, the reaction is promoted by LH rather than ACTH. 

Aminoglutethimide blocks the conversion of androgens to estrogens and decreases the synthesis of glucocorticoids. 

Letrozole is another selective aromatase that inhibits the conversion of androgens to estrogen. Maximum plasma concentrations occur 1 hour after oral dosing concomitant food has not been shown to have an effect on the extent of absorption of letrazole. The terminal half-life is approximately 2 days. Letrozole is used in the treatment of postmenopausal women with hormone-receptor-positive or unknown advanced breast cancer. Side effects include bone pain, hot flushes, back pain, nausea, arthralgia, osteoporosis/bone fractures, and dyspnea. 

Antiandrogens inhibit the formation of the DHT-receptor complex and thereby interfere with androgen-mediated action at the cellular level.22 Megestrol acetate, a progestational agent, also is available and has antiandrogen actions.21 Finally, the conversion of testosterone to DHT may be inhibited by 5-a-reductase inhibitors.6... 

Forbes et al. saw a slight up-regulation of Connexin 43 in PC-3 cells (androgen unresponsive) with pure lycopene treatment but no Connexin 43 expression (with or without lycopene) in the highly metastatic PC-3MM2 variant (Table 21.2) indicating that with increasing metastatic conversion either the ability to turn on Connexin 43 is lost and/or the receptors responsive to lycopene are lost (Forbes et al. 2003). 

Independently, if these cytokines can exert their bone resorption functions without RANKL, they all stimulate the production of RANKL for stromal/OB cells, and conversely RANKL is able to increase IL-1 and TNF-a synthesis in vitro. To complicate this scenario, these systems of cytokines connect with the network of systemic hormones, such as PTH, PTH-related protein (PTHrP), vitamin D3, estrogens, androgens, glucocorticoids, and T4, since the hormones regulate the production of many of these cytokines by stromal/OB cells (Manolagas et al. 1995 Bellido et al. 1995 Lakatos et al. 1997). 

A long-held view is that oestrogens are the hormones that control reproductive activity in the female and that androgens control the activity in the male. Although this is broadly the case, such a complete separation is too simple. For example, testosterone is secreted by the thecal cells in the ovary and although some is taken up by the granulosa cells for conversion to an oestrogen, some remains in the blood, where it has several roles (e.g. stimu-... 

---