Steroidal Hormones PDF

STROIDAL HORMONES Androgens, Male Sex Hormones q Androgens control the development of male sex- characteristics, including, sperm production (spermatogenesis) and growth of the sex organs, prostate, and seminal vesicles as well as controlling metabolic effects during growth in adolescence...

STROIDAL HORMONES Androgens, Male Sex Hormones q Androgens control the development of male sex- characteristics, including, sperm production (spermatogenesis) and growth of the sex organs, prostate, and seminal vesicles as well as controlling metabolic effects during growth in adolescence (androgenic effects). q They cause nitrogen retention by stimulating protein synthesis (anabolic effect) while decreasing the rate of protein catabolism. q Testosterone is the major natural and androgenic hormone. Active form of Testosterone q Important metabolite of testosterone is 5a-dihydrotestosterone (DHT) formed by action of 5a-Reductase enzyme q DHT is considered as the most potent endogenous androgen. q Thus, testosterone is considered as a prohormone. a Testosterone Esters v As other natural steroids، testosterone is inactive orally. v Long duration of action could be obtained by using the ester derivatives. v Esterification of testosterone with acids, affording the cyclopentylpropionate and undecanoate at the 17b-position resulted in agents with an increased duration of action when given IM. Metabolism of Testosterone and 5a-Dihydrotestosterone (5a-DHT) N.B.: Metabolites conjugates are also formed 5/3/24 5 Synthetic androgens and anabolic agents 17a-Methyltestosterone v It is an orally active derivative and has the androgenic and anabolic activity of testosterone. v Increasing the length of 17a-alkyl side chain resulted in decreased activity and the incorporation of 17a-ethynyl group, produced compounds with useful pregestational activity. v It is important to separate the androgenic activity from anabolic activity of testosterone derivatives. v Thus, development of anabolic agents with reduced or no androgenic activity is desirable. Specific anabolic steroids(17a-alkylated steroids) Oxandrolone q It is heterocyclic analog of 17a-methyltestosterone, which contains a lactone in ring A and is therefore, susceptible to hydrolysis. q It has three times the anabolic activity of 17a- methyltestosterone and slight androgenic activity. q It is used as anabolic agent. Stanozolol q It is another heterocyclic compound and used for its anabolic activity. 7 17b-Testosterone acetate derivatives as Anabolic Agents Methenolone acetate q Alkylation in the C1 position of the androstane molecule generally increases anabolic activity. q Although methenolone does not contain 17a-CH3, yet it has potent anabolic activity and used orally. q IM or deep cutaneous injection per week as depot preparation is used for its anabolic action. 19-Norandrogens q Removal of the 19-methyl group provides 19-Norandrogens with more favorable anabolic to androgenic activity. q Nandrolone has 4:1 anabolic to androgenic activity, respectively. q Nandrolone is available as decanoate ester that when administered intramuscularly, slow hydrolysis of the ester in vivo takes place (Depot ). q Nandrolone decanoate is the longer acting ester intended for deep intramuscular injection preferably into the gluteal muscle, in the treatment of anemia associated with renal insufficiency.  Testosterone and synthetic anabolic androgenic steroids v 17b-Esters commonly available for IM injection. 5/5/24 10 Abuse of Steroidal Anabolic Agents to Enhance Athletic Performance q The use of anabolic steroids by athletes began in the late 1940s' and is now widespread. q In late 1987, the FDA issued a special alert about the risks of anabolic steroid use and abuse by athletes As summarized by the FDA and recent reviews, the side effects include of anabolic abuse are: q In males and females: Ø Increased risk of coronary heart disease, stroke, or obstructed blood vessels. Ø Increased aggression and antisocial behavior (known as “steroid rage"). Ø Liver tumors, and jaundice q In men: Ø Testicular atrophy with consequent sterility or decreased sperm count and normal motility and morphology. Ø Enlarged prostate and breast enlargement and impotency. q In women: Ø Beard growth Ø Baldness Ø Deepened voice Ø Breast diminution 11 Antiandrogenic agents v Antagonists of androgens include agents that: 1. Block androgen receptors (competitive antiandrogens) Ø Steroidal competitive antagonists (Cyproterone) Ø Non-steroidal competitive antagonists (e.g. Flutamide) 2. Inhibitors of androgenic biosynthesis (5α-Reductase inhibitors). Antiandrogen (competitive AR antagonist) Cyproterone acetate q Cyproterone acetate blocks androgen receptors which prevents androgens from binding to them and suppresses luteinizing hormone (which in turn reduces testosterone levels). q a synthetic progesterone derivative with antiandrogenic and progesterone-like activity Competitive Nonsteriodal-antiandrogenic compounds (propanamide derivatives) q Flutamide, nilutamide and Bicalutamide are nonsteroidal antiandrogenic drugs. q They act by competing with D for androgen receptors. HT q Flutamide undergoes extensive first-pass metabolism by CYP1A2 to its major metabolite, 2-hydroxyflutamide, that has more powerful antiandrogen in vivo and has higher affinity for the receptors than the parent compound.  Antiandrogenic agents (Inhibitors of androgen biosynthesis) 5α-Reductase inhibitors q Inhibitors of DHT biosynthesis can result in a decrease in DHT concentrations, thus blocking its androgenic action in these tissues. q The critical enzyme targeted for DHT inhibition is 5α-reductase, which converts testosterone to DHT. q Two azasteroid-17-amide derivatives (Finasteride and Dutasteride) are potent irreversible inhibitors of 5α-reductase and approved for the treatment of BPH