androgens control sexual function in the male and are central to the anabolic processes that underlie the development of male sexual and physiological characteristics [ mooradian et al . , serum androgen levels are low prior to puberty and climb exponentially during adolescence in the male , leading to the enhanced muscle growth and lean body mass typical of the gender . in the mature adult they range from 600 to 700 ng / dl . as men age , androgen levels decline during the so - called andropause , reaching 450 to 500 ng / dl in their seventies and eighties [ flynn and hellstrom , 2001 ] . concomitantly , lean body mass decreases and older men are frailer , with a greater tendency to falls and bone fractures . testosterone ( t ) , acting via its more potent natural metabolite , dihydrotestosterone ( dht ) , stimulates maturation of the prostate during sexual development . dht is produced from t by 5--reduction , and it binds to the androgen receptor with about five times greater affinity than t. the enzyme 5--reductase is expressed tissue - specifically , most prominently in prostate and in hair follicles . this has been taken advantage of pharmacologically , with the generation of specific inhibitors of the enzyme for the treatment of androgen - dependent disorders . for example , finasteride is a 5--reductase inhibitor that prevents local synthesis of dht and is used to treat alopecia . t also has important physiological effects that are independent of dht , including anabolic effects on muscle , maintenance of testicular function , and inhibition of pituitary gonadotropin secretion . prostate maturation results in the production of prostatic secretions that form a component of semen , and thus it is essential for normal fertility . removal of circulating androgens by testicular or medical castration in humans and rodents results in apoptosis of prostatic cells and shrinkage of the prostate . the stimulatory effect of androgens on the prostate throughout adulthood is often thought to be primarily responsible for the increased risk of prostate cancer after the age of 40 , although there is no direct proof of this . nevertheless , localized and early stage metastatic prostate cancers are readily treatable by surgery and combined androgen blockade ( cab ) . cab typically consists of treatment with a gonadotropin - releasing hormone ( gnrh ) agonist ( such as leuprolide ) , to shut down physiological sex steroid synthesis ( surgical castration , or orchidectomy , has the same result ) ; and an androgen antagonist ( such as flutamide or bicalutamide ) , to shut down androgen - responsive pathways . androgen antagonists have been approved in the us only for cab of advanced prostate cancer . cab is an expensive therapy and men experience hot flushes and bone loss due to the depletion of anabolic steroids . recently , monotherapy with androgen antagonists has shown to be as effective as cab in preventing disease recurrence [ see et al . , 2002 ] , and some european regulatory authorities have approved the use of bicalutamide for this purpose . however , both currently used androgen antagonists , flutamide ( eulexin ) and bicalutamide ( casodex ) , cause breast tenderness and gynecomastia , which limit their use for monotherapy . these side effects are due to the propensity of the compounds to raise serum estrogen levels , which in turn is due to antagonism of normal feedback inhibition by testicular androgens at the pituitary . with feedback inhibition blunted , t synthesis continues , serum t levels rise , and the excess is aromatized into estrogen [ mcleod and iversen , 2000 ] . benign prostatic hyperplasia ( bph ) is a common condition in middle - aged and older men . the stromal compartment of the prostate grows larger and obstructs urethral flow , resulting in difficulty in urination . the etiology of bph is poorly understood , but the condition can be treated with inhibitors of dht formation ( finasteride ) or with adrenergic antagonists . androgen antagonists are also effective [ stone and clejan , 1991 ] , but they are not used due to their side effects on the male breast . testosterone and dht are also active in the skin , where they appear to maintain normal secretory activity and hair growth . facial hair ( hirsutism ) is a common symptom of hyperandrogenism in women . in the scalp , where androgens have a different mechanism of action , excessive androgen levels cause male - pattern baldness ( alopecia ) . testosterone and dht act via the androgen receptor ( ar ) , which is a member of the nuclear receptor superfamily . binding of an agonist ligand to the receptor induces conformational changes that result in binding of the receptor - ligand complex to dna elements adjacent to target genes in the genome , followed by changes in gene expression . these gene expression changes lead to cellular effects including increases in proliferation and metabolic activity . androgen antagonists bind to the receptor , preventing binding of the natural steroid , but do not produce the correct receptor conformational change . thus , the classic view of receptor - antagonist complexes is that they fail to elicit normal changes in gene expression , disrupting androgen - signaling pathways . , 2000 ; sack et al . , 2001 ] , and it has the typical helical sandwich structure found in other nuclear receptors . in the past several years , the concept of tissue - selective nuclear receptor ligands has emerged . this concept has come to fruition with estrogens , with the successful marketing of drugs such as raloxifene . raloxifene is an estrogen antagonist in some estrogen - responsive tissues ( breast and uterus ) , and an agonist in others ( bone ) . while the molecular mechanism of action of these selective estrogen receptor modulators ( serms ) is not understood , a commonly accepted hypothesis is that tissue - specific coregulators interact with the steroid receptor - ligand complexes to modulate their activities in different ways [ heinlein and chang , 2002 ] . the discovery of serms has raised the possibility of generating selective compounds for other pathways , including androgens ( that is , selective androgen receptor modulators , or sarms ) [ zhi and martinborough , 2001 ] . for example , a compound that is an antagonist at the prostate , but an agonist or weak antagonist at the pituitary , would have an improved side effect profile over currently marketed androgen antagonists . similarly , a compound that is a strong agonist on muscle , but an antagonist or weak agonist on prostate could be used to treat muscle - wasting conditions and age - related frailty , with a reduced concern for the potential to stimulate nascent or undetected prostate cancer . three are non - steroidal and the fourth ( cyproterone ) is a steroid with mixed progestational and androgen antagonist activities . of the non - steroids , bicalutamide is currently the biggest seller , probably due to its long half - life relative to flutamide , which facilitates once - per - day dosing . however , flutamide has recently come on the market as a generic in the united states , which is likely to significantly impact the future sales of bicalutamide here . bicalutamide itself will come off patent in 2008 . nilutamide s patent has also expired , but it was always a poor third to its competitors in terms of side effects and clinical use , and has not been developed as a generic compound . there is a large body of literature supporting their efficacy in animal models of alopecia [ pan et al . , 1998 ; 2000 ] and in clinical trials treating alopecia [ diamanti - kandarakis , 1999 ] , hirsutism [ muderris et al . , 2002 ; venturoli et al . , 1999 ; venturoli et al . , a new androgen antagonist , ru 58841 , is in phase ii clinical trials in europe for the topical treatment of acne and alopecia . as mentioned above , androgen antagonists also have clinical efficacy in bph [ stone and clejan , 1991 ] . to our knowledge , there are no non - steroidal androgens other than ru 58841 in clinical development . a number of companies , including bristol myers squibb , ligand pharmaceuticals , gtx technologies and karo bio have internal sarm research programs . the next section will review new classes of non - steroidal androgen receptor ligands that are in the public domain . some progress has been made in identifying new structural classes of non - steroidal sarms since the launch of flutamide ( figure 1 , structure 1 ) , nilutamide ( figure 1 , structure 2 ) and bicalutamide ( figure 1 , structure 3 ) . among many structures explored , the following three series have received the most attention : 2-quinolone and coumarins ( figure 2 , series 4 ) , phthalimide analogs ( figure 3 , series 5 ) and bicalutamide derivatives ( figure 4 , series 6 ) . as frequently seen in modulators of other steroid receptors such as the progesterone receptor , small structural changes can lead to the reversal of agonistic and antagonistic activity . both 4a and 4b bind to ar in the nanomolar range , with kis of 26 nm and 21 nm , respectively . compound 4a seems more potent and more efficacious in a cv-1 cell functional assay ( 4a : 74% efficacy , 27 nm antagonist potency ; 4b : 39% efficacy , 34 nm antagonist potency ) . in addition , 4b showed some agonist activity in the same cells ( 39% efficacy , 125 nm potency ) . however , in castrated immature male rats , 4b demonstrated better efficacy as an antagonist . it inhibited testosterone - induced increases in prostate weight and seminal vesicle weight ( 4a : ed50 [ prostate ] = 18 mg / kg , ed50 [ seminal vesicle ] = 19 mg / kg ; 4b : ed50 [ prostate ] = 3.1 mg / kg , ed50 [ seminal vesicle ] = 7.5 mg / kg ) , and was orally active [ edwards et al . , 2000 ] . compound 4c binds to ar with similar affinity ( ki = 17 nm ) , but showed very good efficacy as an agonist in cv-1 cell functional assays ( ec50 = 4 nm ) . in intact mature male rats , compound 4a did not raise serum levels of luteinizing hormone or testosterone , at 20 mg / kg or 40 mg / kg by the oral route . this was in contrast to flutamide and bicalutamide , which raised the levels of these hormones two- to eight - fold at these doses [ hamann et al . thus , compound 4a may have an advantage over current androgen antagonists because of its reduced potential for side effects in prostate cancer patients . phthalamides ( figure 3 ) such as 5a were identified as androgens antagonists with more potency than flutamide [ miyachi et al . for example , compound 5b was as potent as bicalutamide in a cwr22 human prostate cancer xenograft model [ salvati et al . , one of the compounds from this series , gtx-007 , showed an agonist effect in increasing the weight of the levator ani muscles of castrated male rats . in addition , the compound did not suppress luteinizing hormone and follicle stimulating hormone levels [ dalton et al . the structures of compounds 4a to 4c represent the 2-quinolones ( figure 2 ) . compounds as frequently seen in modulators of other steroid receptors such as the progesterone receptor , small structural changes can lead to the reversal of agonistic and antagonistic activity . both 4a and 4b bind to ar in the nanomolar range , with kis of 26 nm and 21 nm , respectively . compound 4a seems more potent and more efficacious in a cv-1 cell functional assay ( 4a : 74% efficacy , 27 nm antagonist potency ; 4b : 39% efficacy , 34 nm antagonist potency ) . in addition , 4b showed some agonist activity in the same cells ( 39% efficacy , 125 nm potency ) . however , in castrated immature male rats , 4b demonstrated better efficacy as an antagonist . it inhibited testosterone - induced increases in prostate weight and seminal vesicle weight ( 4a : ed50 [ prostate ] = 18 mg / kg , ed50 [ seminal vesicle ] = 19 mg / kg ; 4b : ed50 [ prostate ] = 3.1 mg / kg , ed50 [ seminal vesicle ] = 7.5 mg / kg ) , and was orally active [ edwards et al . , 2000 ] . compound 4c binds to ar with similar affinity ( ki = 17 nm ) , but showed very good efficacy as an agonist in cv-1 cell functional assays ( ec50 = 4 nm ) . in intact mature male rats , compound 4a did not raise serum levels of luteinizing hormone or testosterone , at 20 mg / kg or 40 mg / kg by the oral route . this was in contrast to flutamide and bicalutamide , which raised the levels of these hormones two- to eight - fold at these doses [ hamann et al . , 1999 ] . thus , compound 4a may have an advantage over current androgen antagonists because of its reduced potential for side effects in prostate cancer patients . phthalamides ( figure 3 ) such as 5a were identified as androgens antagonists with more potency than flutamide [ miyachi et al . , 1997 ] . recently , for example , compound 5b was as potent as bicalutamide in a cwr22 human prostate cancer xenograft model [ salvati et al . , 2002 ] . one of the compounds from this series , gtx-007 , showed an agonist effect in increasing the weight of the levator ani muscles of castrated male rats . in addition , the compound did not suppress luteinizing hormone and follicle stimulating hormone levels [ dalton et al . androgen receptor antagonists have found therapeutic use in the treatment of androgen - responsive prostate cancer for over two decades . in particular , androgen antagonist monotherapy , rather than cab or antagonists in combination with orchidectomy , will likely see increased use , due to its relatively fewer negative effects on quality of life . androgen antagonists will be approved for new clinical uses , including the treatment of hirsutism in women , alopecia in men and acne in both sexes . new sarm antagonists with improved tissue specificity , such as with reduced effects on the hypogonadal axis , will emerge for prostate cancer monotherapy , as well as for skin indications . it is possible that sarm antagonists will find use in bph , provided that they have sufficient efficacy . new laboratory tools , such as the availability of crystal structures of the receptor for rational drug design , will facilitate the discovery of new sarms . a promising area of research is on the development of sarm agonists for increasing lean body mass and muscle strength in hypogonadal men and in cancer and immunodeficient patients . ultimately , sarm agonists may be used to counteract the frailty associated with aging . as well as being extremely safe overall , such drugs will have to stimulate muscle strength without increasing the risk of prostate cancer . nevertheless , it is possible to see a day when tissue - specific androgens of many flavors will be of great medical benefit . 1 , flutamide ; 2 , nilutamide ; 3 , bicalutamide see text for more details . see text for more details see text for more details
in the past several years , the concept of tissue - selective nuclear receptor ligands has emerged . 
 this concept has come to fruition with estrogens , with the successful marketing of drugs such as raloxifene . 
 the discovery of raloxifene and other selective estrogen receptor modulators ( serms ) has raised the possibility of generating selective compounds for other pathways , including androgens ( that is , selective androgen receptor modulators , or sarms ) .