see also androgens; androgen deficiency

• anti-androgens have differing extent of actions depending on level of action:
  • GnRH agonists that block LH secretion:
    • by providing continuous rather than pulsatile activity, these agents lower LH secretion, & although lower testosterone levels by 90% at 1 month, they often transiently increase levels initially
    • often used for metastatic prostate Ca
    • goserelin depo injection every 3 months
    • nafarelin
    • buserelin
    • leuprolide acetate 1mg s/c daily
    • triptorelin
      • introduced in Australia in 2009 for Mx of advanced prostate Ca
      • can be given as monthly IM injections or as long acting formulation every 3 months to suppress androgen production
      • marketed as Diphereline
  • GnRH antagonists that block LH secretion:
    • these avoid the initial testosterone surge seen with GnRH agonists
    • degalerix
      • introduced in Australia in 2010; long acting s/cut injection
  • LH antagonists:
    • under development?
  • 17-alpha hydroxylase inhibitors:
    • spironolactone:
      • an aldosterone antagonist diuretic which also competes for DHT at androgen receptors as well as inhibiting 17-alpha hydroxylase thereby lowering plasma levels of testosterone & androstenedione
      • uses as anti-androgen:
        • hirsutism in women (50-200mg/d)
    • high levels of ketoconazole - not clinically useful
  • 5 alpha reductase inhibitors:
    • these cause:
      • decreased local production of DHT which is a paracrine hormone exerting its action in the tissue of origin.
      • global defect in C19 and C21 5α-metabolism, inhibiting 5α-reduction of progesterone, androstenedione, epitestosterone, cortisol, aldosterone, corticosterone, and deoxycorticosterone
      • Inhibiting DHT synthesis may alter the estrogen to androgen ratio by shifting metabolism of testosterone to estradiol, thus increasing the risk of gynecomastia and male breast cancer (although studies have given variable outcomes) ¹⁾
    • 5 alpha reductase type II inhibitors:
      • this is the main enzyme in prostate & hair follicles, thus the main action of these drugs is on decreasing prostatic size in benign prostatic hypertrophy and preventing androgenetic alopecia
      • HOWEVER the mechanism of action may result in significant adverse effects which appear to be under-reported and poorly studied in trials ²⁾³⁾:
        • there is little available information about the effect of 5α-RI exposure on non-prostate genital tissues in humans. Chronic 5α-RI exposure in rats increases apoptosis and autophagy in corpus cavernosum smooth muscle, attenuating erectile function and in humans, direct adverse effects on penile function include penile desensitisation and erectile dysfunction, and there is evidence that this may be persistent after cessation of Rx
        • 5α-RIs also induce a global defect in C19 and C21 5α-metabolism, inhibiting 5α-reduction of progesterone, androstenedione, epitestosterone, cortisol, aldosterone, corticosterone, and deoxycorticosterone and thereby reducing levels of the brain neurosteroids that increase libido and sexual arousal and thus results in reduced libido and reduced sexual arousal
        • independent, well designed studies are needed to determine the true extent of sexual dysfunction adverse effects
      • the REDUCE trial and the Prostate Cancer Prevention Trial appeared to show that use of 5ARI agents, whilst not affecting overall risk of prostate cancer, did appear to INCREASE risk of Gleason 8-10 high grade cancers, although incidence of these cancers was less than 2% in both studies
      • eg. finasteride, dutasteride
  • androgen receptor antagonists:
    • cyproterone:
      • inhibit the action of androgens on target organs
      • the acetate form also has a marked progestational effect that suppresses the feedback enhancement of LH & FSH, making a more effective anti-androgen effect
      • uses:
        • women with hirsutism
        • men with excessive sex drive
    • flutamide:
      • behaves like a competitive androgen receptor antagonist
      • rapidly metabolised
      • may cause mild gynaecomastia due to increasing testicular oestrogen production
      • may cause mild reversible hepatotoxicity