 |
 |
|
| ANDROGENS Chapter 2 - David J Handelsman MB BS, FRACP, PhD August 17, 2004 |
||
|
|
|
|
| ANDROGENS Chapter 2 - David J Handelsman MB BS, FRACP, PhD August 17, 2004 |
||
|
Testosterone is the principal androgen in the circulation of mature male mammals. An androgen, or male sex hormone, is defined as a substance capable of developing and maintaining masculine sexual characteristics (including the genital tract, secondary sexual characteristics and fertility) and the anabolic status of somatic tissues. Testosterone and synthetic androgens based on its structure may be used clinically at physiological doses for androgen replacement therapy and, at higher doses, for pharmacological androgen therapy. The principal goal of androgen replacement therapy is to restore a physiological pattern of androgen exposure to the body. At present, such treatment is restricted to the major natural androgen, testosterone, and aims to deliver testosterone to replicate physiological circulating testosterone levels. Thus, an understanding of the normal physiology of testosterone is required as a basis for androgen pharmacology (1). Pharmacological androgen therapy exploits the anabolic effects of testosterone or synthetic androgens on muscle, bone or other tissues as hormonal drugs that are judged on efficacy, safety and relative cost-effectiveness. Testosterone is synthesized by an enzymatic sequence of steps from cholesterol (2) (figure 1) within the 500 million Leydig cells located in the interstitial (intertubular) compartment which constitutes about 5% of mature testis volume (3). The cholesterol is predominantly formed by de novo synthesis from acetate although preformed cholesterol either from intracellular cholesterol ester stores or extracellular supply from circulating low-density lipoproteins also contributes (2). Testosterone biosynthesis involves 2 multi-functional cytochrome P450 complexes involving hydroxylations and side-chain scissions (cholesterol side-chain cleavage [C20 and C22 hydroxylation & C20,22 lyase] and 17-hydroxylase/17,20 lyase) together with 3 and 17 ß-hydroxysteroid dehydrogenases and D4,5 isomerase. The highly tissue selective regulation of the 17,20 lyase activity (active in gonads but inactive in adrenals) independently of 17-hydroxylase activity (active in all steroidogenic tissues) when both activities reside in a single, multifunctional protein remains to be fully explained. Testicular testosterone secretion is principally governed by LH through its regulation of the rate-limiting conversion of cholesterol to pregnenolone within Leydig cell mitochondria by the cytochrome-P450 cholesterol side-chain cleavage enzyme complex located on the inner mitochondrial membrane. Cholesterol supply is governed by key proteins including sterol carrier protein 2 (4), which facilitates cytoplasmic transfer of cholesterol to mitochondria as well as StAR (5) and peripheral benzodiazepine receptor (6) which govern cholesterol transport across mitochondrial membranes. All subsequent enzymatic steps are located in the Leydig cell endoplasmic reticulum. The high testicular production rate of testosterone creates both high local concentrations (up to 1 mg/gm tissue) and rapid turn-over (200 times per day) of intratesticular testosterone.
Testosterone is secreted at adult levels during 3 epochs of male life - transiently during the first trimester of intrauterine life (coinciding with genital tract differentiation) and again during neonatal life (with unknown physiological significance) and continually after puberty to maintain virilisation. After middle age, circulating total and free testosterone levels decline gradually as gonadotrophin and SHBG levels increase (7-9) with these trends being exaggerated by the coexistence of chronic illness (8-12). These changes are attributable to impaired hypothalamic regulation of testicular function (13-17) as well as Leydig cell attrition (3) and dysfunction (18, 19) so that multiple functional defects are operative throughout the hypothalamo-pituitary-testicular axis (20, 21). Testosterone and other lipophilic steroids leave the testis by diffusing down a concentration gradient across cell membranes into the bloodstream with smaller amounts secreted into lymphatics and tubule fluid. After puberty, over 95% of circulating testosterone is derived from testicular secretion with the remainder arising from metabolic conversion of precursors of low intrinsic androgenic potency such as dehydroepiandrosterone (DHEA) and androstenedione. These weak androgens, predominantly originating from the adrenal cortex, constitute a large reservoir of precursors for extragonadal conversion to bioactive sex steroids in extra-gonadal tissues including liver, kidney, muscle and adipose tissue. Endogenous adrenal androgens contribute negligibly to direct virilisation of men (22) and residual circulating androgens following medical or surgical castration have minimal biological effect on androgen-sensitive prostate cancer (23). Conversely, however, adrenal androgens make a proportionately larger contribution to the much lower circulating testosterone concentrations in children and women (~5-10% of men) in whom blood testosterone is derived about equally from direct gonadal secretion and indirectly from peripheral interconversion of adrenal androgen precursors. Exogenous DHEA at physiological replacement doses of 50 mg orally per day (24) is incapable of providing adequate androgen replacement in men while producing hyperandrogenism in women (25). Hormone production rates can be calculated by either estimating metabolic clearance rate (from bolus injection or steady-state isotope infusion using high specific activity tracers) and mean circulating testosterone levels (26), or by estimation of testicular arterio-venous differences and testicular blood-flow rate (27). These methods give consistent estimates for testosterone production rate of 3-10 mg per day using tritiated (28, 29) or non-radioactive deuterated (30) tracers with interconversion rates of ~4% to dihydrotestosterone (DHT) (29, 31) and 0.2% to estradiol (32) under the assumption of steady-state conditions (hours to days). These steady-state methods are a simplification which neglects diurnal rhythm (33), episodic fluctuation in circulating testosterone levels over shorter periods (minutes to hours) entrained by pulsatile LH secretion (34) and postural influence on hepatic blood flow (28). The major known determinants of testosterone metabolic clearance rate are circulating SHBG concentration (35) and hepatic blood flow (28). Testosterone circulates in blood at concentrations above its aqueous solubility by binding to circulating plasma proteins. Testosterone binds avidly to sex-hormone binding globulin (SHBG), a dimeric glycoprotein of 95 kD with a single high-affinity androgen binding site and identical with testicular androgen binding protein (36). SHBG is secreted by the liver so its circulating levels are particularly influenced by first-pass effects of oral drugs including sex steroids. Circulating SHBG (and thereby total testosterone) concentrations are characteristically decreased (androgens, glucocorticoids) or increased (estrogens, thyroxine) by supraphysiological hormone concentrations at the liver such as produced by oral administration or by parenteral high-dose injections of hormones. In contrast, endogenous sex steroids as well as parenteral (non-oral) administration, which maintain physiological hormone concentrations (transdermal, depot implants), have minimal effects on blood SHBG levels. Other modifiers of circulating SHBG levels include up-regulation by acute or chronic liver disease and androgen deficiency and down-regulation by obesity, protein-losing states and genetic SHBG deficiency (37). Under physiological conditions, 60-70% of circulating testosterone is SHBG-bound with the remainder bound to lower-affinity, high capacity binding sites (albumin, a1-acid glycoprotein, transcortin) and 1-2% remaining non-protein bound. According to the free hormone hypothesis (38-40), the “free” (non-protein bound) fraction is the most biologically active with the loosely protein-bound testosterone constituting a larger “bioavailable” fraction of circulating testosterone. Nevertheless, “free” and/or “bioavailable” fractions would have enhanced accessibility not only to sites of bioactivity but also sites of inactivation by degradative metabolism. Hence the net significance of such derived measures of testosterone depends on empirical clinical evaluation which is very limited. Free testosterone levels can be measured by the reference methods of tracer equilibrium dialysis or ultrafiltration methods or calculated by a variety of nomograms based on immunoassays of total testosterone and SHBG. Some estimates of free testosterone, notably the direct analog assay (41-43) and the “free testosterone index” (44), are clearly invalid. Overall, the clinical utility of various derived measures of testosterone remain to be established. Circulating testosterone levels demonstrate distinct circhoral and diurnal rhythms. Circhoral LH pulsatility entrains some pulsatility in blood testosterone levels (34) although delays in testosterone secretion and buffering effects of the circulating steroid binding proteins markedly dampens pulsatility of blood testosterone concentrations. Diurnal patterns of morning peak testosterone levels and nadir levels in afternoon are evident in younger men although this pattern is lost in some ageing men (33) possibly due to increased circulating SHBG levels, reduced testosterone secretion and/or neuroendocrine defects (16). Consequently, is it conventional practice to standardise testosterone measurements to morning blood samples on at least two different days. Testosterone undergoes metabolism to both bioactive metabolites and to inactivated oxidised and conjugated metabolites for urinary and/or biliary excretion. A small proportion of circulating testosterone is metabolised to biologically active metabolites in specific target tissues to modulate biological effects. This includes both an activation pathway converting testosterone to the pure androgen dihydrotestosterone (DHT) as well as a diversification pathway whereby the enzyme aromatase that produces estradiol capable of activating estrogen receptors (ER). The amplification pathway involves conversion of a small fraction (~4%) of circulating testosterone to a more potent androgen, DHT (29, 31). DHT has higher binding affinity to the androgen receptor and 3-10-fold greater molar potency than testosterone. In vitro, DHT is a more potent androgen than T due to its higher binding affinity (45) and more efficient transactivation of the androgen receptor (46, 47). Testosterone is converted to the most potent natural androgen DHT by the 5-a reductase enzyme that originates from two distinct genes (I & II) each specified by distinct genes (48). Type 1 5a reductase is expressed in liver, kidney, skin, and brain whereas type 2 5a reductase is characteristically expressed strongly in the prostate but also at lower levels in skin (hair follicles) and liver (48). Congenital 5-a reductase deficiency due to mutation of the type 2 enzyme protein (49) leads to a distinctive form of genital ambiguity causing under-masculinisation of genetic males, who may be raised as females, but in whom puberty leads to marked virilisation including phallic growth and, occasionally, masculine gender reorientation (50) although prostatic development remains rudimentary (51). This remarkable natural history reflects the dependence of full development of urogenital sinus derivative tissues on strong expression of 5-a reductase as a local amplification mechanism. This amplification mechanism for androgen action was exploited in developing azasteroid 5-a reductase inhibitors (52). As the type 2 5-α reductase enzyme resulting in >95% of testosterone entering the prostate being converted to the more potent androgen DHT (53), blockade of that enzyme with expression largely restricted to the prostate facilitates the inhibition of testosterone action on urogenital sinus tissue derivatives, notably the prostate, without blocking all peripheral androgenic action. DHT circulates at ~10% of blood testosterone concentrations, due to spill-over from the prostate (54, 55) and non-prostatic sources (56). Genetic mutations disrupting type 2 5-a reductase lead to disorders of sexual differentiation involving the external genitalia and accessory glands originating from the urogenital sinus (57), which is developmentally dependent upon local amplification of testosterone to DHT. By contrast, genetic inactivation of type 1 5-α reductase has no male phenotype in mice but no analogous human mutations of the type 1 enzyme are yet reported. An important issue is whether eliminating intra-prostatic androgen amplification, by inhibition of 5a reduction, can prevent prostate disease. A major 10 year chemoprevention study randomizing nearly 19,000 men over age 55 years without known prostate disease to daily treatment with an oral 5a-reductase inhibitor, finasteride, or placebo observed a cumulative 25% reduction at 7 years of treatment in early stage, organ-confined low grade prostate cancer. While not designed to determine survival benefit, there was an apparent “stage shift” towards higher grade, but still organ-confined, cancers possibly a medication effect on tumor histology. These findings highlight the importance of androgen amplification within the prostate in the origin of cancer during the long latent pre-malignant phase. Although routine preventative use of prostatic 5a reductase inhibition is not warranted, novel synthetic androgens refractory to 5a reductive amplification may have advantages for clinical development. The diversification pathway of androgen action involves testosterone being converted by the enzyme aromatase to estradiol (32) to activate ERs. Although this only involves only a small proportion (~0.2%) of testosterone output, the much higher molar potency (~100 fold vs testosterone) of estradiol makes aromatisation a potentially important mechanism to diversify androgen action in various tissues via ER mediated effects. This diversification pathway of androgen action is governed by the cytochrome P450 enzyme (CYP19) aromatase (58, 59). In eugonadal men, most (~80%) circulating estradiol is derived from extratesticular aromatisation. The biological importance of aromatisation in male physiology is highlighted by the striking developmental defects in bone and other tissues of a man (60) and mouse line (61) with genetic mutations inactivating the ERa. By contrast, genetic inactivation of the ERb has little effect on male mouse phenotype (62) but human mutations have not been reported. It is likely that extent of aromatisation varies between tissues contributing to variable local modulation of tissue-specific androgen action. The importance of estrogen to male physiology is further highlighted by reports of men with complete genetic estrogen deficiency due to a non-functional mutated aromatase enzyme (63, 64). Men with aromatase deficiency had not only the same phenotype as in estrogen resistance but demonstrated significant bone maturation with estrogen treatment. These observations suggest the importance of aromatisation of testosterone to estradiol for development of some tissues, notably bone. Nevertheless other observations indicate that androgens and androgen receptors have important additional effects on bone. These include the greater mass of bone in men (65) despite very low circulating estradiol concentrations compared with young women, the failure of tfm rats having no functional androgen receptors but normal estradiol and ERs to maintain bone mass of normal males (66) and the ability of a non-aromatisable androgen to increase bone mass in estrogen-deficient women (67). Further studies are needed to fully understand the significance of aromatisation in maintaining androgen action in mature animals. See chapter on Estrogens in the Male. Testosterone is metabolised to inactive metabolites in the liver, kidney, gut, muscle and adipose tissue. Inactivation is predominantly by hepatic oxidases (phase I metabolism) notably cytochrome P450 3A family (68) leading ultimately to oxidation of most oxygen moieties followed by hepatic conjugation to glucuronides (phase II metabolism), which are rendered sufficiently hydrophilic for renal excretion. Metabolic clearance rate of testosterone is reduced by increases in circulating SHBG levels (eg ageing) (35) or decreases in hepatic blood flow (eg posture) (28) or function. Theoretically drugs that influence hepatic oxidase activity could alter metabolic inactivation of testosterone but empirical examples are few. Conversely, age-related rise in SHBG with corresponding decline in testosterone clearance rate may reduce requirement for endogenous production or exogenous replacement dose for testosterone in older men. Rapid hepatic metabolic inactivation of testosterone leads to both a low oral bioavailability (69, 70) and a short duration of action when injected parenterally (71). To achieve sustained androgen replacement, these limitations dictate the need for parenteral depot testosterone formulations (eg injectable testosterone esters, testosterone implants or transdermal testosterone), oral delivery systems which involve portal bypass (buccal (72, 73), sublingual (72, 74), gut lymphatic (75)) or synthetic androgens (76). During sexual differentiation early in intrauterine life, Leydig cell testosterone secretion precedes ontogeny of pituitary gonadotropin secretion. Testosterone is required for masculine sexual differentiation and is secreted by fetal Leydig cells autonomously of gonadotropin stimulation in most mammals (77). Higher primate placenta secretes a chorionic gonadotropin during early fetal life but whether this drives human fetal Leydig cell steroidogenesis is uncertain (78) particularly as male sexual differentiation of sub-primate mammals does not require a chorionic gonadotropin (77). After birth, testicular testosterone output is primarily regulated by pituitary LH secretion, which stimulates Leydig cell steroidogenesis via increasing substrate (cholesterol) availability, activating rate-limiting steroidogenic enzymes and cholesterol transport proteins and enhancing testicular blood-flow. LH is a dimeric glycoprotein consisting of an a subunit common to hCG, FSH and TSH and a ß subunit providing distinctive biological specificity for each dimeric glycoprotein hormone by virtue of its specific binding to the LH/hCG, FSH or TSH receptors (79). These cell surface receptors are highly homologous members of the heptahelical, G-protein linked family of membrane receptors. Functionally hCG is a natural, long-acting analog of LH as their ß subunits are nearly identical except that hCG has a C-terminal extension of 31 amino acids containing 4 O-linked, terminally sialic acid capped carbohydrate side-chains conferring greater resistance to degradation which prolongs circulating residence time and biological activity compared with LH (80). LH receptors are located on Leydig cell surface membranes and utilize signal transduction mechanisms involving both cAMP (81) and calcium (82) as second messengers to cause protein kinase-dependent protein phosphorylation and DNA transcription ultimately resulting in testosterone secretion. Driven by brief episodic bursts of hypothalamic secretion of GnRH into the pituitary portal bloodstream, pituitary gonadotropes secrete LH episodically in pulses of high amplitude at about hourly intervals with little intervening interpulse basal LH secretion so that circulating LH levels are distinctly pulsatile (83). This pattern maintains Leydig cell sensitivity to LH as more continuous exposure causes desensitisation (2). Additional factors regulating testosterone secretion include paracrine factors originating within the testis to influence Leydig cell function usually via indirect effects on Sertoli cells and blood vessels respectively (84). These include inhibin, activin, GnRH, FSH, prolactin, prostaglandins E2 and F2a, growth hormone, insulin-like and other growth factors as well as partially uncharacterised factors secreted by Sertoli cells. LH also influences testicular testosterone output by stimulation of Leydig cell secretion of vasoactive factors that promote testicular blood-flow (85). Testosterone participates in a negative testicular feedback cycle through its inhibition of hypothalamic GnRH and, consequently, pituitary gonadotropin secretion. Such negative feedback involves both testosterone effects on androgen receptors as well as aromatisation to estradiol within the hypothalamus and pituitary (86, 87). The small proportion (20%) of circulating estradiol directly secreted from the testes means that estradiol derived from the bloodstream is minimally regulated physiologically so that it is unlikely to participate significantly in the acute negative feedback regulation of gonadotropin secretion in men. The primary mechanism of biological androgen action is initiated by the binding of testosterone or its analogs to the androgen receptor causing its activation. In addition, testosterone is also converted to its bioactive metabolites, DHT and estradiol. The enzyme 5a-reductase (48) is a local androgen amplification mechanism converting testosterone to the most potent natural androgen, DHT. Further, conversion of testosterone to estradiol by the enzyme aromatase (58) diversifies androgen action by facilitating effects mediated via ERs. The quantitative importance of direct effects on the androgen receptor relative to indirect effects via active metabolites varies between androgens and target tissues, as do the androgenic thresholds and dose-response characteristics for each tissue. The androgen receptor is specified by a single gene located at Xq11-12 that specifies a protein of 919 amino acids which resides in the nucleus (88). Androgen binding to the C-terminal hormone binding domain causes a conformational change in the androgen receptor protein and dimerisation to facilitate receptor binding to segments of DNA featuring a characteristic palindromic motif known as an androgen-response element. Ligand binding leads to shedding of heat-shock proteins that act as a chaperone for the unliganded androgen receptor. Specific binding of the dimerised, ligand-bound androgen receptor complex to tandem androgen-response elements initiates gene transcription so that the androgen receptor acts as a ligand-activated transcriptional factor. Androgen receptor transcriptional activation is governed by a large number of co-regulators (89) whose tissue distribution and modulation of androgen action remain little understood. Mutations in the androgen receptor are relatively common leading to a wide spectrum of effects from functionally silent polymorphisms to androgen insensitivity syndromes that have phenotypes proportionate to the variable degree of blockade of androgen action (88). See also chapter on Androgen Physiology: Receptor and Metabolic Disorders. Indications for androgen therapy Androgen therapy can be classified as physiological or pharmacological according to the dosage and objectives of treatment. Androgen replacement therapy aims to restore tissue androgen exposure in androgen deficient men to levels comparable with eugonadal men. Using the natural androgen, testosterone, and dosage limited to ensure blood testosterone levels within the eugonadal range, androgen replacement therapy aims to restore the full spectrum of androgen effects while replicating the safety experience of eugonadal men of similar age. Androgen replacement therapy is unlikely to prolong life, as androgen deficiency does not shorten life expectancy (90). In contrast, pharmacological androgen therapy utilizes androgens without restriction on androgen type or dosage but aiming primarily to produce androgen effects on muscle, bone, brain or other tissues. In this context, pharmacological androgen therapy requires evaluation by the efficacy, safety, and cost-effectiveness criteria as for any other drug. Many older uses of pharmacological androgen therapy are now considered second-line therapies as more specific treatments are developed. For example, erythropoietin has largely supplanted androgen therapy for anemia due to marrow or renal failure whereas better first-line treatments for endometriosis and advanced breast cancer have similarly relegated androgen therapy to last resort (91). Androgen replacement therapy The main specific clinical indication for testosterone is as androgen replacement therapy for hypogonadal men. The prevalence of male hypogonadism requiring androgen therapy in the general community can be estimated from the known prevalence of Klinefelter's syndrome (1.5-2.5 per 1000 male births (92)) as Klinefelter's syndrome accounts for 35-50% of men requiring androgen replacement therapy (Handelsman, unpublished). The estimated prevalence of 5 per 1000 men in the general community makes androgen deficiency the commonest hormonal deficiency disorder among men. Although not shortening life expectancy (93), androgen deficiency is associated with preventable morbidity and a suboptimal quality of life. Due to its variable and often subtle clinical features, androgen deficiency remains under-diagnosed, thereby denying hypogonadal men simple and effective medical treatment with often striking benefits. Only 25% of men with the distinctive phenotype of Klinefelters syndrome are diagnosed during life (94). Hypogonadism of any cause may require androgen replacement therapy if the deficit in endogenous testosterone production is sufficient to cause clinical and biochemical manifestations of androgen deficiency. The clinical features of androgen deficiency vary according to the severity, chronicity and epoch of life at presentation. These include ambiguous genitalia, microphallus, delayed puberty, sexual dysfunction, infertility, osteoporosis, anemia, flushing, muscular ache, lethargy, lack of stamina or endurance, easy fatigue or incidental biochemical diagnosis (95). As the underlying disorders are mostly irreversible, life-long treatment is usually required. Androgen replacement therapy can rectify most clinical features of androgen deficiency apart from inducing spermatogenesis (96). When fertility is required in gonadotropin-deficient men, spermatogenesis can be initiated by treatment with pulsatile GnRH (97) (if pituitary gonadotrope function is intact (98)) or gonadotropins (99) to substitute for pituitary gonadotropin secretion. Either endogenous LH (stimulated by GnRH) or exogenous hCG act upon Leydig cell LH receptors to stimulate endogenous testosterone production. Where spermatogenesis remains persistently suboptimal, FSH may subsequently be added (99). Once fertility is no longer required, androgen replacement therapy usually reverts to the simpler and cheaper use of testosterone while preserving the ability subsequently to reinitiate spermatogenesis by gonadotropin replacement (99, 100). The potential role for androgen replacement therapy in men with partial or subclinical androgen deficiency states remain to be fully evaluated. Biochemical features of Leydig cell dysfunction, notably persistently elevated LH with low-normal testosterone and/or a high LH/T ratio are observed in ageing men (101) as well as in men with testicular dysfunction associated with male infertility (102) or after chemotherapy-induced testicular damage (103, 104). While it is plausible that such features signify mild androgen deficiency, the clinical benefits remain uncertain (105). The prospect of ameliorating male ageing by androgen therapy has long been of interest and recently been subject to clinical trials. The consensus from population-based cross-sectional (7) as well as longitudinal studies (8, 9) is that circulating testosterone concentrations fall by ~1% per annum from mid-life onwards, a fall accelerated by the presence of concomitant chronic disease (7), and associated with decreases in tissue androgen levels (106). Following a number of randomised, placebo-controlled clinical trials aiming to determine if androgen supplementation ameliorates age-related changes in bone, muscle and other androgen‑dependent tissues, the best available evidence shows no benefits on bone density, muscular strength or consistent effects on quality of life (107, 108). Other studies have shown small changes only in body composition but no consistent benefits in muscle, bone or quality of life measures following treatment with testosterone (109), DHT (110) or hCG (111). The Institute of Medicine report concluded that large and longer studies to balance putative benefits against potential long-term risks of accelerating cardiovascular or prostatic disease will be justified only if unequivocal benefit is established by more powerful, short-term studies (112). At present, androgen treatment for ageing men cannot be recommended as routine treatment. Nevertheless, androgen replacement therapy may be used even in older men who have severe androgen deficiency if contraindications such as prostate cancer are excluded. Hormonal male contraception can be considered a form of androgen replacement therapy since all currently envisaged regimens aiming to suppress spermatogenesis by inhibiting gonadotropin secretion, using testosterone either alone or together with a progestin or a GnRH antagonist (see also chapter on Male Contraception). As a consequence, exogenous testosterone is required to replace endogenous testosterone secretion. Pharmacological androgen therapy Pharmacological androgen therapy utilises androgens to maximal efficacy within adequate safety limits without regard to androgen class or dose. The objectives of pharmacological androgen therapy are, ideally, to improve mortality and morbidity due to an underlying disease. Mortality benefits require androgens modifying the natural history of an underlying disease, a goal not yet achieved for any non-gonadal disorder. Morbidity benefits are more realistic in aiming to improve quality of life by enhancing muscle, bone, brain or other androgen-sensitive function including mood elevation in an adjuvant therapy in non-gonadal diseases. Such treatment is judged by the efficacy, safety and cost-effectiveness standards of other drugs. However, very few studies of pharmacological androgen therapy fulfil the requirements of adequate study design (randomisation, placebo control, objective end-points, adequate power and duration) (91). Pharmacological androgen therapy has not reduced mortality or altered the natural history of any non-gonadal disease but has beneficial effects on morbidity of aplastic anemia (maintaining hemoglobin and reducing transfusion dependence), anemia of end-stage renal failure as a cheaper alternative, and synergistic with, erythropoietin and prevents acute episodes of hereditary angioedema and probably chronic urticaria (91). Pharmacological uses of androgens include treatment of anemia due to marrow or renal failure, osteoporosis, estrogen-receptor positive breast cancer, hereditary angioedema (C1 esterase inhibitor deficiency), immunological, pulmonary and muscular diseases (reviewed (91)). Although these traditional indications for androgen therapy may be surpassed by more specific and effective (and costly) treatments, they usually persist as second line, empirical therapies for which the lower cost and/or equivalent or synergistic efficacy may still favour androgen therapy in some settings. For historical reasons, pharmacological androgen therapy has often involved synthetic, orally active 17‑a alkylated androgens despite their hepatotoxicity (113). Other than in treating angioedema, where direct hepatic effects of 17α alkyl androgens (rather than androgen action per se) appears to be crucial to increasing circulating C1-esterase inhibitor levels to prevent attacks (114, 115), safer (non-hepatotoxic) testosterone preparations should be favoured for long-term clinical use, although the risk-benefit balance may vary according to prognosis. Many important questions and opportunities remain for androgen therapy in non-gonadal disease but careful clinical trials are essential for proper evaluation. The best opportunities for future evaluation of adjuvant use of androgen therapy in men with non-gonadal disease include steroid-induced osteoporosis, wasting due to AIDS and cancer, chronic respiratory, rheumatological and some neuromuscular diseases. In addition, the role of androgen therapy in recovery and/or rehabilitation after severe catabolic illness such as burns, critical illness or major surgery is promising but requires more detailed evaluation. Future studies of adjuvant androgen therapy require high quality clinical data involving randomisation and placebo controls as well as optimal dose finding and real, rather than surrogate, end-points. An important watershed was the proof by a well designed placebo-controlled clinical trial that pharmacological testosterone doses increase muscular size and strength even in eugonadal men (116). The clear dose-dependent effects of testosterone on muscle size and strength (117) and body metabolism (118) through and beyond the physiological range suggests that androgenic effects may be beneficial in reversing the frailty observed in many medical settings. Whether such effects can be applied effectively and safely to improve frailty and quality of life in chronic disease or male ageing remain important unanswered questions. Androgen therapy for HIV has been investigated for its effects on disease-associated morbidity, notably AIDS wasting, but it does not alter the natural history of underlying disease and the objective functional benefits remain modest. The rationale for androgen therapy in AIDS wasting is that body weight loss is an important terminal determinant of survival in AIDS and other fatal diseases (119) with death estimated to occur when lean body mass reaches 66% of ideal (120). This leads to the hypothesis that androgens may delay death by increasing appetite and/or body weight. Several randomised placebo-controlled studies of androgen therapy in HIV-positive men with AIDS wasting have reported increased lean and decreased fat mass due to testosterone with additive effects from resistance training but inconsistent improvement in quality of life (121-123). Among HIV-positive men without wasting, androgen induced changes in body composition are less and unaccompanied by any improvement in quality of life (121, 124). Pharmacological androgen treatment has been advocated for treatment of estrogen-resistant menopausal symptoms such as loss of energy or libido (125). The similarity of blood testosterone in women, children and orchidectomized men indicates that the term androgen deficiency is not meaningful in women (126) with normal adrenal function (127). High dose androgens suitable for androgen replacement in men (128, 129) produces markedly supraphysiological blood testosterone levels and virilization (130, 131). Lower but still supraphysiological testosterone doses increase bone density in menopausal women (132). The efficacy of add-on testosterone therapy for estrogen-resistant menopausal symptoms was evaluated in one randomised, placebo-controlled study of menopausal women (133). This study demonstrated no overall benefits of transdermal testosterone with a claimed benefit for a post-hoc analysis of a subgroup who with supraphysiological blood testosterone concentrations (134). In addition to risk of virilization, safety issues concerning androgen effects on cardiovascular disease and hormone-dependent cancers in women remain to be resolved. Androgen misuse and abuse Misuse of androgens involves medical prescription without a valid clinical indication and androgen abuse is the use of androgens for non-medical purposes. Medical misuse of androgens include prescribing androgens for male infertility or sexual dysfunction in non-androgen deficient men, where there is no likely benefit. The epidemic of androgen ("anabolic steroid") abuse, began in the 1950's, a product of the Cold War (135, 136) and has escalated, being fostered by the rewards of fame and fortune in elite competitive sport. For decades, androgen abuse has been cultivated by underground folklore among athletes and trainers, particularly in power sports and body-builders, that "anabolic steroids" enhance sports performance. Based largely on speculation promulgated in pseudo-scientific underground publications, this folklore promotes the use of prodigious androgen doses in combination ("stacking") regimens. Although the benefits of androgen abuse on muscular performance were long doubted, based on studies (137, 138) and meta-analysis (139) concluding that claimed performance benefits were primarily a placebo response involving motivation, training and diet effects, a pivotal randomised, placebo-controlled clinical study showed that supraphysiological testosterone doses (600 mg testosterone enanthate weekly) for 10 weeks increases muscular size and strength (116). In well-controlled studies of eugonadal young and older men testosterone shows strong linear relationships of dose with muscular size and strength throughout and beyond the physiological range (140). Progressively, the epidemic of androgen abuse has spread from elite power athletes to recreational and cosmetic users wishing to augment body-building as well as to occupational users who work in security-related professions. As an illicit activity, the extent of androgen abuse in the general community is difficult to estimate although point estimates of prevalence are more feasible in captive populations such as high schools. The prevalence of self-reported lifetime ("ever") use is estimated to be 66 in the USA (141), 58 in Sweden (142), 32 in Australia (143) and 28 in South Africa (144) per 1000 boys in high school with much lower prevalence among girls. Voluntary self-report of androgen abuse understates drug usage among weightlifters (145) and prisoners (146, 147). Abusers consume androgens from many sources including veterinary, inert or counterfeit preparations, obtained mostly through illicit sales by underground networks with a small proportion obtained from compliant doctors. Although highly sensitive urinary drug screening methods for synthetic androgens have been adopted by international sporting bodies and legislation has been introduced by some governments to tightly regulate clinical use of androgens, the epidemic of androgen abuse driven by user demands shows little signs of abating (148). Most recently, the first illicit non-marketed designer androgen tetrahydrogestrinone (THG) custom produced for elite athletes to avoid detection have been identified (149, 150) Androgen abuse is associated with reversible depression of spermatogenesis and fertility (151-155), gynecomastia (156), hepatotoxicity due to 17a-alkylated androgens (157), HIV and hepatitis from needle sharing (158-163), local injury and sepsis from injections (164), over-training injuries (165) and mood and/or behavioral disturbances (166, 167). The medical consequences of androgen abuse for the cardiovascular system has been reviewed (168-170) but only anecdotal reports are available relating to prostate diseases (171, 172). Few controlled clinical studies of cardiovascular (173-175) or prostatic (176) effects of androgen abuse, and no systematic, population-based studies, are available so that the overall risks remain ill-defined although some evidence suggests minimal differences in life expectancy comparing power with other elite athletes (177). More definitive studies are required but, at present, largely anecdotal information suggests that serious short-term medical dangers is limited considering the extent of androgen abuse, that androgens are not physically addictive (178, 179) and that most androgen abusers eventually discontinue drug use. Following cessation of prolonged use of high dose androgens, recovery of the hypothalamo-pituitary-testicular axis may be delayed for months creating a transient gonadotropin deficiency state (155, 180, 181). This may lead to temporary androgen deficiency symptoms which eventually abate without requiring additional hormonal treatments which may further delay recovery and perpetuate the drug abuse cycle. The most effective approach for medical intervention to prevent and/or halt androgen abuse is yet to be defined but educational programs (182) as well as support and encouragement comparable with smoking cessation programs may be appropriate. Practical goals of androgen replacement therapy The goal of androgen replacement therapy is to replicate the physiological actions of endogenous testosterone usually for the remainder of life. This requires rectifying the deficit and maintaining androgenic/anabolic effects on bone (183, 184), muscle (185), blood‑forming marrow (186, 187), sexual function (188, 189) and other androgen‑responsive tissues. The ideal preparation for long‑term androgen replacement therapy should be safe, effective, convenient and inexpensive with long‑acting depot properties due to reproducible, zero‑order, release kinetics. Androgen replacement therapy usually employs testosterone rather than synthetic androgens for reasons of safety and ease of monitoring and aims to maintain physiological testosterone levels (95). The practical goal of androgen replacement therapy is therefore to maintain stable, physiological testosterone levels for prolonged periods using convenient depot testosterone formulations that facilitate compliance and avoid either supranormal or excessive fluctuation of androgen levels. The potential for pharmacogenetic tailoring of testosterone replacement dose to an individual’s genetic background of androgen sensitivity was suggested a study demonstrating that prostate growth response to exogenous testosterone for androgen replacement therapy is strongly related to the CAG triplet repeat polymorphism in exon 1 of the androgen receptor (190). Whether this can be applied to other important androgen sensitive endpoints will determine whether the promise of this approach can be fulfilled. Pharmacological features of androgens The major features of the clinical pharmacology of testosterone are its short circulating half-life/transit time and low oral bioavailability, both largely attributable to rapid hepatic conversion to biologically inactivate oxidised and glucuronidated excretory metabolites. The pharmaceutical development of practical testosterone preparations has been geared to overcoming these limitations. This has led to development of parenteral depot formulations (injectable, implantable, transdermal), products to bypass the hepatic portal system (sublingual, buccal, gut lymphatic absorption) and orally active synthetic androgens. Androgens are defined pharmacologically by their binding and activation of the androgen receptor (88). Testosterone is the model androgen featuring a 19 carbon, 4 ring steroid structure with two oxygens (3-keto, 17ß-hydroxy) including a D4 non-aromatic A ring. Testosterone derivatives (see figure 2) have been developed to enhance intrinsic androgenic potency, prolong duration of action and/or improve oral bioavailability of synthetic androgens. Major structural modifications of testosterone include 17ß-esterification, 19-nor methyl, 17-a alkyl, 1-methyl, 7-a methyl and D-homo-androgens (191). Recently the first non-steroidal androgens, modified from non-steroidal anti-androgen structures, have been reported (192, 193).
The identification of a single gene and protein for the androgen receptor (194) explains the physiological observation that, at equivalent doses, all androgens have essentially similar effects (195). Consequently the term "anabolic steroid", referring to an idealised androgen lacking virilising features but maintaining myotrophic properties, is a false distinction and perpetuates an obsolete terminology. Better understanding of the metabolic activation of androgens via 5a-reduction and aromatisation in target tissues has however led to the concept of designer androgens with tissue-specific actions analogous to the development of synthetic estrogen partial agonists with tissue specificity (196). Unmodified testosterone Testosterone implants. Implants of fused crystalline testosterone provide stable, physiological testosterone levels for up to 6 months following a single implantation procedure (197). Typically, four 200 mg pellets are inserted under the skin of the lateral abdominal wall or hip using office-type minor surgery including a local anaesthetic. No suture or antibiotic is required and the pellets are fully biodegradable so do not require removal. This old testosterone formulation (198) has near ideal depot properties with testosterone being absorbed by simple dissolution from a solid reservoir into extracellular fluid at a rate governed by the solubility of testosterone in the extracellular fluid. The long duration of action makes it popular among younger androgen deficient men as reflected by a high continuation rate (199). The major limitations of this form of testosterone administration are the cumbersome implantation procedure and extrusion of a single pellet after 5-10% of procedures. Extrusions are more frequent among men with less subdermal fat and who undertake vigorous physical activities. However, neither surface washing (200) or antibiotic impregnation (201) nor varying the site of implantation (202) prevent extrusions. Other side-effects are rare (bleeding or infection <1%) (203). Despite its clinical advantages and popularity, the commercial unattractiveness of a simple, non-exclusive technology has limited its marketing availability. Transdermal testosterone Delivery of testosterone across the skin has long been of interest (76). In recent decades, testosterone in adhesive dermal patches and gels has been developed that can maintain physiological testosterone levels by daily application. The first transdermal patch was developed for application to the scrotum where the thin, highly vascular skin facilitates steroid absorption (204, 205). The scrotal patches are effective during long-term use (206) and there is minimal skin irritation (207, 208). However they are relatively large, require shaving for adhesion and disproportionately increase blood DHT levels due to 5-a reduction of testosterone during transdermal passage. Subsequently, a smaller patch for non-scrotal skin was developed (209) which is also effective during long-term use (210). The smaller size and application to less permeable dermal sites required inclusion of absorption enhancers that cause skin irritation (207, 208) of varying severity (211). This skin irritation may be prevented or ameliorated by topical corticosteroid cream (212) but discontinuation rates due to dermal intolerance are substantial (10-20%). Dermal testosterone (213) or DHT (214, 215) gels developed in Europe are now more widely available (216-219). They must be applied daily on the trunk and the volatile hydroalcoholic gel base evaporates rapidly and is non-irritating to the skin. A potential problem is the transfer of androgen to the female partner by skin contact (220) although washing off excess gel after a short time may reduce this risk (221). Unlike transdermal patches, gels have considerable misuse and abuse potential. Testosterone microspheres Suspensions of biodegradable microspheres, consisting of poly-glycolide-lactide matrix similar to absorbable suture material and laden with testosterone, can deliver stable, physiological levels of testosterone for 2-3 months following intramuscular injection (222, 223). Recent findings (224) suggest that the practical limitations of microsphere technology such as loading capacity, large injection volumes and batch variability may be overcome. Oral testosterone Micronized oral testosterone has low oral bioavailability requiring high daily doses (200-400 mg) to maintain physiological testosterone levels (69). This heavy androgen load causes prominent hepatic enzyme induction although testosterone itself is not hepatotoxic (225). Although effective in small studies, micronized oral testosterone is little used as it is not commercially available. Buccal or sublingual delivery of testosterone is an old technology (72) designed to bypass the avid first pass hepatic metabolism of testosterone that is inevitable with the portal route of absorption. Recent re-inventions of this technology include testosterone in a sublingual cyclodextrin formulation (74, 226, 227) or a buccal lozenge (73, 228). The multiple daily dosing required by such products to maintain physiological testosterone levels are handicaps for long-term androgen replacement and their acceptability remains to be established. Like all transepithelial (non-parenteral) testosterone delivery systems, disproportionate amounts of testosterone undergo 5α reduction during local absorption resulting in higher blood DHT levels than in eugonadal men. As intraprostatic DHT are unlikely to be elevated and prostate diseases remain rare among men with genuine androgen deficiency receiving androgen replacement therapy, the higher blood DHT levels do not appear to pose any real risk of accelerating prostate disease. Testosterone esters Injectable The most widely used testosterone formulation is intramuscular injection of testosterone esters, formed by 17-b esterification of testosterone with fatty acids of various aliphatic and/or aromatic chain lengths, injected in a vegetable oil vehicle. This depot formulation relies on retarded release of the testosterone ester from the oil vehicle injection depot since esters undergo rapid hydrolysis by ubiquitous esterases to liberate free testosterone into the circulation. The pharmacokinetics and pharmacodynamics of androgen esters is therefore primarily determined by ester side-chain length, volume of oil vehicle and site of injection via hydrophobic physico-chemical partitioning of the androgen ester between the hydrophobic oil vehicle and the aqueous extracellular fluid (229). Testosterone propionate with a short aliphatic side-chain ester has a brief duration of action requiring injections of 25-50 mg at 1-2 day intervals for androgen replacement. In contrast testosterone enanthate has a longer duration of action so that it is routinely administered at doses of 200-250 mg per 10-14 days for androgen replacement therapy in hypogonadal men (230-233). Other testosterone esters (cypionate, cyclohexanecarboxylate) have virtually identical pharmacokinetics making them pharmacologically equivalent to testosterone enanthate (233), the most widely used ester. Mixtures of short and longer acting testosterone esters are available but lack a convincing rationale and remain far from desirable zero-order kinetics release profiles. Recent advances have been the development of new injectable testosterone esters including testosterone undecanoate and buciclate. Testosterone undecanoate in an oil vehicle has a strikingly longer (8-12 weeks) duration of action (234-236), a big advance in depot testosterone products and soon to be marketed. Testosterone buciclate (trans-4-n-butyl cyclohexane carboxylate) is a novel insoluble testosterone ester in an aqueous suspension that produces prolonged slow testosterone release due to steric hindrance of ester side-chain hydrolysis. Although this produces low physiological levels of testosterone lasting up to 4 months following injection in non-human primates (237) as well as hypogonadal (238) and eugonadal (239) men, product development has not progressed. Oral testosterone undecanoate Oral testosterone undecanoate, a suspension of the ester in 40 mg oil-filled capsules, is administered as 160-240 mg in 3-4 doses per day. The hydrophobic, long aliphatic chain ester in an oil vehicle favours preferential absorption into chylomicrons entering the gastrointestinal lymphatics and largely bypassing hepatic first-pass metabolism during portal absorption (75) but is only absorbed when ingested with food (240). Testosterone undecanoate has low and erratic oral bioavailability, short duration of action and causes gastrointestinal intolerance. Widely marketed except in the USA, it has well established safety (241) but its limitations in efficacy make it a second choice (231, 232) unless parenteral therapy has to be avoided (eg bleeding disorders or anticoagulation) or to provide low dose as for induction of male puberty (242)). Synthetic androgens Most oral androgens are hepatotoxic 17-a alkylated androgens (methyltestosterone, fluoxymesterone, oxymetholone, oxandrolone, ethylestranol, stanozolol, methandrostenolone, norethandrolone, danazol) and are unacceptable for long-term androgen replacement therapy. The 1-methyl androgen, mesterolone, is functionally an orally active DHT analog free of hepatotoxicity but is not used for androgen replacement due to the need for multiple daily dosing and its poorly described pharmacology (243). Another potent, synthetic androgen free of hepatotoxicity, 7a-methyl 19-nortestosterone (MENT), is under development as a depot androgen (244) for androgen replacement (245) and male contraception (246). As a nandrolone derivative, MENT has tissue-specific selectivity in being susceptible to aromatisation but not to amplification by 5a-reduction (247) thereby representing a forerunner of designer androgens based on metabolite selectivity. The inability of MENT to maintain bone density in androgen deficient men (248), possibly due to under-dosage rather than intrinsic feature of this synthetic androgen, illustrates the need for thorough dose titration in different tissues for synthetic androgen which may not posses the full spectrum of testosterone effects. Non-steroidal androgens Recently development of the first non-steroidal androgens was reported (192). Based on structural modifications of the non-steroidal class of anti-androgens, such compounds offer the possibility of orally active, potent androgens. They would however be intrinsically non-aromatisable and, if taken orally, subject to first-pass hepatic metabolism and liable to produce disproportionate androgenic effects on the liver. These features suggest they have greater potential for development into pharmacological androgen therapy regimens as tissue-selective androgen partial agonists (“SARM”s) rather than for androgen replacement therapy where the full spectrum of testosterone effects including aromatisation is required. The choice of testosterone formulation for androgen replacement therapy depends on physician experience and patient preference involving factors such as convenience, availability, familiarity, cost and tolerance for frequent injections. Preparations of testosterone or its esters are favoured over synthetic androgens for all androgen applications by virtue of assured safety and efficacy, ease of dose-titration and assay monitoring. The hepatotoxicity of synthetic 17‑a alkylated androgens (113) makes them unsuitable for long‑term androgen replacement therapy. This obsolete class of androgen is being progressively withdrawn from marketing and clinical usage in most countries. Cross-over studies indicate that patients prefer formulations with stable testosterone levels and smoother clinical effects (eg implants (232); transdermal patches (249)) to the wide fluctuations in testosterone levels and effects with intramuscular injections of testosterone esters in an oil vehicle (230, 232, 250). There are few well established formulation or route-dependent differences between various testosterone formulations once adequate doses are administered. As with estrogen replacement, testosterone effects on SHBG may be viewed as manifestations of hepatic overdosage (37) so that oral 17-a alkylated androgens and testosterone undecanoate cause prominent lowering of SHBG levels due to marked first‑pass hepatic effects while intramuscular testosterone ester injections cause transient falls which mirror testosterone levels and long-acting depot testosterone formulations (eg testosterone buciclate, implants & microspheres) have minimal effects (223, 232, 238, 251). Long-acting depot testosterone preparations with zero‑order release patterns (197, 224, 236, 238) which are also convenient and affordable are likely to supplant the present injectable testosterone esters as the mainstays of androgen replacement therapy. Side-effects of androgen therapy Serious adverse effects from androgens are uncommon and are mostly due to either inappropriate treatment (children, women) or the hepatotoxicity of the 17-a alkylated androgens. Virtually all androgenic side-effects are rapidly reversible on cessation of treatment apart from inappropriate virilization in children or women when voice deepening, terminal body hair or stunting of final height may be irreversible. Steroidal effects Androgen replacement activates physical and mental activity to enhance mood, behaviour and libido thereby reversing their impairment during androgen deficiency (252). In healthy eugonadal men, however, administration of additional androgen has negligible effects on mood or behaviour (253-258). This contrasts with androgen abusers among whom high levels of background psychological disturbance (166), drug habituation (178) and anticipation (259) predispose to behavioural disturbances reported during this form of drug abuse (252, 260). Idiosyncratic hypomanic episodes have been reported in a small minority of young having supraphysiological doses of testosterone in some (261-263) but not all (253, 254, 256, 257) clinical studies. Excessive or undesirable androgenic effects may be experienced during androgen therapy due to intrinsic androgenic effects in inappropriate settings (eg virilization in women or children). In some untreated hypogonadal men, particularly older men, initiation of androgen treatment with standard doses occasionally produces an intolerable increase in libido and erection frequency. More gradual acclimatisation to full androgen doses with counselling of men and their partners may be useful in such situations. Seborrhea and acne are commonly associated with high blood testosterone levels, particularly among androgen abusers taking injectable testosterone esters. It has a predominantly truncal distribution in men in contrast to the predominantly facial distribution of adolescent acne. Acne is uncommon during androgen replacement therapy being restricted to a few susceptible individuals treated with intramuscular testosterone esters, probably related to their generation of transient supra-physiological testosterone concentrations in the days following injection (230). Acne is rare with depot testosterone products that maintain steady-state physiological blood testosterone levels. Androgen-induced acne is usually adequately managed with topical measures and/or broad-spectrum antibiotics with switch to steady-state delivery avoiding supraphysiological peaks of plasma testosterone. Increased body hair and temporal hair loss or balding may also be seen. Weight gain reflecting anabolic effects on muscle mass is also common. Gynecomastia is a feature of androgen deficiency in men but may appear during androgen replacement therapy especially during use of aromatisable androgens such as testosterone that increase circulating estradiol levels at times when androgenic effects are inadequate (eg too low or infrequent dose or unreliable compliance with treatment). Obstructive sleep apnea (OSA) causes a mild lowering of blood testosterone concentrations (264) that is rectified by effective continuous positive airway pressure (CPAP) treatment (265). Although testosterone treatment has precipitated OSA (266) and has potential adverse effects on sleep in older men (267), the prevalence of OSA precipitated by testosterone treatment remains unclear. It appears to be a rare idiosyncratic reaction among younger hypogonadal men but the risk may be higher among older men as the background prevalence of OSA rises steeply with age. Hence screening for OSA by asking about daytime sleepiness and partner reports of loud and irregular snoring, especially among overweight men with large collar size is wise for older men starting testosterone treatment although not routinely required for young men with classical hypogonadism. Hepatotoxicity Hepatotoxicity is a well-recognised but uncommon side-effect of 17-a alkylated but not with other androgens (113). Biochemical hepatotoxicity, involving either a cholestatic or hepatitic pattern, usually abates with cessation of steroid ingestion. Hepatic tumors related to androgen usage include peliosis hepatis (blood-filled cysts), adenoma or carcinoma. Prolonged use of 17-a alkylated androgens, if unavoidable, requires regular clinical examination and biochemical monitoring of hepatic function. If biochemical abnormalities are detected treatment with 17-a alkylated androgens should cease and safer androgens may be substituted without concern. Where structural lesions are suspected, radionuclide scan, ultrasound or abdominal CT scan should precede hepatic biopsy during which severe bleeding may be provoked in peliosis hepatis. As equally effective and safer alternatives exist, the hepatotoxic 17-a alkylated androgens should not be used for androgen replacement therapy. Formulation-related Complications related to testosterone formulations are related to mode of administration or idiosyncratic reactions to constitutents. Intramuscular injections of oil vehicle may cause local pain, bleeding or bruising and, rarely, coughing fits or fainting possibly due to oil microembolisation (268). Inadvertent subcutaneous administration of the oil vehicle is highly irritating and may cause pain, inflammation or even dermal necrosis. Allergy to vegetable oil vehicle of testosterone ester injections (sesame, castor, arachis) is very rare and even patients allergic to peanuts may tolerate arachis (peanut) oil without incident. Oral testosterone undecanoate frequently causes gastrointestinal intolerance due to the oleic acid suspension vehicle. Testosterone implants may be associated with extrusion of implants or with bleeding, infection or scarring at implant sites (199). Parenteral injection of newer testosterone esters (238) or biodegradable microspheres (223) involves a large injection volume that may cause discomfort. Non-scrotal transdermal patches frequently cause skin irritation with a significant minority (10-20%) unable to use truncal patches. Topical steroid-impregnated gels may transfer androgens through topical skin-to-skin contact (220). Monitoring of androgen replacement therapy Monitoring of androgen replacement therapy involves primarily clinical observations to optimise androgen effects (including continuation of treatment) and recognise side effects. Once well established, androgen replacement therapy requires only very limited, judicious use of biochemical testing or hormone assays. Testosterone and its esters at conventional doses for replacement therapy are sufficiently safe not to require routine toxicological monitoring. The World Health Organisation has developed guidelines for the therapeutic use of androgens in men (269). Clinical monitoring depends upon observation of serial improvement in the key presenting features of androgen deficiency. Androgen deficient patients may report subjective improvements in energy, well‑being, psychosocial drive, initiative and assertiveness as well as in sexual activity (especially libido and ejaculation frequency), increased sexual hair and muscular strength and endurance. Patients become familiar with their own leading androgen deficiency symptoms and these appear in predictable sequence and at consistent blood testosterone thresholds for symptoms (270). Objective and sensitive measures of androgen action are highly desirable but not available for most androgen responsive tissues (271). The main biochemical measures available for monitoring of androgenic effects include hemoglobin and trough reproductive hormone (testosterone, LH & FSH) levels. Hemoglobin rises by about 10-20 g/L when androgen dosage is adequate (186, 187)). Occasionally excessive hemoglobin responses may create polycythemia requiring venesection and/or anti-coagulation together with temporary interruption. As these idiosyncratic reactions appear related to supraphysiological peak testosterone concentrations, treatment should be resumed with more steady-state testosterone delivery systems if possible. Circulating testosterone and gonadotropin levels must be considered in relation to time since last testosterone dose. Trough levels (immediately prior to next scheduled dose) may be helpful in establishing adequacy of depot testosterone regimens. In the presence of normal testosterone negative feedback on hypothalamic GnRH and pituitary LH secretion (ie men with hypergonadotropic hypogonadism), plasma LH levels are elevated in rough proportion to the degree of androgen deficiency. In severe androgen deficiency, virtually castrate LH levels may be present and, conversely, circulating LH levels provide a sensitive and specific index of tissue testosterone effects (197, 230). Suppression of LH into the eugonadal range indicates adequate androgen replacement therapy, whereas persistent non‑suppression after the first few months of treatment is an indication of inadequate dosage or pattern of testosterone levels. In hypogonadotropic hypogonadism, however, impaired hypothalamo-pituitary function diminishes circulating LH levels regardless of androgen effects, so LH levels do not reflect tissue androgenic effects. Plasma testosterone measurements are of most importance for diagnosis, during initiation and for evaluating adequacy of treatment. Variability between patients in transdermal testosterone absorption makes it useful to check blood testosterone levels early after starting transdermal treatment to guide individual dose optimisation. During depot testosterone treatment where quasi-steady-state plasma testosterone levels are achieved, trough plasma testosterone levels may detect patients whose treatment is suboptimal and where the dose and/or treatment interval need modification. Plasma testosterone levels are not helpful for routine monitoring androgen therapy using any synthetic androgens or oral testosterone undecanoate. Serial evaluation of bone density (especially vertebral trabecular bone) by dual photon absorptiometry at 1-2 year intervals may be helpful in verifying the adequacy of tissue androgen effects (183, 184). Although chronic androgen deficiency protects against prostate disease (51, 272), the prostate of androgen-deficient men receiving androgen replacement therapy is restored to, but does not exceed, age-appropriate norms (273-275). Between-subject variability in response to testosterone replacement is partly explained by genetic sensitivity to testosterone which is inversely related to length of the CAG triplet (polyglutamine) repeat polymorphism in exon 1 of the androgen receptor (190). Furthermore, as endogenous blood testosterone or other androgen concentrations do not predict subsequent development of prostate cancer (276, 277), maintaining physiological testosterone concentrations should ensure no higher rates of prostate disease than eugonadal men of similar age (278). The potential long-term risks for cardiovascular disease of androgen replacement and pharmacological androgen therapy remain uncertain. Although men have 2-3 times the prevalence (279) as well as earlier onset and more severe atherosclerotic cardiovascular disease than women, the precise role of blood testosterone and of androgen treatment in this marked gender disparity is still poorly understood (90, 280). While low blood testosterone concentration is a risk factor for cardiovascular disease and testosterone effects include vasodilation and amelioration of coronary ischemia as well as potentially deleterious effects, it is not possible to predict the net clinical risk-benefit of androgen replacement therapy on cardiovascular disease. Hence during androgen replacement therapy it is prudent to aim at maintaining physiological testosterone concentrations and surveillance for cardiovascular and prostate disease should be comparable with, no more intensive than, eugonadal men of equivalent age (278). The effects of pharmacological androgen therapy, where androgen dosage is not necessarily restricted to eugonadal limits, on cardiovascular and prostate disease are still more difficult to predict and surveillance then depends on the nature, severity and life-expectancy of the underlying disease. Contraindications and precautions for androgen replacement therapy Contraindications to androgen replacement therapy are prostate and breast cancer as these tumors may be androgen responsive and pregnancy where transplacental passage of androgens may disturb fetal sexual differentiation. Despite the contraindication for any androgen therapy in men with active, incurable prostate cancer, testosterone may be used cautiously with appropriate monitoring following cure of localised prostate cancer by radical prostatectomy or radiotherapy or after long-term remission of advanced prostate cancer if androgen deficiency symptoms require treatment. Precautions and/or careful monitoring of androgen use is required in (i) initiating treatment in older men who may experience intolerable changes in libido, (ii) competitive athletes who may be disqualified, (iii) women of reproductive age, especially those who use their voice professionally, who may become irreversibly virilized, (iv) prepubertal children in whom inappropriate androgen treatment risks precocious sexual development and premature epiphyseal closure with compromised final adult height, (v) in patients with bleeding disorders or during anti‑coagulation when parenteral administration may cause severe bruising or bleeding, (vi) sex steroid-sensitive epilepsy or migraine, (vii) those with cardiac or renal failure or severe hypertension susceptible to fluid overload from sodium and fluid retention and (viii) older men with subclinical OSA.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 Top |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
