ABSTRACT

Testosterone, together with its bioactive metabolites dihydrotestosterone and estradiol, determines the development and maintenance of male sexual differentiation and the characteristic mature masculine features. Defects in androgen action at various epochs of life produce characteristic clinical features. From an outline of the biochemistry and physiology of androgen action, the pathophysiology of defects in androgen action are derived and defined. The pharmacology of testosterone and its applications to replacement therapy for pathological hypogonadism as well as for pharmacological androgen therapy based on using either testosterone or synthetic androgens is described. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

An androgen, or male sex hormone, is defined as a substance capable of developing and maintaining masculine characteristics in reproductive tissues (notably the genital tract, secondary sexual characteristics, and fertility) and contributing to the anabolic status of somatic tissues. Testosterone together with its potent metabolite, dihydrotestosterone (DHT), are the principal androgens in the circulation of mature male mammals. Testosterone has a characteristic four ring C18 steroid structure and is synthesized mainly by Leydig cells, located in the interstitium of the testis between the seminiferous tubules. Leydig cell secretion creates a very high local concentration of testosterone in the testis as well as a steep downhill concentration gradient into the bloodstream maintaining circulating testosterone levels which exert characteristic androgenic effects on distant androgen sensitive target tissues. The classical biological effects of androgens are primarily mediated by binding to the androgen receptor, a member of the steroid nuclear receptor superfamily encoded by a single gene located on the X chromosome, which then leads to a characteristic patterns of gene expression by regulating the transcription of an array of androgen responsive target genes. This physiological definition of an androgen in the whole animal is now complemented by a biochemical and pharmacological definition of an androgen as a chemical that effectively competes with testosterone binding to the androgen receptor (1) to stimulate post-receptor functions in isolated cells or cell-free systems. In addition, non-genomic mechanisms of androgen action involving rapid, membrane-mediated nontranscriptional processes in the cytoplasm have been described but not yet fully characterized (2-4).

Testosterone is used clinically at physiologic doses for androgen replacement therapy and, at typically higher doses, testosterone or synthetic androgens based on its structure are also used for pharmacologic androgen therapy. The principal goal of androgen replacement therapy is to restore a physiologic pattern of androgen exposure to all tissues. Such treatment is usually restricted to the major natural androgen, testosterone, and aims to replicate physiological circulating testosterone levels and the full spectrum (including pre-receptor androgen activation) of endogenous androgen effects on tissues and recapitulating the natural history of efficacy and safety. Pharmacologic androgen therapy exploits the anabolic or other effects of androgens on muscle, bone, and other tissues as hormonal drugs that aim to modify the natural history of the underlying disorder and are judged on their efficacy, safety, and relative cost effectiveness like other therapeutic agents. Insight into the physiology of testosterone is a prequisite for understanding and making most effective use of androgen pharmacology (5, 6).

TESTOSTERONE PHYSIOLOGY

Biosynthesis

Testosterone is synthesized by an enzymatic sequence of steps from cholesterol (7, 8) (Figure 1) within the 500 million Leydig cells located in the interstitial compartment of the testis between the seminiferous tubules, which constitutes approximately 5% of mature testis volume (see Endotext, Endocrinology of Male Reproduction, Chapter entitled Endocrinology of the Male Reproductive System and Spermatogenesis, for details) (9). 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 (8). Testosterone biosynthesis involves two multifunctional cytochrome P-450 complexes involving hydroxylations and side-chain scissions (cholesterol side-chain cleavage [CYP11A1 or P450scc which produces C20 and C22 hydroxylation and C20,22 lyase activity] and 17-hydroxylase/17,20 lyase [CYP17A1 or P450c17 which hydroxylates the C17 and then excises two carbons (20 & 21) coverting a 21 to a 19 carbon structure]) together with 3 and 17β-hydroxysteroid dehydrogenases and ∆^4,5 isomerase (8). 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) is a key branch-point in steroidogenic pathways. Both activities reside in a single, multifunctional protein with the directionality of pathway flux determined by enzyme co-factors, notably electron supply from NADPH via the P450 oxidoreductase (POR), a membrane-bound flavoprotein serving diverse roles as a reductase, and cytochrome b₅ (10, 11). In addition, some extragonadal biosynthesis of testosterone and dihydrotestosterone from circulating weak adrenal androgen precursor DHEA within specific tissues has been described (12); however, the net contribution of adrenal androgens to circulating testosterone in men is minor (13, 14) though it makes a much larger proportional contribution to circulating testosterone in women (15, 16).

FIGURE 1.

Pathways of testosterone biosynthesis and action. In men, testosterone biosynthesis occurs almost exclusively in mature Leydig cells by the enzymatic sequences illustrated. Cholesterol originates predominantly by the de novo synthesis pathway from acetyl‑CoA with luteinizing hormone regulating the rate‑limiting step, the conversion of cholesterol to pregnenolone within mitochondria, while remaining enzymatic steps occur in smooth endoplasmic reticulum. The Δ⁵ and Δ⁴ steroidal pathways are on the left and right, respectively. Testosterone and its androgenic metabolite, dihydrotestosterone, exert biological effects directly through binding to the androgen receptor and indirectly through aromatization of testosterone to estradiol, which allows action via binding to the estrogen receptor (ER). The androgen and ERs are members of the steroid nuclear receptor superfamily with highly homologous structure differing mostly in the C-terminal ligand binding domain. The LH receptor has the structure of a G-protein linked receptor with its characteristic seven transmembrane spanning helical regions and a large extracellular domain which binds the LH molecule. LH is a dimeric glycoprotein hormone consisting of an α subunit common to other pituitary glycoprotein hormones and a β subunit specific to LH. Most sex steroids bind to sex hormone binding globulin (SHBG) which binds tightly and carries the majority of testosterone in the bloodstream.

Testicular testosterone secretion is principally governed by luteinizing hormone (LH) through its regulation of the rate-limiting conversion of cholesterol to pregnenolone within Leydig cell mitochondria by the cytochrome P-450 cholesterol side-chain cleavage enzyme complex located on the inner mitochondrial membrane. Cholesterol supply to mitochondrial steroidogenic enzymes is governed by proteins including sterol carrier protein 2 (17). This facilitates cytoplasmic transfer of cholesterol to mitochondria together with steroidogenic acute regulatory protein (18) and translocator protein (19), which govern cholesterol transport across the mitochondrial membrane. 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 μg/g tissue, ~100 times higher than blood concentrations) and rapid turnover (200 times per day) of intratesticular testosterone (20); however, the precise physical state in which such high concentrations of intratesticular testosterone and related steroids exist in the testis remains to be clarified.

Metabolism

After testicular secretion, a small proportion of testosterone undergoes activation to two bioactive metabolites, estradiol and DHT, whereas the bulk of secreted testosterone undergoes inactivation by hepatic phase I and II metabolism to inactive oxidized and conjugated metabolites for urinary and/or biliary excretion (figure 2) (120).

FIGURE 2.

Pathways of Testosterone Action. In men, most (>95%) testosterone is produced under LH stimulation through its specific receptor, a heptahelical G-protein coupled receptor located on the surface membrane of the steroidogenic Leydig cells. The daily production of testosterone (5-7 mg) is disposed along one of four major pathways. The direct pathway of testosterone action is characteristic of skeletal muscle in which testosterone itself binds to and activates the androgen receptor. In such tissues there is little metabolism of testosterone to biologically active metabolites. The amplification pathway is characteristic of the prostate and hair follicle in which testosterone is converted by the type 2 5α reductase enzyme into the more potent androgen, dihydrotestosterone. This pathway produces local tissue-based enhancement of androgen action in specific tissues according to where this pathway is operative. The local amplification mechanism was the basis for the development of prostate-selective inhibitors of androgen action via 5α reductase inhibition, the forerunner being finasteride. The diversification pathway of testosterone action allows testosterone to modulate its biological effects via estrogenic effects that often differ from androgen receptor mediated effects. The diversification pathway, characteristic of bone and brain, involves the conversion of testosterone to estradiol by the enzyme aromatase which then interacts with the ERs α and/or β. Finally, the inactivation pathway occurs mainly in the liver with oxidation and conjugation to biologically inactive metabolites that are excreted by the liver into the bile and by the kidney into the urine.

The amplification pathway converts ~4% of circulating testosterone to the more potent, pure androgen, DHT (50, 52). DHT has higher binding affinity to (121) and 3-10 time greater molar potency in transactivation (122-124) of the androgen receptor relative to testosterone. Testosterone is converted to the most potent natural androgen DHT by the 5α-reductase enzyme that originates from two distinct genes (I and II) (125). Type 1 5α-reductase is expressed in the liver, kidney, skin, and brain, whereas type 2 5α-reductase is characteristically expressed strongly in the prostate but also at lower levels in the skin (hair follicles) and liver (125). Congenital 5α-reductase deficiency due to mutation of the type 2 enzyme protein (126) leads to a distinctive form of genital ambiguity causing undermasculinization of genetic males, who may be raised as females, but in whom puberty leads to marked virilization including phallic growth, normal testis development and spermatogenesis (127) and bone density (128) as well as, occasionally, masculine gender reorientation (129). Prostate development remains rudimentary (130) and sparse body hair without balding is characteristic (131). This remarkable natural history reflects the dependence of urogenital sinus derivative tissues on strong expression of 5α-reductase as a local androgen amplification mechanism for their full development. This amplification mechanism for androgen action was exploited in developing azasteroid 5α-reductase inhibitors (132). As the type 2 5α-reductase enzyme results in over 95% of testosterone entering the prostate being converted to the more potent androgen DHT (133), blockade of that isoenzyme (the expression of which is largely restricted to the prostate) confines the inhibition of testosterone action to the prostate (and other urogenital sinus tissue derivatives) without blocking extra-prostatic androgen action. DHT circulates at ~10% of blood testosterone concentrations, due to spillover from the prostate (134, 135) and nonprostatic sources (136). Whereas genetic mutations disrupting type 2 5α-reductase produce disorders of urogenital sinus derived tissues in men and mice (137), genetic inactivation of type 1 5α-reductase has no male phenotype in mice and no mutations of the human type 1 enzyme have been reported. Whether this reflects the type I enzyme having an unexpected phenotype or an evolutionarily conserved vital function, remains unclear. A third 5α-reductase enzyme (type 3, SRD5A3) has been described (138) but is widely expressed in human tissues, lacks steroidal 5α-reductase activity and has other roles in fatty acid metabolism (139).

An important issue is whether eliminating intraprostatic androgen amplification by inhibition of 5α-reductase can prevent prostate disease. Two major randomized, placebo-controlled studies of men at high risk of (but without diagnosed) prostate cancer have both shown that oral 5α reductase inhibitors (finasteride, dutasteride) reduced the incidence of low-grade prostate cancer as well as prevalence of lower urinary tract symptoms from benign prostate hyperplasia(140, 141). The Prostate Cancer Prevention Trial (PCPT) was a major 10-year chemoprevention study randomizing 18,882 men over 55 years of age without known prostate disease to daily treatment with 5 mg finasteride (inhibitor of type 2 5α reductase) or placebo observed a cumulative 25% reduction after 7 years of treatment in early stage, organ-confined, low-grade prostate cancer. Another study randomized over 8231 men aged 50-75 years with serum PSA <10 ng/mL and negative prostate biopsy to either daily treatment with 0.5 mg dutasteride (inhibitor of both type 1 and 2 5α reductases) or placebo for 4 years observed a 23% reduction in incidence of biopsy-proven prostate cancer. Although neither study was designed to determine mortality benefit, both showed no reduction in higher grade, but still organ-confined, cancers. Although this stage selectivity may be explained by diagnostic biases due to drug effects on prostate size and histology (142, 143), registration for chemoprevention of prostate cancer was refused by FDA (144). Overall, the evidence indicates that 5α-reductase inhibition reduces the incidence of early stage, screen-detected and organ-confined prostate cancers but there is insufficient evidence that such treatment reduces mortality from advanced (metastatic) prostate cancer. Whether or not preventive use of prostatic 5α-reductase inhibition in men with high prostate cancer risk proves warranted, novel synthetic androgens refractory to 5α-reductive amplification may have advantages for clinical development.

The diversification pathway of androgen action involves testosterone being converted by the enzyme aromatase to estradiol (145) to activate estrogen receptors (ERs) (also see Endotext, Endocrinology of Male Reproduction, Chapter entitled Estrogens and Male Reproduction). Although this involves only a small proportion (~0.2%) of testosterone output, the higher molar potency of estradiol (~100-fold higher vs testosterone) makes aromatization a potentially important mechanism to diversify androgen action via ER-mediated effects in tissues where aromatase is expressed. The diversification pathway is governed by the cytochrome P-450 enzyme (CYP19) aromatase (145, 146). In eugonadal men, most (~80%) circulating estradiol is derived from extratesticular aromatization (53). The biological importance of aromatization in male physiology was first recognized in the early 1970’s (147) when the local conversion of testosterone to estradiol within the neural tissues was identified and subseqeuntly shown to have an important role in mediating testosterone action, including negative feedback as well as activational and organisational effects, on the brain (148). More recently the importance of local aromatization in testosterone action has been reinforced by the striking developmental defects in bone and other tissues of men and mice with genetic inactivation of aromatase, leading to complete estrogen deficiency due to genetic inactivation of the aromatase (149). This phenotype is also strikingly similar to that of a man (150) and mice (150) with genetic mutations inactivating ERα. Furthermore, men with aromatase deficiency treated with exogenous estradioll or other estrogens also demonstrated significant bone maturation. By contrast, genetic inactivation of ERβ has no effect on male mice (151) and no human mutations have been reported. Aromatase expression in tissue such as bone (152) and brain (148) may influence development and function by variation in aromatization that modulates local tissue-specific androgen action. By contrast other tissues, like mature liver and muscle, express little or no aromatase. Nevertheless, despite the importance of aromatization for male bone physiology, other observations indicate that androgens acting via androgen receptors have important additional direct effects on bone. These include the greater mass of bone in men despite very low circulating estradiol concentrations compared with young women (153), the failure of androgen insensitive rats lacking functional androgen receptors but normal estradiol and ERs to maintain bone mass of normal males (154) and the ability of nonaromatizable androgens to increase bone mass in estrogen-deficient women (155, 156). Testosterone action on bone and in the brain cannot be accounted for solely as a prohormone for local estradiol production (and action via estrogen receptors α and/or β) and androgen receptor mediated effects are required to manifest the full spectrum of testosterone effects on bone (157, 158) and in the brain (159). Conflicting evidence is available about the need for aromatization to mediate the effects of testosterone on male sexual function. One study using aromatase inhibitor-induced estrogen deficiency showed partial dependence (160) whereas another using DHT-induced estrogen deficiency showing no requirement of male sexual function for aromatization (161). Further studies are needed to fully understand the significance of aromatization in maintaining androgen action in mature male animals (162).

Testosterone is metabolized to inactive metabolites in the liver, kidney, gut, muscle, and adipose tissue. Inactivation is predominantly by hepatic oxidases (phase I metabolism), notably cytochrome P-450 3A family (163) 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. Uridine diphospho (UDP) glucuronosyl transferase (UGT) enzymes UGT2B7, UGT2B15 and UGT2B17 catalyze most phase II metabolism (glucuronidation) of testosterone with 2B17 being quantitatively the most important (164). A functional polymorphism of UGT 2B17, a deletion mutation several times more frequent in Asian than European populations (165), explains the concordant population difference in testosterone to epitestosterone (T/E) ratio (165), a World AntiDoping Agency-approved urine screening test for testosterone doping in sport, which constitutes an ethnic differential, false negative in surveillance for exogenous testosterone doping (166).

The metabolic clearance rate of testosterone is reduced by increases in circulating SHBG levels (57) or decreases in hepatic blood flow (e.g. posture) (49) or liver function. Theoretically, drugs that influence hepatic oxidase activity could alter metabolic inactivation of testosterone, but empirical examples of sufficient magnitude to influence clinical practice are rare. Rapid hepatic metabolic inactivation of testosterone leads to both low oral bioavailability (167, 168) and short duration of action when injected parenterally (169). To achieve sustained androgen replacement, these limitations dictate the need to deliver testosterone via parenteral depot products (e.g., injectable testosterone esters, testosterone implants, transdermal testosterone) or oral delivery systems that either bypass hepatic portal absorption (buccal (170, 171), sublingual (170, 172), gut lymphatic (173)) or use synthetic androgens with substituents rendering them resistant to first pass hepatic inactivation (174).

ANDROGEN RECEPTOR

The androgen receptor is required for masculine sexual differentiation and sexual maturation that ultimately leads to development of a mature testis capable of supporting spermatogenesis and testosterone production that form the basis for male fertility. The human androgen receptor is specified by a single X chromosome encoded gene located at Xq11-12 that specifies a protein of 919 amino acids (1), a classical member of the large nuclear receptor superfamily (228) which includes receptors for the 5 mammalian steroid classes (androgen, estrogen, progesterone, glucocorticoid, mineralocorticoid) as well as for thyroid hormones, retinoic acid and vitamin D and numerous orphan receptors where the ligand was originally not identified (229). Androgen receptor expression is not confined to reproductive tissues and it is ubiquitously expressed, athough levels of expression and androgen sensitivity of non-reproductive tissues vary.

The androgen receptor gene has 8 exons specifying a protein of 919 amino acids with the characteristic structure of mammalian steroid receptors. It has an N-terminal domain (NTD) that specifies a long transactivating functional domain (exon 1), a middle region specifying a DNA-binding domain (DBD) consisting of two zinc fingers (exons 2 and 3) separated by a hinge region from the C-terminal ligand binding domain (LBD) which specifies the steroid binding pocket (exons 4 to 8).

The NTD (exon 1) is relatively long comprising over half (535/919) the overall length of the AR. It has the least conserved sequence compared with other steroid receptors with a flexible and mobile tertiary structure harbouring a transactivation domain (AF-1) that interacts with AR co-regulator proteins and target genes (230). Its loose, naturally disordered structure (231) also contains three homopolymeric repeat sequences (glutamine, glycine, proline) with the most important being the CAG triplet (glutamine) repeat polymorphism (232). The less variable glycine (usually 24 residues) and proline (9 residues) repeat polymorphisms have little apparent independent pathophysiological significance although linkage dysequilibrium between the glutamine and glycine repeat polymorphisms requires haplotype analysis for interpretation (232). Among healthy people, where the glutamine repeat polymorphism has alleles of lengths between 5 and 35 (population mean ~21), the length of the glutamine repeat is inversely proportional to AR transcriptional efficiency so that this polymorphism dictates genetic differences between individuals in the androgen sensitivity of their target tissues (233). This genetic variation in in vivo tissue androgen sensitivity is proven experimentally (234) but, although modest in magnitude, influences physiological responses to endogenous testosterone in prostate size (235) and erythropoeisis (236) in carefully controlled studies. Wider epidemiological implications of population variation in the genetic androgen sensitivity as specified by the polyglutamine repeat have been studied in a variety of potentially androgen sensitive disorders (reviewed in (232)) including reproductive health disorders and hormone dependent cancers in men and women as well as non-gonadal disorders where there are significant gender disparities in prevalence. In men these include prostate (237) and other male preponderant cancers (liver, gastrointestinal, head & neck), prostate hypertrophy, cryptorchidism and hypospadias, male infertility (238) whereas in women they include reproductive health disorders (polycystic ovary syndrome, premature ovarian failure, endometriosis, uterine leiomyoma, preeclampsia) and hormone dependent cancers (breast, ovary, uterus). In addition, studies have also examined risks of obesity and cardiovascular disease, mental and behavioural disorders including dementia, psychosis, migraine, and personality disorders (232). However, as in many large-scale genetic association studies (239), the findings remain mostly inconsistent reflecting methdological limitations notably in recruitment, participation and publication bias as well as multiple hypothesis testing all of which tend to inflate spurious associations.

Remarkably, the pathological elongation of the polygutamine (CAG triplet) repeat to lengths of over 37 cause a neurodegenerative disease, Spinal Bulbar Muscular Atrophy (SBMA, also known as Kennedy’s syndrome). This is a form of late-onset, slow progressing but ultimately fatal motor neuron disease (240), one of several late-onset neurodegenerative polyglutamine repeat disorders (241). Although the extreme length of the polyglutamine repeat does determine mild androgen resistance, these men usually have normal reproductive function including fertility and virilization prior to diagnosis in mid-life (242). Furthermore, since complete androgen receptor inactivation in humans and other mammals does not cause motor neuron disease and female carriers are protected from symptomatic neurodegeneration, SBMA represents a toxic gain-of-function involving pathological protein aggregates of the mutant AR (243) like other genetic polyglutamine repeat neurodegenerative diseases do with other proteins (244). Surprisingly, transgenic mouse models of SBMA suggest that testosterone deprivation by medical castration using a GnRH agonist may slow progression of neuropathy (243) and that genetic (245) or pharmacological (246) administration of IGF-I may slow disease progression. However the first major clinical trial of leuprolide, a GnRH analog, failed to demonstrate neuromuscular benefit in swallowing (247) and further studies of selected subgroups and therapeutic targets are warranted (248, 249).

The DBD (exons 2 and 3) consists of ~70 amino acids with a high proportion of basic amino acids including eight cysteines distributed as two sets of 4 cysteines, each forming a zinc cooordination center for a single zinc atom, thereby creating two zinc fingers. The DBD is highly conserved between steroid receptors reflecting its tightly defined function of forming the two zinc fingers that bind to DNA by intercalating between its grooves. The first zinc finger (exon 2) is directly involved with the major DNA groove of the androgen response element through a proximal (P-box) region whereas the second zinc finger (exon 3) is also responsible for enhancing receptor dimerization through its distal (D-box) region.

The hinge region (first half of exon 4) of ~40 amino acids between the DBD and LBD is considered a flexible linker region but may have additional functions involving interactions with DNA (nuclear localization, androgen response element) and protein (AR dimerization, co-regulators) which influence AR transcriptional activity.

The LBD (mid-exon 4 to 8) of AR comprises ~250 amino acids which specify a steroid binding pocket which creates the characteristic high affinity, stable and selective binding of testosterone, DHT and synthetic androgens. While the LBD’s overall architecture is broadly conserved among nuclear receptors, the AR sequence diverges significantly to ensure the specificity of binding from other steroid classes and their different cognate ligands. Structural studies of the AR’s LBD shows it has similar tertiary conformation as other steroid receptors (most closely resembling PR) with 12 stretches of α helix interspersed with short β pleated sheets. The most C terminal helix 12 seals the binding pocket and influences whether a bound ligand acts as an agonist or antagonist as well as forming a hydrophobic surface for binding of co-regulator proteins that modify transcriptional activity of the androgen target genes. The LBD also participates in receptor dimerization, nuclear localization and transactivation via its activation function (AF-2) domain.

The AR has a predominantly nuclear location in androgen target cells regardless of whether bound to its ligand or not, unlike other steroid receptors which are more often evenly distributed between cytoplasm and nucleus when not bound to their cognate ligands. Androgen binding to the C-terminal LBD causes a conformational change in the androgen receptor protein and dimerization to facilitate binding of the ligand-loaded receptor to segments of DNA featuring a characteristic palindromic motif known as an androgen-response element, located in the promoter regions of androgen target genes. Ligand binding leads to shedding of heat shock proteins 70 and 90 that act as a molecular chaperone for the unliganded androgen receptor (250). Specific binding of the dimerized, ligand-bound androgen receptor complex to tandem androgen-response elements initiates gene transcription so that the androgen receptor acts as a ligand-activated transcription factor. Androgen receptor transcriptional activation is governed by a large number of coregulators (251, 252) whose tissue distribution and modulation of androgen action remain incompletely understood.

PHARMACOLOGY OF ANDROGENS

Androgen Replacement Therapy

The sole unequivocal clinical indication for testosterone treatment is in replacement therapy for androgen deficient men suffering from pathological disorders of their reproductive system (hypothalamus, pituitary, testis) that prevent the testes from producing sufficient testosterone supply to meet the body’s usual needs. Establishing a pathological basis for androgen replacement therapy requires identifying well-defined disorders of the hypothalamus, pituitary or testis which have a known and clearly defined pathological basis. These disorders can, and often do, lead to persistent testosterone deficiency either due to disorders of the testis, where damaged Leydig cells cannot produce sufficient testosterone, or disorders of the hypothalamus and/or pituitary, where impaired pituitary luteinizing hormone (LH) secretion reduces the sole driving force to testosterone production by Leydig cells.

The principal goal of androgen (testosterone) replacement therapy is to restore a physiologic pattern of net tissue androgen exposure in androgen deficient men whose damaged reproductive systems are unable to secrete adequate testosterone to levels comparable with those of eugonadal men. This treatment uses only the natural androgen, testosterone, aimed at restoring a physiologic pattern of androgen exposure using a dose limited to that which maintains blood testosterone levels within the eugonadal range. Such treatment aims to restore the full spectrum of androgen effects when endogenous testosterone production fails due to pathological disorders of the reproductive system (testicular-hypothalamic-pituitary axis). This requires restricting replacement therapy to the major natural androgen, testosterone, which aims to not only replicate physiological circulating testosterone levels but also to provide testosterone’s two bioactive metabolites, DHT and estradiol, so that all 3 bioactive sex steroids are available to androgen target tissues. Synthetic androgens are unsuitable because they are incapable of metabolism to the more potent 5α reduced metabolites or being aromatized to estrogens. The overall goal of such replacement therapy is to replicate the efficacy and safety experience of eugonadal men of similar age by recreating the full spectrum of endogenous natural androgen effects on tissues so as to recapitulate the natural history of efficacy and safety of endogenous testosterone.

The prevalence of male hypogonadism requiring androgen repacement therapy in the general community can be estimated from the known prevalence of Klinefelter’s syndrome (15.6 per 1000 male births in 33 prospective birth survey studies (313)) because Klinefelter syndrome accounts for 25-35% of men requiring androgen replacement therapy. The estimated prevalence of ~5 per 1000 men in the general community makes androgen deficiency the most common hormonal deficiency disorder among men. Although life expectancy is not reduced by castration as an adult (303-307) or only minimally (~2 years) shortened (308) by life-long androgen deficiency, the hormonal deficit causes preventable morbidity and a suboptimal quality of life (313). Due to its variable and often subtle clinical features, androgen deficiency remains significantly underdiagnosed, thus denying sufferers simple and effective medical treatment with often striking benefits. Only ~20% of men with Klinefelter syndrome characterized by the highly distinctive tiny (<4 mL) testes, are diagnosed during their lifetime (314) indicating that most men go through life without a single pelvic examination by any medical professional in stark contrast to the usual expectation of reproductive health care for women.

The testis has two physiological functions, spermatogenesis and steroidogenesis, either of which can be impaired independently, resulting in infertility or androgen deficiency, respectively, so the term hypogonadism is inherently ambiguous. However, 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. Androgen deficiency is a clinical diagnosis with a characteristic presentation and underlying pathological basis in hypothalamus, pituitary or testis disorder, and confirmed by blood hormone assays (see other Endotext chapters for details). 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. For each androgen deficient man, his leading clinical symptoms of androgen deficiency are distinctive, reproducible and corresponds to a specific blood testosterone threshold for any individual but both the symptom(s) and threshold vary between men (315). Because the underlying disorders are mostly irreversible, lifelong treatment is usually required. Androgen replacement therapy can rectify most clinical features of androgen deficiency apart from defective spermatogenesis (316). When fertility is required in gonadotropin-deficient men, spermatogenesis can be initiated by treatment with pulsatile GnRH (317) (if pituitary gonadotroph function is intact (318)) or gonadotropins (319) to substitute for pituitary gonadotropin secretion (320) (see also Endotext, Endocrinology of Male Reproduction, Hypogonadotropic Hypogonadism (HH) and Gonadotropin Therapy). The short half-life of LH would require multi-daily injections rendering it unsuitable for gonadotrophin therapy (321). Instead practical gonadotropin therapy uses hCG, a placental heterodimeric glycoprotein which has a much longer duration of action allowing it to be administered every two or three days. The chorionic gonadotropin hCG consists of an identical α subunit as LH (also the same as in FSH and TSH) combined with a distinct β subunit that is highly homologous to the LH β subunit except for a C terminal extension of 22 amino acids which includes four O-linked sialic acid-capped, carbohydrate side chains. This C terminal extension markedly prolongs the circulating half-life of hCG relative to LH thereby making it a naturally occuring long-acting LH analog. Both endogenous LH and hCG act on the Leydig cell LH/hCG receptor to stimulate endogenous testosterone production. Pharmaceutical hCG, originally purified from pregnancy urine and more recently its recombinant form, can be administered 2-3 times weekly for several months. Where spermatogenesis remains persistently suboptimal, recombinant FSH may subsequently be added (319). Once fertility is no longer required and any pregnancy has passed the 1^st trimester, androgen replacement therapy usually reverts to the simpler and cheaper use of testosterone while preserving the ability subsequently to reinitiate spermatogenesis by gonadotropin replacement (319). The potential value of hCG therapy in gonadotropin-deficient adolescents to produce timely testis growth replicating physiologic puberty (322), rather than reliance on exogenous testosterone which leaves a dormant testis but remains standard management, has yet to be fully evaluated (323, 324).

The extension of testosterone replacement therapy to men with partial, subclinical or compensated androgen deficiency states remain of unproven value (figure 3). Biochemical features of Leydig cell dysfunction, notably persistently elevated LH with low to normal levels of testosterone constituting a high LH/testosterone ratio are observed in aging men (325-327), in men with testicular dysfunction associated with male infertility (328), or after chemotherapy-induced testicular damage (329-332). Although such features may signify mild androgen deficiency, substantial clinical benefits from testosterone replacement therapy remain to be demonstrated (333, 334). Furthermore, testosterone administration may have deleterious effects on spermatogenesis so that its potential adverse effect on men’s fertility must be considered with regard to their marital and fertility status.

Hormonal male contraception can be considered a form of androgen replacement therapy because all currently envisaged regimens aiming to suppress spermatogenesis (and thereby endogenous testosterone production) by inhibiting gonadotropin secretion, use testosterone either alone or with a progestin or a GnRH antagonist (335) (see also Endotext, Endocrinology of Male Reproduction, Male Contraception). As a consequence, exogenous testosterone is required to replace endogenous testosterone secretion.

FIGURE 3.

The Hypothalamo-Pituitary Testicular Axis in Health and Intrinsic and Extrinsic Diseases. Schematic representation of the hypothalamo-pituitary-testicular (HPT) system in health (left panel) and in disease (right panel). Note in the right panel the distinction between organic disorders of the reproductive system causing pathologcal hypogonadism leading to male infertility and/or androgen deficiency and, alternatively, non-reproductive disorders which lead to an adaptive hypothalamic response to systemic non-reproductive disorders. While these non-reproductive disorders may lead to a reduced serum testosterone, that is neither a testosterone deficiency state nor warrants testosterone treatment without convincing evidence of safety and efficacy.

Pharmacologic Androgen Therapy

Pharmacologic androgen therapy uses androgens to maximal therapeutic efficacy within adequate safety limits but without regard to androgen type, dose, duration of treatment, or gender. In this, the goal is to improve mortality and/or morbidity of an underlying non-gonadal disease through eliciting androgen effects on muscle, bone, brain, or other target tissues. To obtain morbidity benefits requires that androgens must modify the natural history of an underlying disease, a goal not yet achieved in any nongonadal disorder. Morbidity benefits are more achievable in aiming to improve quality of life by enhancing muscle, bone, brain, or other androgen-sensitive function (including mood elevation) as an adjuvant therapy in non-reproductive diseases. Such treatment is judged by the efficacy, safety, and cost-effectiveness standards of other drugs but very few studies fulfill the requirements of adequate study design (prospective design, randomization, placebo control, objective and validated end points, adequate power, and appropriate duration) (310, 336). Accordingly, the role of pharmacological androgen therapy is mostly relegated to an affordable but second line, supportive or adjunctive therapy (336).

The range of pharmacologic uses of androgens include: treatment of anemia due to marrow or renal failure; osteoporosis especially where estrogen therapy is contraindicated; advanced ER-positive breast cancer; hereditary angioedema (C1 esterase inhibitor deficiency); and for immunologic, pulmonary, and muscular diseases (reviewed in detail (336)). In anemia due to renal or marrow failure, androgens have proven beneficial effects on morbidity by improving hemoglobin levels, reducing transfusion requirements and improving quality of life. However, characteristically androgens do not improve mortality as they do not change the natural history of the underlying disease. In renal anemia, androgens are equally effective with erythropoeitin in maintaining hemoglobin levels and reducing transfusion requirement (337-339). However, their virilizing effects in women are limiting so that the affordability and augmentation of erythropoeitin effects by androgens provides an ongoing adjuvant role in older men or where erythropoeitin is unavailable (337-339). Similarly, in anemia due to marrow failure androgens reduce transfusion dependence but do not improve survival from the underlying marrow disorders. They remain secondary line, supportive therapy for men in whom marrow transplantation is not feasible or fails.

Although these traditional indications for androgen therapy are often superseded by more specific, effective but costly treatments, androgens usually persist as second-line, empirical therapies for which the lower cost and/or equivalent or synergistic efficacy may still favor androgen therapy in some settings. For historical reasons, pharmacologic androgen therapy has often involved synthetic, orally active 17α-alkylated androgens despite their hepatotoxicity including cholestasis, hepatitis, adenoma and peliosis (340, 341). Other than in treating angioedema, in which direct hepatic effects of 17α-alkyl androgens (rather than androgen action per se) may be crucial to increasing circulating C1 esterase inhibitor levels to prevent attacks (342-344), safer (nonhepatotoxic) testosterone preparations should generally be favored for long-term clinical use, although the risk-benefit balance may vary according to prognosis. For hereditary angioedema, newer mechanism-based, more specific and costly therapies such as purified or recombinant C1 inhibitor and bradykinin or kallekrein antagonists may overtake the traditional role of 17α-alkylated androgens such as danazol for long-term prophylaxis of hereditary angioedema (311, 312, 345) or endometriosis. In most clinical applications, pharmacological androgen therapy remains a cost-effective option relative to newer, more costly therapies.

An important watershed was the proof via a well-designed, placebo-controlled randomized clinical trial that pharmacologic testosterone doses increase muscular size and strength even in eugonadal men (346), overturning prior belief to the contrary (347). Testosterone has clear dose-dependent effects, extending from below to well above the physiological concentrations without evidence of a plateau, on muscle size and strength (but not performance function or fatigue) in young (348) and older (349) men with similar magnitude of ultimate effect (350). Nevertheless, ageing reduced the responsiveness of older muscle to testosterone as the same doses produced higher blood testosterone concentrations in older men. The higher blood testosterone concentrations are the result of decreased testosterone metabolic clearance rate due to age-related higher blood SHBG concentrations (351). Similarly, erythropoeitic effects of testosterone are greater in older men who developed a higher rate of polycythemia (352). Diverse androgen-sensitive effects including changes in metabolic function, cognition, mood and sexual function were minimal at physiological testosterone doses (353, 354). The wide dose-response to testosterone through and beyond the physiologic range suggests that androgens may have beneficial effects in reversing the frailty observed in many medical settings. Whether such effects can be applied effectively and safely (355) to improve frailty and quality of life in chronic disease or in male ageing remains an important challenge to be determined.

Pharmacological androgen therapy for human immunodeficiency virus (HIV) infection in the absence of classical hypogonadism has been investigated for its effects on disease-associated morbidity, notably AIDS wasting. However pharmacologic androgen therapy does not alter the natural history of underlying disease and the objective functional benefits remain modest being confined to reversing some aspects of AIDS wasting. The rationale for pharmacologic androgen therapy in AIDS wasting is that body weight loss is an important determinant of survival in AIDS and other terminal diseases with death estimated to occur when lean body mass reaches 66% of ideal (356). This leads to the hypothesis that androgens may delay death by increasing appetite and/or body weight. Meta-analysis of randomized, placebo-controlled studies of pharmacologic androgen therapy in HIV-positive men with AIDS wasting indicate modest increase in lean and decreased fat mass with additive effects from resistance training but inconsistent improvement in quality of life (357, 358). Among HIV-positive men without wasting there is less improvement in body composition and none in quality of life although, in affluent countries, there is a popular subculture of androgen abuse (359). The oral progestin, megestrol acetate, used alone as an appetite stimulant induces profound gonadotropin and testosterone suppression to castrate levels and predominanty increases fat mass rather than reversing the loss of muscle (360, 361).

It is now well recognized that chronic use of opiates has multiple effects on the human endocrine system (362), including prominent mu-opioid receptor mediated effects on the hypothalamus resulting in suppression of pituitary LH secretion and thereby testicular testosterone production (363, 364). However, despite an open-label study suggesting quality of life benefits for testosterone replacement therapy (365), placebo-controlled studies show no clinically significant benefit (366, 367) possibly due to failure to rectify non-androgenic effects of opiates.

A special application of pharmacologic androgen treatment is its use in women with estrogen-resistant menopausal symptoms such as loss of energy or libido. The similarity of blood testosterone in women, children, and orchidectomized men indicates that the term female androgen deficiency is not meaningful in women (368) with normal adrenal function (369). In women with adrenal failure due to hypothalamo-pituitary or adrenal disease, DHEA replacement therapy (14) has significant but modest clinical benefits in some (369, 370) but not all (371, 372) studies with relatively frequent, mild virilizing side-effects. Similar effects are observed using testosterone instead of DHEA (373). Well controlled studies of testosterone administration for menopausal symptoms or sexual hypofunction in women with normal adrenal function show strong placebo effects (374, 375) but minimal or no consistent symptomatic benefits (376) despite supraphysiological blood testosterone levels (374). High-dose testosterone used at male androgen replacement therapy doses (377, 378) produce markedly supraphysiologic blood testosterone levels and virilization including voice changes and androgenic alopecia (379-381). Lower but still supraphysiologic testosterone doses and blood levels increase bone density in menopausal women (382) but produce virilizing adverse effects (hirsutism, acne) in short-term studies. Overall the long-term efficacy and safety risks for cardiovascular disease and hormone dependent cancers (breast, uterus, ovary) for testosterone therapy in women remain unclear (383-385). Studies of testosterone administration as a form of adjuvant pharmacologic androgen therapy in women with chronic medical disorders such as anorexia nervosa (386), HIV (387) and systemic lupus erythematosus (388) have little consistent effect on disease activity or quality of life including sexual function.

Many important questions and opportunities remain for pharmacologic androgen therapy in nongonadal disease, but careful clinical trials are essential for proper evaluation (336). Recent well designed placebo-controlled clinical studies of pharmacologic androgen therapy in chronic disease have been reported. In men with severe chronic obstructive pulmonary disease it produces modest increases in muscle mass and strength with improved quality of life but no effect on underlying lung function (389-391) whereas oral megestrol administration had similar effects despite marked suppression of blood testosterone levels (392). Similarly, although in an observational study chronic heart failure is associated with lower blood testosterone that is proportional to the decrease in cardiac function and which predicts survival (393), a placebo-controlled prospective study of testosterone administration showed improvement in effort-dependent exercise capacity but not in left ventricular function or survival (394). This discrepancy suggests that the lowered blood testosterone is the consequence of a non-specific adaptive reaction of the reproductive hormonal axis to chronic disease (ontogenic regression (395)) rather than a detrimental effect susceptible to being overcome by androgen supplementation. Both testosterone and its non-aromatizable derivative nandrolone, produce increased bone density in men with glucocorticoid-induced osteoporosis with minimal short-term side-effects (396, 397). The best opportunities for future evaluation of adjuvant use of androgen therapy in men with nongonadal disease include steroid-induced osteoporosis; wasting due to AIDS or cancer cachexia; and chronic respiratory, rheumatologic, and some neuromuscular diseases. In addition, the role of pharmacologic androgen therapy in recovery and/or rehabilitation after severe catabolic illness such as burns, critical illness, or major surgery are promising (398) but requires thorough evaluation because detrimental effects may occur (399). Future studies of adjuvant androgen therapy require high-quality clinical data involving randomization and placebo controls as well as finding the optimal dose and authentic clinical, rather than surrogate, end points.

FIGURE 4.

Serum Testosterone Across the Lifespan in Men and Women. Serum testosterone, SHBG & calculated "free" testosterone in males and females over the lifetime as determined in >100,000 consecutive blood samples from a single laboratory. After Handelsman et al. Ann Clin Biochem 2016.

Formulation, Route, and Dose

UNMODIFIED TESTOSTERONE

Testosterone Implants

Implants of fused crystalline testosterone provide stable, physiologic testosterone levels for as long as 6 months after a single implantation procedure (590). Typically, four 200-mg pellets are inserted under the skin of the lateral abdominal wall or hip using in-office minor surgery and a local anesthetic. No suture or antibiotic is required, and the pellets are fully biodegradable and thus do not require removal. This old testosterone formulation (591) has excellent 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 resulting in a standard 800 mg testosterone dose releasing ~5 mg per day (592) replicating the testosterone production rate in healthy eugonadal men (49-51, 593). The long duration of action makes it popular among younger androgen-deficient men as reflected by a high continuation rate (594). The major limitations of this form of testosterone administration are the cumbersome implantation procedure and extrusion of a single pellet after ~5% of procedures. Extrusions are more frequent among thin men undertaking vigorous physical activities (594) but surface washing (595), antibiotic impregnation (596) or varying the site of implantation or track geometry (597) do not reduce extrusion rate. Other side effects such as bleeding or infection are rare (<1%) (594). Recent studies using a smaller (75 mg) implant reproduce these features although requiring administration of a larger number of pellets (598-600). Despite its clinical advantages and popularity, this simple, non-patented technology has limited commercial marketing appeal and, consequently, is not widely available apart from compounding chemists and niche manufacturers (598).

Transdermal Testosterone

Delivery of testosterone across the skin has long been of interest (174). More recently products delivering testosterone via adhesive dermal patches and gels have been developed to maintain physiologic testosterone levels by daily application. The first transdermal patch was developed for scrotal application where the thin, highly vascular skin facilitates steroid absorption (601, 602) and scrotal patches showed long-term efficacy (603) including minimal skin irritation (604, 605). However, their large size, need for shaving and disproportionately high increase blood DHT levels due to 5α-reduction of testosterone during transdermal passage led to the development of a smaller non-scrotal patch (606) effective for long-term use (607). For non-scrotal patches, the smaller size and application to less permeable non-scrotal (trunk, proximal limb) skin limit testosterone absorption. Although this can be enhanced by heating (608), in practice this required inclusion of absorption enhancers that cause skin irritation (604, 605) of varying severity (609). Although skin irritation may be reduced by topical corticosteroid cream (610), the majority of users experience some skin reaction with ~25% having to discontinue due to dermal intolerance (394).

Dermal testosterone (611) or DHT (612, 613) gels developed in Europe are now more widely available as topical gels (571, 614-619), solution (620) or a cream (72). They must be applied daily on the trunk or axilla, and the volatile hydroalcoholic gel base evaporates rapidly with a short-lived stinging sensation but is relatively nonirritating to the skin so there are few discontinuations for adverse skin reactions (571, 621). Transdermal testosterone delivery depends on a small fraction (typically <5%) of testosterone applied to the skin in the dermal gel or solution transfering into the skin where it forms a secondary reservoir in the stratum corneum. From this depot, testosterone is gradually released into the circulation by diffusion down a concentration gradient into the blood stream. A novel and well accepted form of transdermal testosterone delivery is application of a testosterone cream to the sccrotum taking advantage of the thin, highly vascular scrotal skin which demonstrates an 8-fold greater permeability to testosterone than truncal skin (622). As a large amount of testosterone remains on the skin after topical application, transfer of testosterone by direct skin contact is a risk for an intimate partner (623-625) or children (626-631). Serum testosterone concentrations are increased in non-dosed female partners making direct skin contact with men using transdermal testosterone products (632). Creating a physical barrier such as using a testosterone transdermal patch (633) or covering the application site with clothing (632, 634) reduces this risk. Washing off excess gel from the application site after a short time (<30 min) may reduce the risk of transfer (632, 634, 635) but also reduces effective testosterone absorption in some (636) but not all (637) studies. Unlike transdermal patches, topical gel or solutions have considerable misuse and abuse potential.

Testosterone Microspheres

Suspensions of biodegradable microspheres, consisting of polyglycolide-lactide matrix similar to absorbable suture material and laden with testosterone, can deliver stable, physiologic levels of testosterone for 2 to 3 months after intramuscular injection (638, 639). Subsequent findings (640) suggest that the practical limitations of microsphere technology such as loading capacity, large injection volumes, and batch variability may be overcome.

Oral Testosterone

Finely milled testosterone (167, 641) or testosterone suspended in an oil vehicle (642, 643) have low oral bioavailability requiring high daily doses (200–400 mg) to maintain physiologic testosterone levels. Such a heavy androgen load causes prominent hepatic enzyme induction (644) without hepatotoxicity (645). Although effective in small studies (646), oral testosterone is not commercially available and little used. Sufficiently high oral testosterone doses (400-900 mg daily) also reduce serum SHBG (647) which may explain the concomitant acceleration of testosterone metabolism (167, 646, 648).

Buccal and Sublingual Testosterone

Buccal or sublingual delivery of testosterone is an old technology (170) designed to bypass the avid first-pass hepatic metabolism of testosterone that is inevitable with the portal route of absorption. Once absorbed into the general circulation, however, testosterone is rapidly inactivated in accord with its short circulating half-time. Revivals of this technology include testosterone in a sublingual cyclodextrin formulation (649) and in a buccal lozenge (171, 650). The multiple daily dosing required to maintain physiologic testosterone levels are drawbacks for long-term androgen replacement using such products, and their effectiveness and acceptability remain to be established. Like all transepithelial (nonparenteral) testosterone delivery systems, disproportionate amounts of testosterone undergo 5α-reduction during local absorption, resulting in higher blood DHT levels than those in eugonadal men (651). Because intraprostatic DHT is produced locally within the prostate and unlikely to be affected by changes in circulating DHT levels as well as the fact that prostate diseases remain rare among androgen deficient men receiving androgen replacement therapy, the higher blood DHT levels appear to pose no real risk of accelerating prostate disease (652).

TESTOSTERONE ESTERS

FIGURE 5.

Schematic overview of the pharmacology of testosterone esters. Testosterone is esterified through the 17 β hydroxyl group with fatty acid esters of different aliphatic or other chain length which is a biologically inactive pro-drug. The esterified testosterone in an oil vehicle is injected deeply into a muscle forming a local drug depot from which the testosterone ester is released at a slow rate determined by its physico-chemical partitioning according to the testosterone ester’s hydrophobicity. Once the testosterone ester exits the depot and enters the extracellular fluids, it is rapidly hydrolyzed by ubiquitous non-specific esterases thereby releasing the testosterone into the general circulation.

Injectable Testosterone

The most widely used testosterone formulation for many decades has been intramuscular injection of testosterone esters (figure 5), formed by 17β-esterification of testosterone with fatty acids of various aliphatic and/or aromatic chain lengths, injected in a vegetable oil vehicle (653). This depot product relies on retarded release of the testosterone ester from the oil vehicle injection depot because 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 physicochemical partitioning of the androgen ester between the hydrophobic oil vehicle and the aqueous extracellular fluid (654).

The short 3-carbon aliphatic ester side-chain of testosterone propionate gives the product a brief duration of action requiring injections of 25 to 50 mg at 1-2 day intervals for effective testosterone replacement therapy. In contrast, the 7-carbon side-chain of testosterone enanthate has a longer duration of action so that it is used at doses of 200 to 250 mg per 10 to 14 days for androgen replacement therapy in hypogonadal men (655-657) and has been for decades the most widely used form of testosterone used in replacement therapy. Other testosterone esters (cypionate, cyclohexane carboxylate) have simillar pharmacokinetics making them pharmacologically equivalent to testosterone enanthate (658). Similarly, mixtures of short- and longer acting testosterone esters also have essentially the same pharmacokinetics of the longest ester.

Longer acting testosterone esters, testosterone buciclate and undecanoate, intended to provide depot release over months rather than weeks, have been developed. Testosterone buciclate (trans-4-n-butyl cyclohexane carboxylate) is an insoluble testosterone ester in an aqueous suspension that produces prolonged testosterone release due to steric hindrance of ester side-chain hydrolysis slowing the liberation of unesterified testosterone. Although the buciclate ester produces blood testosterone levels in the low-normal physiologic range for up to 4 months after injection in nonhuman primates (659) as well as hypogonadal (660) and eugonadal (661) men, product development has not progressed. Injectable testosterone undecanoate, an ester of an 11 carbon aliphatic fatty acid, in an oil vehicle provides a longer (~12 weeks) duration of action (662-664) now widely marketed as a long-acting injectable depot testosterone product. Due to its limited solubility in the castor oil vehicle, testosterone undecanoate is administered as a 1000 mg dose in a large (4 mL) injection volume at 12 week intervals after the first and one 6 week loading dose or multiple loading doses (665) or in the USA, 750 mg in 3ml volume administered at the start of treatment and then 4 and subsequently at 10 weekly intervals. Once available, the rapid uptake of long-acting injectables show that they are very popular among younger hypogonadal men whereas transdermal products are more suited for older men in case of need to rapidly discontinue testosterone treatment such as after diagnosis of prostate cancer. The relatively long duration of action is also well suited to male hormonal contraception either alone in Chinese men (666) or as part of an androgen-progestin combination (667-669). For treatment of androgen deficiency, although its longer duration of action entails fewer injections with advantages for convenience and compliance, the efficacy and safety does not differ from that of the shorter acting testosterone enanthae (670).

Although testosterone esters in oil vehicle are approved for im injection, they can be effectively used by subcutaneous injection (671) in their marketed formulation or via a pre-filled autoinjector (672). There is increasing use of subcutaneous injections (1 ml) of medium acting testosterone esters (cypionate or enanthate) in oil vehicle especially for masculinizing female to male transgender (673-675). However, the sc use of larger volume (4 ml) for injecting testosterone undecanoate is feasible but less popular than im injection (676).

Oral Testosterone Undecanoate

Oral testosterone undecanoate, a suspension of the ester in 40-mg oil-filled capsules, is administered as 160 to 240 mg in two or more doses per day (677). The hydrophobic, long aliphatic chain ester in a castor oil/propylene glycol laurate vehicle favors preferential absorption into chylomicrons entering the gastrointestinal lymphatics and largely bypassing hepatic first-pass metabolism (173). Oral testosterone undecanoate is not absorbed under fasting conditions but is taken up when ingested with food (678) containing a moderate amount (at least 19 gm) of fat (679). Although oral testosterone undecanoate produces a disproportionate increase in serum DHT which is unaffected by concomitant administration of an oral 5 α reductase inhibitor (680); such modest increases in circulating DHT would have no impact on prostate size (681) or apparent risk of prostate cancer (454, 682) presumably because DHT of extra-prostatic origin fails to increase intra-prostatic DHT concentrations (683). Its low oral bioavailability (684) and short duration of action requiring high and multiple daily doses of testosterone lead to only modest clinical efficacy compared with injectable testosterone esters (657, 685). Widely marketed, it may cause gastrointestinal intolerance but has otherwise well established safety (682). A new formulation of oral testosterone undecanoate was approved for US marketing in 2019 (686) over four decades after its introduction in Europe (687) to close the gap in the market for a safe non-hepatotoxic oral androgen. Its limitations in efficacy, notably its capricious bioavailability, make it a second choice (657), unless parenteral therapy is best avoided (e.g., bleeding disorders, anticoagulation) or a low dose, as for induction of male puberty, must be provided (688, 689) as a better option than the hepatotoxic alkylated androgen, oxandrolone (690).

SYNTHETIC ANDROGENS

Synthetic androgens include both steroidal and non-steroidal androgens. Synthetic steroidal androgens, most developed by 1970, comprise categories of 17α-alkylated androgens, 1-methyl androgens and nandrolone and its derivatives (figure 6).

FIGURE 6.

Testosterone and its pharmacological derivatives. Listed are the most common synthetic androgens displaying their structural relationship with testosterone.

Steriodal Androgens

Most oral androgens are hepatotoxic 17α-alkylated androgens (methyltestosterone, fluoxymesterone, oxymetholone, oxandrolone, ethylestrenol, stanozolol, danazol, methandrostenolone, norethandrolone) making them unacceptable for long-term androgen replacement therapy. The 1-methyl androgen mesterolone is an orally active DHT analog that undergoes neither amplification by 5α reduction nor aromatization but it is free of hepatotoxicity. Mesterolone is not used for long-term androgen replacement due to the need for multiple daily dosing, its poorly defined pharmacology (691) and suboptimal efficacy at standard dose (570, 577). For historical reasons, the other marketed 1-methyl androgen methenolone is used almost exclusively in anemia due to marrow failure (692, 693) although it has no specific pharmacological advantage over testosterone or other androgens.

Nandrolone (19-nor testosterone) is a widely used injectable androgen in the form of aliphatic fatty acid esters in an oil vehicle mainly for treatment of postmenopusal osteoporosis where it is effective at increasing bone density and reducing fracture rate (694, 695). It is also the most popular androgen abused in sports doping and in body building. Nandrolone is a naturally occuring steroid but is not normally secreted in the human bloodstream although it occurs as an intermediate in the aromatization of testosterone to estradiol by the aromatase enzyme (696). This enzyme complex undertakes two successive hydroxylations on the angular C19 methyl group of testosterone followed by a cleavage of the C10-C19 bond to releases formic acid and aromatize the A ring (697). Nandrolone represents a penultimate step of the molecule undergoing aromatization bound to the enzyme complex with the C19 methyl group excised but a still non-aromatized A ring. Paradoxically, despite being an intermediate in the aromatization reaction, nandrolone is virtually not aromatized after parenteral administration in men (698, 699), presumably because it is a very poor substrate for the human aromatase enzyme (700). It is susceptible to amplification by 5α reductase with its 5α reduced metabolites being moderately activated in androgenic potency (701). The minimal aromatizability of nandrolone makes it suitable for treatment of osteoporosis in women in whom estrogen therapy is contraindicated due to hormone sensitive cancers (breast, uterus) or for older women, although virilization limits its acceptability (702).

Synthetic nandrolone derivatives 7α-methyl 19-nortestosterone (MENT) (703) and 7α, 11β-dimethyl 19-nortestosterone (dimethandrolone) (704) are potent, non-hepatotoxic androgens. MENT is being developed as a depot androgen (705) for androgen replacement (706) and male contraception in an androgen-progestin combination regimen (707) while dimethandrolone has potential for male contraception as a single steroid with dual androgen and progestin activity (708). As nandrolone derivatives, these synthetic androgens are less susceptible to amplification by 5α-reduction (700, 709) whereby their 5α-reduced metabolites have reduced AR binding affinity (710). Disparities in reported susceptibility to aromatization vary from minimal using a recombinant human aromatase assay (700) whereas greater aromatization is reported using purified human or equine placental aromatase (709, 711, 712). The inability of MENT to maintain bone density in androgen deficient men (575) may be due to underdosing rather than an intrinsic feature of this synthetic androgen but illustrates the need for thorough dose titration in different tissues for synthetic androgens that may not possess the full characteristic spectrum of testosterone effects.

Nonsteroidal Androgens

The first nonsteroidal androgen was reported in 1998 (582) and the first placebo-controlled randomized clinical trial in 2013 (713). None are yet approved for clinical use but registration studies are underway for enobosarm (714). Based on structural modifications of the nonsteroidal class of the aryl-propionamide antiandrogens (bicalutamide, flutamide), these compounds offer the possibility of orally active, potent androgens. Subsequently, additional classes of non-steroidal androgen based on structures including quinolines, hydantoins, tetracyclic indoles and oxachrysensones have been reported. Lacking the classical steroid ring structure such androgens are likely to be not subject to androgen activation either by 5α reductase or aromatization but, if taken orally, subject to first-pass hepatic metabolism. Such hepatic metabolism can eliminate in vivo bioactivity of analogs with potent in vitro androgenic effects (715) whereas metabolically resistant analogs can produce potent and disproportionate androgenic effects on the liver in transit. Many of the novel non-steroidal androgens demonstrate potent androgenic effects experimentally on muscle, bone and sexual function while minimizing prostate effects in experimental animals but none have yet undergone full clinical evaluation. These selective effects may be attributable to the tissue-selective distribution of 5α-reductase as a local tissue, pre-receptor androgen amplification mechanism (716) or more complex mechanisms involving ligand-induced receptor conformation changes and/or post-receptor co-regulator interaction mechanisms such as define the tissue selectivity and agonist/antagonist specificity of non-steroidal estrogen partial agonists (717). These features suggest that non-steroidal androgens have potential for development into pharmacologic androgen therapy regimens as tissue-selective mixed or partial androgen agonists (“selective androgen receptor modulators”, SARM) (419, 718). Conversely, they are not ideal for androgen replacement therapy where the full spectrum of testosterone effects including aromatization is idealy required, especially for tissues such as the brain (148, 159) and bone (153) where aromatization is a prominent feature of testosterone action. The clinical efficacy and safety of non-steroidal androgens have yet to be reported and none are yet marketed. Whether the hepatotoxicity of antiandrogens (719, 720) will also be a feature of non-steroidal androgens remains to be determined.

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