The rejuvenation of testosterone: philosopher's stone or Brown-Séquard Elixir?

The rejuvenating properties of testosterone (and various other androgenic agents) have been utilized over several millennia (e.g. testicular extracts from animals were used by the Romans and the ancient Chinese for erectile dysfunction [ED]). However, the idea of hormonal rejuvenation really started in earnest with the acclaimed scientist and endocrinologist, Charles Brown-Séquard. Brown-Séquard regularly injected himself with testicular extracts from guinea pigs or dogs (i.e. the so-called Brown-Séquard Elixir) as a means of restoring vitality [Brown-Séquard, 1889]. More recently, testosterone itself has undergone its own rejuvenation due to increased awareness of its potential benefit in hypogonadism and various other medical states (e.g. HIV-related weight loss, glucocorticoid-treated men). In addition, new testosterone formulations have helped simplify therapy and are generally better tolerated than older regimens.

The normal testis has two major functions: synthesis and secretion of androgenic hormones, particularly testosterone (~6mg/day), dihydro-testosterone (DHT), and androstenedione of Leydig cell origin; and production of mature spermatozoa in the seminiferous tubules.

In the circulation, testosterone exists in a free (unbound) or bound form. The bound forms of testosterone are either weakly attached to albumin (which together with the free testosterone constitutes so-called bioavailable testosterone and is ~ 20–50% of total testosterone) or tightly bound (and acting like a reservoir for testosterone) to sex hormone—binding globulin (SHBG; ~50–80% of total testosterone). Only approximately 2% of circulating testosterone is ‘free’ and therefore able to enter the cell and exert its metabolic effects. Testosterone can also act as a prohormone by being converted to DHT (by 5-α reductase) or aromatized to estradiol (E2) in peripheral tissues [Matfin, 2009].

Testosterone (and DHT) exerts a variety of biologic effects in the male. In the male embryo, testosterone is essential for the appropriate differentiation of the internal and external genitalia, and it is necessary for descent of the testes in the fetus. Testosterone is essential to the development of primary and secondary male sex characteristics during puberty and for the maintenance of these characteristics during adult life. There is also convincing evidence that testosterone has important metabolic and vascular effects [Channer and Jones, 2003].

The synthesis and pulsatile release of the gonadotropic hormones (follicle stimulating hormone [FSH] and luteinizing hormone [LH]) from the anterior pituitary are regulated by gonadotropin-releasing hormone (GnRH), which is synthesized by the hypothalamus. The production of testosterone by the Leydig cells is regulated by LH, whilst FSH binds to Sertoli cells stimulating spermatogenesis.

Diagnosis of male hypogonadism

Androgen deficiency may be suspected by certain clinical features (which includes decreased libido, hot flushes, etc.), however, the diagnosis needs to be confirmed by appropriate laboratory testing. Hypogonadism can be primary (i.e. testicular failure due to a problem in the testes) or secondary (i.e. failure resulting from a lack of stimulation, via gonadotropins [LH and FSH], from the anterior pituitary; or due to decreased/absent/abnormal GnRH secretion from the hypothalamus). Primary hypogonadism is more common than secondary hypogonadism.

The clinical features of male hypogonadism depend on whether the impairment involves only spermatogenesis (FSH increase reflects Sertoli cell damage) and/or if testosterone secretion is also impaired (LH increase reflects Leydig cell damage). There are only two clinical manifestations of impaired spermatogenesis: sub-fertility/infertility and decreased testicular size. Small testicular size (reference range 15–25 ml, approximately 4.5 cm × 3.0 cm) is seen in virtually all cases of male hypogonadism, except those of recent onset. However, because seminiferous tubules comprise most of the testicular volume (~80%), declines in testicular volume usually correlate directly with a decline in sperm production. In contrast, there are several possible clinical manifestations of impaired testosterone secretion, which are determined by its time of onset. Onset occurring in the adult includes: fatigue; depression; hot flushes; decreased sexual desire (i.e. libido) and activity; ED; loss of secondary sex characteristics; changes in body composition (including loss of muscle mass, increase in fat mass); osteoporosis; and subfertility or infertility.

The 2010 Endocrine Society Clinical Practice Guidelines on Male Hypogonadism state that a diagnosis of hypogonadism should only be made ‘in men with consistent symptoms and signs and unequivocally low serum testosterone levels’ [Bhasin et al. 2010]. Diagnosis of hypogonadism includes measurement of total testosterone levels in the ambulatory male (ideally at 08: 00–09: 00 when the testosterone level is at its peak due to the diurnal rhythm in younger men). If the initial total testosterone level is low (i.e. <300ng/dl [<10mmol/l]), the diagnosis of hypogonadism should be confirmed with either a repeat measure of total testosterone or a measure of bioavailable testosterone (free testosterone preferred). Once the diagnosis of hypogonadism is established, the LH and FSH levels should also be determined. A subsequently high LH and FSH indicate a primary hypogonadism (hypergonadotropic hypogonadism); and low or inappropriately normal LH and FSH, a secondary hypogonadism (hypogonadotropic hypogonadism). Seminal fluid analysis (SFA) should be considered if fertility is a concern. In men with hypogonadotropic hypogonadism, further evaluation may include measurement of serum prolactin and iron saturation (to exclude hemochromatosis), assessment of other pituitary hormones and a pituitary magnetic resonance imaging (MRI) performed. In cases of hypergonadotropic hypogonadism, a karyotype analysis may be indicated especially in those with testicular volume less than 6 ml. This is because Klinefelter syndrome is the most common chromosomal abnormality associated with male hypogonadism.

Testosterone (androgen) replacement treatment

Testosterone (or androgen) replacement therapy is a generally well-tolerated and established treatment for male hypogonadism, providing clinical and biochemical relief from the effects of sex-steroid deficiency. Treatment of androgen deficiency with testosterone should only be administered to men with confirmed hypogonadism (as evidenced by a distinctly subnormal serum testosterone concentration). The principal goal of testosterone therapy is to restore the serum testosterone concentration to the normal range (generally lower part of normal range for older men).

There are many routes for the delivery of testosterone replacement. The active moiety is testosterone and so the major differences of each formulation are related to differing pharmacokinetics of the preparation. Testosterone formulations include an injectable form (generally administered every 1–12 weeks depending on the formulation), implantable testosterone pellets, topical gels, transdermal patches, and an oral or buccal system. In certain countries (such as the UK but not US), a long-acting injectable preparation of testosterone undecanoate has become available. This is administered every 10–14 weeks, and gives a smoother testosterone profile and greater stability of mood compared with shorter-acting formulations. Adverse effects of testosterone (androgen) replacement therapy may include acne, gynecomastia, erythrocytosis, worsening of sleep apnea and heart failure, and growth of testosterone-dependent cancers. In addition, formulation-specific adverse effects can occur (e.g. skin reactions with transdermal patches, injection site pain).

Once a patient is on testosterone replacement therapy it is important to periodically review the need for ongoing treatment as hypogonadism can be reversible (e.g. due to changes in comorbid conditions, changes in medications such as glucocorticoids). Even more surprising, up to 10% of men with idiopathic hypogonadotropic hypogonadism (IHH) returned to normal during follow up in one clinical study due to ‘awakening’ of endogenous gonadotropin-driven testosterone secretion, enabling them to discontinue androgen replacement therapy altogether (i.e. so-called ‘IHH with reversal’) [Raivio et al. 2007].

Aging changes and late-onset hypogonadism

Male sex hormone levels, particularly testosterone, decrease with age, but the rate vary in different individuals and are affected by chronic disease and medications [Harman et al. 2001]. Beginning at about age 40 in healthy, nonobese men, testosterone levels gradually decrease at approximately 10% per decade. The term andropause (or late-onset hypogonadism [LOH]) has been used to describe an ill-defined collection of symptoms in aging men, typically those older than 50 years, who have a relative or absolute hypogonadism associated with aging.

Difficulties in diagnosing hypogonadism in older men can occur for a number of reasons. These include lack of a good biomarker of androgen action that is entirely specific; different target organs may have different dose—response curves for testosterone; assessment of androgen status by single blood sample can be misleading (e.g. ~15% of young normal men have testosterone levels below normal during a 24-hour interval); DHT and E2 may mediate the action of testosterone in certain tissues; and polymorphisms in the androgen receptor (CAG repeats) affects the sensitivity of the receptor and may be as important as serum testosterone levels in causing clinical effects.

The International Society for Andrology (ISA), the International Society for the Study of the Aging Male (ISSAM), and the European Association of Urology (EAU) updated recommendations for the investigation, treatment, and monitoring of LOH in 2008 [Wang et al. 2008]. They stated that total testosterone levels above 12nmol/l (~350 ng/dl) do not require testosterone administration, whereas levels below 8 nmol/l (~230 ng/dl) require treatment. In the borderline group between these two levels, measurement of free testosterone levels may help better define the hypogonadal state. However, a 3-month trial of testosterone administration can be given in this group as long as clinical response is reviewed to determine whether any benefit from treatment has occurred before continuing therapy long-term.

Against this backdrop, Wu and colleagues have recently published evidence-based criteria for identifying LOH in the general population [Wu et al. 2010]. In a random population of 3369 men, the presence of at least three sexual symptoms (i.e. decreased frequency of morning erections, decreased frequency of sexual thoughts, and ED) associated with a total testosterone level of <11 nmol/l (~320 ng/dl) could help better define LOH. It was suggested that an even lower threshold of total testosterone of <8mmol/l (~230 ng/dl) in addition to the three sexual symptoms may be preferable for diagnosis. The prevalence of LOH was 2.1% in this study, which is much lower than studies which just define biochemical hypogonadism.

At the present time, it is not recommended that routine treatment of elderly men with testosterone should be undertaken. A trial of testosterone administration, however, might be warranted in an elderly man whose serum testosterone concentration is <300ng/dL (<10mol/l) although some believe it should be even lower (i.e. <200 ng/dl [<7mmol/l]), and who has manifestations of testosterone deficiency [Bhasin et al. 2010]. If treatment is undertaken, the man should be screened before treatment and monitored during therapy for evidence of testosterone-dependent diseases. Preliminary studies of androgen replacement in aging males with low androgen levels show an increase in lean body mass and a decrease in bone turnover. Improvements in other endpoints such as quality-of-life (QOL), sexual function, cognition, depression, and function are less conclusive [Bhasin, 2010; Bhasin et al. 2010; Wang et al. 2008].

On a cautionary note, a recent clinical study of testosterone replacement using testosterone gel in older men with limitations of mobility and multiple comorbidities demonstrated an increase in cardiovascular adverse effects [Basaria et al. 2010]. However, in view of the small size of the study, diverse cardiovascular adverse effects (e.g. hypertension, arrhythmia), very frail study population with multiple comorbidities and medications, and also that the study was not powered for cardiovascular endpoints, it is sensible not to conclude too much from these results. In addition, the testosterone gel dose used was higher than many experts might recommend in this frail, elderly population. It is therefore important that these findings are evaluated in other clinical studies, especially in older individuals with functional limitations and physical disability who are treated with testosterone as a function-promoting anabolic therapy [Bhasin, 2010].

Two important emerging areas related to testosterone (androgen) therapy will be reviewed in Therapeutic Advances in Endocrinology and Metabolism (TAE) by leading investigators in their respective fields. In this issue of TAE, Rosemary Basson comprehensively addresses the evidence-base and ongoing controversies surrounding testosterone (androgen) therapy in females with reduced libido. In addition, Hugh Jones and colleague will explore the relationship of testosterone deficiency and its replacement in type 2 diabetes and the metabolic syndrome in an upcoming TAE article.

Only time will tell whether more widespread testosterone (androgen) therapy (especially in LOH and female androgen-deficient states) or using emerging androgenic agents (e.g. selective androgen receptor modulators [SARMs], that selectively improve muscle/bone mass and other beneficial effects, without having the detrimental prostate and other adverse effects of current androgen formulations) will ultimately prove to be the endocrinologists equivalent of the philosopher's stone (i.e. believed to be an elixir of life, useful for rejuvenation and possibly for achieving immortality), or about as acceptable as the Brown-Séquard Elixir!