Hypogonadism and erectile dysfunction: pathophysiological observations and therapeutic outcomes
A. Morales, MD, Department of Urology, Queen's University & Kingston General Hospital, 76 Stuart St, Kingston, Ontario, Canada, K7L 2V7.
Androgens have a profound effect in male sexual function in general and erectile physiology in particular. Despite the common belief that male sexuality is fully dependent on normal androgens, hypogonadal men are capable of sexual erections; almost a third of men receiving effective antiandrogen therapy can develop erections when tested with an erotic challenge. However, successful hormonal supplementation that results in normal testosterone values does not always restore libido and erectile function. Although the primary goal of treatment for hypogonadism may be to restore sexual function, there will be other significant benefits and potential drawbacks. Libido, general well-being, osteoporosis, muscle strength, mental acuity, and growth hormone levels will all be positively affected by appropriate management of low testosterone levels. Testosterone replacement therapy should maintain not only physiological levels of serum testosterone but also its metabolites, including dihydrotestosterone and oestradiol. The assessment of hypogonadism, its treatment and monitoring, are unavoidable responsibilities of the urologist.
median preoptic area
Sexual dysfunction in general and erectile dysfunction (ED) in particular significantly affect men's quality of life. Both result from the convergence of several sociocultural, demographic and medical factors, among which the remarkable increase in life-expectancy, the emergence of diabetes and obesity, and negative environmental factors are dominant. In 1995 it was estimated that 31 million men in Europe had some degree of ED , and this number is projected to increase to 43 million by 2025. Recent United Nations estimates indicate that 650 million people aged > 60 years will have ED in 2002, but this will reach almost 2 billion by 2050. The worldwide, age-adjusted prevalence of ED will similarly increase during the same period, from 152 million to 322 million. Clearly, ED and other sexual dysfunctions will persist and increase as significant medical problems for the foreseeable future.
ANDROGENS AND ERECTILE FUNCTION: THE PATHOPHYSIOLOGICAL LINKAGE
Hypogonadism is associated with a myriad of abnormalities, ranging from sarcopenia and osteoporosis to depression and sexual dysfunction. The fundamental importance of androgens at most levels of the pathways that serve penile erection, from cortex through midbrain and spinal cord to smooth muscle cells and endothelial function, gives the consideration of androgen status a significant place in the management of most patients with ED. In experimental models, the administration of testosterone re-establishes normal sexual behaviour in hypogonadal animals by restoring dopaminergic activity in the median preoptic area (MPOA) . Peripherally, androgens have a clear major role in maintaining nitric oxide synthase activity . Corresponding findings have been also documented in humans .
Similarly, increased expression of inducible nitric oxide synthase has been reported by Ferrini et al. to result in increased apoptosis in various portions of the hypothalamus, including the MPOA and the supraoptic, paraventricular, and arcuate nuclei. These regions are known to control the synthesis and release of gonadotrophins and oxytocin. The detrimental effect of ageing in these systems translates to fundamental alterations in reproductive physiology, including erectile function. Although these observations have been made in rodents, there is no compelling reason to doubt that similar effects occur in humans.
These physiological studies have major implications on the pharmacological approaches currently available and in development, specifically for dopaminergic agonists and phosphodiesterase inhibitors. As the understanding of the complex and intimate interactions between the central and peripheral areas involved in adequate male sexual functioning improves, it becomes increasingly evident that androgens may become a fundamental component of multi-agent therapy for some more of the most severe erectile difficulties unresponsive to monotherapy. Thus, perhaps there will be a combination of a drugs acting on the CNS (e.g. a dopaminergic agonist), a peripheral vascular drug (e.g. selective phosphodiesterase inhibitor), and an androgen to provide the adequate environment for the neurotransmitters and enzymes to function optimally. Recent limited and early experience supports this view [6–8].
ANDROGEN ABNORMALITIES RELATED TO ED
The attribution of a causal role of endocrine abnormalities to ED has ranged from 2% to 23%, but current understanding of the erectile mechanisms seldom permits the assignment of a single causative factor. Careful assessment frequently exposes relevant comorbidities.
It is commonly agreed that androgens profoundly affect male sexual function overall and erectile physiology specifically. ED and variable degrees of hypogonadism frequently coexist. Older men have more ED and lower serum testosterone levels, but the two are not necessarily causally related. The age-related variation in prevalence of ED is well known from the Massachusetts Male Aging Study and other epidemiological studies , but age is also a significant predictor of serum androgen levels, both testosterone and dehydroepiandrosterone (DHEA) . However, the Massachusetts Male Aging Study failed to show an association between ED and a decrease in the serum levels of testosterone, but did establish a direct correlation between ED and a serum deficit in DHEA. It is possible in a population study to link age and serum testosterone, but the association between low DHEA levels and increasing age is so strong and predictable that the association between hypoadrenalism and ED is difficult to detect. A more recent study supported the closer correlation of lower DHEA levels in patients with ED than in controls .
Low serum testosterone levels frequently result in the combination of low sexual desire and ED. Although this is a practical and attractive concept, the reality is not always as simple or clear. Some severely hypogonadal men may be capable of sexual erections; up to a quarter of men receiving antiandrogen therapy were able to develop erections when tested with an erotic visual challenge . Whether this discordance is a result of residual production of adrenal androgens remains to be elucidated. Also, hormonal supplementation resulting in normal testosterone values does not always result in restoration of libido and quality of erectile function .
Hypogonadism has been shown to reduce the frequency of sexual thoughts and intercourse, and the frequency, volume and quality of ejaculation . The effect of testosterone levels on different components of sexual and erectile function has been studied, and the current thinking is that nocturnal penile tumescence and spontaneous erections may be androgen-dependent. Awake erotic stimulation predominantly causes erections through pathways with mixed androgen sensitivity .
DIAGNOSIS OF HYPOGONADISM
It is beyond the scope of this review to discuss the requirements for diagnosing late-onset hypogonadism in men. However, recent recommendations provide some guidance; a combination of a careful clinical history and physical examination together with an adequate biochemical assessment are required to establish the diagnosis . Morley et al. conclusively showed the need to confirm biochemical results. In addition, older men with erectile problems and primarily testicular failure frequently have a low serum testosterone level, with normal or only minimally elevated gonadotrophins.
Hyperprolactinaemia is an uncommon cause of ED (< 2%) and the need for routine prolactin measurement during evaluation for ED has been questioned . There is evidence that ED can be treated successfully despite potentially significant hyperprolactinaemia , although improvement in sexual desire may remain suboptimal. In the presence of hypogonadism measuring serum prolactin is mandatory, as both endocrinopathies frequently coexist.
OTHER CAUSES OF HYPOGONADISM
Hypogonadism and its effect on erectile function may result from the use and abuse of various pharmaceuticals and environmental compounds. Antiandrogen strategies or surgical castration are usually catastrophic for erectile competence. Several environmental contaminants can interfere with the actions of endogenous hormones and have been termed ‘endocrine disrupters’. Persistent metabolites of the insecticide dichlorodiphenyltrichloroethane have been shown to be androgen-receptor antagonists and can markedly interfere with erectile function after a single dose .
TREATMENT OF HYPOGONADISM RELEVANT TO ED
Androgen replacement therapy should ideally maintain not only physiological levels of serum testosterone but also the metabolites of testosterone, including dihydrotestosterone (DHT) and oestradiol, to optimize maintenance of libido, virilization and sexual function. In the future it may be possible to use new chemical entities that have selective action on certain populations of androgen receptors to achieve discriminating androgenic effects .
Current treatments include oral, buccal, transdermal, intramuscular and implantable pellets. Most options use molecular testosterone or its salts, and the functional and clinical effect of the treatment depend not so much on the molecule but on the details of its delivery. Thus the dose, route of administration, bioavailability and pharmacokinetics are the variables that manufacturers seek to modify to make their products more appealing. Neither injectable preparations nor slow-release pellets reproduce the circadian pattern of testosterone production of the testes. This is accomplished best by transdermal testosterone therapy, although oral testosterone may also approximate a circadian rhythm with suitable dose adjustments. It is not known if the imitation of the circadian rhythm carries therapeutic benefits.
As most oral testosterone preparations undergo rapid hepatic metabolism, they may fail to establish satisfactory serum levels of androgens . Oral agents include the alkylated androgen preparations, which are modified to prevent rapid hepatic metabolism. These agents have a significant risk of hepatotoxic effects. Although not available in the USA, testosterone undecanoate is a safe, orally available androgen widely used throughout the world. As a testosterone ester, it is absorbed through gut lymphatics, free of hepatotoxic effects, and is effective in bringing levels of serum testosterone within the physiological range. However, it can result in supraphysiological levels of DHT and rarely gastrointestinal adverse effects.
What is possibly a more physiological approach to testosterone replacement, transdermal testosterone therapy, is available worldwide in patches and gels. These preparations use molecular testosterone absorbed transdermally, usually with absorption enhancers. To obtain normal serum testosterone levels and reproduce the diurnal physiological variations of testosterone in normal human testosterone secretion, the dose and rate of absorption are carefully regulated. Transdermal testosterone hydroalcoholic gel preparations are well tolerated (no significant skin irritation) and can be applied daily to the same site without increasing dermatological problems or decreasing efficacy. The gel produces levels of DHT above normal. The experience with this form of delivery remains limited .
However, the long-acting intramuscular testosterone preparations are the most cost-efficient methods for androgen replacement. These agents clearly improve libido, sexual function, potency, energy level, bone density and mood, if these abnormalities are caused by androgen deficiency. Common testosterone preparations are shown in Table 1.
Table 1. The most commonly used testosterone preparations
|Testosterone undecanoate||120–240 mg/day|
|Testosterone patch||2.5–5.0 mg/day|
|Testosterone gel||5–10 g/day|
|Testosterone gel||50–100 g/day|
|Testosterone cypionate||200–400 mg every 3–4 weeks|
|Testosterone enanthate||200–400 mg every 4 weeks|
NOVEL ANDROGEN OPTIONS
DHT, a potent, non-aromatizable androgen, reaches the highest concentrations in the prostate and has been postulated as the relevant androgen in erectile function. Paradoxically, it has been considered ‘prostate sparing’ because it cannot be aromatized to oestrogens, which are considered important (together with testosterone) in the development of BPH. Recent publications  have suggested DHT as an alternative to testosterone for treating late-onset hypogonadism and have reported improvements in sexual function, with no adverse effects on the prostate. Both of these studies are short with few patients, many of whom were not biochemically hypogonadal. Although DHT remains an intriguing option, the evidence for its efficacy and safety is lacking.
In the specific area of sexuality, the evidence for any efficacy with DHEA is sparse and inconclusive. In one of the few controlled studies it was equal to placebo in its influence on sexuality. Unfortunately, none of the patients receiving DHEA in this trial was affected by sexual difficulties, a surprising finding considering the age of population under investigation . Until a well-designed study becomes available the most that can be said about DHEA in the treatment of ED is that it appears to be safe.
The fundamental role of androgens for adequate human sexual response is unquestionable. What levels of sex steroids are sufficient in the individual man remains to be determined. This is a difficult proposition, as it is not possible to determine the availability and need for androgens at tissue level, and the degree of deficiency in each patient is unknown. However, it is clear that there is large intra- and inter-individual variability in hormone levels as a function of time. The documentation of hypogonadism in a man complaining of ED is commonly accepted as an indication for androgen replacement therapy. In the absence of contraindications, a trial of androgen administration for 3 months is justified. A clinical response not only confirms the diagnosis but supports continuing a treatment that would have additional benefits in other organ systems. Careful monitoring of the patient is mandatory . However, ‘no response’ suggests that the hypogonadism alone is not the overriding cause of the dysfunction, and comorbidities need to be investigated and treated. The theory that androgens may work synergistically with other pharmacological agents is an attractive possibility for further research.