At first sight the pharmaceutical industry's attitude to the andropause has all the hallmarks of the recent public relations furore about female sexual dysfunction (FSD). In the case of FSD, the industry has been accused of attempting to blur the interface between ‘un-met’ medical need and commercial opportunity. However, in the case of this exclusively male condition, the drive for improved therapy has come largely from outside industry, from well respected physicians such as Dr Alvaro Morales, and from the International Consultation in Urological Disease.
Population projections from the United Nations indicate that diseases associated with ageing will increase significantly during the first half of this century. The population aged> 60 years will increase from 593 million worldwide in 1999 to 1.97 billion in 2050, constituting ≈ 10% of the total population in 1999 and 22% in 2050. Based on the demographics, it has been predicted that the 40 million or so hypogonadal males today will become 160 million by 2050. Another potential ‘driver’ is the predicted accompanying increased interest in men's health.
In men, hypothalamic-pituitary-gonadal function declines progressively with age. In contrast to women, where ovarian failure is predictable and clinically obvious, the signs in men are variable, incomplete and have more subtle clinical manifestations. On this basis, unlike menopause in women, both ‘male menopause’ and ‘andropause’ are inappropriate descriptors in relation to the ageing male. However, true andropause is frequently seen in patients receiving either surgical or chemical androgen ablation for prostate cancer. For the more scholarly, the definition from the International Society of the Study of the Ageing Male is ‘A clinical and biochemical syndrome associated with advancing age and characterised by a deficiency in serum androgen levels with or without a decrease in genomic sensitivity to androgens. It may result in significant alterations in quality of life and adversely affect function of multiple organ systems’. A particularly valuable definition in the busy physician's office!
There is a ‘characteristic’ symptom-complex that may be indicative of ‘hypogonadism’ or ‘androgen decline in the ageing male (ADAM)’, however. The clinical manifestations (and potential basis for diagnosis) include: loss of libido and erectile function; loss of lean body mass and muscle mass; reduced insulin sensitivity; decrease in bone mineral density resulting in osteoporosis; depression, irritability and diminution of mental acuity; fatigue; and vasomotor symptoms (hot flushes). It could be argued that if the men's health lobby was as health-conscious and vociferous as the women's then effective therapy would have been available for decades! To complicate the diagnosis further, the symptoms do not appear simultaneously, may wax and wane, and indeed may never appear.
Not surprisingly, the conclusive diagnosis of hypogonadism is difficult on a purely clinical basis and endocrine confirmation is required. There appears to be a consensus that testosterone should be measured, but less certainty about the relative merits of the ‘total’, ‘free’ and ‘bio-available’ variants. Importantly, other hormonal changes are likely to be involved in the age-associated clinical manifestations described above. Although such changes may be implicated in the oymptomatology of ADAM, therapy is almost exclusively directed towards testosterone replacement and/or supplementation. Generally therapy is only approved for treating hypogonadal conditions. The focus of the pharmaceutical industry has been and remains the development of formulations designed to re-introduce the normal nyctohemeral testosterone rhythm.
The formulations that have been relatively widely used for replacing testosterone in the hypogonadal state are intramuscular injections, oral therapy and the transdermal patch. Each of these has some feature making them less than ideal. Although intramuscular injections are safe and inexpensive, the need for repeated office visits can adversely affect patient compliance. Furthermore, clinically the endocrine ‘roller coaster’ of high serum testosterone levels declining to sub-physiological levels at the end of the injection cycle is not optimal. Oral therapy again is safe and effective, but can be subject to variability because of low bioavailability and/or first-pass metabolism. The pharmacokinetic deficits can be circumvented to a large extent with the use of testosterone undeconate, but this is more expensive. Transdermal patches appear to provide relatively consistent levels of testosterone over the course of the day but dermatitis at the site of application has been noted in up to half of patients. More recently, a novel gel formulation (TestimTM) has been developed by Auxilium and early clinical data appear to show that the benefits of transdermal delivery seen with the patch are retained, but with a much lower incidence of localised skin irritation. A US company is also rumoured to be developing a suppository, specifically for the French market.
Although incompletely defined in both clinical and endocrine terms, there is little doubt that many patients with ADAM can improve with testosterone supplementation. However, we may well be reaching the end of the road as far as the pharmaceutical industry is concerned. It is difficult to imagine that the regulatory authorities will approve any agent claiming to be a general treatment for the ageing male. In addition, the issue of the inter-relationship between androgens and prostate cancer, and to a lesser extent BPH/LUTS, is almost certainly a factor in the decision-making process within industry. Although direct evidence is tenuous, there is a general perception in the medical community that giving testosterone to men who are not hypogonadal will increase the risk of carcinoma. Dislodging this perception and convincing the regulatory authorities would require data from a study at least equivalent in size to that of MTOPS (several thousand patients to be followed up for 7 years). In the absence of this type of data, more general marketing approval would not be given.
On this basis, it is likely that the treatment of ADAM (almost as a consequence of its clinical definition) will be restricted to testosterone-based approaches, an area in which the major pharmaceutical companies will have only limited residual interest. Not surprisingly, however, given the potential magnitude of the opportunity, pharmaceutical companies are interested in men's health and the ageing male. From the scientific literature and the lay press we are already aware of progress in the development of ‘cognition enhancers’ (GSK), and Orion are known to be developing a libido enhancer. The assumption is that although testosterone therapy may not become much more generally acceptable, men's health will continue to be of increasing importance.
Next month I will cover industry advances in clinical uroselectivity.