Notes on ‘Testosterone in Active Ageing’

New Factors Linking Testosterone to Ageing and Disease:

Ageing:  In most developed countries, modern medicine has added years to life, but now we need to be able to add life to years.  Prevention is taken to be better than cure, particularly in the elderly patient where disease processes are more difficult to halt and reverse. Our mental and physical capacity throughout life can be compared to a flight in a glider.  Helped by the hormonal surge in puberty, we are catapulted to the peak of our trajectory in our teens and twenties, and then follow a variable glide path to death.  The rate of descent varies according to our life-style, and social, medical and hormonal history.  Anabolic ‘thermal’ up-currents of success at work or in love, relaxation or recreation, can help us reach new heights.  At other times stress, physical or mental inactivity, or illness, can produce breakdown or catabolic down-drafts which cause us to suddenly fall to lower levels or even into the cloud layer of function, the disability threshold.

     This analogy is consistent with the World Health Organisation policy on ‘Active Ageing’, defined as ‘the process of optimizing opportunities for health, participation and security in order to enhance the quality of life as people age’.  This conference shows how, though only part of the much broader medical, social and economic picture, the prevention and treatment of testosterone deficiency has an important role to play in middle and later life in helping to bring about the goals of this policy.

 

Heart Disease:  There is evidence that men with angina and angiographic proven coronary disease have lower testosterone levels than men with normal coronary arteries. Testosterone is an arterial vasodilator and has been shown in animal and human studies to reduce coronary blood vessel tone and increase coronary blood flow. 25% of men with coronary disease have low serum testosterone levels This represents a large population of men who may benefit symptomatically from testosterone replacement therapy (TRT). When given to men with low or low-normal testosterone levels this produces favourable changes in cardiovascular risk factors. It also improves  haemodynamics in men with heart failure when given acutely. Recently two randomised controlled trials have shown that TRT relieves symptoms and improves effort tolerance in men with heart failure over 3 and 12 months.

 

Obesity:  The lowest levels of total and free testosterone have been  found in men with the most pronounced abdominal obesity. It is likely that decreasing levels of testosterone stimulates this type of fat, and thus could increase the risk of cardiovascular disease and mortality. Total testosterone was inversely associated with systolic blood pressure, and men with hypertension had lower levels of total and free testosterone. Inverse associations were also seen between total testosterone with left ventricular mass, and men with left ventricular hypertrophy had lower levels of total testosterone. Preliminary data also suggests that testosterone levels are inversely associated with intima-media thickness, a measurement of subclinical atherosclerosis. Furthermore it was found that men with diabetes had lower testosterone levels compared to men without a history of diabetes, and an inverse association between testosterone level and long-term rises in blood sugar. ‘In summary, maintaining a testosterone level in the normal range seems beneficial for all men.’

 

The Metabolic Syndrome:  This is an increasingly common disorder associated with abdominal obesity, high cholesterol and triglyceride levels, insulin resistance and other factors leading to cardiovascular disease and diabetes. Obese men whether in good or impaired health have lower testosterone levels than normal-weight controls. Their risk of developing the Metabolic Syndrome and consequently diabetes and cardiovascular diseases is significantly higher than in non-obese men. Studies in diabetic men show that many of the risk factors for diabetes correlate with levels of total and free testosterone. Several intervention studies in patients with visceral obesity, cardiovascular diseases, and diabetes suggest that the normalisation of testosterone levels in patients reduces fat mass, increases lean body mass and gives an overall improvement of the risk factors for the Metabolic Syndrome and its related diseases. .Hormones play a central role in the Metabolic Syndrome by affecting the  balance between fat accumulating and mobilizing hormones. Recent data suggest that a restoration of this balance by TRT may be beneficial for patients suffering from or being at risk of developing the Metabolic Syndrome.

     The findings in women are contrary to those discussed for men, and a relative androgen excess can predispose them to metabolic syndrome. Women with the Metabolic Syndrome are at higher risk for diabetes, gallstones, all forms of cardiovascular disease including myocardial infarction, stroke and peripheral vascular disease, as well as a four-to-sevenfold higher risk of breast and endometrial cancers.

 

Erection Problems:  A questionnaire study in Cologne carried out on 1,786 cyclists showed that the impotence rate among long-distance cyclists was three times higher than in the same age group of non-cyclists. This is quite alarming when one considers that 46% of American adults (62 million American men), rode a bike in the year 2000. Compression of the perineum in the crouched position seems to cause decreased penile perfusion resulting in local reduction of tissue oxygen, as will be demonstrated at the conference. This leads to changes in penile tissue structure that results in erectile dysfunction.  Saddle construction and cycling position are the most important factors influencing penile perfusion.  Cycling in a standing and reclining position caused no alteration in penile blood flow during exercising. Also, it was found that long-distance cycling can cause a significant increase in scrotal skin temperature. However, the results suggest that this temperature increase due to vigorous cycling causes no significant changes in sperm quality.

     Low testosterone was found in 21% of 700 patients in an Italian ED clinic.  Severe hypogonadism in men usually results in lower libido, potency and reduced early morning erections. The evidence suggests that testosterone has a key role in the central and peripheral control of erectile function.

     Russian studies confirm that ЕD is highly prevalent, under-diagnosed and under-treated, especially in diabetics.  Effects of testosterone and a new oral treatment for ED, alpha-lipoic acid, will be reported.

 

Genetic Varation in Testosterone Receptors:  Recent studies from Germany  have shown how variations in the size of a key part of the testosterone receptor, the CAG repeat length, can affect body morphology, physiology and psychology, as well as sensitivity to the actions of testosterone. Presence of long CAG is predictive for greater height, gynaecomastia and smaller testes. Short CAG lengths are associated with greater bone density and arm spans relative to body height, together with stable partnerships and professions requiring higher standards of education. The shorter CAG repeat, is associated with more severe coronary disease, which suggests a role for the sensitivity to androgens in the increased frequency of this in men.  In addition, a protective role of endogenous estrogen, which is higher in the long AR subgroup, can contribute to the observed difference.  These findings may provide the basis for individualised TRT by adjusting the dose to the AR type.

     The latest studies from the Oxford Project To Investigate Memory and Ageing (OPTIMA) have shown that variations in this receptor could be related to the risk of Alzheimer’s Disease (AD) in men as it could affect it’s sensitivity to testosterone levels.  Other findings from the study findings combine to suggest that TRT may be most effective for men of a certain age-group (i.e. those younger than 72 years of age) and/or who are genetically at risk and/or who have lower levels of free (‘active’) testosterone.

 

Dementia and Alzheimer’s Disease:  Studies from the University of Southern California, LA, have shown that brain levels of testosterone and dihydrotestosterone, but not oestrogen, are lower in men with moderate to severe AD in comparison to neuropathologically normal men. Supportive evidence that the low testosterone levels in AD cases is a contributing factor to, rather than a consequence of, the disease process, was obtained by examining the brain levels of sex steroid hormones in men that exhibited the earliest evidence of AD-like neuropathology. Importantly, significantly lower T and DHT levels were found in men with mild neuropathology, suggesting testosterone depletion precedes the development of AD.  Recent work from Australia has emphasised two important neural functions of testosterone: neuroprotection and regulation of beta-amyloid, the protein implicated in AD pathogenesis. Androgen depletion in men acts as a risk factor for the development of AD.  Further studies of the functions of testosterone in the aging brain may provide innovative pharmacological targets to combat AD.

 

Prostatic Health and Testosterone Treatment: The UK Andropause Study (UKAS) of 1,500 men studied for up to 15 years (2,200 man years of treatment), has shown that the risk of prostate cancer in a pre-screened and carefully monitored population treated for androgen deficiency appears low, and treatment can be offered early.  Similarly a Canadian study of over 6 years of oral TRT supports its prostatic safety.

 

Diagnosis of Testosterone Deficiency:  The AMS scale showed a convincing ability to measure treatment effects on quality of life across the full range of severity of complaints before TRT. The distribution of complaints of testosterone deficient men before therapy almost returned to normal values after 12 weeks of testosterone treatment. Though laboratory assays can support a diagnosis of androgen deficiency, they should not be used to exclude it.  Overall, UK data suggests testosterone results should be interpreted with much caution, and that perhaps using the patient as a bioassay is as good as current direct immunoassays. There should be greater reliance on the clinical features in each case, careful evaluation of the symptomatology, and where necessary a therapeutic trial of TRT given.

 

Sexual Dysfunction in Women:  An estimated 40% of women experience some form of sexual dysfunction, highlighting the need for research in this field in order to define the potential contribution of testosterone deficiency.  TRT results in improvements in libido and sexual function, mood and well-being.  Evidence points to other potential benefits of androgen treatment, including preservation of bone mass and potential beneficial effects on cognition.  Adverse effects of androgen treatment in women are dose-dependent and include virilisation, mood disturbance and acne, requiring the need for close clinical and biochemical monitoring.

 

The Roles of Estrogens in Men: In men and women, all oestrogens arise from testosterone precursors, almost a Biblical metaphor about Adam’s rib. Oestrogen excess, either genetically through testicular over-production or local tissue over-production, may result in widespread pathologic changes. The ingestion of highly active xeno-estrogens from plastics, pesticides or other chemicals contaminated in the environment, such as dioxins or PCBs adds to the complexity. This diverse impact of oestrogens can be the source of many of the chronic changes and diseases associated with aging. The endocrine disruptive effects of altered oestrogen receptors and pathways of metabolism may account for many of the observed changes associated with endocrine deficiency.