Other than type 2 diabetes, testosterone deficiency syndrome (TDS) is the most common endocrine disorder in men and yet is the least commonly diagnosed and treated, according to the President of the Society for the Study of Androgen Deficiency.
Speaking at a recent meeting on ‘Testosterone and Men’s Health’ in Dublin, Dr Malcolm Carruthers said an estimated 110,000 Irish men are suffering the symptoms of TDS but only about one per cent are receiving treatment.
According to Dr Carruthers, TDS is on the rise. The most common symptoms of TDS are reduced libido and drive, depression, memory loss, aches and pains, sweats, hot flushes and dry skin.
He pointed towards an over-reliance on laboratory tests as part of the reason why so few men with TDS are ever diagnosed or treated.
Unfortunately, he continued, the validity of androgen assays is questionable as levels can be affected by a host of factors including circadian and seasonal changes, diet, alcohol, smoking, ethnicity, medications and illnesses.
Consequently, the diagnosis and treatment of TDS should be based on the presence and severity of symptoms and not on serum testosterone levels.
h4. Erectile dysfunction
Erectile dysfunction (ED) is one condition in which it is accepted that testosterone plays an important role. Mr Mark Feneley, Consultant Urologist at University College Hospital, London, pointed out that in addition to its effects on stimulation, libido and arousal, testosterone has direct effects at the level of the penis.
Testosterone regulates PD5 and nitric oxide synthetase isoform expression and activity in the penis, as well as affecting smooth muscle growth, vasodilation, connective tissue metabolism, extracellular matrix deposition and alpha-adrenoreceptor expression.
Mr Feneley advised that testosterone levels should be assessed as part of the management of ED patients.
He recommended that where patients fail to respond to PDE5 therapy, a trial of testosterone replacement therapy (TRT) should be initiated.
Testosterone is a safe and effective therapy for ED, Mr Feneley said. It can improve spontaneous morning erections, nocturnal tumescence, total erections and ejaculations, sexual interest and satisfaction and can augment PDE5 responsiveness. It may even negate the need for PD5 inhibitors.
h4. Bone health
Prof Moira O’Brien, President of the Irish Osteoporosis Society, told the meeting that testosterone deficiency is the most common cause of osteoporosis in men. This is particularly important, she said, given that osteoporosis in men is associated with a much poorer prognosis than in women.
Up to 30 per cent of hip fractures occur in men, and these are associated with substantially greater morbidity and mortality rates than in women. Up to 20 per cent of vertebral fractures occur in men and hypogonadism is implicated in 16 per cent of these cases, she added.
Consequently, the management of osteoporosis in men should include the identification and treatment of the underlying cause of secondary osteoporosis, where possible. She advised assessing the patient for hypogonadism, hyperthyroidism, hyperparathyroidism, vitamin D deficiency and gluten sensitivity, as well as considering family history.
Treatment should include advice on alcohol and smoking, as well as a recommendation for 30 minutes of weight-bearing exercise per day. Calcium and vitamin D should be prescribed as well as testosterone, bisphosphonates, strontium ranelate or teriparatide where appropriate, she said.
The most important thing, said Prof O’Brien, is to dispel the myth that osteoporosis is an old lady’s disease. One in five men over the age of 50 will develop an osteoporotic fracture, despite the fact that osteoporosis is preventable and treatable.
Men should be screened for osteoporosis if they are at risk of osteoporotic fracture, she advised. Doctors should be particularly alert to the condition in men who have hypogonadism, coeliac disease, Klinefelter’s syndrome, Kallman’s syndrome, Prader-Willi syndrome, haemochromatosis, pituitary dysfunction as well as athletes and those receiving corticosteroid treatment, she added.
h4. Testosterone and CVD
It is now emerging that TDS has much wider health implications. It appears that testosterone deficiency is also associated with an increased risk of cardiovascular disease.
Dr Carruthers reported that studies have shown that MI patients tend to have low testosterone levels. Also, the Framingham study found that hyperoestrogenaemia was significantly correlated with an increased risk of coronary heart disease (CHD). In one study of 1,146 men presenting for coronary angiography, 23.4 per cent had testosterone levels less than 7.5nmol/l. In 1999, a study of 201 men with CHD found a negative correlation between testosterone and the level of atherosclerosis.
Testosterone levels have also been found to be substantially lower in post-stroke patients and those with angina pectoris.
TRT has been shown to have a beneficial effect on angina and the level of workload tolerated by patients with symptomatic CHD. Dr Carruthers said the evidence indicates that testosterone has an anti-ischaemic effect on the heart, an anti-atherosclerotic effect in the aorta and carotid arteries and a direct relaxation effect on the coronary vessels.
h4. Diabetes
Testosterone has also been implicated in the development of diabetes and metabolic syndrome. Prof Gerald Tomkin, Diabetes Institute of Ireland, pointed out the clear relationship between testosterone levels and obesity. Men with higher body mass index are known to have lower levels of testosterone. Research has shown that testosterone inhibits adipogenic differentiation, Prof Tomkin said.
The DIMALITE (Diabetes Management by Lifestyle and Testosterone) study found that in 32 newly diagnosed type 2 diabetic men, a combination of diet, exercise and TRT was associated with a significant effect on waist circumference, blood pressure, triglyceride levels, HDL levels and insulin resistance – the hallmarks of the metabolic syndrome.
Approximately 20 per cent of type 2 diabetic men have testosterone levels below 8nmol/l. Close to 50 per cent have levels less than 12nmol/l.
Prof Farid Saad, Bayer Schering Pharma AG, Berlin, said that at least four studies have now shown that low testosterone is a predictor for the development of diabetes.
Studies on men with induced hypogonadism as a result of GnRHA treatment for prostate cancer show a causative link between testosterone deficiency and reduced insulin sensitivity. In some studies, three months of treatment with GnRHA agents produced an increase in fasting insulin of approximately 7mU/l.
Prof Saad also said that research has shown that this reduced insulin sensitivity is a direct result of the hypogonadism induced by the GnRHA therapy and is not linked to the prostate cancer itself.
Prostate cancer patients treated with androgen deprivation therapy (ADT) typically have fasting insulin levels twice as high as those seen in prostate cancer receiving non-ADT treatment. Fasting glucose levels are also significantly higher in prostate cancer patients receiving ADT compared to those being treated with non-ADT therapies.
Dr Tom Trinick, Consultant Physician at the Ulster Hospital in Belfast, said testosterone status can also influence the decision on which anti-diabetic medication to use. In recent times, there has been increasing concern about the possible link between glitazones and cardiovascular risk. Studies to date have suggested an increased incidence of MI and congestive heart failure with these therapies.
Dr Trinick theorised that the adverse clinical events seen with this class of drugs could be a result of induced androgen deficiency.
Glitazones have been used for almost a decade to treat polycystic ovarian syndrome because of their recognised anti-androgen action. In healthy men, glitazones produce a decrease in total testosterone and dihydrotestosterone (DHT), he reported.
Furthermore, the literature suggests that glitazones interfere with androgen action at the level of the androgen receptor, he said.
Dr Trinick believes that it is the ability of glitazones to reduce circulating levels of testosterone and to interfere with binding at the androgen receptor, which results in their negative cardiovascular effects. However, he said, additional research is required to support or refute this theory.
h4. Safety concerns
It is obvious that there is much to be gained from adopting a pro-active approach to sub-optimal testosterone levels. However, doctors still appear to be reluctant to initiate TRT. Mr Eamonn Rogers, Consultant Urologist at University College Hospital, Galway, believes this reluctance reflects ongoing fears about the safety of TRT, particularly in relation to prostate cancer.
Mr Rogers acknowledged that the growth and maintenance of the prostatic epithelium is facilitated by testosterone and DHT. Testosterone is also known to affect DHT, causing mitosis. The paradox, he said, is that prostate cancer tends to develop in older men when testosterone levels are known to be in decline. The question is whether TRT can cause prostate cancer.
Mr Rogers explained that there is no proof that testosterone causes prostate cancer but, once a cancer is established, androgens do stimulate its growth. Consequently, established prostate cancer remains an exclusion criterion for TRT.
A study of hypogonadal men treated with TRT for six months found no change in the occurrence of occult cancer, levels of prostatic androgens, prostate tissue composition, biomarkers of cell proliferation or angiogenesis, or expression of prostatic oncogenes compared to placebo.
In a separate study, one year of TRT did not increase the risk of cancer in hypogonadal men with high-grade prostatic intraepithelial neoplasia (PIN).
It is recommended that patients be screened for prostate cancer and BPH before initiating TRT therapy. Mr Rogers also advised that patients receiving TRT should be screened regularly for prostate disease if undergoing therapy for more than six months. He added that a biopsy should be carried out if prostate specific antigen (PSA) parameters change during this period.
h4. Summary
TDS is a prevalent condition yet it commonly goes undiagnosed and untreated. The Society for the Study of Androgen Deficiency believes that part of the reason for the underdiagnosis of TDS is a lack of awareness of the symptoms and long-term health implications of the condition, and an over-reliance on laboratory assays to diagnose patients.
Dr Carruthers recommended basing the decision to treat on the presence of symptoms and not on laboratory tests. Initiating TRT in hypogonadal men is particularly important, given the increased risk of CVD and diabetes seen in TDS. There also appears to be a generally reluctance among doctors to initiate TRT.
However, Mr Rogers said that there is no evidence to support a causative link between testosterone and prostate cancer, although cancer remains a contraindication for TRT. He stated that TRT is a safe and effective treatment for TDS and should not be avoided provided patients are screened for prostate cancer in advance of initiating treatment and PSA levels are regularly checked through the treatment period.
* In association with Bayer Healthcare
About Gary Culliton
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