Year : 2006 | Volume
: 22 | Issue : 1 | Page : 15--22
Ageing male and testosterone: Current status and treatment guidelines
Diacon Institute of Neurourology and Andrology, NU Trust, Manipal Hospital - ART centre, Bangalore, India
S S Vasan
Diacon Institute of Neurourology and Andrology, C/o Diacon Hospital, 359-360, 19th Main, I Block, Rajajinagar, Bangalore - 560010
Because the decline in androgens is generally gradual and not a complete deficiency, clinical significance of this decline is still unclear, and there is controversy as to whether a specific syndrome of androgen deficiency or «SQ»andropause«SQ» exists. The term andropause or androgen deficiency in aging males (ADAM) underwent revisions to, partial androgen deficiency in aging male (PADAM), late onset hypogonadism (LOH) and now symptomatic late onset hypogonadism (SLOH), signifying, the evolving nature of this phenomenon. Since this happens at a time of life, when many men have associated comorbities, it«SQ»s difficult to assess the exact impact of androgen decline, due to which, the issues surrounding androgen replacement therapy in men with symptomatic late-onset hypogonadism have been marred in controversy. Although with age, a decline in testosterone levels will occur in virtually all men, there is no way of predicting, who, will experience andropausal symptoms of sufficient severity and also long-term safety data on testosterone administration in this setting, is lacking. This article will focus on the controversies and practices of androgen replacement.
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Vasan S S. Ageing male and testosterone: Current status and treatment guidelines.Indian J Urol 2006;22:15-22
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Vasan S S. Ageing male and testosterone: Current status and treatment guidelines. Indian J Urol [serial online] 2006 [cited 2020 Dec 3 ];22:15-22
Available from: https://www.indianjurol.com/text.asp?2006/22/1/15/24647
Late-onset hypogonadism (LOH) or the earlier term Partial androgen deficiency of the ageing male (PADAM) is defined as a clinical and biochemical syndrome associated with advancing age and characterized by a variety of symptoms and a deficiency in serum testosterone levels. When the term andropause was first defined, it created a lot of controversy, because in men, there was no equivalent of menopause. In fact, in men, contrary to women, there is no cessation of gonadal functions, fertility, ejaculation but only a gradual, age related decline in endocrine function. However, with demographics clearly demonstrating evidence of an ageing population, adverse effects on organ systems and poor quality of life in ageing men, has become a topic of increasing interest and debate throughout the world. Recent WHO data shows a worldwide total of 400 million people aged 65 and older in the year 2000, a figure estimated to double by 2025 and to eventually reach 2 billion by 2050. Ageing is accompanied by a series of signs and symptoms, many of which are rather similar to those observed in young hypogonadal males. The etiology of these signs and symptoms are often multifactorial, making the diagnosis of andropause from clinical signs difficult, which leads to distrust of the symptoms, as well as the diagnostic tools. Androgen replacement therapy in hypogonadal men has many potential benefits: improved sexual function, an enhanced sense of well-being, increased lean body mass, decreased body fat and increased bone density. However, it also carries potential risks, including the possibility of stimulating the growth of an occult prostate cancer. The benefits of androgen therapy outweigh the risks in men with classic hypogonadism. However, for men with mild hypogonadism or andropause, the balance between benefits and risks is not always clear. Nevertheless, there is good evidence that the age associated decrease in testosterone levels is at least a co-determinant of these symptoms and testosterone supplementation has shown favorable effects on many of them. Side effects of this substitutive therapy are minimal when care is taken to keep plasma testosterone levels within the physiological range. Unfortunately, studies to date have included too small a number of patients and have been too short in duration to provide meaningful data on the long-term risks versus the benefits of androgen substitutive therapy in these populations.(sample sizes in the studies conducted to date have been inadequate in number and the duration too has not been adequate enough to provide any reliable conclusions as to the long-term risks versus the benefits of androgen substitutive therapy in these populations)
Present data supports the concept, that testosterone falls progressively with advancing age and a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of the young adult (age 20-30 years) men. The principal questions raised by these observations are:
1 Whether older hypogonadal men will benefit from testosterone treatment,
2. How to identify them when associated with a multitude of ageing symptoms and
3. What will be the risks associated with substitution therapy.
Late-onset hypogonadism (LOH) is a syndrome characterized primarily by:
The easily recognized features of diminished sexual desire (libido) and quality and frequency, particularly of nocturnal erections. Other features are changes in mood with concomitant decreases in intellectual ability, congnitive functions, spatial orientation ability, fatigue, depressed mood, irritability, sleep disturbances, decrease in lean body mass with associated diminution, increase in visceral fat, decrease in body hair, skin alterations and decreased bone mineral density resulting in osteopenia, osteoporosis and increased risk of bone fractures.
Ageing and testosterone
Testosterone is one of the prerequisites for male differentiation during embryonic development. Physiologic serum testosterone levels are also necessary for many organ and cell functions by its stimulatory effects on bones, bone marrow, muscles, liver, skin with sebaceous glands, melanocytic cells, hair, spermatogenesis, prostate gland, penis and renal erythropoietin producing cells.
After the age of 50, testosterone levels decline by 1% per year and after 60 years of age, 1 in 5 men live with serum testosterone (ST) levels below the range for young males. Although a great inter individual variation exists among elderly men in the decline of ST levels, a large body of evidence suggests that decreased ST levels contribute, at least in some men, to age-associated physiological processes that may affect the function of multiple organ systems. Although so far inconclusive, there is progressively more evidence indicating that decreased ST levels are involved, in causing a significant detriment to the quality of life of the ageing male and on this hypothesis testosterone substitution is proposed as a treatment of hypogonadism in adult men leading to an improvement in bone mineral density, quality of life, muscle mass, libido and mood.
However in the aged, the problem is compounded by a plethora of other co morbid conditions which may coexist. Associating everything with a decline in testosterone would be too simplistic. When we look at the hypothalamic-pituitary-testicular axis sensitivity in an ageing male, there is a slight decrease of testicular activity, which is associated with the modest increase in LH increase inadequate to compensate testosterone decrease due to reduced mean LH pulse amplitude and altered GnRH secretion. Despite the slight endocrinal changes, sensitivity of the gonadal axis is preserved in ageing men. Several postulated theories of ageing are genetic mutations, cell loss, wear and tear, waste product accumulation, protein cross-linking, free radicals, immune alterations, defects in repair mechanisms and neuroendocrine alterations. Ageing is also dependent on other factors like genetics, socio-economics, geopolitics and it impacts every single compartment in an integrated manner. One endocrinal change that is now well-established is a decrease in androgens, particularly the free fraction of testosterone, in the blood (with ageing). While the age-associated decrease in testosterone levels is well-established, it is relatively modest and does not necessarily occur in every man. Therefore its importance is unclear. For example, from several studies, it is clear that total testosterone does not change with age. On the other hand, there is a clear age-dependent increase in sex hormone binding globulin (SHBG) concentrations, resulting in significant decrease in free testosterone and bio-available testosterone (with age). Conversely Receptor Polymorphism, namely, longer CAG repeats, age-related receptor decline or down regulation, excessive protein binding, increase in sex hormone binding globulin, variation in 5 alpha reductase - aromatase activity due to genetic polymorphism and environmental factors such as xenoestrogens and antiandrogens, can all combine to induce androgen resistance, which is equally as important, as insufficient androgen production and this may also induce the same symptomatology and pathology as androgen deficiency.
Although it may appear desirable, no evidence exists for or against the need to maintain the physiological circadian rhythm of serum testosterone levels.
Recommendation: The challenge in managing men's health and ageing is to:
1) Avoid a simplistic or symptomatic approach to the management of ageing,
2) Develop a comprehensive diagnostic paradigm
3) Establish an integrated, holistic approach for their management.
Assessment of androgen deficiency - testosterone assay
The present assay reference ranges of testosterone and bio available testosterone provided by clinical laboratories may be an inaccurate way to stratify patients. It leads to confusion in determining which patients are truly "hypogonadal". Further laboratory tests are needed to examine the actual end-organ response to testosterone in LOH with less dependence on traditional parameters. The current problems with measurement of testosterone are:
1. Lack of adequate precision and specificity
2. Availability of different assays with no standardization as regards to assays as well as effect of drugs, proteins, sample tubing, timing of the sample and other constituents on the sample
3. Should we be measuring free testosterone as well as, or instead of, total testosterone? If so, is an androgen index (testosterone/SHBG) as good as free testosterone determination? The current practices are:
Recommendation: A serum sample should be obtained between 0700 and 1100 hours. The most widely accepted parameters to establish the presence of hypogonadism are the measurement of total testosterone and free testosterone calculated from measured total testosterone and SHBG or measured by a reliable free testosterone dialysis method. Direct radio immunoassays of free testosterone should not be used.
If testosterone levels are below or at the lower limit of the accepted normal adult male values, it is recommended to perform second determinations together with assessment of serum luteinizing hormone and prolactin. Salivary testosterone has been shown to be a reliable substitute for free testosterone measurements, but cannot be recommended at this time since the methodology has not been standardized and adult male ranges are not available in most hospitals or reference laboratories.
Based on the data currently available, the measurement of total blood testosterone is the most appropriate and widely available test to confirm hypogonadism. Subject to future research, a total testosterone level of 300 ng/dl measured in the morning, using a reliable assay, may be used as a threshold below which an individual can be considered hypogonadal.
Questionnaires - rating scales
Due to limitations in the assay, a thorough clinical history and physical examination remain important in the decision making algorithm for testosterone replacement therapy. Several questionnaires have been used to collect symptoms or complaints of patients with androgen deficiency (AD), but very few are sufficiently validated. For state of the art validation a scale should be able to (a) compare relevant symptoms, (b) evaluate the severity of complaints over time and (c) measure changes pre and post androgen replacement therapy.
Recommendation: In order to differentiate late onset hypogonadism or simply ageing itself several questionnaires are used and the most popular is the ageing male symptoms scale (AMS). There is an increasing symptom profile, measured by AMS scale, observed among ageing men with increasing age, which is independent from medical conditions as well as other confounding factors.
Ageing - sexual dysfunction and LUTS
Understanding the natural course of disease is critical to interventions to slow or reverse its progression. The most important pathway underlying the penile erection is the nonadrenergic / noncholinergic signaling, which through the release of nitric oxide, leads to an intracellular increase of cyclic GMP, the main secondary messenger mediating tumescence in the penis. Interestingly, both cGMP formation and degradation are affected by testosterone. In fact, beyond the well-known role of testosterone in regulating sexual desire and nitric oxide release, recent experimental evidences, showed that testosterone also regulates the expression of phosphodiesterase type 5 (PDE5), the hydrolytic enzyme involved in cGMP breakdown. This antithetic role of testosterone seems to be the main way through which the peripheral hormonal regulation of penile erections occurs. Because Testosterone positively controls both the initiation (NOS) and the end (PDE5) of the erectile process, its net effect on erection is null. Hence, erections are still possible in hypogonadal conditions where a decreased cGMP formation, due to impaired NO production, is counterbalanced by a reduced cGMP hydrolysis. The main action of testosterone is therefore to timely adjust the erectile process as a function of sexual desire, therefore finalising erections to sex.
Some men with erectile dysfunction and low serum testosterone may not respond adequately under testosterone treatment alone. In these cases, addition of phosphodiesterase 5 - inhibitors may be indicated. Similarly, men with erectile dysfunction not responding to phosphodiesterase 5 - inhibitors may have low serum testosterone and require testosterone substitution.
The Multinational Survey of the Ageing Male (MSAM-7) provided strong evidence of the relationship between Age, Lower Urinary Tract Symptoms (LUTS) severity and Erectile Dysfunction (ED). They demonstrated that for each decade of age, the percentage of men with moderate or severe LUTS increases and for each LUTS severity groups (mild, moderate and severe), the frequency of sexual activity declines and the prevalence of ED increases. However this failed to answer whether it was only a coincidence or if ED is increased because of bothersome nature of LUTS or are there common pathophysiological / biological factors. Some existing hypotheses to explain the phenomena are,,
1. Nitric oxide synthase (NOS) / Nitric oxide (NO) pathway: Propagates reduced production of NOS/NO in the pelvis - including the penis and prostate. It is known that decreased NO can promote ED and can also lead to prostatic tone relaxation, resulting in an altered neurogenic influence on the voiding function. Phosphodiesterase (PDE) type 5, which is normally related to a decrease of NO in the corpora cavernosa, has a counter part, in the form of presence of PDE 11A in the prostate, evoking the possibility of similar actions.
2. Autonomic hyperactivity and metabolic syndrome effect on LUTS and ED: This theory proposes that the Metabolic Syndrome, in the form of increased BMI (obesity), hyperinsulinemia, increased age and decreased physical activity, increases the autonomic hyperactivity. This eventually increases sympathetic tone, increases BPH growth, causes development of LUTS and also increases vasoconstrictive factors that results in ED.
3. Alpha adrenoreceptors:, Alpha 1 adrenergic receptors play an important role in mediating the tone of smooth muscle cells of the lower urinary tract. LUTS causes a high sympathetic status in the pelvis and this state, leads to the contraction of the prostatic smooth muscle via alpha adrenergic receptors. This state also promotes an increase in the local norepinephrine levels, which, act on the alpha receptors, in the penile cavernous smooth muscle inducing its contraction, as also vascular contraction, which promotes a flaccid state, maybe contributing to ED.
4. Rho-kinase activation: Rho-kinase promotes smooth muscle contraction and is probably involved in the mechanism of the flaccid state of the penis. LUTS may also be affected by the Rho-kinase action. Men with LUTS have a chronic exposure to procontractile endothelins and alpha receptor agonists and this up-regulates the Rho-kinase pathway that increases the contraction and impairs the bladder muscle relaxation, contributing to LUTS.
5. Pelvic atherosclerosis: This theory links ED and LUTS through the ischemia caused by diffuse atherosclerosis of prostate, penis and bladder, that leads to the loss of smooth muscle cells and replacement with collagen deposition and fibrosis.
6. Sex hormones: Dihydrotestosterone (DHT): Which has have a high affinity for androgen receptors is predominantly produced peripherally from testosterone via 5 alpha reductase and these levels increase with ageing. Androgen receptors which are present, both in the stroma and the epithelium of the prostate, may play a role in their interaction. Age related changes in circulating hormone levels may contribute to the pathophysiology of BPH and ED.
Recommendation: In ageing men with the major complaint of erectile dysfunction and luts0 androgen deficiency should be assessed and if need be treated.
Ageing and prostate
There is conclusive evidence that prostate cancer is androgen sensitive and changes in circulating testosterone may either result in an inhibition or activation of the biological activity. Morgentaler et al . published many years ago that the incidence of Prostate Carcinoma (PC) is higher in men with low testosterone levels. The reasons for these phenomena remain unclear, although PSA gene polymorphism and AR genes are suspected. Inhibin is also suspected to influence the pituitary gonadal axis by negative feed back mechanism.
Obviously, exclusion of prostate cancer prior to testosterone supplementation of hypogonadal ageing men is essential. The combination of PSA and digital rectal examination (DRE) has acceptable positive predictive values and has resulted in a significant increase in the diagnosis of early stages of prostate cancer. However, PSA has shortcomings due to low cancer specificity. Further, the expression of PSA is androgen dependent and hypogonadal men may have lower PSA which could mask pre-existing prostate cancer. Continuing PSA and clinical monitoring prior to the institution of treatment with testosterone and at regular intervals during therapy is important to detect preexisting tumors and to avoid adverse effects of exogenous testosterone. A rise in PSA shortly after the institution of treatment may unmask prostate cancer.,
Recommendation: Currently available data obtained from relatively small studies support the short term safety of testosterone replacement therapy with regard to risk for possible development or stimulation of sub clinical prostate cancer, although the long term risk remains undetermined., In case of abnormal digital rectal examinations and, or, consistently elevated, PSA levels, additional laboratory tests, including hematocrit and free PSA level, a urological evaluation including trans-rectal ultrasound and biopsy of the prostate should be performed prior to initiation of testosterone therapy.
However before initiation of therapy following definite contraindications needs to be ruled out: Significant polycythemia, untreated sleep apnea, severe heart failure, severe symptoms of lower urinary tract obstruction (as evidenced by high scores in the International Prostate Symptoms Score (IPSS)) and clinical findings of bladder outflow obstruction (increased post micturition residual volume, decreased peak urinary flow, pathological pressure flow studies) due to an enlarged, clinically benign prostate. However, age, as such, is not a contra indication to initiate testosterone supplementation. Moderate obstruction represents partial contraindication, while carcinoma of the prostate or breasts are also absolute contraindications.
Men, while on testosterone therapy need periodic monitoring, subject to individual clinical response and this evaluation is recommended at 3 and 6 months after initiation of therapy and then followed up with a yearly evaluation. A physical examination, including digital rectal examination of the prostate, a prostate specific antigen (PSA) level and hematocrit, should be performed, at 3, 6, 12 months and then annually. As prostate cancer cannot be definitely excluded by PSA testing and DRE, there is controversy over prostate biopsies before treatment in men with low PSA. Men successfully treated for prostate cancer and suffering from confirmed symptomatic hypogonadism are candidates for testosterone substitution after a prudent interval if there is no evidence of residual cancer. The risk and benefits must be clearly understood by the patient and the follow up, must be particularly careful, especially for this group. However it needs to be understood that no reliable evidence exists in favor of or against this recommendation. The clinician must exercise good clinical judgment together with adequate knowledge of the advantages and disadvantages of testosterone therapy in this situation.
Ageing and metabolic syndrome: Interplay between obesity and androgens
The co-existence of visceral obesity, increased blood lipids, hypertension and impaired glucose tolerance is known as the metabolic syndrome and is an important determinant of morbidity and premature mortality. Interestingly, obesity and type 2 diabetes are frequently associated with low testosterone levels in men. The decline of testosterone levels occurring in obese or diabetic men, as well as in older males, usually it is not accompanied by a compensatory rise in gonadotrophins. For this reason, in a rather simplistic way, the hypogonadism of diabetics has been often labeled as exclusively hypogonadotropic. However, there are a number of publications showing that this phenomenon has a combined etiology, central and peripheral. More importantly, in obese and insulin resistant subjects, the frequently described hypogonadism may have a peripheral origin. It has been shown that ageing is associated with a defective LH signal transduction in Leydig cells and it has been demonstrated that in male obesity, the defect in Leydig cells testosterone production correlates with insulin resistance and is not the consequence of a chronic alteration in the hypothalamic-pituitary function. Further, in obese adult obese men, Leydig cell output is progressively reduced with increasing adiposity and that adipocyte derived products, such as leptin, are also likely to be involved. Since higher testosterone is associated with a higher insulin sensitivity and a reduced risk of the metabolic syndrome, it is conceivable to hypothesize that testosterone may exert a protective role in the development of the metabolic syndrome and insulin resistance in ageing and obese men.
Recommendation: Though diabetes Mellitus type 2 is a frequent disorder of ageing men, it is unclear at the present time what effect testosterone has on blood sugar and insulin sensitivity. Thus, until positive effects of testosterone on blood sugar control are definitively demonstrated, diabetics should be evaluated and treated before or simultaneously with testosterone substitution only if found to be hypogonadal. It is also recognized that significant alternations in other endocrine systems occur in association with ageing, but the significance of these changes is not well understood in general terms. Determinations of thyroid hormones, cortisol, DHEA, DHEA-S, melatonin, growth hormone and insulin like growth factor-1, are not indicated in the uncomplicated evaluation of late onset hypogonadism. If endocrine disorders are suspected, assessment of these and other hormones may be warranted.
Ageing and cardiovascular disease
The adverse affection of arterial endothelium is a pivotal step in atherosclerosis and is closely linked to the metabolic syndrome, a complex disorder with a high prevalence in developed countries and an increasing prevalence in less developed regions. Cross-sectional and longitudinal epidemiological studies show that low testosterone levels are more common in patients with the metabolic syndrome, cardiovascular diseases, or diabetes type 2 than in the normal population. Adiposity is also closely related to the development of type 2 diabetes mellitus by fostering insulin resistance. In this clinical entity, high levels of insulin promote atherosclerotic events, by adverse effects on the vessel wall and by facilitating high cytokine concentrations. Interestingly, type 2 diabetes mellitus impairs the hypothalamic-pituitary axis, resulting in secondary hypogonadism. Several smaller intervention studies in patients with visceral obesity, cardiovascular diseases and diabetes type 2 suggest that the normalisation of testosterone levels reduces fat mass and an inflammatory marker increases lean body mass and shows an overall improvement of the risk factors for the metabolic syndrome and cardiovascular diseases. Nevertheless, adverse effects of testosterone on HDL-cholesterol concentrations and arterial vasoreactivity have also been reported. It remains to be elucidated by larger long-term studies whether testosterone substitution can decrease the incidence of cardiovascular events.
Recommendation: In ageing men with the major complaint of lipids and cardiovascular status comprehensive assessment is advocated before deciding on treatment.
Ageing and osteoporosis
Osteoporosis in ageing men is a major problem of public health, because the number of fragility fractures in men, increases rapidly. Two principal risk factors of fragility fractures in elderly men have been studied: low areal bone mineral density (aBMD) and low bone size. Decrease in aBMD is associated with an exponential increase in the fracture risk. The low aBMD is determined by low peak bone mass acquired during the growth and accelerated ageing-related bone loss due to the increased bone resorption which is only partly matched by bone formation. The principal risk factors of bone loss in elderly men are hypogonadism, low level of bioavailable 17 beta-estradiol, low body mass index, tobacco smoking, corticosteroid therapy and poor health status. In men with prostate cancer, androgen deprivation therapy induces a rapid acceleration of the bone turnover and bone loss which results in the increased risk of fracture.
Low bone size is associated with an increased fracture risk regardless of aBMD. Specific determinants of low bone size in men are only partly studied. Potential determinants are: genetic factors, nutritional status, low muscle mass, sedentarity and delayed puberty. Low bone size is associated with the lower bending strength which confers higher susceptibility to fractures by bending and torsion.
However, several major aspects of the pathophysiology of the osteoporosis in men remain to be elucidated. The study of association between bone geometry and fracture risk based on parameters estimated from DXA scans (dual X-ray absorptiometry) and measurements by using peripheral quantitative computerised tomography are needed. Interaction of different factors, leading to the increased fracture risk, by different mechanisms (hypogonadism, vitamin D deficit, muscle mass) need to be studied. Qualitative parameters of bone tissue (trabecular micro architecture, degree of mineralization, microstructure of type I collagen) and their specific role as determinants of bone strength (or fragility) in elderly men have not been studied.
Recommendation: There is generally no accepted diagnostic criterion of osteoporosis in men. Data on the prediction of bone loss and fragility fractures by the biochemical bone turnover markers in elderly men is limited.
Ageing and frailty - sarcopenia
Geriatricians often define frailty, as a syndrome, of decreased reserve and resistance to stressors characterized by a high degree of vulnerability to negative health outcomes such as disability, co morbidity and mortality. Even though there is still no consensus definition of frailty, some clinical features have been identified as: muscle weakness, poor exercise tolerance, factors related to body composition, sarcopenia and lower mobility. Till now, studies have also tried to identify biological markers associated with such features, due to the fact that biological changes may be paralleled by important changes in physiological systems.
Sarcopenia is the excessive loss of muscle and older people who develop sarcopenia have an increased disability. The causes of sarcopenia are multifactorial. It is due in part to the decreased activity that occurs with ageing. In some older individuals peripheral vascular disease and decline in testosterone and IGF-1 have been associated with changes in muscle mass, strength and poor physical performance. Mechanogrowth factor (MGF) also plays a major role in the determination of the quality of muscle as it falls with ageing and increases with resistance exercise. Cytokines (Tumor necrosis factor X and Interleukin-6) and Myostatin also cause loss of lean tissue.
Recommendations: At present, management of sarcopenia focuses on resistance exercises and possibly testosterone replacement, though data is inconclusive.
Ageing and brain
A decline of cognitive abilities, adverse mood shifts and depressive disorders are all observed in ageing men and hormonal effects on cerebral functions are a focus of interest.
Firstly, a multitude of sub dimensions exist concerning cognitive functions: memory has verbal and visuospatial properties, acute task-solving abilities comprising visuomotor capacities, as well as, processing visuospatial input, performing constructional tasks and verbal functions related to fluency of recognition and output. Secondly, testosterone undergoes aromatization to estradiol, which has properties of modulating cerebral functions on its own. Thirdly, despite having lower levels of testosterone, women do not show accelerated cognitive decline when compared to the men. In addition, castration has not necessarily shown a decline in cognitive functions. The associations of deteriorating cognitive functions with declining androgen concentrations, which are described by cross-sectional or longitudinal observation studies, have not been corroborated by interventional trials.
Recommendations: Testosterone normally results in improvements in mood and well-being, provided, there is proven hypogonadism. The developments of negative behavioural patterns, during treatment, calls for dose modifications or discontinuation of therapy and available data in this field is highly controversial.
Ageing and Sperm motility
In contrast to the female, male reproductive functions do not cease abruptly, but may continue lifelong. However, a distinct decrease in the concentration of free testosterone and sperm motility has repeatedly been described. During spermiogenesis, zinc is actively incorporated in the outer dense layers of sperm but removed again during epididymal maturation. As epididymal function is obligatorily testosterone-dependent, it appears that the removal of zinc from the sperm flagella is also hormone-dependent. Thus, during ageing, the epididymis seems to become dysfunctional resulting in poor motility.
Recommendations: Patient should be informed that the testosterone therapy will be affect spermatogenesis and their fertility potential during treatment and for sometime following cessation of therapy.
Testosterone replacement therapy - general guidelines to treatment
Testosterone replacement therapy in ageing men is indicated when both clinical findings and signs are suggestive of androgen deficiency, in the form of decreased testosterone levels are present, provided, that the possible adverse effect of testosterone therapy are evaluated by pretreatment screening. Pre treatment screen should include, medical history for potential sleep apnea, congestive heart failure, symptoms consistent with lower urinary tract obstruction and personal or family history of prostate or breast carcinoma. Physical examination, includes a digital rectal examination of the prostate. Improvement in signs and symptoms of testosterone deficiency should be sought and failure to benefit in clinical manifestations should result in discontinuation of treatment and further investigation for other causes, is then mandatory.
There is a general agreement that total testosterone level above 12 nmol/L (346 ng/dl), or free testosterone levels above 250 pmol/L (72 pg/ml) do not require substitution. Similarly, based on the data of younger men, there is consensus that serum total testosterone levels below 8 nmol/L (231 ng/dl) or free testosterone below 180 pmol/L (52 pg/ml) require substitution. There are no generally accepted lower limits of normal and it is unclear whether geographically different thresholds depend on ethnic differences or on the physician's perception. Since symptoms of testosterone deficiency become manifest between 12 and 8 mmol/L, trials of treatment can be considered in those in whom alternative cause of these symptoms have been excluded.
Testosterone replacement therapy has been associated with increased haematocrit and hemoglobin, oiliness of skin and acne. Testosterone therapy needs to be altered or ended if the hematocrit exceeds 52%. Contra indications to therapy include a history of prostate cancer, breast cancer, untreated sleep apnoea and untreated and / or severe congestive heart failure. Exacerbation of sleep apnoea and obstructive uropathy related to benign prostatic hyperplasia needs careful monitoring, but is not an absolute contraindication.
Type of replacement therapy
Injectable long acting testosterone esters, transdermal patches, gels, subcutaneous pellets, oral testosterone and undecanoate have all been used. Since the possible development of a contraindication during treatment (especially prostate carcinoma) requires rapid discontinuation of testosterone substitution, short- acting (transdermal, oral, buccal) preparations are preferred over long-acting (intramuscular, sub dermal) depot preparation in patients with LOH. Androgen preparations such as DHEA, DHEA-S androstenediol, or androstenedione are not used for treatment and alkylated androgen preparation, such as, 17a -methyl testosterone, are absolutely contraindicated. Though HCG stimulates testosterone production of Leydig cells, albeit at a lower rate, this form of treatment is not recommended in LOH.
Long term data on the effect of testosterone treatment in the older population is limited and specific risk data on the prostate and cardiovascular systems is still needed. Answers to key questions regarding the functional benefits that may retard frailty of the elderly, are not available. The definition of hypogonadism in ageing in men is still controversial. In the absence of total agreement, a combination of clinical signs, physical findings and plasma testosterone concentration may be used to determine whether testosterone replacement therapy is indicated.
|1||Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, et al . Investigation, Treatment and Monitoring of Late-Onset Hypogonadism in Males: ISA, ISSAM and EAU Recommendations. J Androl 2006;27:135-7.|
|2||Hochreiter WW, Ackermann DK, Brutsch HP. Andropause. Ther Umsch 2005;62:821-6.|
|4||Schubert M, Jockenhovel F. Late-onset hypogonadism in the aging male (LOH): definition, diagnostic and clinical aspects. J Endocrinol Invest 2005;28:23-7.|
|5||Bhasin S, Woodhouse L, Storer TW. Androgen effects on body composition. Growth Horm IGF Res 2003;13:S63-71|
|6||Lunenfeld B. Androgen therapy in the aging male. World J Urol 2003;21:292-305.|
|7||Vinkers DJ, Stek ML, van der Mast RC, de Craen AJ, Le Cessie S, Jolles J, et al . Generalized atherosclerosis, cognitive decline and depressive symptoms in old age. Neurology 2005;65:107-12.|
|8||Sohal RS, Mockett RJ, Orr WC. Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic Biol Med 2002;33:575-86.|
|9||Anawalt BD, Merriam GR. Neuroendocrine aging in men. Andropause and somatopause. Endocrinol Metab Clin North Am 2001;30:647-69.|
|10||Linja MJ, Visakorpi T. Alterations of androgen receptor in prostate cancer. J Steroid Biochem Mol Biol 2004;92:255-64.|
|11||Goncharov N, Katsya G, Dobracheva A, Nizhnik A, Kolesnikova G, Todua T, et al. Serum testosterone measurement in men: evaluation of modern immunoassay technologies. Aging Male 2005;8:194-202.|
|12||Lunenfeld B, Saad F, Hoesl CE. ISA, ISSAM and EAU recommendations for the investigation, treatment and monitoring of late-onset hypogonadism in males: Scientific background and rationale. Aging Male 2005;8:59-74.|
|13||Heinemann LA, Saad F, Heinemann K, Thai DM. Can results of the Aging Males' Symptoms (AMS) scale predict those of screening scales for androgen deficiency? Aging Male 2004;7:211-8.|
|14||Morales A, Buvat J, Gooren LJ, Guay AT, Kaufman JM, Tan HM, et al. Endocrine aspects of sexual dysfunction in men. J Sex Med 2004;1:69-81.|
|15||Lue TF, Giuliano F, Montorsi F, Rosen RC, Andersson KE, Althof S, et al . Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004;1:6-23.|
|16||Rosen R, Altwein J, Boyle P, Kirby RS, Lukacs B, Meuleman E, et al . Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 2003;44:637-49.|
|17||Musicki B, Burnett AL. eNOS function and dysfunction in the penis. Exp Biol Med (Maywood) 2006;231:154-65.|
|18||Miner M, Rosenberg MT, Perelman MA. Treatment of lower urinary tract symptoms in benign prostatic hyperplasia and its impact on sexual function. Clin Ther 2006;28:13-25.|
|19||Rosen RC. Update on the relationship between sexual dysfunction and lower urinary tract symptoms/benign prostatic hyperplasia. Curr Opin Urol 2006;16:11-9.|
|20||Lowe FC. Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: sexual function. BJU Int 2005;95:12-8.|
|21||Rosen RC. Update on the relationship between sexual dysfunction and lower urinary tract symptoms/benign prostatic hyperplasia. Curr Opin Urol 2006;16:11-9.|
|22||Burnstein KL. Regulation of androgen receptor levels: implications for prostate cancer progression and therapy. J Cell Biochem 2005;95:657-69.|
|23||Dehm SM, Tindall DJ. Molecular regulation of androgen action in prostate cancer. J Cell Biochem 2006.|
|24||Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol 2000;163:824-7.|
|25||Konstantinos H. Prostate cancer in the elderly. Int Urol Nephrol 2005;37:797-806.|
|26||Barqawi A, Crawford ED. Testosterone replacement therapy and the risk of prostate cancer. Is there a link? Int J Impot Res 2005.|
|27||Guay AT, Perez JB, Fitaihi WA, Vereb M. Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer. Endocr Pract 2000;6:132-8.|
|28||Ebert T. Clinical experiences with testosterone therapy: prostate safety. Aging Male 2004;7:304-11.|
|29||Tan RS, Salazar JA. Risks of testosterone replacement therapy in ageing men. Expert Opin Drug Saf 2004;3:599-606.|
|30||Gerstenbluth RE, Maniam PN, Corty EW, Seftel AD. Prostate-specific antigen changes in hypogonadal men treated with testosterone replacement. J Androl 2002;23:922-6.|
|31||Jimenez-Cruz JF, Broseta E. Diagnostic challenges of prostatic carcinoma. Br J Urol 1992;70:39-42.|
|32||Vermeulen A, Kaufman JM, Giagulli VA. Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males. J Clin Endocrinol Metab 1996;81:1821-6.|
|33||Giagulli VA, Kaufman JM, Vermeulen A. Pathogenesis of the decreased androgen levels in obese men. J Clin Endocrinol Metab 1994;79:997-1000.|
|34||Testosterone Replacement Therapy for Male Aging: ASA Position Statement. J Androl 2006;27:133-4.|
|35||Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypogonadism and testosterone therapy. Am J Cardiol 2005;96:67M-72M. Epub 2005 Dec.|
|36||Kapoor D, Malkin CJ, Channer KS, Jones TH. Androgens, insulin resistance and vascular disease in men. Clin Endocrinol (Oxf) 2005;63:239-50|
|37||Berruti A, Tucci M, Terrone C, Gorzegno G, Scarpa RM, Angeli A, et al . Background to and management of treatment-related bone loss in prostate cancer. Drugs Aging. 2002;19:899-910.|
|38||Isidori AM, Giannetta E, Pozza C, Bonifacio V, Isidori A. Androgens, cardiovascular disease and osteoporosis. J Endocrinol Invest 2005;28:73-9.|
|39||Guillet C, Boirie Y. Insulin resistance: a contributing factor to age-related muscle mass loss? Diabetes Metab 2005;31:20-6.|
|40||Muhlberg W, Sieber C. Sarcopenia and frailty in geriatric patients: Implications for training and prevention. Z Gerontol Geriatr 2004;37:2-8.|
|41||Hogervorst E, Bandelow S, Moffat SD. Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review. Curr Drug Targets CNS Neurol Disord 2005;4:531-40.|
|42||Lessov-Schlaggar CN, Reed T, Swan GE, Krasnow RE, DeCarli C, Marcus R, et al . Association of sex steroid hormones with brain morphology and cognition in healthy elderly men. Neurology 2005;65:1591-6.|
|43||Henkel R, Maass G, Schuppe HC, Jung A, Schubert J, Schill WB. Molecular aspects of declining sperm motility in older men. Fertil Steril 2005;84:1430-7.|
|44||Meriggiola MC, Pelusi G. Advances in male hormonal contraception. Exp Opin Invest Drugs 2006;15:389-97.|
|45||Morales A. Testosterone treatment for the aging man: The controversy. Curr Urol Rep 2004;5:472-7.|
|46||Darby E, Anawalt BD. Male hypogonadism: an update on diagnosis and treatment. Treat Endocrinol 2005;4:293-309.|
|47||Jockenhovel F. Testosterone supplementation: What and how to give. Aging Male 2003;6:200-6.|