A4339 age male vol 5 no 2.vp

Color profile: Generic CMYK printer profileComposite Default screen Standards, Guidelines and Recommendationsof The International Society forThe Study of the Aging Male (ISSAM) Investigation, treatment and
monitoring of late-onset
hypogonadism in males
Official Recommendations of ISSAM
Department of Urology, Queen’s University Kingston, Ontario, Canada; *Faculty of Life Sciences Bar-Ilan Key words: AGING, HYPOGONADISM, TESTOSTERONE REPLACEMENT INTRODUCTION
The field of hormonal alterations in the aging male
(PADAM), also widely known as andropause, is a is attracting increasing interest in the medical com- fast-developing field (since there is no consensus munity and the public at large. Simultaneously, on nomenclature, the terms late-onset hypo- industry has realized the growing importance and enormous potential of the impact of a rapidly acceptable and used interchangeably). The under- mounting population of males over the age of standing of ADAM among large sections of the 50 years. This population will be positioned for medical profession dealing with mature men (i.e.
special health needs in the first quarter of this primary care, internists, urologists, etc.) has not century and probably beyond. Among these needs, kept pace with the developments in the field. The hormone replacement therapy will find its proper International Society for the Study of the Aging place, as it has for postmenopausal women over Male (ISSAM) believes that it is somewhat premature to provide guidelines for the diagnosis, It is fully recognized that the endocrinological treatment and monitoring of men diagnosed with changes associated with male aging are not limited or suspected of suffering from ADAM. On the to sex hormones. On the contrary, profound other hand, a great deal of confusion and mis- changes occur in other hormones such as growth understanding exists surrounding the same three issues (diagnosis, treatment and monitoring) of the melatonin and, to a lesser extent, thyroxin. How- condition. Therefore, ISSAM – in fulfilling its ever, androgen decline in the aging male (ADAM), mandate – considers that this is an opportune time or partial androgen deficiency of the aging male to provide factual information on the various Correspondence: Professor A. Morales, Kingston General Hospital, Kingston, Ontario, Canada, K7L 2V7 STANDARDS, GUIDELINES AND RECOMMENDATIONS Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen clinical aspects of the andropause in the form of of early androgen preparations. The diagnostic cri- a set of practical recommendations dealing teria are presently better understood. For instance, exclusively with ADAM and androgen replace- recently, a couple of validated questionnaires4,5 ment therapy (ART). It is anticipated that further have been proposed for either screening, diag- recommendations and guidelines on other similar nosing and/or assessing response to therapy5.
areas of competence for ISSAM will be produced More sophisticated diagnostic and monitoring questionnaires are in development. Although they may prove useful for screening and diagnosis hormone replacement in aging change frequently of ADAM, all require further, wider experience, and long-held views are now being vigorously particularly in their transcultural applicability.
challenged. The material in these Recommenda- tions represents recent information on the andro- pause; however, it may require frequent updates as Definition: A biochemical syndrome associated with new and relevant data become available. At the advancing age and characterized by a deficiency in serum appropriate time, they may also be upgraded to androgen levels with or without a decreased genomic guidelines for the evaluation and treatment of sensitivity to androgens. It may result in significant alterations in the quality of life and adversely affect the A draft of Society’s Recommendations was function of multiple organ systems. previously published in this Journal1 to give the opportunity for discussion at the 2002 biannual DIAGNOSIS
meeting of ISSAM. The Recommendations were reviewed by a panel of experts, a number of sugges- Clinical
tions were submitted by well-informed physicians The clinical picture is described in the definition as well as representatives of industry and the docu- below. It should be remembered that there is ment was presented and discussed in Berlin during significant interindividual variability in the onset, velocity and depth of the androgen decline approved in principle. Further opportunity was associated with age, and no factors have emerged given to the membership for criticisms. Some were that predict the characteristics or effects of the received and incorporated when deemed appro- age-related hypogonadism. As a rule of thumb, the mean serum testosterone level decreases after the age of 50 years at a rate of approximately 1% per DEFINITION
year. This is by no means a constant phenomenon: biochemical hypogonadism is detected in only In men, gonadal function is affected in a slow pro- about 7% of the age group less than 60 years old but gressive way as part of the normal aging process2.
increases to 20% in those over 60 years of age6. It This process, leading to hypogonadism is variously may be argued, therefore, that only a minority of known as male climacteric, andropause or, more individuals develop ADAM. This may not be the case. Associated with advancing age, there is also andropause and male climacteric are biologically an increase in the levels of sex hormone binding wrong and clinically inappropriate, but they globulin (SHBG) which translates into a further adequately convey the concept of emotional and decrease in bioavailable testosterone (free plus physical changes that, although related to aging in albumin-bound fractions). When the diagnosis general, are also associated with significant hor- is based on the measurement of bioavailable monal alterations. The clinical manifestations of testosterone, up to 70% of men over the age of 60 male secondary hypogonadism have been well were found to be hypogonadal4. To compound the defined over 50 years3 but ART was not widely difficulties in establishing biochemical and clinical accepted, in part due to unrealistic expectations correlates, there are three important areas that and adverse effects due to improper management Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen (1) It is not yet known what level of serum (These manifestations need not all be present to identify testosterone defines deficiency in an older the syndrome. In addition, the severity of one or more of man, although it is generally accepted that them does not necessarily match the severity of the others, 2 standard deviations below normal values nor do we yet understand the uneven appearance of these manifestations. Moreover, the clinical picture may or may (11 nmol/l total testosterone or 0.255 nmol/l not be associated with low testosterone. Therefore, the clinical diagnosis should be supported by biochemical tests described by Vermeulen and colleagues7.
confirming the presence of hypogonadism). For bioavailable testosterone the value of 3.8 nmol/l has been recommended. A tool for calculating free and bioavailable testosterone Biochemistry
Establishing the presence of slight hypogonadism on a purely clinical basis is, in most cases, difficult significantly from laboratory to laboratory, the and unreliable. Only the more severe cases lead results from each patient should be compared to clinical suspicion. Despite this, there is some with the normal ranges established by each controversy as to the need for hormonal evaluation of the aging man. For instance, hormonal evalua- (2) In older men, there may be variable responses tion in men with erectile dysfunction has been by the target organs (brain, bone, prostate, questioned on the basis that it is not cost- muscle, etc.) to the levels of androgens.
effective14. Although this scepticism is not shared by others15,16, there are several reasons to justify, (3) The response by target organs may be influ- at least, basic hormonal assessment of men with enced by a variety of endocrine disruptors, erectile dysfunction. It is commonly accepted that the nature of which is only beginning to be the combination of low sexual desire and erectile difficulties may be the result of serious hormonal The combination of these three uncertainties abnormalities. The reality is not as simple or clear- is important: deficiency may become clinically cut as that. Not only may hypogonadal men be apparent at different points within an individual capable of adequate sexual erections but hormonal or a population, depending on the marker used supplementation resulting in normal testosterone (e.g. androgen levels, bone mineral density).
values does not always result in restoration of libido and improvement in the quality of erectile ADAM or the andropause is a syndrome characterized In men at risk, or suspected of having hypo- gonadism, the ideal test would be the measurement (1) The easily recognized features of diminished sexual of free testosterone by the equilibrium dialysis desire and erectile quality, particularly nocturnal method. This method, however, is difficult to perform, not automated and largely inaccessible to most clinicians. Measurement of ‘free testoster- (2) Changes in mood with concomitant decreases one’ by radioimmunoassay is widely available but in intellectual activity, spatial orientation ability, should be discouraged due to its unreliability.
fatigue, depressed mood and irritability9; Determination of bioavailable testosterone is (3) Decrease in lean body mass with associated attainable in some parts of the world but it is diminution in muscle volume and strength10,11; expensive and not readily accessible. Measurement of total testosterone is readily available but the (4) Decrease in body hair and skin alterations12; results need to be interpreted with caution, (5) Decreased bone mineral density resulting in particularly in the elderly and the obese in factual hypogonadism that is not disclosed by the results of a total testosterone determination.
Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen The calculated free testosterone is an adequate DHEA and DHEA-S
compromise when only determinations of total testosterone and SHBG are available7. The formula for calculated free testosterone is avail- DHEA-S is a more constant feature of advancing able from the Society’s web page. Calculated free age than hypogonadism. By the fifth decade, the testosterone is an indirect but reliable method.
levels of DHEA decrease to less than 30% of those ‘The evaluation of aged men’s androgenicity in men under the age of 30 years19. There is a should rely on at least one of these assessments’ widespread belief that declining levels of DHEA (bioavailable testosterone or calculated free run in parallel with a decrease in well-being and that supplemental exogenous DHEA results in an It should be remembered, however, that the improvement in quality-of-life parameters20. More methodology for assessment of SHBG is not recently, a study in healthy aging men found no standardized and that the results of calculated free beneficial effect of DHEA over placebo21.
testosterone may vary among different areas of the secreted primarily by the adrenal glands. Their role in the maintenance of an adequate androgen milieu is not known with certainty but appears to be In patients at risk or suspected of hypogonadism the limited. Limited trials22 have shown that exo- following biochemical investigations should be done: genous DHEA does not have a detrimental effect (1) Serum sample for testosterone determination on prostate-specific antigen (PSA) values; how- between 08.00 and 11.00. The most reliable and ever, only properly controlled long-term studies widely acceptable parameter to establish the presence will provide a clear picture on the effectiveness of hypogonadism is the measurement of bioavailable and safety of adrenal androgens in the treatment testosterone or, alternatively a calculated free testos- of global androgen deficiency states. Behavioral correlates of DHEA and DHEA-S in the male are inconsistent23 and consensus on their usefulness (2) If testosterone levels are below or at the lower limit of the accepted normal values, it is prudent to confirm the results with a second determination together with assessment of follicle stimulating hormone (FSH), Growth hormone
luteinizing hormone (LH) and prolactin. The production of growth hormone (GH), after puberty, also decreases with age, about 14% per decade25,26. Since the production of circulating OTHER ENDOCRINOLOGICAL
insulin-like growth factor-I (IGF-I) is controlled ALTERATIONS ASSOCIATED WITH
by GH levels, both decline together. This reduc- ADVANCING AGE
tion is associated with changes in lean muscle mass, bone density, hair distribution and the pattern of It is important to dispel the concept that endo- obesity also described in hypogonadal states27,28.
crinopathies of elderly men are narrowly focused Administration of GH can reverse these altera- on testosterone. Although hypotestosteronemia is tions29 and does so more efficiently in eugonadal the most widely recognized and investigated men than in their hypogonadal counterparts30.
hormonal alteration associated with the aging Whether the possible clinical improvement after process, the production of several other hormones GH administration will be outweighed by undesir- is also profoundly affected by age. Increasing atten- able side-effects and whether the improvements tion is being paid to these hormones because would be sufficient to justify the financial burden, changes in their levels can be responsible for deserve further inquiry. The same applies to the use some of the manifestations previously attributed of the newer, orally active GH-releasing peptides exclusively to testosterone deficiency.
and related non-peptide secretagogues.
Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen Melatonin
contrast, leptin, a relatively recently described Melatonin secretion by the pineal gland in hormone from adipocytes, is altered in hypo- response to hypoglycemia and darkness also gonadism which explains, in part, some the decreases with age regardless of these stimuli31. The changes in fat distribution observed in these men38.
physiological role of the pineal gland is not com- Levels of leptin can be brought down by androgen pletely understood but it is involved in gonadal supplementation39 that usually results in a decrease function and regulation of biorhythms32. Other physiological effects ranging from analgesic and The following recommendation is put forward antioxidative33 to immunomodulating34 properties regarding other endocrine alterations associated have been attributed to melatonin. Olcese presented evidence indicating that administration of melatonin slows the growth of cancer cells in It is recognized that significant alterations in other rodents35. However, the large popular enthusiasm endocrine systems occur in association with aging but around the hormone has a precarious scientific the significance of these changes is not well understood. basis. It is likely that administration of melatonin In general terms, determinations of DHEA, DHEA-S, may improve the significant sleep disorders melatonin, GH and IGF-I are not indicated in the frequently seen in the elderly. As mentioned uncomplicated evaluation of ADAM. Under special before, profound hypogonadism is associated circumstances, or for well-defined clinical research, with alterations in melatonin production11, assessment of these and other hormones may be therefore making difficult the attribution of some symptoms (sleep disturbances) exclusively to deficits of one or the other hormone. Evidence is emerging of a wide range of direct and indirect TREATMENT
activities of melatonin on many human organ Indications
It is common clinical wisdom that a firm diagnosis Thyroxin
is desirable prior to embarking on any therapeutic plan. This also applies to the treatment of the With aging, there is an increase in serum thyroid hypogonadal man. The goals of treatment most stimulating hormone (TSH) levels and a decrease commonly include the restoration of sexual func- in thyroxin, although TSH levels in the elderly tioning as well as libido and sense of well-being.
who have hypothyroidism are lower than in Equally important, androgen replacement can younger patients with the same disease. Hypo- prevent or improve already established osteo- thyroidism should be suspected if there are occur- porosis and optimize bone density, restore rences of unexplained high levels of cholesterol muscle strength and improve mental acuity and and creatinine phosphokinase, severe constipation, normalize GH levels, especially in elderly congestive heart failure with cardiomyopathy and males32,41. Testosterone replacement therapy unexplained macrocytic anemia. In the elderly should maintain not only physiological levels of there may be overt and subclinical thyroid serum testosterone but also the metabolites of deficiency. The diagnosis may not be clinically testosterone including estradiol, to optimize evident, and only an index of suspicion supported maintenance of bone and muscle mass, libido, by biochemical evidence confirms the diagnosis.
virilization and sexual function. Since some of the Symptoms of hypothyroidism may mask those of manifestations of ADAM are shared with other conditions independent of a man’s androgenic status, appropriate biochemical confirmation of The production of corticosteroids and estradiol in This recommendation is considered mandatory males, remains fairly constant throughout life. In Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen of testosterone production by the testes. This is A clear indication (a clinical picture together with bio- accomplished best by the transdermal preparations, chemical support) should exist prior to initiation of although oral testosterone may also approximate a circadian rhythm by dose adjustments. The relevance of reproducing a circadian rythmicity during ART remains unknown. Common testos- terone preparations and their recommended doses As mentioned previously, aging of the pituitary– gonadal axis is progressive. Hence, age more likely correlates with the severity of the bio- chemical changes and clinical manifestations.
These aging men, however, because of associated infirmities and other socioeconomic reasons, are Oral androgen preparations have become popular less likely to be considered for treatment.
because of their convenience aspects (such as dose Therefore, the following recommendation applies: flexibility, possibility of immediate discontinua- tion, self-administration). However, they demand special consideration because they undergo rapid In the absence of defined contraindications, age is not hepatic and intestinal metabolism. Therefore, a limiting factor to initiate ART in aged men with special precautions may be necessary in order to achieve adequate serum androgen levels.
An oral preparation that is widely used through- Preparations
out the world (and which is currently in clinical Current, generally available treatment options undecanoate. As the only effective and safe oral include buccal and oral tablets and capsules, intra- testosterone ester, it circumvents the first passage muscular preparations, both long- and short- through the liver, it is free of liver toxicity and acting, implantable long-acting slow-release pellets brings serum testosterone levels within the and transdermal scrotal and non-scrotal patches physiological range. It is liposoluble and for and gels. Neither injectable preparations nor this reason it must be taken with meals. Studies slow-release pellets reproduce the circadian pattern have shown that oral testosterone undecanoate Table 1 Most frequently used testosterone preparations
*17α-alkylated testosterone preparations fluoxymesterone and methyltestosterone are both associated with serious liver Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen improves libido, erectile function and general The most widely used parenteral preparations well-being, increases bone mineral density and are the 17β-hydroxyl esters of testosterone which include the short-acting propionate and In order to prevent the rapid metabolic break- the longer-acting enanthate and cypionate. The down in the liver, some oral agents available in propionate is rarely used because its short half- some countries (particularly in the USA) are life requires administration every other day. The chemically modified. These alkylated androgens enanthate and cypionate esters of testosterone, on generally provide erratic androgenic activity and the other hand, can be administered at the dose of exhibit a potential for significant liver toxicity 200–400 mg every 10–21 days to maintain normal which includes hepatocellular adenomas and average testosterone levels46. Higher doses will not carcinomas, cholestatic jaundice and hemorrhagic maintain testosterone levels in the normal range beyond the 3-week limit. Another option is a Finally, the oral dihydrotestosterone (DHT) preparation containing a mixture of four test- derivative mesterolone is available in some osterone esters (propionate, phenylpropionate, countries. The compound is not aromatizable and isocaproate and decanoate), each with a different cannot therefore be biotransformed into estradiol.
elimination half-life, which is claimed to prolong As a consequence, it only exerts a partial andro- genic effect, making it a suboptimal treatment Appropriate treatment of hypogonadism with injectable esters of testosterone has been shown to None of the oral medications results in a improve libido, sexual function, energy levels, faithful reflection of the circadian level variations.
mood and bone density if they are caused by an androgen deficiency47. Persistent supraphysio- and amount of the dosing may ameliorate this logical levels of serum testosterone may result in infertility due to suppression of LH and FSH production48. Although concern exists about the psychosexual effects of markedly elevated levels of testosterone in serum, evidence has been presented Injectable esters of testosterone have been available indicating that, even in eugonadal men, amounts for the longest time and their effects are well recog- up to five times the physiological replacement nized. They are inexpensive and safe but their use doses of testosterone cypionate have only minimal carries several major drawbacks which include: (1) The need for periodic (every 2–3 weeks) deep (2) Wide swings in serum levels, initially (in Transdermal testosterone therapy (TTT) offers about 72 h), result in supraphysiological levels a close reflection on the variable levels in test- of serum testosterone followed by a steady osterone production manifested in normal men decline over the next 10–14 days45.
over the 24-h circadian cycle. TTT is available in (3) The steady decline frequently results in a very both scrotal and non-scrotal patches and in a gel low nadir immediately before the next injec- form. The scrotal TTT lost its appeal due to incon- veniences such as the inability to remain in place swings in mood and well-being – the roller- and the need for frequent shaving of the scrotal coaster effect – which is disconcerting and skin. In addition, due to the high concentrations upsetting to both patients and their partners.
of 5α-reductase in the scrotal skin, they produce abnormally high levels of DHT50. Transdermal (4) Parenteral androgens do not provide the non-scrotal patches produce normal levels of normal circadian patterns of serum testoster- estradiol but, as opposed to the scrotal ones, result one and the intermittent supraphysiological in normal levels of DHT51. In addition, to pro- ducing physiologically appropriate serum levels of testosterone, they lower levels of SHBG, promote virilization and increase bone mineral density52.
Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen Also, the testosterone patches, as compared to injectable forms, minimize excessive erythro- Liver function studies are advisable prior to onset of poiesis and suppression of gonadotropins53. Most therapy, quarterly during the first year and on a yearly common side-effects of the body patches are basis thereafter during treatment. related to the need to use enhancers to facilitate absorption; this frequently results in various degrees of skin reactions, occasionally reaching Lipid and cardiovascular safety
significant chemical burns. This may be prevented The relationship between hypogonadism and with the use of triamcinolone. The testosterone gel alterations of the lipid profile remains to be com- offers all the advantages of the patches54, without pletely resolved. Evidence is emerging supporting the frequent skin reactions. Its only drawbacks the concept that hypogonadism is associated with reside in the potential for contamination of others potentially unfavorable changes in triglycerides and the lack of long-term studies with its use. The and high-density lipoprotein cholesterol and that efficacy of transdermal DHT therapy has been such abnormalities can be corrected by restoring a physiological androgen milieu57. Other studies support the view that low testosterone is a signifi- therapy, the following two recommendations are cant risk factor for coronary artery disease58–60.
Although most recent evidence continues to support the concept of a beneficial effect of Currently available preparations of testosterone (with the androgens in coronary artery disease61, the rela- exception of the alkylated ones) are safe and effective. The tionships between androgens and cardiovascular treating physician should have sufficient knowledge and risk factors are complex and still understood only adequate understanding of the advantages and drawbacks imperfectly. Similarly, the relationships between androgen levels in the serum and other lipoprotein sub-fractions have not been fully investigated62.
Therefore, caution is advisable when supplement- The purpose of ART is to bring and maintain serum ing androgens in men with significant risk factors testosterone levels within the physiological range. Supra- for cardiovascular disease. The picture is further physiological levels are to be avoided. blurred by the fluid retention associated with androgen administration; this may add to any possible adverse effect of androgen therapy to the ADVERSE EFFECTS
Like most medications, androgens have a potential for undesirable side-effects. These concerns are, primarily in regard to the liver, the prostate, lipid profile and cardiovascular system, hematological A fasting lipid profile prior to initiation of treatment changes, sleep patterns and social behavior and and at regular intervals (no longer than 1 year) during Prostate safety
Reports of liver toxicity manifested by jaundice It is well established that, in the absence of suffi- and alteration of liver function, as well as the cient androgens the prostate gland fails to develop.
development of hepatic tumors, have been limited Most studies, however, have shown no significant almost exclusively to cases in which the alkylated increases in PSA or prostate volume following forms of testosterone have been used. Invariably, administration of androgens to hypogonadal inserts of commercial preparations mention the men63. Evidence from placebo-controlled studies potential for liver toxicity. Therefore, regardless of of men receiving androgen supplementation the form of ART employed, this recommendation indicate that the differences between the men on hormones and those on placebo were insignificant Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen in regard to prostate volume, PSA or obstructive obstruction has been successfully treated, these men are symptoms64,65. Although testosterone has not been candidates for androgen supplementation. implicated in the development of benign prostate hypertrophy (BPH), nevertheless, in the presence of severe lower urinary tract obstructive symptoms Mood and behavior
(LUTOS), the administration of testosterone may The consequences of testosterone deficiency result in the development of urinary retention.
in mood regulation are widely accepted69,70 to Whether testosterone promotes the development the point that, recently, a hypothesis has been of prostate cancer remains to be elucidated.
advanced suggesting that perinatal androgen Current evidence indicates that serum levels of deficiency promotes deficient cognitive develop- sex hormones bear no relation to the development ment71. However, concerns exist regarding the of prostate cancer and there is either no promotion of sexually aggressive behavior change or only a modest increase in PSA levels following testosterone administration. Significant after testosterone administration66. The suspicion behavioral changes can be observed with supra- of prostate cancer is, however, an absolute contra- physiological levels of androgens. Proper treatment, indication for androgen therapy. On the other aimed at maintenance of physiological plasma hand, prostatic biopsies prior to onset of ART levels, makes this a rare occurrence and certainly in the absence of an abnormal digital rectal not a sufficient cause to withhold treatment72.
indicated. However, a rapid increase in PSA or the appearance of abnormalities in the DRE are ART normally results in improvements in mood clear indications for a thorough evaluation of the and well-being. The development of negative behavioral prostate to rule out the presence of carcinoma. In patterns during treatment calls for dose modifications or this situation the administration of testosterone may have served as an early warning to the presence of an occult prostatic malignancy67.
The issue of prostate safety and exogenous Hematology
androgens is, perhaps, the gravest concern. The The stimulatory effect of testosterone administra- topic was recently reviewed68. The following three tion on bone marrow has long been recognized separate recommendations were considered and even in the presence of advanced malignant disease73. Testosterone therapy in older men often can result in a significant increase in red blood cell Digital rectal examination (DRE) and determination of mass and hemoglobin levels74. In younger, serum prostate-specific antigen (PSA) are mandatory in healthier individuals, such as those receiving men over the age of 40 years as baseline measurements of androgens for sexual dysfunction, the effects can prostate health prior to therapy with androgens, at quar- also be marked75. Therefore, dose adjustments or terly intervals for the first 12 months and yearly thereaf- phlebotomies may be necessary. Rarely, ART has ter. Transrectal ultrasound-guided biopsies of the prostate to be discontinued due to polycythemia.
are indicated only if the DRE or the PSA are abnormal. Polycythemia occasionally develops during ART. Androgen administration is absolutely contraindicated in Periodic hematological assessment is indicated. Dose men suspected of having carcinoma of the prostate or breast Sleep apnea
Androgen supplementation is contraindicated in men Other possible effects of testosterone treatment with severe bladder outlet obstruction due to an enlarged, include exacerbation of sleep apnea76 although clinically benign prostate. Moderate obstruction represents hypotestosteronemia has been cited as a cause of a partial contraindication to ART. Once the urinary Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen CONCLUSIONS
There is insufficient evidence for a recommendation regarding safety of ART in men with sleep apnea. It is There is clear evidence that advancing age is suggested, therefore, that good clinical judgement and associated with a decline in the production of caution be employed in this situation. several hormones. The most prominent alterations are related to the sex steroids but other hormones MONITORING PATIENTS ON ART
also profoundly affected. The clinical syndrome of Hormonal replacement may be initiated for a ADAM or andropause has been described but a variety of indications but treatment is normally for direct causality between its manifestations and the life. Monitoring of these patients is also a lifetime alterations in a specific hormone are not yet fully commitment that cannot be taken lightly.
established. There is, however, a growing body Monitoring, of course requires to be tailored to the of literature supporting the concept of a clinical indications and the individual needs of the patient.
picture associated with hypogonadism in aging For instance, if the indication is osteoporosis, men that impacts significantly on the quality of life.
serial bone mineral density determinations are the Equally, there is sufficient evidence to support the method for monitoring therapeutic response. In concept that appropriate treatment of these men this regard, the studies by Behre and colleagues78 results in alleviation of some of the manifestations provide an elegant and graphic illustration on the of the andropause. It behoves a variety of medical effectiveness of chronic testosterone supplemen- specialties to be familiar with the consequences tation in increasing bone mineral density and in of this condition, its investigation, treatment and moving older men out of the range of high fracture risk. Another common indication for testosterone Our understanding of ADAM is still incomplete administration is for treatment of sexual dysfunc- and there exist a number of controversial issues in tion. In this situation, a simple and effective rule regard to hormonal replacement in elderly men.
of monitoring is that, frequently, the patient’s Standards or guidelines on the subject are, there- report is the most reliable indicator of treatment fore, premature. Recommendations, however, are effectiveness59. In addition to the specific areas of justified with the present state of knowledge.
interest, long-term monitoring of these patients Recommendations79 and guidelines80–82 in the centers on six domains in which concerns have area of ART require frequent updates as further existed for possible serious adverse events: the liver, information emerges. We provide this set of lipid profile and cardiovascular disease, erytho- Recommendations for physicians interested in the poiesis, the prostate, sleep disorders and social diagnosis and treatment of aging men with symptoms of hypogonadism. Recommendations, guidelines and standards are, normally, work in progress. They will be discussed again at the Monitoring during ART is a shared responsibility. The biannual meeting of ISSAM in Prague, February physician must emphasize to the patient the need for periodic evaluations and the patient must agree to comply with these requirements. Since ART is normally for life, monitoring is also a lifetime mutual duty. References
1. Morales A, Lunenfeld B. Androgen replacement 3. Werner AA. The male climacteric. J Am Med Assoc therapy in aging men with secondary hypogonad- ism. Draft recommendations for endorsement by 4. Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for androgen defi- 2. Kaufman JM. Hypothalamic–pituitary–gonadal ciency in aging males. Metabolism 2000;49:1239 funtion in aging men. Aging Male 1999;2:157 Z:\Customer\PARTHEN\AGE-M\A4339 Age Male Vol 5 No 2.vp Color profile: Generic CMYK printer profileComposite Default screen 5. Heinemann LAJ, Saad F, Thiele K, Wood- 19. Herbert J. The age of dehydroepiandrosterone.
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20. Morales AJ, Nolan JJ, Nelson JC, et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol hypothalamo–pituitary–testicular axis in men.
21. Arlt W, Callies F, Koehler L, et al. Dehydroepi- 7. Vermeulen A, Verdonck L, Kaufman JL. A critical androsterone supplementation in healthy men with evaluation of simple methods for the estimation of an age related decline of dehydroepiandrosterone free hormones in serum. J Clin Endocrinol Metab secretion. J Clin Endocrinol Metab 2001;86:4686 22. Vaughn ED, Cox DS. Chronic administration 8. Morales A, Heaton JPW. Hormonal erectile of dehydroepiandrosterone (DHEA) does not dysfunction: evaluation and management. Urol Clin increase serum testosterone or prostatic specific antigen (PSA) in normal men. J Urol 1998;159: Davidson T, McDonald V, Steiner B, et al.
23. Christiansen KH. Behavioral correlates of Androgen behavior correlations in hypogonadal dehydroepiandrosterone and dehydroepiandro- and eugonadal men: cognitive abilities. Horm Behav sterone sulfate. Aging Male 1998;1:103–12 24. Weksler ME. Hormone replacement for men – not enough evidence to recommend routine treatment with dehydroepiandrosterone. Br Med J 1996;312: Testosterone administration to elderly men increases skeletal muscle strength and protein 25. deBoer H, Block GJ, van der Veen EA. Clinical synthesis. Am J Physiol 1995;269:820 aspects of growth hormone deficiency in adults.
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