- Email: [email protected]
The metabolic syndrome: when is testosterone treatment warranted
Original article
The metabolic syndrome: when is testosterone treatment warranted Keywords Testosterone
Louis Gooren, MD, PhD Endocrinology, Vrije Universiteit medical center, Amsterdam, the Netherlands Siegfried Meryn, MD Institute for Medical Education, University of Vienna, Vienna, Austria Ridwan Shabsigh, MD Division of Urology, Maimonides Medical Center, Columbia University, Brooklyn, NY, USA E-mail: [email protected]
Online 4 June 2008
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Louis Gooren, Siegfried Meryn and Ridwan Shabsigh Abstract With aging a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men [1,2]. This contribution focuses on the relevance of declining serum testosterone levels to the metabolic syndrome. Four studies have found that a low testosterone level is a predictor of mortality in elderly men [3–6], but another study did not confirm this [7]. While disagreeing on the relationship between plasma testosterone and over-all mortality the latter study demonstrated that a low testosterone level was predictive of mortality from ischemic heart disease and respiratory disease and that research into this relationship may be warranted. It would seem that a low testosterone level is a marker, an indicator of disease, and it is plausible that disease predicts mortality. Obviously, epidemiological studies cannot unravel causerelationships but the evidence is convincing that the decline in testosterone levels with aging is accounted for rather by (age-related) disease than the calendar age of men. Intervention studies provide potential answers to the causality of the relationship. Numerous studies have found associations between features of the metabolic syndrome and plasma testosterone [8 –13]. So, while it is clear that disease, and in the context of this contribution, in particular the metabolic syndrome can suppress circulating testosterone levels, it has also been documented that low testosterone levels induce the metabolic syndrome [14,15], dramatically demonstrated by findings in men with prostate cancer who undergo androgen ablation therapy [16,17]. A recent study showed convincingly that acute androgen deprivation reduces insulin sensitivity in young men [18]. Very well documented is that androgen deprivation leads to osteoporosis and increases bone fractures [19]. So, it is evident that low testosterone levels are a factor in the etiology of common ailments of elderly men such as the metabolic syndrome and osteoporosis. The question arises then whether testosterone treatment has role to play in the treatment of the metabolic syndrome and its sequels such as diabetes mellitus type 2 and cardiovascular disease. There is increasing evidence of a beneficial effect of testosterone treatment on visceral fat and other elements of the metabolic syndrome [20–22]. Evidently, the justification for testosterone treatment lies in a proper diagnosis of testosterone deficiency. It has to be kept in mind that changes in lifestyle (diet / exercise) might partially prevent or redress the metabolic syndrome and its associated decline of androgen levels with aging [23–25] and therefore should be part of the treatment strategy. ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
With aging a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men [1,2]. This contribution focuses on the relevance of declining serum testosterone levels to the metabolic syndrome.
Vol. 5S, pp. S40–S45, September 2008
Four studies have found that a low testosterone level is a predictor of mortality in elderly men [3–6], but another study did not confirm this [7]. While disagreeing on the relationship between plasma testosterone and over-all mortality the latter study demonstrated that a low testosterone level was predictive of
ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
Original article mortality from ischemic heart disease and respiratory disease and that research into this relationship may be warranted. It would seem that a low testosterone level is a marker, an indicator of disease, and it is plausible that disease predicts mortality. Obviously, epidemiological studies cannot unravel cause-relationships but the evidence is convincing that the decline in testosterone levels with aging is accounted for rather by (age-related) disease than the calendar age of men. Intervention studies provide potential answers to the causality of the relationship. Numerous studies have found associations between features of the metabolic syndrome and plasma testosterone [8–13]. So, while it is clear that disease, and in the context of this contribution, in particular the metabolic syndrome can suppress circulating testosterone levels, it has also been documented that low testosterone levels induce the metabolic syndrome [14,15], dramatically demonstrated by findings in men with prostate cancer who undergo androgen ablation therapy [16,17]. A recent study showed convincingly that acute androgen deprivation reduces insulin sensitivity in young men [18]. Very well documented is that androgen deprivation leads to osteoporosis and increases bone fractures [19]. So, it is evident that low testosterone levels are a factor in the etiology of common ailments of elderly men such as the metabolic syndrome and osteoporosis. The question arises then whether testosterone treatment has role to play in the treatment of the metabolic syndrome and its sequels such as diabetes mellitus type 2 and cardiovascular disease. There is increasing evidence of a beneficial effect of testosterone treatment on visceral fat and other elements of the metabolic syndrome [20–22]. Evidently, the justification for testosterone treatment lies in a proper diagnosis of testosterone deficiency. It has to be kept in mind that changes in lifestyle (diet / exercise) might partially prevent or redress the metabolic syndrome and its associated decline of androgen levels with aging [23–25] and therefore should be part of the treatment strategy.
Diagnosing testosterone deficiency A diagnosis of androgen deficiency should be based on consistent symptoms and signs and
unequivocally low serum testosterone levels. It is recommended to measure morning total testosterone level by a reliable assay as the initial diagnostic test. The use of accurate assays is pivotal for a proper diagnosis. Particularly in elderly men the result may often be ambiguous and provide no clear-cut outcome confirmation of the diagnosis of testosterone deficiency. Then, repeating the measurement of morning total testosterone is recommended, in some patients complemented by measurement of the free or bioavailable testosterone level, particularly if there are reasons to believe plasma levels of sex hormone-binding globulin may be abnormal (thyroid disease, liver disease, obesity). Testosterone therapy should be reserved, first of all, for men with symptoms of androgen deficiency, who have indeed low testosterone levels. Professional organizations have formulated guidelines / recommendations for the administration of testosterone to elderly men. One set of guidelines has been adopted by the International Society of Andrology, the International Society for the Study of the Aging Male and the European Association of Urology [26,27]. The other one has been proposed by a task force of the Endocrine Society [28]. One set of guidelines defines the reference values of testosterone as follows: Normal: total testosterone >12 nmol/l (346 ng/dl) and free testosterone >250 pmol/l (72 pg/ ml). Treatment may be considered if there are symptoms and the value of total testosterone is 8–12 nmol/l (231–346 ng/dl). A value of total testosterone <8 nmol/l (231 ng/dl) and free T <180 pmol/l (52 pg/ml) is an indication for treatment [26,27]. The guidelines of the Endocrine Society specify that there is as yet no consensus what constitutes low testosterone values but regards as low a value of total <6.9–10.4 nmol/l (200–300 ng/dl) and of free testosterone < 0.17 nmol/l (50 pg/ml [28]. According to the guidelines, when testosterone therapy is instituted, achieved testosterone levels during treatment should be in the mid-normal range [28,29]. The formulation of testosterone should be chosen on the basis of the patient’s preference, consideration of pharmacokinetics, treatment burden, and cost [28]. Men receiving testosterone therapy should be monitored using a standardized plan, detailed in the above guidelines.
Vol. 5S, pp. S40–S45, September 2008
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Original article The intricacies of androgen action As indicated above the guidelines of the Endocrine Society specify that there is as yet no consensus what constitutes low testosterone values and it may turn out to be impossible to define precise values of normal/abnormal due to inherent properties of the biological action of testosterone on the organism. Testosterone exerts most of its actions via testosterone receptors leading to gene transcription though some effects are non-genomic membrane effects. Complete or partial dysfunctions of the androgen receptor are associated with clinical syndromes, such as the androgen insensitivity syndrome or the Reifenstein syndrome. The gene for the androgen receptor is located on the X-chromosome. In exon 1 there is a variable number of CAG triplet repeats. The higher the number of CAG repeats, the lower the transcriptional activity of the androgen receptor [30–32]. The issue of CAG repeats and its clinical implications has been authoritatively reviewed [33] and, indeed, the literature provides evidence that the biological effects of androgen are modified by the number of CAG repeats of the androgen receptor. Men with lower numbers of CAG repeats are more predisposed to develop prostate cancer [34]. In the presence of normal plasma testosterone levels the effects of testosterone (hairiness, prostate volume) are more pronounced with lower numbers of CAG repeats [35]. While prostate volumes in the hypogonadal state are not strongly affected by the number of CAG repeats, the increase in prostate volume upon testosterone administration to hypogonadal men is inversely correlated with the number of CAG repeats [36]. These findings have potential implications for interpretation of epidemiological studies, diagnosis of hypogonadism in borderline situations, and possibly individualization of androgen therapies in men [37].
Individual thresholds for androgen action Blood testosterone thresholds for androgen deficiency symptoms are highly consistent within a person but differ between men [38]. Hypogonadal men who receive androgen
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treatment perceive the threshold for androgen deficiency symptoms at individually highly reproducible blood testosterone levels. This distinctively individual trigger level for androgen deficiency symptoms differs widely between men. The threshold varies from very low to values above the lower limit of the eugonadal reference range. On average it approximates the lower limit of the eugonadal reference range for young men [38]. The factors which define this symptomatic threshold are as yet unknown but, as indicated above, it is reasonable to assume that genetic polymorphisms of the androgen receptors influencing androgen sensitivity play a significant role [33,39]. The impact of the aging process and acquired chronic disease with aging on the threshold for androgen deficiency symptoms is presently uncharted territory [38].
Symptoms of androgen deficiency and testosterone levels In another study of elderly men it appeared also that, overall, complaints of testosterone deficiency cannot be related to a specific threshold of testosterone concentrations, but that thresholds vary with the various symptoms of testosterone deficiency [40]. In a cohort of men androgen-related loss of libido or vigor became more prevalent when testosterone concentrations fell below 15 nmol/l, while depression and diabetes mellitus type 2 (also in non-obese men) were significantly more present in men with testosterone concentrations below 10 nmol/l. In this study erectile dysfunction was identified as a composite pathology of metabolic risk factors, smoking, and depression, and only testosterone concentrations below 8 nmol/l contributed to that symptom. Symptoms related to androgen deficiency in this study could be subdivided in three independent groups: psychosomatic complaints, metabolic disorders, and sexual health problems. Patients suffering from one of these three groups exhibit distinct features in terms of androgen levels, age, and body mass index. So, complaints are not only linked to androgen levels, but age and body mass index carried weight as well in the manifestation of signs and symptoms of androgen deficiency [40].
Original article When is an aging man hypogonadal indication for testosterone treatment. The presenting symptom of hypogonadism in a man and qualifies for testosterone may or may not be unambiguously related to treatment? The above studies demonstrate that there is no clear dividing line in normal and subnormal blood testosterone levels defining whether a man is hypogonadal or not. Rather, symptoms accumulate gradually with decreasing testosterone levels, with the levels of testosterone differing between individuals and within a subject not all symptoms of testosterone deficiency will manifest themselves at the same blood testosterone levels. The diagnosis of late onset hypogonadism (LOH) and, certainly, the decision to provide androgen treatment must be made with caution, taking the specific increment of symptom prevalence in relation to testosterone levels into account. The various symptoms of LOH might start at various concentrations of androgens. With a given plasma testosterone level, some complaints might be present and others not. This has also been confirmed in other studies establishing symptomspecific thresholds of androgen levels [2,41]. As argued above, diagnosis and the decision to treat are complicated by the fact that symptoms of LOH do not manifest themselves at uniform threshold values of testosterone [1,27,42]. It therefore comes as no surprise that there is a significant variation among clinics and European countries in their application of threshold values of testosterone signifying hypogonadism which range from 7.5 to 12.0 nmol/l [43]. Almost certainly a factor in this observation is that physicians in different countries will have different concepts of what constitutes the core symptoms of hypogonadism. On the basis of the above observations it is clear that the symptoms of testosterone deficiency are not uniformly and predictably related to values of blood testosterone, which may lead to different diagnostic criteria for testosterone deficiency. So, the conclusion seems inevitable that the clinical manifestations of hypogonadism are multifactorially determined and that the diagnosis should not only depend on the measurement of testosterone but proper assessment should comprise somatic and psychological aspects in addition to measurement of testosterone [44]. The above being the case, it is virtually impossible to take a blood testosterone value as an
that testosterone value, though the lower the value of blood testosterone, the greater the likelihood. A decision to provide androgen treatment must not only be guided by the levels of blood testosterone but more the likelihood that symptoms are related to those particular testosterone levels, based on clinical judgment. The decision to treat will have an element of arbitrariness unless testosterone levels are truly low (<6 nmol/l)(certainly treat) or truly in the normal range (>15 nmol/l)(certainly not). A case can be made for a therapeutic trial of testosterone if the interpretation of clinical and laboratory data provide an ambiguous outcome [45].
Conclusion In conclusion, physicians have to be aware that testosterone plays a significant, but not an alldecisive role in older male patients and that replacement options should be based firstly on symptoms and secondly on hormone concentrations, which should be evaluated on a symptom-specific basis. Physicians treating elderly men should have expertise in the signs and symptoms of testosterone deficiency which have a broad spectrum of psychological, metabolic and sexual symptoms. Naturally, testosterone cannot be expected to be a panacea of all the mental and somatic problems men encounter in the process of aging and indiscriminate use within men who present with vague symptoms will have many failures to remedy complaints of aging men. Individual and symptom-oriented testosterone treatment might be warranted in the future if this assumption of variations in hormone-symptom-relationships has been further elaborated and corroborated in clinical studies.
Conflict of interest Professor Gooren declares there are no competing interests with regard to the contents of the manuscript, and no funding received. Professor Meryn has served as speaker for BSP symposia, otherwise no conflict of interest or
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Original article funding source to report. Doctor Shabsigh has acted as consultant or advisor for Indevus Pharmaceuticals, Pfizer, Bayer Schering Pharma, American Medical Systems, Auxilium,
Johnson & Johnson, Lilly, Boehringer Ingelheim; as Investigator for Auxilium, Plethora; and as Meeting Participant or Lecturer for Lilly; no funding source to report.
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The metabolic syndrome: when is testosterone treatment warranted Keywords Testosterone
Louis Gooren, MD, PhD Endocrinology, Vrije Universiteit medical center, Amsterdam, the Netherlands Siegfried Meryn, MD Institute for Medical Education, University of Vienna, Vienna, Austria Ridwan Shabsigh, MD Division of Urology, Maimonides Medical Center, Columbia University, Brooklyn, NY, USA E-mail: [email protected]
Online 4 June 2008
S40
Louis Gooren, Siegfried Meryn and Ridwan Shabsigh Abstract With aging a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men [1,2]. This contribution focuses on the relevance of declining serum testosterone levels to the metabolic syndrome. Four studies have found that a low testosterone level is a predictor of mortality in elderly men [3–6], but another study did not confirm this [7]. While disagreeing on the relationship between plasma testosterone and over-all mortality the latter study demonstrated that a low testosterone level was predictive of mortality from ischemic heart disease and respiratory disease and that research into this relationship may be warranted. It would seem that a low testosterone level is a marker, an indicator of disease, and it is plausible that disease predicts mortality. Obviously, epidemiological studies cannot unravel causerelationships but the evidence is convincing that the decline in testosterone levels with aging is accounted for rather by (age-related) disease than the calendar age of men. Intervention studies provide potential answers to the causality of the relationship. Numerous studies have found associations between features of the metabolic syndrome and plasma testosterone [8 –13]. So, while it is clear that disease, and in the context of this contribution, in particular the metabolic syndrome can suppress circulating testosterone levels, it has also been documented that low testosterone levels induce the metabolic syndrome [14,15], dramatically demonstrated by findings in men with prostate cancer who undergo androgen ablation therapy [16,17]. A recent study showed convincingly that acute androgen deprivation reduces insulin sensitivity in young men [18]. Very well documented is that androgen deprivation leads to osteoporosis and increases bone fractures [19]. So, it is evident that low testosterone levels are a factor in the etiology of common ailments of elderly men such as the metabolic syndrome and osteoporosis. The question arises then whether testosterone treatment has role to play in the treatment of the metabolic syndrome and its sequels such as diabetes mellitus type 2 and cardiovascular disease. There is increasing evidence of a beneficial effect of testosterone treatment on visceral fat and other elements of the metabolic syndrome [20–22]. Evidently, the justification for testosterone treatment lies in a proper diagnosis of testosterone deficiency. It has to be kept in mind that changes in lifestyle (diet / exercise) might partially prevent or redress the metabolic syndrome and its associated decline of androgen levels with aging [23–25] and therefore should be part of the treatment strategy. ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
With aging a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men [1,2]. This contribution focuses on the relevance of declining serum testosterone levels to the metabolic syndrome.
Vol. 5S, pp. S40–S45, September 2008
Four studies have found that a low testosterone level is a predictor of mortality in elderly men [3–6], but another study did not confirm this [7]. While disagreeing on the relationship between plasma testosterone and over-all mortality the latter study demonstrated that a low testosterone level was predictive of
ß 2008 WPMH GmbH. Published by Elsevier Ireland Ltd.
Original article mortality from ischemic heart disease and respiratory disease and that research into this relationship may be warranted. It would seem that a low testosterone level is a marker, an indicator of disease, and it is plausible that disease predicts mortality. Obviously, epidemiological studies cannot unravel cause-relationships but the evidence is convincing that the decline in testosterone levels with aging is accounted for rather by (age-related) disease than the calendar age of men. Intervention studies provide potential answers to the causality of the relationship. Numerous studies have found associations between features of the metabolic syndrome and plasma testosterone [8–13]. So, while it is clear that disease, and in the context of this contribution, in particular the metabolic syndrome can suppress circulating testosterone levels, it has also been documented that low testosterone levels induce the metabolic syndrome [14,15], dramatically demonstrated by findings in men with prostate cancer who undergo androgen ablation therapy [16,17]. A recent study showed convincingly that acute androgen deprivation reduces insulin sensitivity in young men [18]. Very well documented is that androgen deprivation leads to osteoporosis and increases bone fractures [19]. So, it is evident that low testosterone levels are a factor in the etiology of common ailments of elderly men such as the metabolic syndrome and osteoporosis. The question arises then whether testosterone treatment has role to play in the treatment of the metabolic syndrome and its sequels such as diabetes mellitus type 2 and cardiovascular disease. There is increasing evidence of a beneficial effect of testosterone treatment on visceral fat and other elements of the metabolic syndrome [20–22]. Evidently, the justification for testosterone treatment lies in a proper diagnosis of testosterone deficiency. It has to be kept in mind that changes in lifestyle (diet / exercise) might partially prevent or redress the metabolic syndrome and its associated decline of androgen levels with aging [23–25] and therefore should be part of the treatment strategy.
Diagnosing testosterone deficiency A diagnosis of androgen deficiency should be based on consistent symptoms and signs and
unequivocally low serum testosterone levels. It is recommended to measure morning total testosterone level by a reliable assay as the initial diagnostic test. The use of accurate assays is pivotal for a proper diagnosis. Particularly in elderly men the result may often be ambiguous and provide no clear-cut outcome confirmation of the diagnosis of testosterone deficiency. Then, repeating the measurement of morning total testosterone is recommended, in some patients complemented by measurement of the free or bioavailable testosterone level, particularly if there are reasons to believe plasma levels of sex hormone-binding globulin may be abnormal (thyroid disease, liver disease, obesity). Testosterone therapy should be reserved, first of all, for men with symptoms of androgen deficiency, who have indeed low testosterone levels. Professional organizations have formulated guidelines / recommendations for the administration of testosterone to elderly men. One set of guidelines has been adopted by the International Society of Andrology, the International Society for the Study of the Aging Male and the European Association of Urology [26,27]. The other one has been proposed by a task force of the Endocrine Society [28]. One set of guidelines defines the reference values of testosterone as follows: Normal: total testosterone >12 nmol/l (346 ng/dl) and free testosterone >250 pmol/l (72 pg/ ml). Treatment may be considered if there are symptoms and the value of total testosterone is 8–12 nmol/l (231–346 ng/dl). A value of total testosterone <8 nmol/l (231 ng/dl) and free T <180 pmol/l (52 pg/ml) is an indication for treatment [26,27]. The guidelines of the Endocrine Society specify that there is as yet no consensus what constitutes low testosterone values but regards as low a value of total <6.9–10.4 nmol/l (200–300 ng/dl) and of free testosterone < 0.17 nmol/l (50 pg/ml [28]. According to the guidelines, when testosterone therapy is instituted, achieved testosterone levels during treatment should be in the mid-normal range [28,29]. The formulation of testosterone should be chosen on the basis of the patient’s preference, consideration of pharmacokinetics, treatment burden, and cost [28]. Men receiving testosterone therapy should be monitored using a standardized plan, detailed in the above guidelines.
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Original article The intricacies of androgen action As indicated above the guidelines of the Endocrine Society specify that there is as yet no consensus what constitutes low testosterone values and it may turn out to be impossible to define precise values of normal/abnormal due to inherent properties of the biological action of testosterone on the organism. Testosterone exerts most of its actions via testosterone receptors leading to gene transcription though some effects are non-genomic membrane effects. Complete or partial dysfunctions of the androgen receptor are associated with clinical syndromes, such as the androgen insensitivity syndrome or the Reifenstein syndrome. The gene for the androgen receptor is located on the X-chromosome. In exon 1 there is a variable number of CAG triplet repeats. The higher the number of CAG repeats, the lower the transcriptional activity of the androgen receptor [30–32]. The issue of CAG repeats and its clinical implications has been authoritatively reviewed [33] and, indeed, the literature provides evidence that the biological effects of androgen are modified by the number of CAG repeats of the androgen receptor. Men with lower numbers of CAG repeats are more predisposed to develop prostate cancer [34]. In the presence of normal plasma testosterone levels the effects of testosterone (hairiness, prostate volume) are more pronounced with lower numbers of CAG repeats [35]. While prostate volumes in the hypogonadal state are not strongly affected by the number of CAG repeats, the increase in prostate volume upon testosterone administration to hypogonadal men is inversely correlated with the number of CAG repeats [36]. These findings have potential implications for interpretation of epidemiological studies, diagnosis of hypogonadism in borderline situations, and possibly individualization of androgen therapies in men [37].
Individual thresholds for androgen action Blood testosterone thresholds for androgen deficiency symptoms are highly consistent within a person but differ between men [38]. Hypogonadal men who receive androgen
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treatment perceive the threshold for androgen deficiency symptoms at individually highly reproducible blood testosterone levels. This distinctively individual trigger level for androgen deficiency symptoms differs widely between men. The threshold varies from very low to values above the lower limit of the eugonadal reference range. On average it approximates the lower limit of the eugonadal reference range for young men [38]. The factors which define this symptomatic threshold are as yet unknown but, as indicated above, it is reasonable to assume that genetic polymorphisms of the androgen receptors influencing androgen sensitivity play a significant role [33,39]. The impact of the aging process and acquired chronic disease with aging on the threshold for androgen deficiency symptoms is presently uncharted territory [38].
Symptoms of androgen deficiency and testosterone levels In another study of elderly men it appeared also that, overall, complaints of testosterone deficiency cannot be related to a specific threshold of testosterone concentrations, but that thresholds vary with the various symptoms of testosterone deficiency [40]. In a cohort of men androgen-related loss of libido or vigor became more prevalent when testosterone concentrations fell below 15 nmol/l, while depression and diabetes mellitus type 2 (also in non-obese men) were significantly more present in men with testosterone concentrations below 10 nmol/l. In this study erectile dysfunction was identified as a composite pathology of metabolic risk factors, smoking, and depression, and only testosterone concentrations below 8 nmol/l contributed to that symptom. Symptoms related to androgen deficiency in this study could be subdivided in three independent groups: psychosomatic complaints, metabolic disorders, and sexual health problems. Patients suffering from one of these three groups exhibit distinct features in terms of androgen levels, age, and body mass index. So, complaints are not only linked to androgen levels, but age and body mass index carried weight as well in the manifestation of signs and symptoms of androgen deficiency [40].
Original article When is an aging man hypogonadal indication for testosterone treatment. The presenting symptom of hypogonadism in a man and qualifies for testosterone may or may not be unambiguously related to treatment? The above studies demonstrate that there is no clear dividing line in normal and subnormal blood testosterone levels defining whether a man is hypogonadal or not. Rather, symptoms accumulate gradually with decreasing testosterone levels, with the levels of testosterone differing between individuals and within a subject not all symptoms of testosterone deficiency will manifest themselves at the same blood testosterone levels. The diagnosis of late onset hypogonadism (LOH) and, certainly, the decision to provide androgen treatment must be made with caution, taking the specific increment of symptom prevalence in relation to testosterone levels into account. The various symptoms of LOH might start at various concentrations of androgens. With a given plasma testosterone level, some complaints might be present and others not. This has also been confirmed in other studies establishing symptomspecific thresholds of androgen levels [2,41]. As argued above, diagnosis and the decision to treat are complicated by the fact that symptoms of LOH do not manifest themselves at uniform threshold values of testosterone [1,27,42]. It therefore comes as no surprise that there is a significant variation among clinics and European countries in their application of threshold values of testosterone signifying hypogonadism which range from 7.5 to 12.0 nmol/l [43]. Almost certainly a factor in this observation is that physicians in different countries will have different concepts of what constitutes the core symptoms of hypogonadism. On the basis of the above observations it is clear that the symptoms of testosterone deficiency are not uniformly and predictably related to values of blood testosterone, which may lead to different diagnostic criteria for testosterone deficiency. So, the conclusion seems inevitable that the clinical manifestations of hypogonadism are multifactorially determined and that the diagnosis should not only depend on the measurement of testosterone but proper assessment should comprise somatic and psychological aspects in addition to measurement of testosterone [44]. The above being the case, it is virtually impossible to take a blood testosterone value as an
that testosterone value, though the lower the value of blood testosterone, the greater the likelihood. A decision to provide androgen treatment must not only be guided by the levels of blood testosterone but more the likelihood that symptoms are related to those particular testosterone levels, based on clinical judgment. The decision to treat will have an element of arbitrariness unless testosterone levels are truly low (<6 nmol/l)(certainly treat) or truly in the normal range (>15 nmol/l)(certainly not). A case can be made for a therapeutic trial of testosterone if the interpretation of clinical and laboratory data provide an ambiguous outcome [45].
Conclusion In conclusion, physicians have to be aware that testosterone plays a significant, but not an alldecisive role in older male patients and that replacement options should be based firstly on symptoms and secondly on hormone concentrations, which should be evaluated on a symptom-specific basis. Physicians treating elderly men should have expertise in the signs and symptoms of testosterone deficiency which have a broad spectrum of psychological, metabolic and sexual symptoms. Naturally, testosterone cannot be expected to be a panacea of all the mental and somatic problems men encounter in the process of aging and indiscriminate use within men who present with vague symptoms will have many failures to remedy complaints of aging men. Individual and symptom-oriented testosterone treatment might be warranted in the future if this assumption of variations in hormone-symptom-relationships has been further elaborated and corroborated in clinical studies.
Conflict of interest Professor Gooren declares there are no competing interests with regard to the contents of the manuscript, and no funding received. Professor Meryn has served as speaker for BSP symposia, otherwise no conflict of interest or
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Original article funding source to report. Doctor Shabsigh has acted as consultant or advisor for Indevus Pharmaceuticals, Pfizer, Bayer Schering Pharma, American Medical Systems, Auxilium,
Johnson & Johnson, Lilly, Boehringer Ingelheim; as Investigator for Auxilium, Plethora; and as Meeting Participant or Lecturer for Lilly; no funding source to report.
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