Improving the Lives of Your Aging Male Patients: Considering Whether Testosterone Plays a Meaningful Role

Chair: David Greenberg, BA, MD, *Co-chair of Membership Committee, Canadian Society for the Study of the Aging Male, Toronto, ON; Member Of Executive, Department of Family & Community Medicine, St. Joseph's Health Centre, Toronto, ON.

The Prevalence of Hypogonadism among Men who Have Type 2 Diabetes and/or the Metabolic Syndrome—Is it
Clinically Relevant?

Speaker: Jeremy Gilbert, MD, FRCPC, Endocrinology and Metabolism, Sunnybrook Health Sciences Centre, Toronto, ON.

Dr. Jeremy Gilbert addressed the clinical relevance of the association between type 2 diabetes/the metabolic syndrome and hypogonadism among aging males. He described the theme as particularly worthy of attention given the increasingly epidemic status of diabetes and the metabolic syndrome, and their growing prevalence among an aging population.

Referring to a common clinical scenario of low testosterone in the presence of metabolic syndrome, Dr. Gilbert described a 55-year-old male patient complaining of tiredness, poor concentration, low libido, and muscle weakness. The patient’s metabolic state (blood pressure 140/90, waist circumference 102 cm, body mass index [BMI] 29, fasting blood sugar 6.7, cholesterol 5.7, HDL 0.9, LDL 3.5, triglycerides 2.8) corresponded to the metabolic syndrome; his total testosterone level ranked low at 9 nmol/L. How, clinically, should his T level be approached? How concerning is it?

This hypothetical case typifies the kind of patient he sees with metabolic syndrome. Dr. Gilbert emphasized the number of patients with similar health conditions: currently, 2.4 million Canadians have diabetes; additionally, an estimated 570,000 have undiagnosed type 2 diabetes. Approximately 6 million Canadians have pre-diabetes or are at high risk for developing type 2 diabetes. Within the large burden posed by these conditions, certain ethnic and age subgroups have higher levels of disease or disease risk. Currently available data may underestimate disease risk and prevalence, especially among patients of advanced age.

The estimated prevalence of hypogonadism ranges from 20–64%, depending on the study source. Testosterone levels are consistently shown to bear an inverse relationship to BMI. Dr. Gilbert cited data from several studies, including a JAMA meta-analysis of patients with diabetes showing that the prevalence of patients with hypogonadism among patients with type 2 diabetes is 2–3 times higher. The cross-sectional studies examined indicated that testosterone level was significantly lower in men with type 2 diabetes (mean difference, –76.6 ng/dL; 95% confidence interval [CI], –99.4 to –53.6), and prospective studies showed that men with higher testosterone levels (range, 449.6–605.2 ng/dL) had a 42% lower risk of type 2 diabetes (RR, 0.58; 95% CI, 0.39 to 0.87).¹

Dr. Gilbert described the data supporting the association as robust. He cited a Finnish study that assessed the association of low testosterone and sex hormone–binding globulin (SHBG) with the development of the metabolic syndrome and diabetes.² Of the 702 subjects studied (with no diabetes or metabolic syndrome at baseline) 147 developed metabolic syndrome and 57 developed diabetes over the 11-year follow-up. They found that the metabolic syndrome was 2–3 times more common among those with low testosterone. The study authors concluded that hypogonadism is an early marker for disturbances in insulin and glucose metabolism and serves as a predictor of progression to the metabolic syndrome or frank diabetes.

Dr. Gilbert also drew attention to results of the Hypogonadism in Males (HIM) study, which showed the large prevalence of hypogonadism among aging men with the metabolic syndrome.³ Researchers documented the prevalence of hypogonadism via measurements of total testosterone in men aged ≥45 years (mean age was 60.5 years) visiting primary care practices in the United States. They found an overall prevalence of 38%. Importantly, the study captured the comorbid conditions that may occur with hypogonadism in men who present to primary care: the greater the risk factors for metabolic syndrome, the more likely patients were, according to the study, to have lower testosterone.

Given the strong association between the metabolic syndrome and hypogonadism, could treatment of low testosterone correct the components of the metabolic syndrome? It is known that in men with androgen deficiency, testosterone treatment results in improved memory, better mood, stronger libido, better body composition with more lean mass and less body fat, lower body mass, and increased muscle size and strength, as well as improved bone density (Figure 1). But what are the implications of treating hypogonadism for diabetes and/or the metabolic syndrome? The data show that supplemental testosterone leads to generation of muscle, inhibits development of pre-adipocytes, and enhances insulin sensitivity of muscle cells. Dr. Gilbert cited two studies that have examined the correlation.

 

He mentioned a double-blind placebo-controlled crossover study in 24 hypogonadal men with type 2 diabetes that found testosterone replacement therapy significantly improved insulin resistance and improved glycemic control.⁴ Additionally, a second study published in early 2009 of 95 middle-aged to older hypogonadal men showed improvement of markers of the metabolic syndrome upon testosterone administration.⁵

When clinicians encounter a patient in their clinical practice paralleling the symptom profile of the 55-year-old patient with metabolic syndrome of Dr. Gilbert’s example, he recommended that testosterone levels be checked. Those in primary care and internal medicine should consider testosterone more often, he stated.

Given that it has been demonstrated that the odds of having metabolic syndrome are 2–3 times greater in those with hypogonadism, testosterone replacement may be useful clinically to improve parameters of the metabolic syndrome. However, Dr. Gilbert advised that more evidence from large controlled trials is necessary to confirm the clinical utility of testosterone therapy in heart outcomes (e.g., CVD prevention) associated with metabolic syndrome in the context of hypogonadism.

References

1. Ding EL, Song Y, Malik VS, et al. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006;295:1288–99.
2. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27:1036–41.
3. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006;60:762–9.
4. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154:899–906.
5. Haider A, Gooren LJ, Padungtod P, et al. Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia 2009;41:7–13.

Sponsored by an unrestricted educational grant from Solvay Pharma Inc.

L’amélioration de la vie chez les hommes vieillissants : envisager l’importance de la testostérone

Président : David Greenberg, B.A., M.D., co-président du comité d’adhésion, Canadian Society for the Study of the Aging Male, Toronto, ON; membre de la direction, département de la médecine familiale et communautaire, St. Joseph's Health Centre, Toronto, ON.

La prévalence de l’hypogonadisme parmi les hommes souffrant du diabète de type 2 ou du syndrome métabolique — est-ce pertinent sur le plan clinique?

Conférencier : Jeremy Gilbert, M.D., FRCPC, Endocrinologie et métabolisme, Sunnybrook Health Sciences Centre, Toronto, ON.

Le D^r Jeremy Gilbert a discuté de la pertinence clinique du lien entre le diabète de type 2/ le syndrome métabolique, et l’hypogonadisme parmi les hommes vieillissants. Il a souligné que c’est un thème qui mérite une certaine attention, étant donné la situation épidémique croissante du diabète et du syndrome métabolique, et leur prévalence croissante chez une population vieillissante.
À titre d’exemple d’un scénario cli-nique commun où il y a un faible taux de testostérone en présence du syndrome métabolique, le D^r Gilbert a décrit un patient de sexe masculin âgé de 55 ans se plaignant de fatigue, mauvaise concentration, baisse de la libido et faiblesse musculaire. L’état métabolique du patient (pression artérielle de 140/90, tour de taille de 102 cm, indice de masse corporelle [IMC] de 29, une glycémie à jeun de 6.7, cholestérol de 5.7, HDL de 0.9, LDL de 3.5, triglycérides de 2.8) correspondait au syndrome métabolique; il possédait un faible taux total de testostérone de 9 nmol/L. Comment ce taux de testostérone devrait-il être envisagé de façon clinique? Jusqu’à quel point la situation est-elle inquiétante?

Ce cas hypothétique est caractéristique du type de patient qu’il rencontre, qui souffre du syndrome métabolique. Le D^r Gilbert a souligné le fait que d’autres patients souffrent de conditions de santé semblable : 2.4 millions de Canadiens souffrent actuellement du diabète; de plus, on estime que 570,000 souffrent de diabète de type 2 non diagnostiqué. Approximativement 6 millions de Canadiens sont atteints de prédiabète ou sont à haut risque de développer le diabète de type 2. Cet important fardeau posé par ces conditions comprend certains sous-groupes d’ethnicité et d’âge où les taux de maladie ou de risque de maladie sont plus élevés. Les données actuellement disponibles sous-estiment possiblement le risque et prévalence de maladie, surtout parmi les patients d’âge avancé.

La prévalence estimée de l’hypogonadisme varie entre 20 et 64 %, d’après l’étude. Il a été démontré de façon consistante que les taux de testostérone ont une relation inverse à l’IMC. Le D^r Gilbert a cité des données de plusieurs études, y compris une méta-analyse du JAMA chez des patients diabétiques, démontrant que la prévalence de patients souffrants d’hypogonadisme parmi des patients atteints du diabète de type 2 est de 2 à 3 fois plus élevée. Les études transversales étudiées indiquent que les taux de testostérone sont significativement plus faibles chez les hommes souffrant de diabète de type 2 (différence moyenne, –76.6 ng/dL; intervalle de confiance [IC] à 95 %, -99.4 à –53.6). Des études prospectives ont démontré qu’un taux plus élevé de testostérone chez les hommes (étendue de 449.6 à 605.2 ng/dL) les rend 42 % moins susceptibles d’être atteint du diabète de type 2 (RR, 0.58; IC à 95 %, 0.39 à 0.87).¹

Le D^r Gilbert a énoncé que les données qui supportent le lien sont robustes. Il a cité une étude finlandaise qui a évalué le lien entre un faible taux de testostérone et la globuline liant les hormones sexuelles (SHBG), et le développement du syndrome métabolique et du diabète.² De tous les 702 sujets étudiés (sans diabète ou syndrome métabolique en début d’étude), 147 ont développé le syndrome métabolique et 57 ont développé le diabète, au cours des 11 années du suivi. Il a été constaté que le syndrome métabolique est 2 à 3 fois plus commun parmi ceux avec un faible taux de testostérone. Les auteurs de l’étude ont conclu que l’hypogonadisme est un indicateur précoce des perturbations de l’insuline et du métabolisme du glucose, et peut donc prédire la progression au syndrome métabolique ou au diabète.

Le D^r Gilbert a aussi souligné les résultats de l’étude, L’hypogonadisme chez les hommes, où une prévalence importante d’hypogonadisme parmi les hommes vieillissants atteints du syndrome métabolique a été démontrée.³ Les chercheurs ont documenté la prévalence de l’hypogonadisme en mesurant les taux complets de testostérone chez les hommes âgés de ≥45 ans (âge moyen de 60.5 ans) visitant des pratiques de soins primaires aux États-Unis. Ils ont observé une prévalence totale de 38 %. L’étude a démontré, ce qui est important, lesquels des facteurs de comorbidité peuvent se manifester chez les hommes atteints d’hypogonadisme recevant des soins primaires : plus les risques d’être atteint du syndrome métabolique sont élevés, plus il est probable que les taux de testostérone des patients soient faibles. Puisqu’il existe un lien important entre le syndrome métabolique et l’hypogonadisme, serait-il possible de corriger les composantes du syndrome métabolique en ajustant les taux de testostérone? Il est un fait établi que chez les hommes souffrant d’une carence androgénique, un traitement de remplacement de testostérone entraîne une amélioration de la mémoire, une meilleure humeur, une augmentation de la libido, une meilleure composition corporelle avec plus de masse maigre et moins de réserves de gras, une masse corporelle plus faible, et une augmentation du volume et de la force des muscles, aussi bien qu’une meilleure densité osseuse (Figure 1). Mais quelles sont les implications du traitement de l’hypogonadisme pour le diabète ou le syndrome métabolique? Les données démontrent que des suppléments de testostérone entraînent la croissance des muscles, empêchent le développement des préadipocytes et augmentent la sensibilité des cellules musculaires à l’insuline. Le D^r Gilbert a cité deux études qui ont analysé cette corrélation.

 

Il a parlé d’un essai croisé à double insu, contrôlé par placébo, chez 24 hommes souffrant d’hypogonadisme et de diabète de type 2, où il fut démontré que la thérapie de remplacement de la testostérone améliore significativement l’insulinorésistance et le contrôle glycémique.⁴ De plus, une deuxième étude publiée en début de 2009, chez 95 hommes d’âge moyen et d’âge plus avancé, atteints d’hypogonadisme, démontra une amélioration des indicateurs du syndrome métabolique après l’administration de la testostérone.⁵
Le D^r Gilbert a recommandé que lorsqu’un patient se présente en clinique avec des symptômes équivalents à ceux du patient de 55 ans souffrant du syndrome métabolique, tel son exemple, qu’une vérification des taux de testostérone soit faite. Il affirme que les cliniciens qui offrent des soins de santé primaire et qui travaillent en médecine interne devraient plus fréquemment prendre la testostérone en considération.

Étant donné qu’il a été démontré que la probabilité d’être atteint du syndrome métabolique est de 2 à 3 fois plus élevée chez ceux souffrant d’hypogonadisme, le remplacement de la testostérone pourrait s’avérer d’une utilité clinique pour améliorer les paramètres du syndrome métabolique. Le D^r Gilbert a cependant conseillé que des données additionnelles d’essais comparatifs plus considérables sont nécessaires pour démontrer l’utilité clinique de la thérapie de remplacement de la testostérone pour des résultats cardiologiques (p. ex. maladie cardio-vasculaire) liés au syndrome métabolique dans le contexte de l’hypogonadisme.

Références

1. Ding EL, Song Y, Malik VS, et al. Sex diffe-rences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006;295:1288–99.
2. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27:1036–41.
3. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006;60:762–9.
4. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154:899–906.
5. Haider A, Gooren LJ, Padungtod P, et al. Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia 2009;41:7–13.

Symposium parrainé par Solvay.

Pamela Katz, MD, Department of Endocrinology and Metabolism, University of Toronto, Toronto, ON.
Jeremy Gilbert, MD, FRCPC, Staff Endocrinologist, Toronto General Hospital, University Health Network, Toronto, ON.

The global prevalence of diabetes has increased substantially in recent years, attributable to an increase in new cases and declining mortality. Aging is associated with changes in beta cell function and insulin resistance that predispose to diabetes. Cardiovascular disease is the leading cause of death among older adults with diabetes. In order to reduce the excessive risk of cardiovascular disease, all coronary risk factors must be addressed and treated aggressively. This article will focus on the importance of blood pressure and glycemic control and lipid lowering with statin therapy. Specific considerations in this patient population include high rates of comorbid disease, shorter life expectancy, polypharmacy and falls risk. These factors may alter the therapeutic goals. Treatment should therefore be individualized with consideration given to patient preference and quality of life.
Key words: diabetes, cardiovascular disease, older adults, metabolic syndrome.

Muhammad Firdaus, MD, FACP, Section of Endocrinology, Department of Medicine, University of Oklahoma Health Sciences Center; Veterans Affairs Medical Center, Oklahoma City, OK, USA.
Timothy J Lyons, MD, FRCP, Section of Endocrinology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

The metabolic syndrome, though controversial due to lack of a uniform pathophysiological mechanism, is a useful clinical tool for identifying persons at risk for diabetes and cardiovascular disease. It indicates the cumulative cardiometabolic risk exerted by abdominal obesity, hyperglycemia, high triglyceride, low high density lipoprotein cholesterol (HDL-C), and high blood pressure. Lifestyle factors, high calorie intake, and less physical activity have been implicated in the causation of the metabolic syndrome, and thus older adults are at particular risk for the development of this syndrome. Current evidence indicates that the components of the metabolic syndrome can be targeted with lifestyle interventions to prevent the complications of diabetes and cardiovascular disease. This paper reviews various diagnostic criteria, etiological factors, and lifestyle interventions to combat the metabolic syndrome in order to prevent diabetes and cardiovascular disease in older adults.
Key words: metabolic syndrome, prevention, lifestyle modification, diet, physical activity.

Krupa Shah, MD, MPH, Geriatric Fellow, Washington University at St. Louis, Division of Geriatric and Nutritional Science, St. Louis, MO, USA.
Dennis Villareal, MD, Associate Professor, Washington University at St. Louis, Division of Geriatric and Nutritional Science, St. Louis, MO, USA.

Obesity is associated with significant morbidity and mortality. In older adults, obesity can exacerbate declining physical function and quality of life that often accompanies aging, and can cause frailty. The value of treatment for obesity in older adults has been under debate because of the uncertain effectiveness of obesity therapies in this population as well as the potentially harmful effects of weight loss. However, current evidence shows that weight-loss treatment improves physical function and quality of life, and also eases the medical complications associated with obesity in older adults. Therefore, moderate weight loss that minimizes muscle and bone loss is recommended for obese older adults who have functional decline or medical complications.
Key words: obesity, body mass index, metabolic syndrome, weight loss, lifestyle modification.

Isabelle J. Dionne, PhD, Faculty of Physical Activity and Sports, University of Sherbrooke; Research Centre on Aging, Geriatric Institute of Sherbrooke University, Sherbrooke, QC.
Martin Brochu, PhD, Faculty of Physical Activity and Sports, University of Sherbrooke; Research Centre on Aging, Geriatric Institute of Sherbrooke University, Sherbrooke, QC.

There is a high prevalence of obesity in older adults up to the age of 80. While women generally gain body weight during the menopausal transition, men tend to accumulate an excess of fat mass earlier in life for as yet unknown reasons. Consequently, an increasing proportion of older adults are now obese. Obesity’s association with metabolic diseases such as metabolic syndrome, type II diabetes, and cardiovascular disease is widely recognized. However, recent evidence shows that, in older adults, obesity is also related to functional impairment and decreased quality of life. This review addresses the actual prevalence and definition of obesity in older adults, the energy-balance equation, and the known consequences of obesity. Finally, the heterogeneity of obesity in older adults regarding its association with metabolic diseases and functional capacity will be discussed, as well as how obesity treatment should be conducted in this population.

Key words: obesity, metabolic syndrome, diabetes, weight loss, impaired functional capacity.