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Metabolic Syndrome in Men With Prostate Cancer Undergoing Long-Term Androgen-Deprivation Therapy

Milena Braga-Basaria, Adrian S. Dobs, Denis C. Muller, Michael A. Carducci, Majnu John, Josephine Egan, Shehzad Basaria

From the Department of Medicine, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine; National Institute on Aging, National Institutes of Health; and the Department of Oncology, Prostate Cancer Research Program, Kimmel Cancer Center at Johns Hopkins, Baltimore, MD

Address reprint requests to Shehzad Basaria, MD, Department of Medicine, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Bayview Medical Center, 4940 Eastern Ave, Ste B-114, Baltimore, MD 21224; e-mail: sbasari1{at}jhmi.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Prostate cancer (PCa) is one of the most common cancers in men. Men with recurrent or metastatic PCa are treated with androgen-deprivation therapy (ADT), resulting in profound hypogonadism. Because male hypogonadism is a risk factor for metabolic syndrome and men with PCa have high cardiovascular mortality, we evaluated the prevalence of metabolic syndrome in men undergoing long-term ADT.

PATIENTS AND METHODS: This was a cross-sectional study. We evaluated 58 men, including 20 with PCa undergoing ADT for at least 12 months (ADT group), 18 age-matched men with nonmetastatic PCa who had received local treatment and were recently found to have an increasing prostate-specific antigen (non-ADT group), and 20 age-matched controls (control group). Men in the non-ADT and control groups were eugonadal. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria.

RESULTS: Mean age was similar among the groups. Men on ADT had significantly higher body mass index and lower total and free testosterone levels. The prevalence of metabolic syndrome was higher in the ADT group compared with the non-ADT (P < .01) and control (P = .03) groups. Among the components of metabolic syndrome, men on ADT had a higher prevalence of abdominal obesity and hyperglycemia. Androgen-deprived men also had elevated triglycerides compared with controls (P = .02). The prevalence of hypertension and low high-density lipoprotein levels were similar.

CONCLUSION: These data suggest that metabolic syndrome was present in more than 50% of the men undergoing long-term ADT, predisposing them to higher cardiovascular risk. Abdominal obesity and hyperglycemia were responsible for this higher prevalence. We recommend prospective studies to further delineate this association.

	INTRODUCTION

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Prostate cancer (PCa) is one of the most common cancers in men with an increasing incidence.¹ Local surgery and/or radiation therapy are the preferred treatment modalities in men with locally confined PCa. However, in men with recurrent or metastatic PCa, androgen-deprivation therapy (ADT) is used. This is achieved either with bilateral orchiectomy or with gonadotropin-releasing hormone agonists. The resulting profound hypogonadism is responsible for adverse consequences such as an increase in body mass index (BMI), increased fat mass, reduced lean body mass (LBM) and muscle strength, osteoporosis, sexual dysfunction, and poor quality of life.^2,3 These adverse effects are a direct consequence of hypogonadism because they have significantly higher prevalence in men on ADT compared with men with PCa who underwent local surgery and/or radiation therapy and age-matched controls.²

Recently, male hypogonadism has emerged as an independent risk factor in the development of metabolic syndrome. Cross-sectional studies have shown that men with low testosterone levels have a higher prevalence of metabolic syndrome after controlling for other risk factors.⁴ Similarly, longitudinal studies indicate that lower testosterone levels in men independently predict the development of metabolic syndrome.⁵ These results support prior observations in men that indicated that lower androgen levels were independently associated with the development of type 2 diabetes mellitus.⁶ Interventional studies also demonstrate improved insulin sensitivity in obese men when treated with testosterone.⁷ These studies suggest that male hypogonadism is an independent risk factor for the development of metabolic syndrome and diabetes.

Recent research has shown that men with PCa have a higher cardiovascular mortality.⁸ A recent report showed that death from cardiovascular disease (CVD) has become the most common cause of non-PCa–related deaths in these men.⁹ Short-term prospective studies of ADT in men with PCa have shown development of insulin resistance and arterial stiffness.^10,11 We recently showed that men with PCa on long-term ADT had significantly higher levels of fasting insulin and glucose compared with men with PCa not on ADT and age-matched controls.¹² Because insulin resistance is independently associated with cardiovascular mortality,¹³ it is possible that this, at least partly, may explain the higher cardiovascular mortality in this population (with hypogonadism as the main trigger of these events). Metabolic syndrome is a known risk factor for cardiovascular mortality¹⁴; however, the presence of metabolic syndrome in men with PCa undergoing ADT has not been evaluated. Because hypogonadism is an independent risk factor for metabolic syndrome, we evaluated the prevalence of metabolic syndrome in men on long-term ADT and compared it with the prevalence in disease- and age-matched controls.

	PATIENTS AND METHODS

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Study Design and Patients
The study design was cross sectional. We studied the following three groups of men: (1) 20 men with PCa who were undergoing ADT (for recurrent or metastatic disease) for at least 12 months before the onset of the study and were in clinical and biochemical remission (ADT group); (2) 18 age-matched men with nonmetastatic PCa who had undergone prostatectomy and/or radiotherapy and were recently found to have an increasing prostate-specific antigen (PSA) level but had not received ADT and were eugonadal (non-ADT group); and (3) 20 age-matched healthy eugonadal men with a normal PSA (control group). The normal serum total testosterone level was defined as more than 280 ng/dL. The average duration of ADT (ADT group) was 45 months (range, 12 to 101 months). Three patients in the ADT group had undergone orchiectomy, whereas the remaining 17 men were on gonadotropin-releasing hormone agonists. None of the patients were on androgen receptor antagonists. Only two men (one each in the ADT and the non-ADT groups) had a known history of diabetes mellitus. These men were also included in the analysis.

The men undergoing ADT provided an excellent model (since they have profound hypogonadism) to determine the association between hypogonadism and the metabolic syndrome. The evaluation of the non-ADT group allowed us to account for any influence of the disease (PCa) itself on metabolic syndrome, and the control group allowed us to account for any influence of aging.¹⁵ Men in the ADT and non-ADT groups were recruited consecutively at their clinic visits at the Kimmel Cancer Center at Johns Hopkins. The age-matched control group was recruited randomly from a database of eugonadal men at the Johns Hopkins Hospital Clinical Trials Unit. All men signed informed consent that was approved by the Institutional Review Board of the Johns Hopkins Medical Institutions.

Exclusion Criteria
Men were excluded from the study if they had any of the following: liver function tests or serum creatinine more than 2x the upper limit of normal, glucocorticoid use in the previous 3 months, history of thyroid disease, history of any form of hypogonadism before the diagnosis of PCa (both ADT and non-ADT groups), and any history of cytotoxic chemotherapy use.

Definition of Metabolic Syndrome
The metabolic syndrome was defined according to the Adult Treatment Panel III criteria.¹⁶ A participant was classified as having metabolic syndrome if three of the following five criteria were met: fasting plasma glucose level more than 110 mg/dL, serum triglyceride level 150 mg/dL, serum high-density lipoprotein level less than 40 mg/dL, waist circumference more than 102 cm, and blood pressure of 130/85 mmHg. Participants on antihypertensives and lipid-lowering medications were classified as positive for the respective criterion.

Hormonal Methods
All hormonal parameters were obtained early in the morning after an overnight fast. Total and free testosterone, PSA, lipid profile, and glucose levels were measured commercially (Quest Diagnostics, Lyndhurst, NJ). The normal range for total testosterone was 241 to 827 ng/dL, and the normal range for free testosterone was 8 to 24 ng/dL. Total testosterone was measured by radioimmunoassay with a sensitivity of 20 ng/dL. The intra- and interassay coefficients of variation were 6.8% and 8.3%, respectively. The free testosterone was measured by equilibrium dialysis.

Statistical Analysis
All data were analyzed using SAS version 9.1 (SAS Institute, Cary, NC). Standard methods were used to compute means, SEs, and linear regression models. ² tests were performed to compare prevalence rates among the three groups. One-way analysis of variance was used to compare confounders among the three groups. Bonferroni's multiple comparison post hoc tests were used to compare the mean values. All significance tests for the comparisons were two sided, and P < .05 was considered statistically significant.

	RESULTS

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Demographic and Hormonal Data
There was no significant difference in mean age between the three groups (P = .41; Table 1). Men in the ADT group had significantly higher BMI compared with the other two groups (P = .001). The serum levels of total (P < .0001) and free (P < .0001) testosterone were significantly lower in the ADT group compared with the other two groups. Men in the non-ADT and control groups were eugonadal, with no significant difference between their testosterone levels. Men in the ADT group had significantly higher fasting glucose levels compared with men in the other two groups (P = .002).

View larger version (21K): [in this window] [in a new window]   Fig 1. The prevalence of metabolic syndrome and its individual features in the three study groups. ADT, androgen-deprivation therapy; HDL, high-density lipoprotein.

	DISCUSSION

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Epidemiologic evidence suggests that low testosterone levels in men predict the development of metabolic syndrome.^4,5 Because men with PCa undergoing ADT have castrate levels of testosterone, they provide an excellent model to study the association between hypogonadism and metabolic syndrome. We found that more than half of the men receiving long-term ADT had metabolic syndrome compared with one fifth of the men in the other two groups. Hyperglycemia and abdominal obesity were the major determinants of the higher prevalence of metabolic syndrome in this group. Because men in the three groups were of similar age and race, these observations suggest that hypogonadism in men on ADT may directly influence the development of metabolic syndrome.

Review of the literature suggests that hypogonadism in men has been linked to each aspect of the metabolic syndrome. Male hypogonadism of any etiology is associated with a decrease in LBM and an increase in fat mass.¹⁷ We had previously shown that men with PCa undergoing long-term ADT have reduced LBM and higher fat mass.² This increase in fat mass is secondary to the deposition of both subcutaneous and visceral fat, resulting in abdominal obesity.^2,4 The increase in visceral fat results in elevated levels of adipokines, which, in turn, are responsible for causing insulin resistance.¹³ In contrast to women, in whom hyperandrogenism is associated with insulin resistance and diabetes,¹⁸ hypoandrogenism in men leads to an adverse metabolic profile. Indeed, low testosterone levels in men are associated with insulin resistance and frank diabetes.^6,19 Furthermore, androgen replacement in obese men improves insulin sensitivity (and men with the lowest testosterone levels benefit the most).⁷ We have recently shown that men with PCa on long-term ADT have elevated levels of fasting insulin and glucose compared with eugonadal men with PCa (not on ADT) and age-matched controls.¹² This significance was maintained even after adjustment for age and BMI.¹² Low testosterone levels are also associated with an adverse lipid profile,²⁰ and testosterone replacement in hypogonadal men results in a decrease in serum triglyceride and low-density lipoprotein levels.²¹ Finally, in epidemiologic studies, low testosterone levels in men have shown to be independently associated with hypertension.²² Indeed, a recent study in patients with PCa undergoing short-term ADT showed a significant decrease in systemic arterial compliance compared with baseline.¹¹ Hence, the current evidence suggests that low testosterone levels in men are not only associated with the development of abdominal obesity (the inciting event that leads to a constellation of metabolic alterations that comprise metabolic syndrome), but they are also associated to each component of the metabolic syndrome.

Only a few studies have evaluated the metabolic alterations that occur as a result of ADT in men with PCa. A recent short-term prospective study of 22 men with PCa undergoing ADT showed a significant increase in insulin levels after 3 months of treatment compared with baseline; however, there was no significant change in plasma glucose levels.¹⁰ Another short-term study showed that ADT for 3 months resulted in a 63% increase in fasting insulin levels without any changes in fasting glucose.¹¹ These observations suggest that insulin resistance (manifested by hyperinsulinemia) develops within a few months of starting ADT; however, this hyperinsulinemia is sufficient to prevent the development of hyperglycemia. We recently showed that men on long-term ADT (at least 12 months) were not only insulin resistant but also had developed frank hyperglycemia.¹² No study has looked at the prevalence of metabolic syndrome in this patient population. To the best of our knowledge, this is the first study in the English literature showing the high prevalence of metabolic syndrome in androgen-deprived men with PCa.

Recent studies have shown that approximately half of men with PCa die of causes unrelated to the cancer itself, with CVD being the most common noncancer etiology. An earlier report had shown that, after the deaths directly attributable to PCa and its complications, CVD was the second leading cause of death (responsible for 27% of the deaths).⁸ However, a recent report showed that non-PCa–related deaths now exceed PCa-related mortality, with CVD being the single most common cause of non-PCa–related deaths.⁹ Metabolic syndrome is a known cause for increased cardiovascular mortality. Men with metabolic syndrome are three times more likely to die of coronary heart disease and other CVD even after adjustment for other risk factors.^23,24 The prevalence of metabolic syndrome among the adult US population is between 22% and 24%.¹⁴ In our study, the participants in the non-ADT (22%) and control (20%) groups had similar rates of metabolic syndrome; however, the rate was much higher (55%) in the ADT group. On the basis of the findings of our study, one might speculate that the higher prevalence of metabolic syndrome in men on long-term ADT may be, at least partly, responsible for higher cardiovascular mortality in this population. Because low testosterone levels are a risk factor for metabolic syndrome, the profound hypogonadism in patients undergoing ADT may be responsible for high cardiovascular mortality. These findings are in agreement with the evidence suggesting that male hypogonadism is associated with higher cardiovascular mortality²⁵ and that testosterone replacement in hypogonadal men results in coronary vasodilation,²⁶ improvement in angina,²⁷ and a beneficial effect on lipid profile.²⁸

Our study has several strengths. First, we studied men who had been on ADT for a long period of time (range, 1 to 9 years). Second, we included two different groups of men to compare with the ADT group. The evaluation of the non-ADT group allowed us to account for any influence of PCa itself on the metabolic syndrome, and the control group provided us the opportunity to account for any influence of age on the development of metabolic syndrome. Furthermore, the majority of the participants in all three groups were white, thus negating any influence of ethnicity on the diagnosis of metabolic syndrome. Our results suggest that the high prevalence of metabolic syndrome in the ADT group may be a direct result of profound hypogonadism and independent of any influence of age, race, and disease (PCa). One may argue that men in the ADT group had more advanced disease (and hence on ADT) compared with the non-ADT group; however, all men in the ADT group were in clinical and biochemical remission, and all men in the non-ADT group had an increasing PSA level at the time of recruitment, suggesting biochemical recurrence. To the best of our knowledge, our study is the only study that has evaluated the presence of metabolic syndrome in men undergoing ADT. Our study also has a few limitations. First, this was a cross-sectional study, and we recommend prospective studies in this patient population. Second, the majority of men in the three groups were white; hence, future studies should include patients from diverse ethnic backgrounds. Finally, although our sample size was comparable to most studies done in this field,^10,11 it was still relatively small, and future studies should include larger numbers of men.

In conclusion, more than half of the men with PCa undergoing long-term ADT met the criteria for metabolic syndrome. The metabolic syndrome in this population was independent of age and race and implicates hypogonadism as the likely cause. These complications of ADT impart an increased cardiovascular risk and may be responsible for the increased cardiovascular mortality seen in men with PCa. Long-term studies are needed to determine the timing of the onset of the metabolic syndrome and the role of diet, exercise, and insulin sensitizers in this patient population.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Adrian S. Dobs, Michael A. Carducci, Josephine Egan, Shehzad Basaria Administrative support: Adrian S. Dobs, Shehzad Basaria Provision of study materials or patients: Adrian S. Dobs, Michael A. Carducci Collection and assembly of data: Milena Braga-Basaria, Adrian S. Dobs, Denis C. Muller, Shehzad Basaria Data analysis and interpretation: Milena Braga-Basaria, Adrian S. Dobs, Denis C. Muller, Michael A. Carducci, Majnu John, Josephine Egan, Shehzad Basaria Manuscript writing: Milena Braga-Basaria, Adrian S. Dobs, Denis C. Muller, Michael A. Carducci, Josephine Egan, Shehzad Basaria Final approval of manuscript: Milena Braga-Basaria, Adrian S. Dobs, Denis C. Muller, Michael A. Carducci, Majnu John, Josephine Egan, Shehzad Basaria

 

	NOTES

 
Supported by the Johns Hopkins University School of Medicine General Clinical Research Center Grant No. M01RR00052.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted January 31, 2006; accepted June 7, 2006.

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