The Metabolic Syndrome and Disturbances in Hormone Levels in Long-Term Survivors of Disseminated Testicular Cancer
http://www.100md.com
《临床肿瘤学》
the Departments of Medical Oncology, Vascular Medicine, Endocrinology, and Surgical Oncology, University Hospital Groningen, 9700 RB Groningen, the Netherlands
ABSTRACT
PURPOSE: The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men.
PATIENTS AND METHODS: We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone–binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine.
RESULTS: Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FSH were higher, and inhibin B and total and free testosterone were lower in chemotherapy patients than controls. Adrenal and thyroid hormone production were unaffected. Chemotherapy patients with the metabolic syndrome (n = 22; 26%) had a higher body mass index (BMI) pretreatment, a larger BMI increase during follow-up, lower total testosterone, and higher urinary cortisol metabolite excretion than those patients without the metabolic syndrome. BMI and insulin were associated with the metabolic syndrome, while total testosterone and urinary cortisol metabolite excretion were associated with BMI.
CONCLUSION: We found gonadal dysfunction, but normal adrenal and thyroid function. Through its association with BMI, testosterone may play a role in the development of the metabolic syndrome in long-term TC survivors.
INTRODUCTION
In survivors of testicular cancer, cardiovascular morbidity is increasingly recognized as a long-term complication of bleomycin- and cisplatin-containing chemotherapy. Hypertension, dyslipidemia, overweight, and insulin resistance, all components of the metabolic syndrome, have been reported in many, though not all, studies.1-6 Although the etiology of the metabolic syndrome and its related features in testicular cancer survivors is not clear, this syndrome may increase the risk for cardiovascular disease.7 Components of the metabolic syndrome together with early signs of atherosclerosis have been reported in testicular cancer survivors several years postchemotherapy.8 Furthermore, recent studies have shown an increased risk for cardiovascular events 10 or more years after treatment,9-11 justifying concern for long-term vascular toxicity.
Gonadal dysfunction is considered another long-term complication of treatment. Radiotherapy and chemotherapy, but also surgery alone, are associated with an increased risk of either overt or compensated (normal total testosterone, but elevated luteinizing hormone [LH] levels) Leydig cell dysfunction.12 Gonadal hormones have been associated with an increased cardiovascular risk and with severity of atherosclerosis in diabetes mellitus patients and healthy men. Furthermore, low levels of serum testosterone and sex-hormone–binding globulin (SHBG) have been associated with obesity, dyslipidemia, and insulin resistance, and with markers of vascular damage in cross-sectional studies.13-17 Recently, Laaksonen et al18 have specifically investigated the associations between sex hormones and the metabolic syndrome. In a large population-based study, they found that nondiabetic middle-aged men with low-normal concentrations of total and free testosterone and SHBG were more likely to have the metabolic syndrome and its associated features than men with high-normal sex hormone levels, independent of body mass index (BMI).
Associations have also been reported between the components of the metabolic syndrome and adrenal, thyroid, and pituitary hormones. Low levels of dehydroepiandrosterone sulfate, cortisol excess, growth-hormone deficiency, and hypothyroidism are associated with cardiovascular risk factors, like obesity, dyslipidemia, and insulin resistance.19-21 Furthermore, cortisol metabolism has been implicated in the development of the metabolic syndrome.22
Few previously conducted studies have investigated gonadal function in large groups of testicular cancer survivors.12,23 In the remaining studies, patient numbers were usually small and comparisons with healthy men were generally lacking. In most cases, only LH and total testosterone were analyzed, and no data on other hormones were reported. Moreover, the relationships between hormone levels and cardiovascular risk factors have not been investigated in testicular cancer survivors. Hormone levels in blood may differ between testicular cancer patients and healthy men, either as an adverse effect of treatment or as a result of endocrine disruption related to the development of testicular cancer. We hypothesize that alterations in hormone levels affect the development of the metabolic syndrome in testicular cancer survivors, contributing to an increased risk for cardiovascular disease. Relevant hormones may form potential targets for intervention in this population.
The present trial was carried out to investigate (1) whether gonadal, adrenal, thyroid, and pituitary hormonal disturbances were present in long-term survivors of testicular cancer, (2) which factors contributed to hormonal disturbances, and (3) whether hormonal disturbances were associated with the metabolic syndrome and its related features in these testicular cancer survivors. Measurements were performed in disseminated nonseminomatous testicular cancer patients who had been treated with unilateral orchidectomy and cisplatin-based chemotherapy, in stage I testicular cancer patients who had been treated with unilateral orchidectomy only, and in healthy men of comparable age.
PATIENTS AND METHODS
Patients
All patients with disseminated nonseminomatous testicular cancer who had been successfully treated with unilateral orchidectomy and cisplatin-based chemotherapy at the University Hospital Groningen (Groningen, the Netherlands) between July 1988 and April 1999 were approached to participate. Extragonadal testicular cancer, radiotherapy, testosterone replacement therapy, and age older than 55 years at the start of chemotherapy were exclusion criteria. Patients with stage I nonseminomatous testicular cancer, free of disease after unilateral orchidectomy only, and apparently healthy men were also included. Healthy men were recruited through advertisements in our hospital and in a local newspaper, and originated from the same geographic area (the northern part of the Netherlands) as patients. The study was approved by the medical ethical review committee of the University Hospital Groningen, and written informed consent was obtained from each participant.
Cardiovascular Risk Factors
Data on patient weight before start of chemotherapy were collected from medical records. During follow-up investigations, a physical examination was performed with measurements of weight, height, hip circumference (broadest part), and waist circumference (at umbilical level). BMI was calculated by dividing weight (in kilograms) by height (in meters) squared. Waist-hip ratio (WHR) was calculated by dividing waist circumference by hip circumference. Blood pressure was measured using a standard sphygmomanometer.
Fasting blood samples were analyzed for lipids (triglycerides, total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and total cholesterol/HDL cholesterol ratio), glucose, and insulin levels. Insulin-to-glucose ratio (IGR), a measure of insulin resistance, was calculated by dividing fasting serum insulin (pmol/L) by fasting plasma glucose (mmol/L).
Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III).24 According to the NCEP ATP III, the metabolic syndrome was determined by three or more of the following criteria: abdominal obesity (waist circumference > 102 cm), a high triglyceride concentration ( 1.7 mmol/L), a low HDL cholesterol concentration (< 1.0 mmol/L), a high fasting plasma glucose concentration ( 6.1 mmol/L), or high blood pressure ( 130/85 mmHg). Microalbuminuria (defined as a urinary albumin excretion of 30-300 mg/24 hours), plasminogen activator inhibitor type 1 (PAI-1), tissue-type plasminogen activator (t-PA), and high-sensitivity C-reactive protein (hs-CRP), were also determined, because these factors have been associated with the metabolic syndrome in the general population, and have been previously described8 to be increased in chemotherapy-treated testicular cancer patients compared with controls. PAI-1 antigen (reference values, 4 to 43 ng/mL) and t-PA antigen (reference values, 1 to 10 ng/mL) were measured using an enzyme-linked immunosorbent assay (ELISA) (Asserachrom, Diagnostica Stago, Asnieres-sur-Seine, France), and hs-CRP (lower limit of detection, 0.16 mg/L) was measured using the BNII Nephelometer (Dade Behring, Brussels, Belgium).
Hormones
Blood samples for all hormone measurements were taken in the morning after an overnight fast. LH (reference values, 2.1 to 10.0 U/L), follicle-stimulating hormone (FSH; reference values, 1.8 to 7.2 U/L), and thyroid-stimulating hormone (TSH; reference values, 0.4 to 5.0 mU/L) were measured using a fluoroimmunoassay (AutoDelfia, PerkinElmer/Wallac Oy, Turku, Finland).9 Estradiol (reference values, 0.05 to 0.22 nmol/L), dehydroepiandrosterone sulfate (DHEAS), and total testosterone were measured using a radioimmunoassay (Packard 1500/1600/2700, PerkinElmer, Groningen, the Netherlands).9 Insulin-like growth factor type 1 (IGF-1) was measured using a chemiluminescent microparticle immunoassay (Advantage, Nichols Institute Diagnostics, San Juan Capistrano, CA), after which z scores were calculated. Inhibin B was measured using an ELISA (Oxford Bio-Innovation LTD, Oxfordshire, United Kingdom; lower limit of detection, 10 ng/L)25and SHBG (reference values, 12 to 30 nmol/L) was measured using a binding assay. Free testosterone was calculated using the formula by Vermeulen et al,26 in which testosterone concentration is corrected for both SHBG and albumin levels. Primary hypogonadism, defined as a total testosterone concentration less than 10 nmol/L and/or an LH concentration 10 U/L, was also determined.
Excretion of the cortisol metabolites tetrahydrocortisone (THE), tetrahydrocortisol (THF), and alloTHF was measured in 24-hour urine samples. Total metabolite excretion (THE + THF + alloTHF) was used as a measure of cortisol excretion rate.27
Statistical Analysis
For continuous variables, differences between the three groups were evaluated by analysis of ranks (Kruskal Wallis), using Duncan's method for correction of multiple testing. Differences between two groups were tested using either a t test or a Mann-Whitney test for normally distributed and skewed data, respectively. Categoric variables were evaluated using a Pearson 2 test. Double-sided P values less than .05 were considered to be significant.
Linear regression analyses were performed to test the effects of different variables on the metabolic syndrome and its components. Age at follow-up, age at time of treatment, chemotherapy treatment, duration of follow-up, BMI at follow-up, WHR, and hormone levels were entered as independent variables in the regression models. A P value of < .10 was used to enter, and P < .05 to remove, variables from the models.
RESULTS
Eighty-six chemotherapy patients, 44 stage I patients, and 47 healthy male controls participated. Most chemotherapy-treated patients (80%) had received a combination of bleomycin, etoposide, and cisplatin, while the remaining patients had received either etoposide and cisplatin (9%), or another cisplatin-based chemotherapeutic regimen (11%). Duration of follow-up was similar in chemotherapy-treated and stage I patients (median follow-up, 7 years; range, 3 to 13 years) and all groups were comparable with respect to age (median age of chemotherapy patients, 37 years; range, 20 to 65 years; median age of stage I patients, 36 years; range, 24 to 63 years; median age of controls, 37 years; range, 22 to 55 years).
Cardiovascular Risk Factors
Cardiovascular risk factors are listed in Table 1. Although differences were small, chemotherapy patients had significantly higher levels of triglycerides and total cholesterol, a significantly higher total cholesterol/HDL cholesterol ratio, and a significantly increased BMI and WHR compared with controls. According to NCEP ATP III criteria, the metabolic syndrome was present in 22 chemotherapy patients (26%), in 16 stage I patients (36%), and in four controls (9%). Presence or absence of the metabolic syndrome could not be determined in two chemotherapy patients and in one control, due to missing variables. Prevalence of the metabolic syndrome was significantly different between both patient groups and controls (chemotherapy group v controls, P = .017; stage I group v controls, P = .002), but not between chemotherapy and stage I patients (P = .232). In chemotherapy patients with the metabolic syndrome compared with those without, PAI-1 (median, 55.0 ng/mL [range, 18.2 to 183.0 ng/mL] v median, 18.5 ng/mL [range, 3.0 to 113.0 ng/mL]; P = .000) and t-PA (mean ± standard deviation[SD], 11.3 ± 4.1 ng/mL v 7.1 ± 3.3 ng/mL; P = .000) were both increased, whereas hs-CRP and the prevalence of microalbuminuria did not differ.
Hormones
Table 2 lists the endocrine profiles of the three groups. Levels of total and free testosterone were lower and LH and estradiol higher in chemotherapy patients than in controls. SHBG concentrations did not differ between patients and controls. Inhibin B was decreased in chemotherapy patients compared with both stage I patients and controls, whereas FSH was increased. Stage I patients had lower free testosterone and inhibin B levels and higher LH and FSH concentrations than controls. Hypogonadism was present in 18 chemotherapy-treated testicular cancer patients (21%), in three stage I patients (7%), and in none of the controls (chemotherapy group v controls, P = .000; chemotherapy group v stage I group, P = .045).
Mean z scores of plasma IGF-1 were similar in all groups, suggesting normal growth hormone secretion. Mean TSH concentration did not differ between chemotherapy patients and controls, whereas TSH was more than 5 mU/L in one chemotherapy patient, in two controls, and in none of the stage I patients. Total urinary cortisol metabolite excretion and mean serum DHEAS concentration were comparable between groups, indicating normal adrenal function.
Hormones and the Metabolic Syndrome in Testicular Cancer Patients
Chemotherapy-treated testicular cancer patients with and without the metabolic syndrome had a similar age at follow-up and duration of follow-up, while BMI pretreatment, absolute BMI increase, and BMI at follow-up were increased in patients with the syndrome (Table 3). Furthermore, total urinary cortisol metabolite excretion was increased and total testosterone and SHBG concentrations were decreased in patients with the metabolic syndrome compared with those without (Table 3). Thyroid, adrenal, and pituitary hormones did not differ between chemotherapy patients with and without the metabolic syndrome.
In testicular cancer patients, the effects on the metabolic syndrome and its components were tested for several variables: age at follow-up, age at time of treatment, chemotherapy treatment, duration of follow-up, BMI at follow-up, WHR, and the following hormones: insulin, total testosterone, SHBG, free testosterone, DHEAS, estradiol, TSH, IGF-1, and total urinary cortisol metabolites. Regression analysis showed that a model with BMI and insulin as independent variables was significantly associated with the metabolic syndrome (BMI, beta coefficient =.048; P < .001; insulin, beta coefficient =.025; P = .001; R-value of model, 0.616). BMI was significantly associated with a regression model containing insulin (beta coefficient = .273; P < .001), urinary cortisol metabolite excretion (beta coefficient =.054; P = .031), and serum total testosterone concentration (beta coefficient = –.129; P = .001) as independent variables (R-value of model, 0.667). One SD change in total testosterone concentration and total urinary cortisol metabolite excretion was associated with only small changes in BMI (–0.83 kg/m2 change in BMI per 6.4 nmol/L change in total testosterone; 0.78 kg/m2 change in BMI per 14.4 μmol/24 hours change in urinary cortisol metabolite excretion).
The metabolic syndrome was present in 5 (29%) of 17 chemotherapy patients with hypogonadism and in 17 (25%) of 67 chemotherapy patients with normal testosterone and LH levels, which was not significantly different. However, chemotherapy patients with hypogonadism had a higher PAI-1 concentration (median, 35.0 ng/mL [range, 11.8 to 160.0 ng/mL] v median, 23.5 ng/mL [range, 3.0 to 183.0 ng/mL]; P = .048), a higher WHR (mean ± SD, 0.95 ± 0.07 v 0.91 ± 0.06; P = .045), and a higher diastolic blood pressure (mean ± SD, 94 ± 13 mmHg v 86 ± 12 mmHg; P = .014) than chemotherapy patients without. Chemotherapy patients with an elevated PAI-1 concentration (> 43 ng/mL in 25 [29%] of 86 patients) had lower concentrations of total testosterone (median, 15 nmol/L [range, 5 to 31 nmol/L] v median, 19 [range, 11 to 37 nmol/L]; P = .002), SHBG (mean ± SD, 20.4 ± 7.2 nmol/L v 25.4 ± 9.2 nmol/L; P = .020), and free testosterone (mean ± SD, 0.422 ± 0.122 nmol/L v 0.502 ± 0.146 nmol/L; P = .020) than chemotherapy patients with a normal PAI-1 concentration.
DISCUSSION
Long-term survivors of testicular cancer have an increased risk for cardiovascular events 10 or more years after chemotherapy.9,10 The metabolic syndrome may be an important factor in the development of this increased cardiovascular risk. We investigated the associations between the metabolic syndrome and gonadal, adrenal, and thyroid hormones in long-term survivors of testicular cancer. Relevant hormonal axes may form important targets for intervention with the aim to reduce cardiovascular risk.
Gonadal endocrine function was clearly disturbed. Compared with healthy men from the general population, LH levels were increased in both patient groups, while total testosterone and free testosterone, the biologically active fraction, were decreased in chemotherapy-treated patients only. Decreased Leydig cell function following surgery alone could reflect a testicular cancer-related pre-existing impairment in testosterone production. However, increased LH levels have also been described in healthy men with unilateral orchidectomy because of trauma to or a benign lesion of the testes compared with controls,28,29 suggesting a compensatory reaction to decreased production by the remaining testicle. Therefore, increased LH levels in testicular cancer patients are likely to result from deleterious effects of both surgery and chemotherapy on overall testosterone production.
Inhibin B is a glycoprotein hormone that forms a negative feedback loop with FSH. Chemotherapy-induced testicular damage results in decreased inhibin B and increased FSH levels in patients with hematologic malignancies.30,31 Petersen et al previously demonstrated that inhibin B levels are impaired in testicular cancer patients before orchidectomy32 and further decrease after surgery.33 Inhibin B production is drastically reduced by cisplatin in vitro,34 but has not been studied in testicular cancer patients following cisplatin-based chemotherapy. We have now demonstrated that, while inhibin B is decreased and FSH is increased after orchidectomy only, cisplatin-based chemotherapy induces even lower inhibin B and higher FSH levels in testicular cancer survivors, suggesting additional damage to the remaining testicle.
Hypothyroidism has been described as a long-term complication of chemotherapy for testicular cancer. Two previously conducted studies with small patient numbers35,36 found higher TSH concentrations in chemotherapy-treated patients than in testicular cancer patients after orchidectomy only. In the present study, TSH was increased in one chemotherapy patient, in two controls, and in none of the stage I patients, whereas the mean TSH concentration was similar in all groups. Because our study comprised a larger group of patients, follow-up was more extended, and comparisons were made with healthy men as well, we feel that our results more accurately reflect long-term thyroid function, which is unaffected in most patients.
Adrenal and pituitary hormone production were also not affected by chemotherapy. Total urinary cortisol metabolite excretion and serum levels of DHEAS and IGF-1 did not differ between testicular cancer patients and controls, suggesting normal endocrine function.
In summary, only gonadal endocrine function is affected in long-term survivors of testicular cancer. Gonadal dysfunction may contribute to the development of the metabolic syndrome and its components in these men, similar to the development of hyperinsulinemia and an increased body fat mass in prostate cancer patients on androgen suppression therapy.37,38
The metabolic syndrome, a combination of hypertension, central obesity, and dyslipidemia, is associated with an increased risk of cardiovascular disease.39,40 After a median follow-up of 7 years, this syndrome was present in 26% and 36% of chemotherapy-treated patients and stage I patients, respectively. The metabolic syndrome was more prevalent in our testicular cancer survivors than in both our controls and most population studies.41,42 It was associated with increased concentrations of PAI-1 and t-PA, but not with microalbuminuria and hs-CRP. Treatment received, age at follow-up, and duration of follow-up were not associated with the metabolic syndrome. BMI and insulin, in contrast, were positively associated with the metabolic syndrome. This relation between obesity, insulin resistance, and the metabolic syndrome has already been demonstrated in the general population.43,44
Excessive increases in BMI following chemotherapy for testicular cancer have been previously reported,4 but the etiology is still unknown. Changes in BMI are probably not directly affected by treatment received, since BMI is similar in chemotherapy-treated and stage I patients in the present study and most other studies.9 Furthermore, testicular cancer survivors have similar or even slightly higher activity levels than men from the general population,45 suggesting that reduced physical activity will probably also not completely explain the development of obesity.
Hormonal dysfunction may form an alternative explanation for excessive BMI increase in testicular cancer survivors. Cortisol excess, hypogonadism, and hypothyroidism have been associated with increases in fat mass and decreases in lean body mass in otherwise healthy men. Furthermore, sex hormones and cortisol have been associated with obesity and the metabolic syndrome in the general population.13,18,46 In the present study, total testosterone and total urinary cortisol metabolite excretion, a measure of cortisol metabolism, were associated with BMI in chemotherapy-treated and stage I patients together. Furthermore, chemotherapy-treated patients with the metabolic syndrome had both an increased BMI and altered testosterone and urinary cortisol levels compared with patients without the syndrome. Although we cannot infer any causal relationships from these cross-sectional data, we hypothesize that hormonal alterations induce obesity, which, subsequently, induces insulin resistance and other components of the metabolic syndrome. Alternatively, obesity may develop as a result of other unknown factors, and induce hormonal changes, insulin resistance, and other components of the metabolic syndrome. Chemotherapy-treated patients with the metabolic syndrome not only had a higher BMI at follow-up, but they were already more obese at the time of treatment than patients without the syndrome. However, decreased testosterone production in testicular cancer survivors has been shown to be, at least partially, treatment-related in the present study and in previous studies.12 Therefore, although an effect of obesity on testosterone and urinary cortisol levels cannot be excluded, these hormonal alterations may themselves induce weight gain, and through this association, influence the development of the metabolic syndrome in testicular cancer survivors. Obviously, a prospective trial is needed to test the associations that were found in this cross-sectional study.
Testicular cancer and other disorders of male reproduction, such as impaired semen quality and undescended testis, have been suggested to be more or less severe symptoms of one underlying entity, the so-called testicular dysgenesis syndrome.47 Testicular dysgenesis may result from fetal exposure to endocrine disruptors (estrogens, antiandrogens) together with genetic factors. It is conceivable that these endocrine disruptors do not only influence the development of testicular cancer, but also that of the metabolic syndrome. Therefore, an increased incidence of the metabolic syndrome may also be intrinsically present in patients with testicular cancer, independent of an effect of treatment.
If we assume that androgens play a role in the development of the metabolic syndrome, testosterone supplementation may be useful.48 Replacement studies in overtly hypogonadal men have demonstrated a reduction in fat mass and an increase in lean body mass. To date, only one testosterone replacement study has been performed in cancer patients,49 in which 35 men with mild androgen deficiency, as a result of chemotherapy for hematologic malignancies a median of 8 years earlier, were treated with androgen replacement therapy for 12 months. Treatment resulted in a small but significant reduction in LDL cholesterol, but no changes in other lipids, BMI, or fat mass. Therefore, while testosterone replacement therapy has positive effects on cardiovascular risk factors in men with overt hypogonadism, the benefits may be insufficient in those with only mild androgen deficiency. However, the effects of testosterone replacement therapy in survivors of testicular cancer are unknown, because no studies have specifically investigated the effects of testosterone supplementation on cardiovascular risk factors in survivors of testicular cancer who have only one remaining testicle. Therefore, it would be interesting to investigate the effects of testosterone replacement in testicular cancer survivors with low androgen levels in a randomized controlled trial.
In conclusion, we have investigated disturbances in hormone levels and their associations with the metabolic syndrome in testicular cancer survivors following cisplatin-based chemotherapy. We found impaired gonadal endocrine function, but no disorders of the adrenal, thyroid, and pituitary axes. Total testosterone levels were decreased and urinary cortisol metabolite excretion was increased in chemotherapy-treated patients with the metabolic syndrome. These hormonal alterations were also associated with BMI and may, through this association, play a role in the development of the metabolic syndrome, which is associated with an increased risk of cardiovascular disease.39,40 The impact of the metabolic syndrome may be more pronounced in testicular cancer survivors, who are known to have decreased fibrinolysis and a high prevalence of microalbuminuria.8 The benefits of pharmacologic intervention, either by testosterone supplementation or by the use of insulin-sensitizing agents as a more direct approach to treat the metabolic syndrome, should be tested in a randomized controlled trial.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant RUG2000-2177 from the Dutch Cancer Society.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Howell SJ, Radford JA, Adams JE, et al: Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy. Clin Endocrinol (Oxf) 55:315-324, 2001(Janine Nuver, Andries J. )
ABSTRACT
PURPOSE: The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men.
PATIENTS AND METHODS: We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone–binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine.
RESULTS: Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FSH were higher, and inhibin B and total and free testosterone were lower in chemotherapy patients than controls. Adrenal and thyroid hormone production were unaffected. Chemotherapy patients with the metabolic syndrome (n = 22; 26%) had a higher body mass index (BMI) pretreatment, a larger BMI increase during follow-up, lower total testosterone, and higher urinary cortisol metabolite excretion than those patients without the metabolic syndrome. BMI and insulin were associated with the metabolic syndrome, while total testosterone and urinary cortisol metabolite excretion were associated with BMI.
CONCLUSION: We found gonadal dysfunction, but normal adrenal and thyroid function. Through its association with BMI, testosterone may play a role in the development of the metabolic syndrome in long-term TC survivors.
INTRODUCTION
In survivors of testicular cancer, cardiovascular morbidity is increasingly recognized as a long-term complication of bleomycin- and cisplatin-containing chemotherapy. Hypertension, dyslipidemia, overweight, and insulin resistance, all components of the metabolic syndrome, have been reported in many, though not all, studies.1-6 Although the etiology of the metabolic syndrome and its related features in testicular cancer survivors is not clear, this syndrome may increase the risk for cardiovascular disease.7 Components of the metabolic syndrome together with early signs of atherosclerosis have been reported in testicular cancer survivors several years postchemotherapy.8 Furthermore, recent studies have shown an increased risk for cardiovascular events 10 or more years after treatment,9-11 justifying concern for long-term vascular toxicity.
Gonadal dysfunction is considered another long-term complication of treatment. Radiotherapy and chemotherapy, but also surgery alone, are associated with an increased risk of either overt or compensated (normal total testosterone, but elevated luteinizing hormone [LH] levels) Leydig cell dysfunction.12 Gonadal hormones have been associated with an increased cardiovascular risk and with severity of atherosclerosis in diabetes mellitus patients and healthy men. Furthermore, low levels of serum testosterone and sex-hormone–binding globulin (SHBG) have been associated with obesity, dyslipidemia, and insulin resistance, and with markers of vascular damage in cross-sectional studies.13-17 Recently, Laaksonen et al18 have specifically investigated the associations between sex hormones and the metabolic syndrome. In a large population-based study, they found that nondiabetic middle-aged men with low-normal concentrations of total and free testosterone and SHBG were more likely to have the metabolic syndrome and its associated features than men with high-normal sex hormone levels, independent of body mass index (BMI).
Associations have also been reported between the components of the metabolic syndrome and adrenal, thyroid, and pituitary hormones. Low levels of dehydroepiandrosterone sulfate, cortisol excess, growth-hormone deficiency, and hypothyroidism are associated with cardiovascular risk factors, like obesity, dyslipidemia, and insulin resistance.19-21 Furthermore, cortisol metabolism has been implicated in the development of the metabolic syndrome.22
Few previously conducted studies have investigated gonadal function in large groups of testicular cancer survivors.12,23 In the remaining studies, patient numbers were usually small and comparisons with healthy men were generally lacking. In most cases, only LH and total testosterone were analyzed, and no data on other hormones were reported. Moreover, the relationships between hormone levels and cardiovascular risk factors have not been investigated in testicular cancer survivors. Hormone levels in blood may differ between testicular cancer patients and healthy men, either as an adverse effect of treatment or as a result of endocrine disruption related to the development of testicular cancer. We hypothesize that alterations in hormone levels affect the development of the metabolic syndrome in testicular cancer survivors, contributing to an increased risk for cardiovascular disease. Relevant hormones may form potential targets for intervention in this population.
The present trial was carried out to investigate (1) whether gonadal, adrenal, thyroid, and pituitary hormonal disturbances were present in long-term survivors of testicular cancer, (2) which factors contributed to hormonal disturbances, and (3) whether hormonal disturbances were associated with the metabolic syndrome and its related features in these testicular cancer survivors. Measurements were performed in disseminated nonseminomatous testicular cancer patients who had been treated with unilateral orchidectomy and cisplatin-based chemotherapy, in stage I testicular cancer patients who had been treated with unilateral orchidectomy only, and in healthy men of comparable age.
PATIENTS AND METHODS
Patients
All patients with disseminated nonseminomatous testicular cancer who had been successfully treated with unilateral orchidectomy and cisplatin-based chemotherapy at the University Hospital Groningen (Groningen, the Netherlands) between July 1988 and April 1999 were approached to participate. Extragonadal testicular cancer, radiotherapy, testosterone replacement therapy, and age older than 55 years at the start of chemotherapy were exclusion criteria. Patients with stage I nonseminomatous testicular cancer, free of disease after unilateral orchidectomy only, and apparently healthy men were also included. Healthy men were recruited through advertisements in our hospital and in a local newspaper, and originated from the same geographic area (the northern part of the Netherlands) as patients. The study was approved by the medical ethical review committee of the University Hospital Groningen, and written informed consent was obtained from each participant.
Cardiovascular Risk Factors
Data on patient weight before start of chemotherapy were collected from medical records. During follow-up investigations, a physical examination was performed with measurements of weight, height, hip circumference (broadest part), and waist circumference (at umbilical level). BMI was calculated by dividing weight (in kilograms) by height (in meters) squared. Waist-hip ratio (WHR) was calculated by dividing waist circumference by hip circumference. Blood pressure was measured using a standard sphygmomanometer.
Fasting blood samples were analyzed for lipids (triglycerides, total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and total cholesterol/HDL cholesterol ratio), glucose, and insulin levels. Insulin-to-glucose ratio (IGR), a measure of insulin resistance, was calculated by dividing fasting serum insulin (pmol/L) by fasting plasma glucose (mmol/L).
Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III).24 According to the NCEP ATP III, the metabolic syndrome was determined by three or more of the following criteria: abdominal obesity (waist circumference > 102 cm), a high triglyceride concentration ( 1.7 mmol/L), a low HDL cholesterol concentration (< 1.0 mmol/L), a high fasting plasma glucose concentration ( 6.1 mmol/L), or high blood pressure ( 130/85 mmHg). Microalbuminuria (defined as a urinary albumin excretion of 30-300 mg/24 hours), plasminogen activator inhibitor type 1 (PAI-1), tissue-type plasminogen activator (t-PA), and high-sensitivity C-reactive protein (hs-CRP), were also determined, because these factors have been associated with the metabolic syndrome in the general population, and have been previously described8 to be increased in chemotherapy-treated testicular cancer patients compared with controls. PAI-1 antigen (reference values, 4 to 43 ng/mL) and t-PA antigen (reference values, 1 to 10 ng/mL) were measured using an enzyme-linked immunosorbent assay (ELISA) (Asserachrom, Diagnostica Stago, Asnieres-sur-Seine, France), and hs-CRP (lower limit of detection, 0.16 mg/L) was measured using the BNII Nephelometer (Dade Behring, Brussels, Belgium).
Hormones
Blood samples for all hormone measurements were taken in the morning after an overnight fast. LH (reference values, 2.1 to 10.0 U/L), follicle-stimulating hormone (FSH; reference values, 1.8 to 7.2 U/L), and thyroid-stimulating hormone (TSH; reference values, 0.4 to 5.0 mU/L) were measured using a fluoroimmunoassay (AutoDelfia, PerkinElmer/Wallac Oy, Turku, Finland).9 Estradiol (reference values, 0.05 to 0.22 nmol/L), dehydroepiandrosterone sulfate (DHEAS), and total testosterone were measured using a radioimmunoassay (Packard 1500/1600/2700, PerkinElmer, Groningen, the Netherlands).9 Insulin-like growth factor type 1 (IGF-1) was measured using a chemiluminescent microparticle immunoassay (Advantage, Nichols Institute Diagnostics, San Juan Capistrano, CA), after which z scores were calculated. Inhibin B was measured using an ELISA (Oxford Bio-Innovation LTD, Oxfordshire, United Kingdom; lower limit of detection, 10 ng/L)25and SHBG (reference values, 12 to 30 nmol/L) was measured using a binding assay. Free testosterone was calculated using the formula by Vermeulen et al,26 in which testosterone concentration is corrected for both SHBG and albumin levels. Primary hypogonadism, defined as a total testosterone concentration less than 10 nmol/L and/or an LH concentration 10 U/L, was also determined.
Excretion of the cortisol metabolites tetrahydrocortisone (THE), tetrahydrocortisol (THF), and alloTHF was measured in 24-hour urine samples. Total metabolite excretion (THE + THF + alloTHF) was used as a measure of cortisol excretion rate.27
Statistical Analysis
For continuous variables, differences between the three groups were evaluated by analysis of ranks (Kruskal Wallis), using Duncan's method for correction of multiple testing. Differences between two groups were tested using either a t test or a Mann-Whitney test for normally distributed and skewed data, respectively. Categoric variables were evaluated using a Pearson 2 test. Double-sided P values less than .05 were considered to be significant.
Linear regression analyses were performed to test the effects of different variables on the metabolic syndrome and its components. Age at follow-up, age at time of treatment, chemotherapy treatment, duration of follow-up, BMI at follow-up, WHR, and hormone levels were entered as independent variables in the regression models. A P value of < .10 was used to enter, and P < .05 to remove, variables from the models.
RESULTS
Eighty-six chemotherapy patients, 44 stage I patients, and 47 healthy male controls participated. Most chemotherapy-treated patients (80%) had received a combination of bleomycin, etoposide, and cisplatin, while the remaining patients had received either etoposide and cisplatin (9%), or another cisplatin-based chemotherapeutic regimen (11%). Duration of follow-up was similar in chemotherapy-treated and stage I patients (median follow-up, 7 years; range, 3 to 13 years) and all groups were comparable with respect to age (median age of chemotherapy patients, 37 years; range, 20 to 65 years; median age of stage I patients, 36 years; range, 24 to 63 years; median age of controls, 37 years; range, 22 to 55 years).
Cardiovascular Risk Factors
Cardiovascular risk factors are listed in Table 1. Although differences were small, chemotherapy patients had significantly higher levels of triglycerides and total cholesterol, a significantly higher total cholesterol/HDL cholesterol ratio, and a significantly increased BMI and WHR compared with controls. According to NCEP ATP III criteria, the metabolic syndrome was present in 22 chemotherapy patients (26%), in 16 stage I patients (36%), and in four controls (9%). Presence or absence of the metabolic syndrome could not be determined in two chemotherapy patients and in one control, due to missing variables. Prevalence of the metabolic syndrome was significantly different between both patient groups and controls (chemotherapy group v controls, P = .017; stage I group v controls, P = .002), but not between chemotherapy and stage I patients (P = .232). In chemotherapy patients with the metabolic syndrome compared with those without, PAI-1 (median, 55.0 ng/mL [range, 18.2 to 183.0 ng/mL] v median, 18.5 ng/mL [range, 3.0 to 113.0 ng/mL]; P = .000) and t-PA (mean ± standard deviation[SD], 11.3 ± 4.1 ng/mL v 7.1 ± 3.3 ng/mL; P = .000) were both increased, whereas hs-CRP and the prevalence of microalbuminuria did not differ.
Hormones
Table 2 lists the endocrine profiles of the three groups. Levels of total and free testosterone were lower and LH and estradiol higher in chemotherapy patients than in controls. SHBG concentrations did not differ between patients and controls. Inhibin B was decreased in chemotherapy patients compared with both stage I patients and controls, whereas FSH was increased. Stage I patients had lower free testosterone and inhibin B levels and higher LH and FSH concentrations than controls. Hypogonadism was present in 18 chemotherapy-treated testicular cancer patients (21%), in three stage I patients (7%), and in none of the controls (chemotherapy group v controls, P = .000; chemotherapy group v stage I group, P = .045).
Mean z scores of plasma IGF-1 were similar in all groups, suggesting normal growth hormone secretion. Mean TSH concentration did not differ between chemotherapy patients and controls, whereas TSH was more than 5 mU/L in one chemotherapy patient, in two controls, and in none of the stage I patients. Total urinary cortisol metabolite excretion and mean serum DHEAS concentration were comparable between groups, indicating normal adrenal function.
Hormones and the Metabolic Syndrome in Testicular Cancer Patients
Chemotherapy-treated testicular cancer patients with and without the metabolic syndrome had a similar age at follow-up and duration of follow-up, while BMI pretreatment, absolute BMI increase, and BMI at follow-up were increased in patients with the syndrome (Table 3). Furthermore, total urinary cortisol metabolite excretion was increased and total testosterone and SHBG concentrations were decreased in patients with the metabolic syndrome compared with those without (Table 3). Thyroid, adrenal, and pituitary hormones did not differ between chemotherapy patients with and without the metabolic syndrome.
In testicular cancer patients, the effects on the metabolic syndrome and its components were tested for several variables: age at follow-up, age at time of treatment, chemotherapy treatment, duration of follow-up, BMI at follow-up, WHR, and the following hormones: insulin, total testosterone, SHBG, free testosterone, DHEAS, estradiol, TSH, IGF-1, and total urinary cortisol metabolites. Regression analysis showed that a model with BMI and insulin as independent variables was significantly associated with the metabolic syndrome (BMI, beta coefficient =.048; P < .001; insulin, beta coefficient =.025; P = .001; R-value of model, 0.616). BMI was significantly associated with a regression model containing insulin (beta coefficient = .273; P < .001), urinary cortisol metabolite excretion (beta coefficient =.054; P = .031), and serum total testosterone concentration (beta coefficient = –.129; P = .001) as independent variables (R-value of model, 0.667). One SD change in total testosterone concentration and total urinary cortisol metabolite excretion was associated with only small changes in BMI (–0.83 kg/m2 change in BMI per 6.4 nmol/L change in total testosterone; 0.78 kg/m2 change in BMI per 14.4 μmol/24 hours change in urinary cortisol metabolite excretion).
The metabolic syndrome was present in 5 (29%) of 17 chemotherapy patients with hypogonadism and in 17 (25%) of 67 chemotherapy patients with normal testosterone and LH levels, which was not significantly different. However, chemotherapy patients with hypogonadism had a higher PAI-1 concentration (median, 35.0 ng/mL [range, 11.8 to 160.0 ng/mL] v median, 23.5 ng/mL [range, 3.0 to 183.0 ng/mL]; P = .048), a higher WHR (mean ± SD, 0.95 ± 0.07 v 0.91 ± 0.06; P = .045), and a higher diastolic blood pressure (mean ± SD, 94 ± 13 mmHg v 86 ± 12 mmHg; P = .014) than chemotherapy patients without. Chemotherapy patients with an elevated PAI-1 concentration (> 43 ng/mL in 25 [29%] of 86 patients) had lower concentrations of total testosterone (median, 15 nmol/L [range, 5 to 31 nmol/L] v median, 19 [range, 11 to 37 nmol/L]; P = .002), SHBG (mean ± SD, 20.4 ± 7.2 nmol/L v 25.4 ± 9.2 nmol/L; P = .020), and free testosterone (mean ± SD, 0.422 ± 0.122 nmol/L v 0.502 ± 0.146 nmol/L; P = .020) than chemotherapy patients with a normal PAI-1 concentration.
DISCUSSION
Long-term survivors of testicular cancer have an increased risk for cardiovascular events 10 or more years after chemotherapy.9,10 The metabolic syndrome may be an important factor in the development of this increased cardiovascular risk. We investigated the associations between the metabolic syndrome and gonadal, adrenal, and thyroid hormones in long-term survivors of testicular cancer. Relevant hormonal axes may form important targets for intervention with the aim to reduce cardiovascular risk.
Gonadal endocrine function was clearly disturbed. Compared with healthy men from the general population, LH levels were increased in both patient groups, while total testosterone and free testosterone, the biologically active fraction, were decreased in chemotherapy-treated patients only. Decreased Leydig cell function following surgery alone could reflect a testicular cancer-related pre-existing impairment in testosterone production. However, increased LH levels have also been described in healthy men with unilateral orchidectomy because of trauma to or a benign lesion of the testes compared with controls,28,29 suggesting a compensatory reaction to decreased production by the remaining testicle. Therefore, increased LH levels in testicular cancer patients are likely to result from deleterious effects of both surgery and chemotherapy on overall testosterone production.
Inhibin B is a glycoprotein hormone that forms a negative feedback loop with FSH. Chemotherapy-induced testicular damage results in decreased inhibin B and increased FSH levels in patients with hematologic malignancies.30,31 Petersen et al previously demonstrated that inhibin B levels are impaired in testicular cancer patients before orchidectomy32 and further decrease after surgery.33 Inhibin B production is drastically reduced by cisplatin in vitro,34 but has not been studied in testicular cancer patients following cisplatin-based chemotherapy. We have now demonstrated that, while inhibin B is decreased and FSH is increased after orchidectomy only, cisplatin-based chemotherapy induces even lower inhibin B and higher FSH levels in testicular cancer survivors, suggesting additional damage to the remaining testicle.
Hypothyroidism has been described as a long-term complication of chemotherapy for testicular cancer. Two previously conducted studies with small patient numbers35,36 found higher TSH concentrations in chemotherapy-treated patients than in testicular cancer patients after orchidectomy only. In the present study, TSH was increased in one chemotherapy patient, in two controls, and in none of the stage I patients, whereas the mean TSH concentration was similar in all groups. Because our study comprised a larger group of patients, follow-up was more extended, and comparisons were made with healthy men as well, we feel that our results more accurately reflect long-term thyroid function, which is unaffected in most patients.
Adrenal and pituitary hormone production were also not affected by chemotherapy. Total urinary cortisol metabolite excretion and serum levels of DHEAS and IGF-1 did not differ between testicular cancer patients and controls, suggesting normal endocrine function.
In summary, only gonadal endocrine function is affected in long-term survivors of testicular cancer. Gonadal dysfunction may contribute to the development of the metabolic syndrome and its components in these men, similar to the development of hyperinsulinemia and an increased body fat mass in prostate cancer patients on androgen suppression therapy.37,38
The metabolic syndrome, a combination of hypertension, central obesity, and dyslipidemia, is associated with an increased risk of cardiovascular disease.39,40 After a median follow-up of 7 years, this syndrome was present in 26% and 36% of chemotherapy-treated patients and stage I patients, respectively. The metabolic syndrome was more prevalent in our testicular cancer survivors than in both our controls and most population studies.41,42 It was associated with increased concentrations of PAI-1 and t-PA, but not with microalbuminuria and hs-CRP. Treatment received, age at follow-up, and duration of follow-up were not associated with the metabolic syndrome. BMI and insulin, in contrast, were positively associated with the metabolic syndrome. This relation between obesity, insulin resistance, and the metabolic syndrome has already been demonstrated in the general population.43,44
Excessive increases in BMI following chemotherapy for testicular cancer have been previously reported,4 but the etiology is still unknown. Changes in BMI are probably not directly affected by treatment received, since BMI is similar in chemotherapy-treated and stage I patients in the present study and most other studies.9 Furthermore, testicular cancer survivors have similar or even slightly higher activity levels than men from the general population,45 suggesting that reduced physical activity will probably also not completely explain the development of obesity.
Hormonal dysfunction may form an alternative explanation for excessive BMI increase in testicular cancer survivors. Cortisol excess, hypogonadism, and hypothyroidism have been associated with increases in fat mass and decreases in lean body mass in otherwise healthy men. Furthermore, sex hormones and cortisol have been associated with obesity and the metabolic syndrome in the general population.13,18,46 In the present study, total testosterone and total urinary cortisol metabolite excretion, a measure of cortisol metabolism, were associated with BMI in chemotherapy-treated and stage I patients together. Furthermore, chemotherapy-treated patients with the metabolic syndrome had both an increased BMI and altered testosterone and urinary cortisol levels compared with patients without the syndrome. Although we cannot infer any causal relationships from these cross-sectional data, we hypothesize that hormonal alterations induce obesity, which, subsequently, induces insulin resistance and other components of the metabolic syndrome. Alternatively, obesity may develop as a result of other unknown factors, and induce hormonal changes, insulin resistance, and other components of the metabolic syndrome. Chemotherapy-treated patients with the metabolic syndrome not only had a higher BMI at follow-up, but they were already more obese at the time of treatment than patients without the syndrome. However, decreased testosterone production in testicular cancer survivors has been shown to be, at least partially, treatment-related in the present study and in previous studies.12 Therefore, although an effect of obesity on testosterone and urinary cortisol levels cannot be excluded, these hormonal alterations may themselves induce weight gain, and through this association, influence the development of the metabolic syndrome in testicular cancer survivors. Obviously, a prospective trial is needed to test the associations that were found in this cross-sectional study.
Testicular cancer and other disorders of male reproduction, such as impaired semen quality and undescended testis, have been suggested to be more or less severe symptoms of one underlying entity, the so-called testicular dysgenesis syndrome.47 Testicular dysgenesis may result from fetal exposure to endocrine disruptors (estrogens, antiandrogens) together with genetic factors. It is conceivable that these endocrine disruptors do not only influence the development of testicular cancer, but also that of the metabolic syndrome. Therefore, an increased incidence of the metabolic syndrome may also be intrinsically present in patients with testicular cancer, independent of an effect of treatment.
If we assume that androgens play a role in the development of the metabolic syndrome, testosterone supplementation may be useful.48 Replacement studies in overtly hypogonadal men have demonstrated a reduction in fat mass and an increase in lean body mass. To date, only one testosterone replacement study has been performed in cancer patients,49 in which 35 men with mild androgen deficiency, as a result of chemotherapy for hematologic malignancies a median of 8 years earlier, were treated with androgen replacement therapy for 12 months. Treatment resulted in a small but significant reduction in LDL cholesterol, but no changes in other lipids, BMI, or fat mass. Therefore, while testosterone replacement therapy has positive effects on cardiovascular risk factors in men with overt hypogonadism, the benefits may be insufficient in those with only mild androgen deficiency. However, the effects of testosterone replacement therapy in survivors of testicular cancer are unknown, because no studies have specifically investigated the effects of testosterone supplementation on cardiovascular risk factors in survivors of testicular cancer who have only one remaining testicle. Therefore, it would be interesting to investigate the effects of testosterone replacement in testicular cancer survivors with low androgen levels in a randomized controlled trial.
In conclusion, we have investigated disturbances in hormone levels and their associations with the metabolic syndrome in testicular cancer survivors following cisplatin-based chemotherapy. We found impaired gonadal endocrine function, but no disorders of the adrenal, thyroid, and pituitary axes. Total testosterone levels were decreased and urinary cortisol metabolite excretion was increased in chemotherapy-treated patients with the metabolic syndrome. These hormonal alterations were also associated with BMI and may, through this association, play a role in the development of the metabolic syndrome, which is associated with an increased risk of cardiovascular disease.39,40 The impact of the metabolic syndrome may be more pronounced in testicular cancer survivors, who are known to have decreased fibrinolysis and a high prevalence of microalbuminuria.8 The benefits of pharmacologic intervention, either by testosterone supplementation or by the use of insulin-sensitizing agents as a more direct approach to treat the metabolic syndrome, should be tested in a randomized controlled trial.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant RUG2000-2177 from the Dutch Cancer Society.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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