Prostate cancer (PCa) is the most common malignancy in men. In 1941, Huggins and Hodges described the androgen-dependence of PCa and showed that castration decreases its growth. Six decades later, androgen-deprivation therapy (ADT) has become a common therapeutic option in men with recurrent or metastatic PCa. The modalities of ADT include surgery (orchiectomy) or medical therapy (gonadotropin releasing hormone GnRH agonists or antagonists), with most patients choosing the medical option. In some cases, androgen receptor antagonists are used in conjunction with GnRH analogues to prevent any influence of androgens derived from the adrenal glands on the prostate tissue. This is called combined androgen blockade. The adjuvant use of ADT in men with locally advanced PCa has resulted in a decrease in recurrence rate and an improvement in survival. A recent meta-analysis also found ADT to be effective for palliation in patients with advanced PCa and to improve survival in high-risk patients when used in combination with radiation therapy. Recently, there has been a trend of using ADT even in patients with early stage PCa, even though no survival advantage has been shown.
The aim of ADT is to achieve serum testosterone levels as low as possible, with current guidelines recommending levels <50 mg/dl (1.7 nmol/L)(normal range in young men being 300-1000 ng/dl). Male hypogonadism (of any etiology) is associated with numerous adverse effects. These include decreased libido, impotence, decreased lean body mass and muscle strength, increased fat mass, decreased quality of life and osteoporosis. Although these complications of hypogonadism are well known, newer complications have recently surfaced. Population studies have shown that testosterone levels below the normal male range are an independent risk factor for diabetes and metabolic syndrome. Since men undergoing ADT have castrate levels of testosterone, they may be at a higher risk of developing these metabolic complications. At a time when this link between male hypogonadism and diabetes is emerging, studies show that cardiovascular disease has recently become the most common cause of mortality in men with PCa, overtaking PCa-related mortality. Hence, it is conceivable that the use of ADT (and resulting hypogonadism) may trigger the development of these metabolic complications, which in-turn may lead to increased cardiovascular disease. A prospective study of 22 men with PCa undergoing ADT showed a significant increase in serum insulin levels from a baseline of 11.8 mU/l to 19.3 mU/l after three months of ADT;however, there was no significant change in plasma glucose levels. Another 3-month prospective study showed that ADT resulted in a 63% increase in fasting insulin, without any changes in fasting glucose. A recent 3-month prospective study using combined androgen blockade showed a 26% increase in insulin from baseline, again indicating the development of insulin resistance. Although there was no significant change in glucose levels, a significant increase (3%) in glycosylated hemoglobin was seen. These observations suggest that insulin resistance (manifested by hyperinsulinemia) develops within a few months of ADT;however, this compensatory hyperinsulinemia is sufficient to prevent the development of diabetes for a while. But eventually it is not, and so glucose levels rise. A recent cross-sectional study evaluated metabolic complications of long-term ADT. A total of 53 men were evaluated, 18 with PCa undergoing ADT for at least 12 months (ADT group), 17 age-matched eugonadal men with non-metastatic PCa who had undergone prostatectomy and/or radiotherapy and were not androgen-deprived and were recently found to have a rising PSA (non-ADT group) and 18 age-matched eugonadal controls (Control Group). None of the men had known history of diabetes mellitus. The mean duration of ADT was 45 months (range 12-101 months). The non-ADT group was enrolled to account for any influence of the disease (PCa) on these metabolic parameters and the control group was enrolled to control for metabolic changes that occur with aging. After adjusting for age and BMI, men in the ADT group had significantly higher insulin levels and insulin resistance, measured as Homeostasis Model Assessment for Insulin Resistance (HOMAIR), compared to the other two groups. However, the key finding of the study was the prevalence of fasting hyperglycemia in the ADT group. The mean glucose level in the ADT group was 131 mg/dl compared to 103 mg/dl and 99 mg/dl in the non-ADT and control groups, respectively. Interestingly, 44% of men in the ADT group had fasting glucose level >126 mg/dl (a criterion for the diagnosis of diabetes mellitus) compared to 12% and 11% in the non-ADT and control groups, respectively. Since the data were adjusted for age and BMI, it appears that these metabolic changes could be directly attributed to hypogonadism in the ADT group. The authors concluded that the reason for the higher prevalence of hyperglycemia in the ADT group was the longer duration of ADT compared to previous reports. Since then, a 6-month prospective study has also shown significant hyperglycemia;however, insulin levels were not evaluated. Though ADT is beneficial in a subset of patients with PCa, it is associated with a host of endocrine complications. Among these, metabolic complications such as insulin resistance, hyperglycemia and metabolic syndrome have recently surfaced and may be responsible for the increased cardiovascular mortality seen in men with PCa. Although the studies in this field are limited, it appears that short-term ADT (3-6 months) leads to the development of insulin resistance without causing hyperglycemia. However, long-term ADT (12 months or longer) is associated with frank diabetes. Furthermore, metabolic syndrome is present in more than half of the men undergoing long-term ADT. It appears that hypogonadism resulting from ADT leads to adverse body composition (increased fat mass) which leads to elaboration of inflammatory cytokines. This leads to insulin resistance and over time, frank diabetes. However, the long-term studies of ADT are cross-sectional and do not establish causality between hypogonadism and the development of these metabolic complications. Therefore, prospective studies are needed in men with newly diagnosed PCa who are hormone-naive and follow them long-term to determine the timing of onset of these metabolic complications and to identify patients who are at risk of developing them. Furthermore, prevention of these metabolic complications with insulin sensitizers needs to be studied. Hence, we plan to embark upon a long-term prospective study to answer these questions.
