150 levels in patients with pancreatic adenocarcinoma were sim- ilar to the levels in control subjects [9]. Another study that evaluated gonadal hormonal function of 44 adult males with disseminated cancer found a prevalence of hypogonadism of 43% and 66% on the basis of total testosterone and free testosterone, respectively. However, this study included pri- marily malnourished cancer patients, in which 82% of patients were less than 90% of ideal body weight [10]. Sex hormone binding globulin (SHBG) levels are increased in cancer patients, so measuring free and bioavailable testoster- one is a more reliable and accurate way of determining the gonadal status of male patients than total testoste- rone level. Strasser et al. [3] reported a prevalence of hypogonadism of 64% in advanced incurable cancer patients based on free testosterone levels <35 ng/ml. Our group published data showing that cancer patients had mean total testosterone levels similar to the levels in an age-matched non- cancer control group but signifi- cantly lower levels of free and bioavailable testosterone [7]. Recently, Fleishman et al. reported the prevalence of hypogonadism in cancer patients based on total testos- terone (TT, <300 ng/dl), free testosterone (FT, <52 pg/dl), and bioavailable testosterone (BT, <95 ng/dl) to be 48%, 78%, and 66%, respectively [11]. Prevalence of hypogonadism is even higher in cancer patients with a history of cachexia (described as weight loss over the previous 6–12 months greater than 5%). In a Dutch study, male cancer patients who had lost less than 10% of their body weight had higher serum testosterone levels than those with weight loss greater than 10% [12]. Our group recently reported a strong association between BT and SHBG and appetite levels [7]. Post-hoc analyses showed a higher prevalence of hypogonadism defined as a BT <70 ng/ ml in cachectic subjects when compared to non-cachectic subjects in this cohort. 3 Pathogenesis of hypogonadism in cancer Although the exact mechanism of hypogonadism in cancer patients is not entirely known, it is thought to be multi- factorial. Patients with cancer may have a component of both types of hypogonadism: primary (testicular, hypergonadotro- phic, or with elevated luteinizing hormone—LH—and follic- ular stimulating hormone—FSH) and secondary (central, hypogonadotrophic, or with low or inappropriately normal FSH and LH). Factors associated with primary hypogonadism in this patient population include inflammatory cytokines and chemotherapeutic agents. On the other hand, factors respon- sible for the secondary/central hypogonadism include opioids, glucocorticosteroids, low leptin levels, and/or high concentra- tions of ghrelin (Fig. 1). J Cachexia Sarcopenia Muscle (2012) 3:149–155 3.1 Inflammation Inflammation is thought to play an important role in the pathogenesis of hypogonadism in cancer patients. Can- cer like other chronic diseases is a pro-inflammatory state with elevated levels of inflammatory cytokines [13, 14]. It has been postulated that cytokines may have a direct effect on the hypothalamic–pituitary–gonadal axis. This was supported by a study of 15 healthy male subjects who were injected with subcutaneous recombi- nant IL-6. Results showed that testosterone levels were suppressed acutely in these healthy individuals after IL-6 administration without apparent changes in gona- dotrophin levels [15]. Also, animal data have suggested that inflammatory cytokines may have an inhibitory effect on Leydig cell steroidogenesis, thereby affecting the hypothalamic–pituitary–gonadal axis at the level of testes [16–18]. The mechanism by which IL-6 inhibits the Leydig cell steroidogenesis is unclear, but it has been postulated that it may negatively affect the activity of 3β-hydroxysteroid dehydrogenase, one of the key enzymes for testosterone synthesis [17]. On the other hand, Malkin et al. showed that 1 month of testosterone replacement given to 27 male patients with hypogonadism resulted in a statistically significant reduction in inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1β [19], and Kalinchenko et al. showed that testosterone replacement decreased C-reactive protein (CRP), IL-1β, and TNF-α in hypogonadal men with the metabolic syndrome [20]. Similar immunosuppressive and anti- inflammatory actions of androgens were seen in study of patients with rheumatoid arthritis who were treated with oral testosterone [21]. In light of these studies, inflammation is likely to play a very important role in the pathogenesis of hypogonadism in cancer patients, and low testosterone can, in turn, exacerbate or maintain the pro-inflammatory state forming a vicious circle. 3.2 Leptin Leptin is a hormone secreted by adipocytes in propor- tion to fat mass, and it is responsible for regulating energy homeostasis (food intake and energy expendi- ture) at the level of the hypothalamus. Also, it is re- quired for normal LH and FSH secretion centrally and production of testosterone in the gonads, providing the link between nutrition and reproduction. It has been proposed that low leptin levels (as seen in starvation or in the setting of cachexia) function as a nutrient sensor and provide a peripheral signal to the brain that the environment may not be favorable for reproduction due to unavailability of food, leading to a decrease in