J Cachexia Sarcopenia Muscle (2012) 3:149–155 151 Fig. 1 Illustration of pituitary– gonadal axis in healthy individuals (a) and in cancer patients (b). Increased ghrelin, decreased leptin, and medications (opioids and glucocorticoids) suppress LH production, thereby causing central hypogonadism. Increased inflammation, certain chemotherapeutic agents, and changes in ghrelin and leptin may also contribute to hypogonadism by downregulating testicular production of testosterone directly. Dashed lines indicate a decrease in the pathway a b Leptin LH/FSH Ghrelin Muscle mass/strength Mood & libido Testosterone Mood & libido Sexual function Muscle mass/strength Testosterone Sexual function Opioids Glucocorticoids LH/FSH Ghrelin Leptin Cytokines Chemotherapy sex hormones. Both animal and human models have shown that restoring normal levels of leptin results in normalization of the hypothalamic–pituitary–gonadal axis and reversal of infertility and delayed puberty [22, 23], providing further support to this hypothesis. Leptin replacement also has resulted in normalization of starvation-induced fall in reproductive hormones in male subjects [24]. As leptin is secreted by adipocytes, fat atrophy can potentially cause hypogonadism by decreas- ing leptin levels [25]. This could potentially explain the higher prevalence of hypogonadism in cancer cachexia subjects as they suffer from significant fat mass loss and have been shown to have lower leptin levels than subjects with cancer but without cachexia [26]. 3.3 Ghrelin Ghrelin is a 28-amino acid peptide which is primarily involved in the control of food intake and growth hor- mone secretion. Its levels increase in anticipation of a meal and with weight loss correlating inversely with leptin levels. Based on this, it also has been proposed as a nutrient signal that links reproduction and nutrition. Animal data show that systemic or intracerebral adminis- tration of ghrelin causes significant inhibitory responses in the secretion of LH and to a lesser extent FSH [27–29]. In a male rat model, chronic ghrelin adminis- tration resulted in a significant drop in serum LH and testosterone levels [30]. In a healthy human study of ten