152 male subjects, ghrelin administration was associated with significantly lower mean plasma levels of both LH and testosterone than placebo [31]. Similar effects of ghrelin on LH were published by Lanfranco et al. [32]. We published that cancer patients had significantly higher active ghrelin levels than healthy controls, and the ghre- lin levels correlated inversely with free and bioavailable testosterone [7]. All of these studies suggest that higher levels of ghrelin through its inhibitory effects on LH can contribute to hypogonadism in the setting of negative energy balance as seen in patients with advanced cancer. 3.4 Opioids Use of opioids in cancer patients is very common as these patients suffer from significant pain from their primary disease. It has been shown that opioids have the potential of causing secondary hypogonadism in non-cancer patients with pain [33–35]. The exact mechanism by which opioids cause hypogonadism is not entirely known; however, a few theories have been suggested. Opioids cause the disruption of the normal pulsatility of gonadotrophin releasing hor- mone (GnRH) secretion through δ-receptors present on GnRH neurons [36]. They are also occasionally reported to increase prolactin levels, thereby reducing testosterone secretion [37]. Moreover, testosterone concentrations drop more than 50% within a few hours of taking an opioid, usually returning to baseline within 24–72 h after withdrawal [38]. In a small observational study of 54 men taking oral opioids including methadone for non-malignant pain, levels of free and total testosterone were subnormal in 56% and 74% of patients, respectively [39]. Similar results have been seen in cancer patients. Fraser et al. reported a hypogonadism preva- lence of 75% in male cancer subjects receiving oral opioids for chronic pain [40]. In another study, 18 out of 20 of male cancer survivors who had received high-dose opioids orally had lower total testosterone level compared to 8 out of 20 matched cancer survivors who did not receive opioids [8]. Taken together, the data strongly suggest that opioids play an important role in the pathogenesis of hypogonadism in cancer patients. 3.5 Chemotherapy Alkylating and other chemotherapeutic agents at high doses are known to cause hypogonadism in cancer patients. This is believed to be related to the dose-dependent direct toxic effect of these agents on the gonads especially on Leydig cell function [41]. There have been multiple studies showing elevated LH levels and low to normal testosterone levels in cancer patients receiving chemotherapy, suggesting damage of the hypothalamic–pituitary–gonadal axis at the testicular level [42, 43]. Howell et al. [41] measured testosterone and J Cachexia Sarcopenia Muscle (2012) 3:149–155 LH levels in 135 men treated for lymphomas. They found 44 men (31%) with significantly higher LH level compared to a cohort of age-matched controls in the presence of a testoster- one levels in the lower half of the normal range or frankly low. However, it is important to note that non-standard, high cumulative doses of chemotherapy are required to cause significant and persistent impairment of Leydig cell func- tion and subsequent hypogonadism in cancer patients. 4 Hypogonadism, symptom burden, and quality of life in cancer patients It has been suggested that androgen deficiency is an important component of the Cancer Anorexia–Cachexia Syndrome (CACS) [44]. Hypogonadism due to any cause significantly affects quality of life in affected individuals and is associated with symptoms such as decreased appetite, decreased energy level and fatigue, insomnia, low libido, sexual dysfunction, depressed mood, fatigue, sarcopenia, and weakness [45, 46]. Appetite and body weight are affected in cancer patients with hypogonadism. In our previous work, we found a direct correlation between appetite scores and free and bioavailable testosterone in cancer patients [7]. Skipworth et al. showed that hypogonadal cancer male patients experienced greater percentage weight loss than eugonadal cancer patients (16.7% vs. 11.3%) [47]. Chlebowski et al. reported a 66% prevalence of hypogonadism in metastatic cancer patients, where >80% of the patients were at <90% of ideal body weight [10]. Todd and colleagues reported a negative cor- relation of total testosterone with BMI and mid-arm cir- cumference in men with advanced cancer [9]. Hypogonadism also affects the functional and emotional well-being in cancer subjects. In a recently published study, cancer survivors with hypogonadism had lower scores in short-term health survey and functional assessment of chronic illness—fatigue (FACIT-F) questionnaire suggesting poor quality of life and increased fatigue in cancer patients [48]. Fleishman and colleagues [11] showed similar results in hypo- gonadal cancer patients. They used Functional Assessment of Cancer Therapy—Prostate (FACT-P) questionnaire to mea- sure different aspects of quality of life and found that hypo- gonadal cancer patients scored worse in the total as well as physical and functional well-being component of the ques- tionnaire when compared to eugonadal cancer subjects. Strasser et al. showed that hypogonadal patients with cancer (on the basis of low free testosterone) had higher scores in anxiety and depression measured by Hospital Anxiety and Depression Scale, lower functional and emotional well-being measured by Functional Assessment of Cancer Therapy, and higher fatigue measured by FACIT-F [3]. Sexual dysfunction is another problem that hypogonadal cancer patients encounter. Most of the data on sexual