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BACKGROUND: The objective of this study was to determine whether hypogonadism and autonomic dysfunction contribute substantially to cancer-related fatigue, decreased sexual desire, and depression in male patients with advanced, incurable cancer. METHODS: Forty-eight patients who had received no major antineoplastic intervention for at least 2 weeks were tested for autonomic dysfunction by using Ewing tests. Total and free testosterone levels were measured. Multivariate analyses were performed to test the relation of these factors with the Functional Assessment of Cancer Therapy (FACT) (the Functional Assessment of Anorexia/Cachexia Therapy [FAACT] scale and the Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] subscale), the Hospital Anxiety and Depression Scale (HADS), the Edmonton Symptom Assessment Scale, the Sexual Desire Inventory, and sexual function (Cancer Rehabilitation Evaluation System subscale). Common causes for fatigue (anemia, depression, malnutrition, symptom distress, and medications) also were considered. RESULTS: Thirty-eight of 47 patients (81%) had autonomic dysfunction, although it was not associated significantly with the other variables examined. Twenty-nine of 45 patients (64%) had a low level of free testosterone (hypogonadism), which was correlated with the HADS Anxiety score (P = .002), the FACT Emotional Well-Being score (P = .02), and the HADS Depression score (P = .04). Hypogonadal men also had lower scores on the FACT Functional Well-Being scale (P = .01) and the FACIT-F subscale (P = .05). Men who reported symptoms related to weight loss (FAACT scale) had significantly lower levels of free testosterone (r = 0.34; P = .02) but did not differ from the other group in actual weight loss (P = .22). The total testosterone level was not appropriate for screening of hypogonadism unless the patients had values <100 ng/ mL. Logistic regression analysis failed to reveal a distinct multivariate model of autonomic dysfunction or hypogonadism that predicted clinical outcomes. CONCLUSIONS: Hypogonadism is a frequent condition in patients with advanced, incurable cancer and is associated with negative mood, fatigue, and symptoms related to anorexia/cachexia.