Objectives: Opioid analgesics are the main stay for cancer pain management; however, long-term opioid treatment (L-TOT) may suppress the endocrine system. This systemic review aimed at investigating effects of L-TOT on the endocrine system in patients with cancer-related pain. Methods: A search on MEDLINE, EMBASE and Web of Science databases was performed. Inclusion criteria were clinical studies investigating endocrine measures in adult patients with cancer-related pain in L-TOT (≥4 weeks). Outcomes and quality of evidence were assessed. Results: A total of 252 abstracts were identified; out of which 247 were excluded and five cross-sectional studies were included and analyzed. L-TOT was associated with lower serum concentration levels of total- and free testosterone in males, follicular stimulating hormone in females, and luteinizing hormone in both sexes. Moreover, higher morphine equivalent daily doses (MEDDs) were correlated with higher levels of cortisol and lower levels of LH in both sexes, and lower levels of total- and free testosterone in males. Sexual dysfunction was associated with low sex hormone levels. Level of evidence was low/very low. Conclusions: The studies identified demonstrated that patients with cancer-related pain in L-TOT may have gonadal hypofunction causing sexual dysfunction, which may be correlated with opioid dose level. In addition, high serum concentrations of cortisol were positively correlated with high opioid dose levels. However, the evidence was weak and further research is necessary. PROSPERO, ID-number: CRD42020213059.