Opioids and the Hypothalamic-Pituitary-Gonadal (HPG) Axis


Context: Hypogonadism is a well-established consequence of opioid use. It has been reported in both men and women, although more widely studied in men.

Evidence Acquisition: PubMed was searched for articles in English until December 2019 for opioids and hypogonadism. Bibliography of retrieved articles was searched for relevant articles.

Evidence Synthesis: The prevalence of opioid-induced hypogonadism (OIH) varies between studies but was reported to be 69% in a recent systematic review. There is large heterogeneity in the studies, with different factors shown to have a stronger association with hypogonadism such as specific types of opioids, higher doses, and longer durations of use. The consequences of OIH include sexual dysfunction, depression, decreased quality of life, and low bone density. There is a paucity of randomized controlled trials assessing the efficacy of testosterone replacement therapy (TRT) for OIH in men, and even fewer studies on treating OIH in women. TRT studies in men reported varying outcomes with some studies favoring and others showing no clear benefit of TRT on different measures.

Conclusions: Despite the high prevalence of OIH, it remains underrecognized and undertreated with multiple endocrine and metabolic consequences. A reasonable approach in patients using opioids includes informing them of this complication and its potential consequences, screening for signs and symptoms of hypogonadism then sex hormone levels if prolonged opioid use > 3 months, and treating patients diagnosed with hypogonadism, if and when clinically indicated, with sex hormones if chronic opioids are planned to be continued for ≥ 6 months. (J Clin Endocrinol Metab 105: 1–9, 2020)


Opioid-induced hypogonadism is a well-established problem during the opioid epidemic, with a high prevalence of 69% reported based on a recent systematic review and meta-analysis (17). The prevalence in the literature varies widely depending on multiple factors, such as the definition of hypogonadism, type and duration of action of opioid, and dose, indication, and duration of opioid use. Opioid-induced hypogonadism has multiple endocrine and metabolic consequences including reduced quality of life, sexual dysfunction, and low BMD. However, there is a paucity of RCTs assessing the efficacy of TRT in male opioid-induced hypogonadism and there are even fewer studies on treating opioid-induced hypogonadism in women. The studies evaluating TRT in men are mostly observational, with conflicting results. We need more RCTs to better inform our treatment decisions and assess the benefits of TRT in this population. Despite our lack of understanding of the effects of TRT on opioid-induced hypogonadism in men, it might be reasonable to consider treatment to improve bone health and possibly sexual dysfunction symptoms because of the discontinuation or at least dose reduction of opioids is not always feasible. Given the lack of recognition of this condition, it is important for endocrinologists to recognize, screen for, diagnose, and treat this condition, in the absence of contraindications, to possibly improve patient outcomes. A reasonable approach is outlined in Figure 2 and would include informing all patients on opioids or planned to start prolonged opioid treatment of this complication to the gonadal axis and its potential consequence, screening all patients on chronic opioids for more than 3 months for signs and symptoms of hypogonadism and sex hormone levels if present, and treating patients diagnosed with hypogonadism, if clinically indicated, with sex hormones if chronic opioids are planned to be continued for at least 6 months.



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Figure 2. Suggested algorithm for the evaluation and management of opioid-induced hypogonadism (OIH). Reduced sexual function, reduced QoL, depression, decreased BMD, decreased muscle mass, increased fat mass. §Men: decreased libido, decreased erections, depression, anemia, decreased muscle mass/strength; women: amenorrhea, menstrual irregularities. Abbreviations: E2, estradiol; HRT, hormonal replacement therapy; PRL, prolactin; S&S, signs, and symptoms; T, testosterone; TRT, testosterone replacement

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