Opioids and Their Endocrine Effects

A Systematic Review and Meta-Analysis

Friso de Vries; Mees Bruin; Daniel J. Lobatto; Olaf M. Dekkers; Jan W. Schoones; Wouter R. van Furth; Alberto M. Pereira; Niki Karavitaki; Nienke R. Biermasz; Amir H. Zamanipoor Najafabadi


J Clin Endocrinol Metab. 2020;105(4) 

In This Article

Abstract and Introduction


Context: The increased use of opioids has resulted in an unprecedented opioid epidemic. Chronic opioid use causes hypogonadism, but its frequency, as well as the effects of opioids on other hypothalamo–pituitary–end organ hormone axes, remains unclear.

Objective: The aim of this systematic review and meta-analysis was to assess the effects of opioid use on pituitary function.

Methods: Eight electronic databases were searched for articles published up to May 8, 2018. Fixed or random effects meta-analysis was performed to estimate pooled proportions with 95% confidence intervals (CI). This study is reported following the PRISMA and MOOSE guidelines.

Data synthesis: 52 studies (22 low risk of bias) were included describing 18 428 subjects, consisting of patients with chronic pain (n = 21 studies) or on maintenance treatment for opioid addiction (n = 9) and healthy volunteers (n = 4). The most frequently used opioid was methadone (n = 13 studies), followed by morphine (n = 12). Prevalence of hypogonadism was 63% (95% CI: 55%–70%, 15 studies, 3250 patients, 99.5% males). Prevalence of hypocortisolism relying on dynamic and nondynamic testing was 15% (95% CI: 6%–28%, 5 studies, 205 patients, 57.5% males) and including only studies using the insulin tolerance tests 24% (95% CI 16%–33%, 2 studies, n = 97 patients). In 5 out of 7 studies, hyperprolactinemia was present. No clear effects on the somatotropic and hypothalamo–pituitary–thyroid axes were described.

Conclusions: Hypogonadism occurs in more than half of male opioid users, and hypocortisolism in approximately one-fifth of all patients. Periodical evaluation of at least the gonadal and adrenal axes is therefore advisable


Over the past two decades, the use of opioids and the number of opioid overdose-related deaths has steadily increased.[1] In the United States alone, there were more than 11 million people with misused prescription opioids and 42 000 opioid-related deaths were reported in 2016.[2–4] Long-term opioid use is associated with adverse effects, the most common being constipation, nausea, and dyspepsia.[5,6] In addition, several studies suggest that the endocrine system is affected in opioid users.[7,8]

In addition, many animal studies have been performed on the mechanisms of opioid-induced endocrine effects. It has been shown that opioids inhibit the gonadal axis in the hypothalamus via ε-receptors and stimulate prolactin secretion via μ-, κ-, and δ-receptors. Thus, gonadotropin-releasing hormone (GnRH) release and the gonadal axis may be additionally suppressed by opioid-induced hyperprolactinemia.[2] Lastly, opioids induce the conversion of testosterone to dihydrotestosterone.[9] The corticotropic axis may be modulated via effects on the κ- and δ-receptors in the hypothalamus and pituitary gland and the somatotroph axis via μ-, κ-, and δ-receptors in the hypothalamus.[2]

Although hypogonadism and, to a lesser extent, hypocortisolism are recognized endocrine side effects, their prevalence remains unclear.[10,11] Dysfunction of both axes may result in significant, often incapacitating symptoms.[2] Both male and female patients with hypogonadism may suffer from sexual dysfunction and decreased libido. Male patients can present with erectile dysfunction, impotence, and gynecomastia, while female patients can have menstrual irregularities. In addition, hypocortisolism can manifest a wide variety of symptoms, such as fatigue, malaise, abdominal discomfort, anorexia, and orthostatic hypotension. Possible effects of opioids on the secretion of growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin remain unelucidated and have not been systematically reviewed.[2,12–17]

Due to the increased use of opioids, it has become increasingly important to identify the prevalence and impact of opioid exposure-related endocrine deficits. Our goal was, therefore, to assess the reported effects of opioids on the endocrine system through a systematic review and meta-analysis.