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Background Whereas biochemical response is often used as a primary study outcome, improvement in symptoms and health-related quality of life (HRQoL) is the relevant goal for patients to consider treatment successful. We performed a systematic review and meta-analysis to assess the effect of treatment on symptoms and HRQoL in acromegaly. Methods Seven electronic databases were searched for longitudinal studies assessing patient-reported symptoms or HRQoL in acromegaly. Meta-analyses were performed to assess differences during treatment for the Acromegaly Quality of Life Questionnaire (AcroQoL) and Patient-Assessed Acromegaly Symptom Questionnaire (PASQ), and standardized mean difference (SMD) for individual symptoms (interpretation: 0.2 small, 0.5 moderate, and 0.8 large effect). Treatment-naive and previously treated patients were assessed separately. Results Forty-six studies with 3301 patients were included; 24 contributed to quantitative analyses. Thirty-six studies used medication as main treatment, 1 transsphenoidal adenomectomy, and 9 various treatments. Symptoms and HRQoL both improved: AcroQoL increased 2.9 points (95% CI, 0.5 to 5.3 points), PASQ decreased –2.3 points (95% CI, –1.3 to –3.3 points), and individual symptom scores decreased for paresthesia –0.9 (95% CI, –0.6 to –1.2), hyperhidrosis –0.4 (95% CI, –0.1 to –0.6), fatigue –0.3 (95% CI, –0.1 to –0.6), arthralgia –0.3 (95% CI, –0.1 to –0.5), headache –0.3 (95% CI, 0.0 to –0.6), and soft-tissue swelling –0.2 (95% CI, 0.0 to –0.4). Conclusion Symptoms and HRQoL improved during acromegaly treatment. Consensus is needed on which symptoms should be included in a potential core outcome set, taking into account symptom frequency, severity, and sensitivity to change, which can be used in clinical practice and as outcome in trials.

ContextThe 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.ObjectiveThe aim of this systematic review and meta-analysis was to assess the effects of opioid use on pituitary function.MethodsEight 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 synthesis52 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.ConclusionsHypogonadism 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.

OBJECTIVE The increased use of opioids has resulted in an unprecedented opioid epidemic, with non-negligible numbers of opioid-induced deaths. It is well-known that chronic opioid use affects the activity of the gonadal axis, but the frequency of this and other potential pituitary hormone deficiencies remains unclear. The aim of this systematic review and meta-analysis was to systematically review the effect of exogenous opioids on endocrine function METHODS Following the PRISMA statement, eight electronic databases were searched in May 2018 for randomized, and observational studies assessing endocrine function in patients using exogenous opioids. A random effects model meta-analysis was performed to obtain weighted proportions of hypogonadism and hypocortisolism with a 95% confidence interval. Due to the heterogeneity in studies, meta-analysis for the effects on other axes, and for subgroups could not be performed, and is systematically reviewed. RESULTS 52 articles were included with 18.428 patients in total. The patient population consisted mainly of pain patients (n=21 studies), patients on maintenance treatment for opioid addiction (n=9) and healthy volunteers (n=4) with similar opioid effects between these groups. Morphine (n=17) was mostly used, followed by methadone (n=15) and opioid dose defined as morphine equivalent daily dose (MEDD) (n=14) with no difference in effects between groups. Based on 15 studies containing 3.250 patients (% male: 99.5) on chronic opioids, the prevalence of hypogonadism was 65% (95% CI: 57% to 73%, I2=91.16%). Based on 5 studies with a total of 207 patients (% male: 57.5), the prevalence of hypocortisolism, based on non-dynamic testing, was 19% (95% CI: 10%, 29%, I2=74.21). Results of the systematic review showed an increasing trend for serum prolactin concentrations, and no clear effects on the somatotropic (n=5) and thyrotropic axes (n=7). Six studies reported that testosterone replacement in opioid induced hypogonadism increased testosterone levels, but clinical effects were not reported. CONCLUSION While the evidence on other endocrine axes remains insufficient, hypogonadism occurs in more than half of the male chronic opioid users, and hypocortisolism in approximately a fifth of all patients. Periodical evaluation of endocrine function, especially of the activity of the gonadal and adrenal axes, is mandatory in these patients. More studies are needed on the effects of chronic opioid use on the female gonadal axis and the other endocrine axes, also focusing on experienced symptoms and symptom management.