The effects of opioids on the endocrine system: an overview.

Opioids commonly used for pain relief may lead to hypogonadism, which is characterised by suppression of production of the gonadotropin-releasing hormone (GnRH) resulting in inadequate production of sex hormones. The aim of this narrative review was to highlight the effects of opioids on the endocrine system and the development of hypogonadism. MEDLINE, EMBASE and Cochrane Library were searched for relevant articles investigating hypogonadism in patients undertaking opioid therapy by using a combination of both indexing and free-text terms. The suppression of GnRH leading to a decrease in sex hormones has been described as the principal mechanism of opioid-induced hypogonadism. However, there is no consensus on the threshold for the clinical diagnosis of hypogonadism. Evidence indicates that chronic opioid use can lead to hypogonadism. Clinicians should be aware of symptomatology associated with hypogonadism and should regularly monitor patients with appropriate laboratory investigations.

Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance.

PPARgamma is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARgamma in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARgamma coactivators and inhibit coexpressed wild-type receptor. Expression of PPARgamma target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARgamma action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. METHODS: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. RESULTS: 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7-0.79) vs. 0.66 mm (0.61-0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4-41.8) vs. 2.65 (0.94-7.44), p = 0.0004]. CONCLUSIONS: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.

HbA1c predicts the likelihood of having impaired glucose tolerance in high-risk patients with normal fasting plasma glucose.

BACKGROUND: Although the oral glucose tolerance test (OGTT) is the 'gold standard' for diagnosing prediabetes/diabetes, it is inconvenient for the patient and time consuming. The only alternative simple screening test is fasting plasma glucose (FPG). FPG concentrations of > 6.0 mmol/L represent prediabetes/diabetes. FPG concentrations of < or = 6.0 mmol/L may be considered 'normal', although some such patients will demonstrate abnormal glucose tolerance when subjected to an OGTT. We have evaluated the use of glycated haemoglobin (HbA1c) as a screening test for diabetes or impaired glucose tolerance (IGT) in patients who have risk factors for diabetes but FPG < or = 6.0 mmol/L. METHODS AND RESULTS: A total of 580 patients with at least two risk factors for diabetes underwent an OGTT and HbA1c measurement. In all, 225 patients had a FPG < or = 6.0 mmol/L and met the inclusion criteria. Of these, 23.1% (n=52) had an abnormal OGTT result (45 had IGT and 7 had diabetes). Subjects with abnormal glucose tolerance had a higher percentage of HbA1c than subjects with normal glucose tolerance (P<0.001). An HbA1c of 5.6% gave an optimal sensitivity of 72% and specificity of 77% to predict a 2 h plasma glucose > or = 7.8 mmol/L. CONCLUSION: The use of FPG concentration followed by selective measurement of HbA1c in patients who are at high risk of developing diabetes may represent a reasonable approach to identifying patients requiring an OGTT.

Prevalence and influence of diagnostic criteria in the assessment of hypogonadism in intrathecal opioid therapy patients.

BACKGROUND: Hypogonadism is frequently diagnosed based on total testosterone (TT) levels alone. However, 99% of testosterone is bound to the sex hormone-binding globulin (SHBG) with only 1% free testosterone. Alternative assessment methods consist of assay of free testosterone (FT) or bioavailable testosterone (BT) by equilibrium dialysis, calculation of FT and BT through the Vermeulen equations, and calculation of the free androgen index (FAI). OBJECTIVES: The aim of this study was to investigate the prevalence of hypogonadism in male chronic non-cancer pain patients undertaking long-term intrathecal opioid therapy and the existence of diagnostic discrepancies according to the criteria used. STUDY DESIGN: Prospective observational study. SETTING: Department of Pain Management, Russells Hall Hospital, Dudley, United Kingdom. METHODS: Twenty consecutive male patients undertaking long-term intrathecal opioid therapy had the gonadal axis evaluated by assays of luteinising hormone (LH), follicle stimulating hormone (FSH), TT, SHBG and by calculating the FT, BT and FAI. RESULTS: Hypogonadism was present in 17 (85%) of the patients based on TT; 17 (85%) according to FT and BT calculations; and 14 (70%) when calculating FAI. Based on either TT or FT being low or borderline/low, 19 (95%) of the investigated patients were biochemically hypogonadal. Significant differences were observed between diagnosis based on FT and FAI (P < 0.05). No significant differences were observed between diagnosis based on TT and FT (P = 0.40) or TT and FAI (P = 0.20). CONCLUSION: Hypogonadism is common in patients undertaking intrathecal opioid therapy for the management of chronic non-malignant pain; however, diagnostic criteria can influence the diagnosis of this side effect. The assessment of the hypothalamic-pituitary-gonadal axis should include evaluation of total serum testosterone, free testosterone, or bioavailable testosterone.

Hypogonadism and low bone mineral density in patients on long-term intrathecal opioid delivery therapy.

OBJECTIVES: This study aimed to investigate the hypothalamic-pituitary-gonadal axis in a sample of male patients undertaking intrathecal opioid delivery for the management of chronic non-malignant pain and the presence of osteopaenia and/or osteoporosis in those diagnosed with hypogonadism. DESIGN: Observational study using health data routinely collected for non-research purposes. SETTING: Department of Pain Management, Russells Hall Hospital, Dudley, UK. PATIENTS: Twenty consecutive male patients attending follow-up clinics for intrathecal opioid therapy had the gonadal axis evaluated by measuring their serum luteinising hormone, follicle stimulating hormone, total testosterone, sex hormone binding globulin and calculating the free testosterone level. Bone mineral density was measured by DEXA scanning in those patients diagnosed with hypogonadism. RESULTS: Based on the calculated free testosterone concentrations, 17 (85%) patients had biochemical hypogonadism with 15 patients (75%) having free testosterone <180 pmol/L and 2 patients (10%) between 180 and 250 pmol/L. Bone mineral density was assessed in 14 of the 17 patients after the exclusion of 3 patients. Osteoporosis (defined as a T score ≤-2.5 SD) was detected in three patients (21.4%) and osteopaenia (defined as a T score between -1.0 and -2.5 SD) was observed in seven patients (50%). Five of the 14 patients (35.7%) were at or above the intervention threshold for hip fracture. CONCLUSIONS: This study suggests an association between hypogonadism and low bone mass density in patients undertaking intrathecal opioid delivery for the management of chronic non-malignant pain. Surveillance of hypogonadism and the bone mineral density levels followed by appropriate treatment may be of paramount importance to reduce the risk of osteoporosis development and prevention of fractures in this group of patients.

Redefining overweight and obesity in rheumatoid arthritis patients.

OBJECTIVES: To assess whether body mass index (BMI) and body fat (BF) differ between rheumatoid arthritis (RA) patients, patients with non-inflammatory arthritis (osteoarthritis, OA) and healthy individuals, and whether disease specific measures of adiposity are required to accurately reflect BF in these groups. METHODS: 641 individuals were assessed for BMI (kg/m(2)) and BF (bioelectrical impedance). Of them, 299 (174 RA, 43 OA and 82 healthy controls (HC)) formed the observation group and 342 (all RA) the validation group. RA disease characteristics were collected. RESULTS: ANOVA revealed significant differences between disease groups for BMI (p<0.05) and BF (p<0.001). ANCOVA showed that age accounted for the differences in BMI (F(1,294) = 5.10, p<0.05); age (F(1,293) = 22.43, p<0.001), sex (F(1,293) = 380.90, p<0.001) and disease (F(2, 293) = 18.7, p<0.001) accounted for the differences in BF. For a given BF, patients with RA exhibited BMI levels reduced by 1.83 kg/m(2) (p<0.001) compared to HC; there were no significant differences between OA and HC. A predictive model for BF was developed (R(2) = 0.769, p<0.001) and validated using limits of agreement Analysis against measured BF in the validation group (95%LIM(AG) = 6.17; CV = 8.94). CONCLUSIONS: In individuals with RA, BMI cut-off points should be reduced by 2 kg/m(2) (that is, to 23 kg/m(2) for overweight and 28 kg/m(2) for obesity). The equation developed can be used to accurately predict BF from BMI in RA patients. These findings may be important in the context of the cardiovascular comorbidity of RA.

The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency.

OBJECTIVE: The 1 microg ACTH stimulation test has been introduced to improve the sensitivity of ACTH as a test of the integrity of hypothalamic-pituitary-adrenal axis (HPAA). This study aims to compare the sensitivity, specificity and diagnostic accuracy of the "low-dose" 1 microg ACTH (LDACTH) test and the "standard dose" 250 microg ACTH (SDACTH) test, with the overnight metyrapone test (OMT) which assesses the entire HPAA. DESIGN: A prospective evaluation of the performance of SDACTH and LDACTH screening tests in a diverse cohort of patients with possible adrenal insufficiency as routinely encountered in clinical practice using the OMT as the reference method. PATIENTS: A total of 51 patients (26 with asthma on inhaled glucocorticoid, nine with hypopituitarism, three with hypothyroidism, one with hyponatraemia, one with Crohn's disease, one with encephalitis and 10 with non-specific symptoms) each underwent SDACTH, LDACTH and OMT tests in random sequence at least 1 week apart. MEASUREMENTS: Blood was sampled for plasma cortisol levels at 0 and 30 min after intravenous administration of 1 microg and 250 microg of ACTH. Metyrapone 30 mg/kg body weight was taken orally at midnight, and plasma samples were taken for measurement of 11-deoxycortisol and cortisol next morning between 08.00 and 09.00 h. The OMT was deemed to be abnormal when both 11-deoxycortisol and cortisol levels were less than 200 nmol/l. RESULTS: The sensitivity and specificity at an empirical "normal" plasma cortisol threshold value of 500 nmol/l were 67% and 100% for the SDACTH test, and 73% and 81% for the LDACTH test, respectively. As the plasma cortisol cut-off value was increased to 550 nmol/l and 600 nmol/l, the sensitivity of the SDACTH test was 67% and 80% and specificity was 97% and 92%, respectively. The sensitivity of the LDACTH test increased from 93% at plasma cortisol cut-off value of 550 nmol/l to 100% at plasma cortisol cut-off value of 600 nmol/l. However, the specificity of the LDACTH test fell from 72% to 56% as the plasma cortisol cut-off value was increased from 550 nmol/l to 600 nmol/l. A receiver operating characteristic curve demonstrated that the specificity of the SDACTH test was higher than the specificity of the LDACTH test at any given level of sensitivity. CONCLUSIONS: Both the LDACTH and SDACTH tests fail to achieve acceptable levels of sensitivity and specificity to be useful as screening tests for secondary adrenal insufficiency. In this context the OMT can be safely used to assess the integrity of the entire HPAA.