Adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas leading to Cushing's disease are rare with an incidence of 1.2-2.4 per million per year, but are the most common cause of endogenous hypercortisolism. 1,2 Elevated ACTH stimulates excessive adrenal cortisol production leading to the classic clinical and biochemical features of Cushing's syndrome with associated increased morbidity and mortality. 2 Hypothalamic-pituitary-adrenal (HPA) axis dysregulation due to Cushing's disease also affects other pituitary hormones causing secondary hypothyroidism, hypogonadotropic hypogonadism, decreased antidiuretic hormone (ADH) and growth hormone (GH) secretion. 3,4 The HPA axis and the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis are closely regulated. Glucocorticoids are required for physiological GH secretion, however supraphysiological glucocorticoid levels lead to disorderly GH secretion with variable serum IGF-1 concentrations reported, 5 which may confound the assessment of pituitary tumour secretory status. GH is secreted in a pulsatile manner and binds to receptors on hepatocytes and systemic tissues leading to increased IGF-1. 6 Circulating IGF-1 is approximately 99% bound to IGF-binding proteins (IGFBPs), prolonging Summary Objective: To determine if patients with untreated Cushing's disease have higher serum insulin-like growth factor-1 (IGF-1) compared to matched controls, and if IGF-1 decreases following remission of Cushing's disease.Design: Retrospective case-control study matching Cushing's disease cases to control patients for adenoma size, age, sex, diabetic and gonadal status, body mass index and serum IGF-1 measured within one year. Paired analysis of pre-operative (untreated) and >3 months post-operative (remission) serum IGF-1 for cases.
Patients and measurements: All patients were investigated at the Princess AlexandraHospital Endocrine Unit between 2005 and 2017. Serum IGF-1 was measured in 25 cases and 49 controls, 23 case-control pairs and 13 cases pre-and post-operatively.Results: Mean serum IGF-1 in cases was significantly higher compared to controls-32 ± 12 nmol/L compared to 25 ± 8 nmol/L, (P = 0.005). The proportion of cases with elevated serum IGF-1 above an age-adjusted reference range was higher compared to 1:1 matched controls (8/23 (35%) vs 1/23 (4%), P = 0.02). In 13 cases in remission post-operatively, serum IGF-1 decreased significantly from 31 (IQR 29-40.5) nmol/L to 23 (IQR 15-28.5) nmol/L, (P < 0.001), despite no difference in the prevalence of pre-vs post-operative pituitary hormone dysfunction (P = 0.47).
Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene encoding menin, is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (NETs). Development of these tumours is associated with wide variations in their severity, order and ages (from <5 to >80 years), such that life-long screening is required. To improve tumour surveillance and quality of life, better circulating biomarkers, particularly for pancreatic NETs that are associated with a higher mortality, are required. We therefore examined the expression of circulating microRNAs (miRNAs) in serum of MEN1 patients. Initial profiling analysis followed by qRT-PCR validation studies identified miR-3156-5p to be significantly downregulated (-1.3-5.8-fold, p<0.05-0.0005) in 9 MEN1 patients, compared to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human pancreatic NET cells resulted in reduced MEN1 (49%, p<0.05), menin (54%, p<0.05) and miR-3156-5p expression (20%, p<0.005), compared to control-treated cells, suggesting that miR-3156-5p downregulation is a consequence of loss of MEN1 expression. In silico analysis identified mortality factor 4 like 2 (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, p<0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 expression (1.5-fold, p<0.05), compared to control treated cells, thereby confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse relationship between miR-3156-5p and MORF4L2 expression represents a potential serum biomarker that could facilitate the detection of NET occurrence in MEN1 patients.
Overnight metyrapone test within the first week after pituitary surgery was no better than an early morning cortisol level at predicting glucocorticoid requirement at 6 months. OMT at week 6 demonstrated recovery of HPA axis in a substantial proportion of participants who failed earlier assessments; thus, definitive testing should be delayed until 6 weeks post-operatively.
Objective
To determine whether early (4‐8h) post‐operative ACTH after trans‐sphenoidal surgery (TSS) predicts long‐term hypothalamic–pituitary–adrenal (HPA) axis function and to investigate early morning day 1 ACTH/cortisol variability using rapid sampling.
Design
Prospective observational study.
Methods
Participants undergoing TSS were included; those treated with glucocorticoids pre‐operatively received 100 mg intravenous hydrocortisone on anaesthetic induction. ACTH and cortisol were measured post‐operatively at + 4h and + 8h after induction and on day 1 every 10 minutes between 0700h and 0900h. Primary outcome: glucocorticoid requirement at 6 months.
Results
Nineteen participants (10F, 9M): 6/19 (32%) were treated with replacement glucocorticoids pre‐operatively; 4 had ceased by 6 weeks post‐operatively. One patient developed new hypopituitarism post‐operatively meaning 3/19 (16%) required glucocorticoids at 6 months. Post‐operative + 4h ACTH < 14.3 pmol/L (65 ng/L) predicted secondary adrenal insufficiency (SAI) (sensitivity 100%, specificity 75%), whilst no participant with a post‐operative + 4h ACTH ≥ 14.3 pmol/L (65 ng/L) required glucocorticoids at 6 months. Day 1 ACTH and cortisol showed a significant circadian fall between 0700h‐0900h; ACTH 4.2 pmol/L (IQR 2.9‐5.9) to 3.7 pmol/L (IQR 2.9‐5.1) P = .006 and cortisol 549 nmol/L (IQR 337‐618) to 439 nmol/L (IQR 315‐606) P < .001, with clinically insignificant ultradian secretory pulses.
Conclusions
No participant with a post‐operative + 4h ACTH ≥ 14.3 pmol/L (65 ng/L) required glucocorticoids at 6 months; however, given only 3/19 participants had the primary outcome of interest, this must be confirmed in a larger cohort. The timing of a day 1 morning cortisol between 0700h and 0900h influences the accuracy of a single cut‐off to diagnose SAI after pituitary surgery.
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