Cushing\'s syndrome (CS) secondary to adrenocorticotropic hormone (ACTH) producing tumours is a severe condition with a challenging diagnosis. Ectopic ACTH-secretion often involves neuroendocrine tumours (NET) in the respiratory tract. ACTH-secreting small intestine neuro-endocrine tumours (siNET) are extremely rare entities barely reported in literature. This review is illustrated by the case of a 75-year old woman with fulminant ectopic CS caused by a ACTH-secreting metastatic siNET. Severe hypokalemia, fluid retention and refractory hypertension were the presenting symptoms. Basal and dynamic laboratory studies were diagnostic for ACTH-dependent CS. Extensive imaging studies of the pituitary and thorax-abdomen areas were normal, while [68Ga]Ga-DOTATATE PET-CT revealed increased small intestine uptake in the left iliac fossa. The hypercortisolism was well controlled with somatostatin analogues, after which a debulking resection of the tumour was performed. Pathological investigation confirmed a well-differentiated NET with sporadic ACTH immunostaining and post-operative treatment with somatostatin analogues was continued with favourable disease control.

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and \"symptomatic\" etiology. Obesity and Cushing\'s syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.

Measurement of basal adrenocorticotropic hormone (ACTH) concentration is the most commonly used diagnostic test for pituitary pars intermedia dysfunction (PPID). Although several pre-analytical and analytical factors have been reported to affect basal ACTH concentrations in equids, the extent to which these have been evaluated in the context of PPID diagnosis is unclear. The objectives of this scoping review were to identify and systematically chart current evidence about pre-analytical and analytical factors affecting basal ACTH concentrations in adult domestic equids. Systematic searches of electronic databases and conference proceedings were undertaken in June 2022, repeated in October 2022 and updated in August 2023. English language publications published prior to these dates were included. Screening and data extraction were undertaken individually by the authors, using predefined criteria and a modified scoping review data extraction template. After removal of duplicates, 903 publications were identified, of which 235 abstracts were screened for eligibility and 134 publications met inclusion criteria. Time of year, exercise, breed/type and transportation were the factors most frequently associated with significant increases in ACTH concentration (n = 26, 16, 13 and 10 publications, respectively). Only 25 publications reported inclusion of PPID cases in the study population, therefore the relationship between many factors affecting basal ACTH concentration and diagnostic accuracy for PPID remains undefined. However, several factors were identified that could impact interpretation of basal ACTH results. Findings also highlight the need for detailed reporting of pre-analytical and analytical conditions in future research to facilitate translation of evidence to practice.

Data on silent corticotroph tumor (SCT) are still heterogeneous and controversial. In this study, we aimed to compare the demographic, clinicopathological manifestations, postoperative complications, and patient outcomes of SCTs with other non-functioning pituitary neuroendocrine tumor (NFT) and functioning corticotroph tumor (FCT) or so-called Cushing disease adenoma.
We searched PubMed and Web of Science for data of interest. Odds ratio (OR), mean difference (MD), hazard ratio (HR), and their 95% confidence intervals (CI) were pooled using the random-effect model.
Twenty-nine studies with 985 SCTs were included in meta-analyses. In comparison to other NFTs, SCTs were more commonly associated with female gender, younger age, cavernous sinus invasion, apoplexy, and radiotherapy administration. Postoperatively, SCT patients were more likely to experience hypocortisolism, new-onset visual disturbances, and a higher risk for tumor progression than other NFTs. We did not find any significant differences between SCT type I and type II. Compared to FCTs, SCTs were more likely male, older age, and had larger tumor sizes. The prevalence of a USP8 mutation was significantly higher in FCT than in SCT.
SCT was demographically, clinicopathologically, and prognostically distinct from other NFTs and FCTs. These tumors should be considered high-risk; appropriate treatment decisions and more stringent follow-up should be tailored to improve patient outcomes.

We aimed to perform a retrospective analysis of a rare subtype of corticotroph adenoma, Crooke\'s cell adenoma, to better understand its clinical features.
We collected T-PIT-positive pituitary adenomas and screened Crooke\'s cell adenomas from January 2020 to December 2021 in our center. Case reports of such tumors were also collected through a literature search. Clinical data such as biochemical tests, imaging examinations, and pathological data of the above cases were analyzed.
A total of 101 T-PIT-positive patients were treated in our center in the last 2 years, and 4 were finally pathologically diagnosed with Crooke\'s cell adenomas. All of these patients were male with elevated adrenocorticotropic hormone levels, and 50.0% presented with hypercortisolemia, Cushing\'s syndrome, visual impairment, and headache. The tumor diameter was significantly larger in these 4 patients (37.0 mm) than in the other patients (26.0 mm), and their tumor invasive behavior was more pronounced. Cases reported in the literature were mainly female (72.8%), and the clinical presentation was also dominated by Cushing\'s syndrome (65.1%) and hormonal dysfunction. Tumors were more common as macroadenomas (33.2 mm) and suprasellar growths (63.8%). The tumor recurrence rate was as high as 55.6%, with 6 cases progressing to pituitary carcinomas and 7.7% of tumor-related deaths. Our further integrated analysis of our center and reported cases revealed that gender, Cushing\'s syndrome, visual dysfunction, hormonal disorders, and tumor growth characteristics were statistically different in different tumor categories.
Crooke\'s cell adenoma is a tumor subtype with obvious clinical aggressive behavior, and an in-depth analysis of its clinical characteristics may assist in developing a comprehensive treatment plan.

OBJECTIVE: The limitations of adrenocorticotrophic hormone (ACTH) treatment for infantile spasms (ISs), such as high costs, limited availability, and adverse effects (AEs), make it necessary to explore whether corticosteroids are optimal alternatives. Many other compelling treatments have gone through trials due to the suboptimal effectiveness of hormonal therapy. A systematic review and meta-analysis were performed to evaluate the effectiveness and safety of hormonal therapy for patients with ISs.
METHODS: EMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and online registers were searched through April 2021 for randomized controlled trials (RCTs).
RESULTS: A total of 19 RCTs (N = 1,279) were included. There was no significant difference in the effectiveness of oral corticosteroids and ACTH in electro-clinical response (risk ratio [RR] = 0.85, 95% CI 0.41-1.76). Low-dose ACTH had similar effectiveness in electro-clinical response compared to usual-dose group (RR = 0.94, 95% CI 0.60-1.47) but conferred a lower risk of AEs (RR = 1.71, 95% CI 1.08-2.71). ACTH was more beneficial in controlling spasms than vigabatrin (VGB) (RR = 1.31, 95% CI 1.05-1.64) for patients without tuberous sclerosis complex (TSC). All RCTs were connected through network meta-analysis, and we found that ketogenic diet (KD), zonisamide, methylprednisolone, or combined treatment of hormonal therapy with topiramate (TPM) or pyridoxine was not different in electro-clinical response compared to usual-dose ACTH.
CONCLUSIONS: Our analysis showed that oral corticosteroids could be optional alternatives when ACTH is not applicable, and ACTH is more beneficial for patients without TSC. Moreover, low-dose ACTH is recommended due to comparative effectiveness but lower risk of AEs. However, due to the high heterogeneity of included patients and treatment protocols, these results must be interpreted with caution. RCTs with multicentric involvement and larger sample size are needed for solid evaluation of other alternative treatments.

BACKGROUND: Accuracy of baseline ACTH for the diagnosis of PPID in horses varies between studies.
OBJECTIVE: To estimate the diagnostic accuracy of ACTH as a biomarker for PPID in adult horses and appraise potential causes of heterogeneity.
METHODS: Systematic review and meta-analysis.
METHODS: A literature review identified studies reporting diagnostic accuracy data for extraction. Risk of bias was evaluated using QUADAS-2. Two random-effects models, the hierarchical summary receiver operating curve (HSROC) and the bivariate binomial normal model (BBN) were used to pool accuracy measurements. We performed meta-regression using study-level variables. The impact of diagnostic test accuracy on the frequency of false-positive and false-negative results at various pretest probabilities was calculated using the BBN model\'s accuracy results.
RESULTS: Patient selection and index test evaluation demonstrated significant risk of bias. Mean and 95% confidence intervals for sensitivity and specificity for all studies (n = 11) based upon the HSROC model were (0.72, 95% CI: 0.62 to 0.82) and (0.88, 95% CI: 0.79 to 0.93), respectively. When studies with a common positivity threshold of 35 pg/mL ACTH were evaluated (n = 6), sensitivity and specificity were (0.66, 95% CI:0.54 to 0.77) and (0.87, 95% CI: 0.74 to 0.94). In a hypothetical group of one thousand horses with PPID prevalence of 2%, 20%, and 90%, the frequency of resulting false-positive and false-negatives would be (127 and 7), (104 and 68) and (13 and 306), respectively. Factors leading to increased accuracy were case-control design, clinical reference standard and data-driven choice of ACTH threshold.
UNASSIGNED: A small number of primary studies (n = 11) were available, demonstrating significant biases.
CONCLUSIONS: Less biased studies examining diagnostic accuracy of ACTH are needed. In horses with a high pretest probability of PPID, ACTH may be a functional \"rule-in\" test. Baseline ACTH is not recommended for screening purposes or use in horses without clinical signs of PPID.

The \"fight or flight\" response to critical illness relies on increased cortisol availability, traditionally attributed to several-fold-increased cortisol production via hypothalamus-pituitary-adrenal-axis activation. Recent studies provided evidence against this concept with clinical implications. First, high cortisol availability during critical illness is driven by suppressed cortisol binding and reduced cortisol breakdown rather than increased cortisol production. This implies reduction of hydrocortisone doses when prescribed in ICU. Second, plasma ACTH is low, explained by feedback inhibition by peripherally driven high free cortisol and/or other central glucocorticoid-receptor ligands. Third, ICU patients have elevated plasma concentrations of the ACTH-precursor hormone, pro-opiomelanocortin, because of impaired pituitary processing into ACTH, and pro-opiomelanocortin could drive some adrenocortical cortisol production in face of low ACTH. Fourth, in prolonged critically ill patients, endogenously suppressed ACTH, aggravated by exogenous corticosteroids, associates with poor outcome. In long-stay ICU patients, central adrenal insufficiency may occur due to lack of trophic ACTH signaling. Finally, the Cosyntropin test is not suitable to assess adrenocortical reserve in ICU patients as the test is confounded by increased cortisol distribution volume. These insights necessitate further research focusing on the need, if any, of treating ICU patients with corticosteroids, and timing thereof, outside indications for pharmacological anti-inflammatory drugs.

Measurement of basal adrenocorticotrophic hormone (ACTH) is currently used to diagnose pituitary pars intermedia dysfunction (PPID) in horses, yet a systematic review of the evidence for its use has not been undertaken. This study aimed to systematically review evidence regarding the sensitivity and specificity of the basal ACTH diagnostic test. Electronic databases were systematically searched in January 2019, September 2020 and January 2021, for English language publications published prior to these dates. Screening, data extraction and quality assessment of publications was undertaken by the authors using predefined criteria. Study design, methodology and information reported in included studies were assessed using Standards for Reporting of Diagnostic Accuracy (STARD) checklists. Risk of bias and applicability were appraised using the Quality Assessment tool for Diagnostic Accuracy Studies (QUADAS-2) quality assessment tool. Due to identified biases and marked between-study variations, meta-analysis was not undertaken. After removal of duplicates, 415 publications were identified, of which 25 were evaluated in full, with 11 of these meeting inclusion criteria. In most studies, basal ACTH was reported to have good sensitivity (overall median 75.5%; interquartile range [IQR], 64.0-86.5%; range, 36.0-100%) and excellent specificity (overall median, 95.2%; IQR, 84.2-98.9%; range, 63.3-100%). However, QUADAS-2 and STARD assessment highlighted that studies did not utilise optimal study design and/or study populations for the evaluation of a diagnostic test and the majority were subject to bias, or provided insufficient information to fully assess possible biases. Based on this review, basal ACTH performed better at ruling out PPID than detecting it.

Scientific evidence related to the aromatase reaction in various biological processes spanning from mid-1960 to today is abundant; however, as our analytical sensitivity increases, a new look at the old chemical reaction is necessary. Here, we review an irreversible aromatase reaction from the substrate androstenedione. It proceeds in 3 consecutive steps. In the first 2 steps, 19-hydroxy steroids are produced. In the third step, estrone is produced. They can dissociate from the enzyme complex and either accumulate in tissues or enter the blood. In this review, we want to highlight the potential importance of these 19-hydroxy steroids in various physiological and pathological conditions. We focus primarily on 19-hydroxy steroids, and in particular on the 19-hydroxyandrostenedione produced by the incomplete aromatase reaction. Using a PubMed database and the search term \"aromatase reaction,\" 19-hydroxylation of androgens and steroid measurements, we detail the chemistry of the aromatase reaction and list previous and current methods used to measure 19-hydroxy steroids. We present evidence of the existence of 19-hydroxy steroids in brain tissue, ovaries, testes, adrenal glands, prostate cancer, as well as during pregnancy and parturition and in Cushing\'s disease. Based on the available literature, a potential involvement of 19-hydroxy steroids in the brain differentiation process, sperm motility, ovarian function, and hypertension is suggested and warrants future research. We hope that with the advancement of highly specific and sensitive analytical methods, future research into 19-hydroxy steroids will be encouraged, as much remains to be learned and discovered.