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The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single‐nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular‐endothelial cells and cortical‐neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/β‐catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single‐nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma‐specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal‐related pathologies. [ABSTRACT FROM AUTHOR]

Objective: Adrenal haemorrhage (AH) is an uncommon, usually incidental imaging finding in acutely unwell patients. AH has been reported during coronavirus disease 2019 (COVID‐19) infection and following ChAdOx1 nCoV‐19 (Oxford‐AstraZeneca) vaccination. The Society for Endocrinology (SfE) established a task force to describe the UK experience of COVID‐19‐related AH. Design: A systematic literature review was undertaken. A survey was conducted through the SfE clinical membership to identify patients with COVID‐19‐related AH using a standardized data collection tool. Results: The literature search yielded 25 cases of COVID‐19‐related AH (19 bilateral; 13 infection‐related, and 12 vaccine‐related). Eight UK centres responded to the survey with at least one case. A total of 18 cases were included in the descriptive study, including 11 from the survey and 7 UK‐based patients from the systematic review. Seven patients (4 males; median age 53 (range 26–70) years), had infection‐related AH (four bilateral). Median time from positive COVID‐19 test to AH detection was 8 (range 1–30) days. Eleven cases of vaccine‐related AH (eight bilateral) were captured (3 males; median age 47 (range 23–78) years). Median time between vaccination (nine Oxford‐AstraZeneca and two Pfizer‐BioNTech) and AH was 9 (range 2–27) days; 9/11 AH occurred after the first vaccine dose. Acute abdominal pain was the commonest presentation (72%) in AH of any cause. All 12 patients with bilateral AH and one patient with unilateral AH required glucocorticoid replacement. Conclusion: Adrenal haemorrhage with consequential adrenal insufficiency can be a complication of COVID‐19 infection and vaccination. Adrenal function assessment is mandatory to avoid the potentially fatal consequences of unrecognized adrenal insufficiency. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with still partially unknown pathogenesis, heterogenous clinical behaviour and no effective treatment for advanced stages. Therefore, there is an urgent clinical unmet need for better prognostication strategies, innovative therapies and significant improvement of the management of the individual patients. In this review, we summarize available studies on molecular prognostic markers and markers predictive of response to standard therapies as well as newly proposed drug targets in sporadic ACC. We include in vitro studies and available clinical trials, focusing on alterations at the DNA, RNA and epigenetic levels. We also discuss the potential of biomarkers to be implemented in a clinical routine workflow for improved ACC patient care. [ABSTRACT FROM AUTHOR]

The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin-like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF-1 and IGF-2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF-1 receptors. Interestingly, apparently non-functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors. [ABSTRACT FROM AUTHOR]

Objective LIN28 control cells reprogramming and pluripotency mainly through mi RNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic role of LIN28 and its regulatory mi RNAs in a large cohort of adrenocortical tumours ( ACTs). Patients and methods LIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analysed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let-7 family, mir-9, mir-30 and mir-125 in 28 carcinomas. Results LIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and nonaggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease-free survival in ACC patients ( P = 0·01), but for overall survival only a trend was detectable ( P = 0·117). In the multivariate analysis, only Ki67 index ≥10% ( HR 4·6, P = 0·000) and weak LIN28 protein expression ( HR 2·0, P = 0·03) were independent predictors of recurrence in ACC patients. Interestingly, mir-9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in nonaggressive ACCs [2076 (from 36 to 9307) vs 133·4 (from 2·4 to 5193); P = 0·011] and was highly associated with reduced overall ( P = 0·01) and disease-free survival ( P = 0·01). However, mir-9 prognostic role should be further evaluated in a larger cohort. Conclusion Weak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome. [ABSTRACT FROM AUTHOR]

Objective A common polymorphic variant of the growth hormone receptor (GHR) is because of genomic deletion of exon 3 and has been linked with increased responsiveness to exogenous GH. The impact of this polymorphism in acromegaly, a disease characterized by endogenous excess of GH and partial loss of IGF-I feedback on tumoural GH secretion, is not clear. The aim of this study was to investigate possible influences of d3GHR on the GH/IGF-I relationship and metabolic parameters in acromegaly. Design and methods Retrospective study on 76 acromegalic patients. Genotype analysis was carried out on leucocyte DNA by multiplex PCR assay. Clinical, hormonal and biochemical parameters at diagnosis were collected from patients’ medical records. Results Forty-two patients (55·3%) were homozygotes for the allele encoding the full-length GHR (fl/flGHR), 27 patients were heterozygotes (fl/d3) and seven homozygotes (d3/d3) for the genomic deletion of exon 3. Heterozygotes and homozygotes for the d3 allele were considered together (d3GHR) and compared with fl/flGHR patients. d3GHR and fl/flGHR patients showed no difference in GH and IGF-I levels or in the relationship between these two parameters. Patients bearing d3GHR had a lower body mass index (BMI) than patients bearing fl/flGHR (25·8 ± 2·1 vs. 28·1 ± 4·8 kg/m2, P < 0·05). Diabetes mellitus and hypertension were equally distributed, but more d3GHR patients had a normal glucose tolerance (66·7% vs. 56·3%, P < 0·05). The presence of d3GHR allele, and not BMI or age, was a significant negative predictor of insulin levels 120 min after oral glucose load ( β = −80·8, P < 0·05). Conclusions This study supports the hypothesis that the d3GHR is functionally different from the fl/fl variant mostly for the effects on body weight regulation and on glucose metabolism. [ABSTRACT FROM AUTHOR]

Objective The long-term efficacy and safety of stereotactic radiosurgery by gamma knife (GK) still remain unknown. The aim of the study was to investigate the long-term efficacy and tolerability of GK in acromegalic patients. Design and patients Retrospective analysis for a median follow-up of 10 years. Thirty-five acromegalic patients from two referral centres in Milan submitted to GK (median margin dose: 20 Gy, median % isodose: 50) between 1995 and 2004. Main outcome measures GH/IGF-I secretion, anterior pituitary function, radiological imaging and ophthalmological data. Results Cure rate improved over time (up to 46% at 10 years), as did the proportion of patients achieving control on somatostatin analogues (from 12·5% at baseline to 50% at 10 years). Normal IGF-I values were observed in 82% of patients at their last visit. No visual impairment, disease recurrence, tumour growth or secondary cerebral tumour occurred. Half of the patients developed one or more new deficiencies, while two patients normalized their prior failures. In particular, new onset of clinical or subclinical hypoadrenalism occurred in 12/30 patients (40%), hypothyroidism in 3/28 (11%), hypogonadism in 2/15 (13%) and GH deficiency in 2/35 (6%). GH value at the time of GK was the best negative predictor of cure and margin dose was the best positive predictor of new hypopituitarism. Conclusions Over a 10-year period after GK radiosurgery, an increasing percentage of patients achieve cure, or adequate control of the disease on pharmacological therapy, at the expense of increasing novel pituitary deficiencies. [ABSTRACT FROM AUTHOR]

Objective Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11β-hydroxysteroid dehydrogenase type 1 isoenzyme (11βHSD1) activity and reducing cortisone to cortisol conversion. The aim of the present study was to evaluate the hypothalamic–pituitary–adrenal (HPA) axis in children with idiopathic isolated GHD and normal pituitary magnetic resonance imaging (MRI) both before and during rhGH therapy. Design and patients This was a single-centre study of 10 consecutive children [five males and five females, mean age: 12·2 ± 1·0 year]. Evaluation was performed at baseline and on rhGH (mean duration: 10·9 ± 2·9 months, mean dose: 0·030 ± 0·002 mg/kg bw/day). Measurements HPA function was assessed by serum cortisol levels before and after appropriate provocative stimuli, that is, 1 µg ACTH test ( N = 5 patients) or insulin tolerance test (ITT, N = 5 patients), evaluating all children with the same stimulation test both before and during rhGH therapy. Central hypoadrenalism was excluded by the presence of either a peak of > 500 nmol/l or a rise in cortisol levels of > 200 nmol/l, after both tests. Results On rhGH therapy, serum IGF-I levels normalized, while serum cortisol and ACTH levels did not significantly differ from those recorded at baseline. The mean serum cortisol peak after both provocative tests was not significantly different on rhGH therapy and at baseline (498 ± 41 vs. 580 ± 35 nmol/l, respectively, P = 0·06), the mean cortisol rise being 280 ± 45 and 270 ± 36 nmol/l on rhGH and at baseline, respectively. Conclusions According to the diagnostic criteria, no child became hypoadrenal on rhGH, contrary to what observed in patients with organic GHD, further supporting the view that only in patients with organic multiple pituitary hormone deficiency GHD masks the presence of a hidden central hypoadrenalism. [ABSTRACT FROM AUTHOR]

Objective Some authors proposed to lower the present postglucose GH nadir cut-off (i.e. < 1 µg/l) to that obtained in healthy subjects to establish remission of acromegaly. The aim of the study was to correlate GH nadir with hormonal and metabolic parameters and to confirm the adequacy of the current limit to define disease remission. Design and patients Retrospective study of 40 acromegalic patients cured by surgery, followed by radiotherapy when appropriate, studied at the time of disease remission (Phase 1) and re-evaluated after at least 3 years’ follow-up (median 6·5 year, Phase 2). GH nadir was evaluated in 44 sex- and age-matched controls. Measurements Symptom score, pituitary function, neuroradiological imaging, metabolic parameters (BMI, glucose metabolism, insulin sensitivity, lipid profile, blood pressure). Results The upper limit of the ‘normal’ GH nadir was fixed at 0·26 µg/l (mean + 2SD of controls). In Phase 1, GH nadir was < 0·26 µg/l in 16 patients (Group A) and > 0·26 µg/l in 24 patients (Group B). Group B had only slightly higher IGF-1 SDS (0·4 ± 1·0 vs.– 0·1 ± 1·0, P = ns) and lower body mass index (BMI) than Group A (26·2 ± 2·4 vs. 30·6 ± 4·5 kg/m2, P < 0·005). GH nadir positively correlated with IGF-1 ( P < 0·05, r = 0·32) and negatively with BMI ( P < 0·05, r = 0·42). In Phase 2, all patients had IGF-1 levels in the normal range and GH nadir < 1 µg/l, both parameters being even lower than those found at the time of remission. No patient had either clinical or neuroradiological evidence of disease recurrence. Conclusions The current GH nadir limit is still adequate to define both short- and long-lasting remission of acromegaly, independently of the type of definitive treatment. Patients with the lowest GH nadir should probably be monitored long-term for adequacy of their GH secretion. [ABSTRACT FROM AUTHOR]

Objective Previous evidence indicated that, in adults with organic hypopituitarism, GH deficiency (GHD) may mask the presence of other pituitary deficits, in particular central hypothyroidism and hypoadrenalism. Little and conflicting information is available about the relationship between GHD, rhGH therapy and gonadal function in males. The aim of the present study was to investigate the hypothalamic–pituitary–gonadal axis (HPG) in male adults with organic GHD and normal HPG axis. Patients Twelve male adults (mean age 48 ± 7 years) with organic GHD and normal HPG axis. Measurements Serum levels of testosterone, LH and FSH (basal and after GnRH stimulation test), SHBG and IGF-I and percentage body fat (BF%) were evaluated before and during rhGH (mean dose 0·24 ± 0·02 mg/day for 13 ± 1 months) treatment. Results Serum IGF-I levels normalized during rhGH treatment and BF% significantly decreased. Serum testosterone levels significantly decreased (from 18·1 ± 1·7 to 14·2 ± 1·6 nmol/l, P = 0·01), with a parallel and significant decrease of serum SHBG (from 31·1 ± 3·6 to 24·3 ± 2·3 nmol/l, P < 0·05). Thus, calculated free testosterone (cFT) did not change (from 0·39 ± 0·17 to 0·33 ± 0·14 nmol/l, P = ns). Finally, no difference was found in basal and GnRH stimulated gonadotrophins levels. Conclusions In conclusion, the condition of GHD does not seem to mask central hypogonadism, in contrast to what is observed for central hypothyroidism and hypoadrenalism. However, the significant decrease in serum testosterone levels, strictly related to SHBG decrease, suggests that evaluation of the HPG axis during rhGH treatment cannot be based on the measurement of total testosterone levels, but should mainly rely on calculation of cFT and a careful clinical evaluation, in order to avoid unnecessary replacement therapy. [ABSTRACT FROM AUTHOR]

To evaluate circulating levels of ghrelin and adiponectin (ApN) in GH-deficient (GHD) adults before and after short- and long-term recombinant human GH (rhGH) administration. Twenty-three patients were studied. Seventeen subjects (Group A, 12 men, five women) were evaluated at baseline and after 1 year rhGH therapy (dose mean ± SD: 0·3 ± 0·1 mg/day) with the assessment of serum IGF-I, ghrelin, ApN, leptin, insulin and glucose levels, percentage of body fat (BF%), HOMA-IR and QUICKI. Seventeen age-, sex- and body mass index (BMI)-matched healthy subjects were recruited for comparisons. Six patients (Group B, three men, three women) underwent IGF-I generation test (rhGH 0·025 mg/kg/day for 7 days), blood sampled at baseline and on day 8 for determination of IGF-I, ghrelin and ApN levels. Group A: at baseline GHD patients showed low IGF-I levels and BF% significantly higher than controls (31·4 ± 2·5 vs. 26·4 ± 1·3, P < 0·05). Glucose, insulin, leptin, tryglicerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as HOMA-IR and QUICKI values were similar in the two series, while total cholesterol levels were higher in GHD. In GHD, ghrelin levels were significantly lower than in controls (193·9 ± 27·1 vs. 298·1 ± 32·5 pmol/l, respectively, P = 0·02), while ApN levels were similar (10·2 ± 1·1 and 9 ± 1 mg/l, respectively, P = ns). After 1 year of rhGH therapy, BF%, BMI, serum total and LDL cholesterol significantly decreased, serum leptin levels showed a trend to decrease, while HOMA-IR and QUICKI did not change. Ghrelin and ApN levels significantly increased from 193·9 ± 27·1 to 232·4 ± 26·3 pmol/l ( P < 0·01) and from 8·6 ± 0·8 to 10·3 ± 1·1 mg/l ( P < 0·05), respectively. In group B, the expected increase in IGF-I levels was associated with a significant decrease in ghrelin levels, while ApN did not change. GHD patients showed serum ghrelin lower than controls, probably due to the higher BF%. No difference in ApN was observed. Ghrelin and ApN increments induced by long-term treatment may be related to the significant BMI and BF% reduction that is the predominant metabolic effect of rhGH therapy. Conversely, the decrease in ghrelin levels observed after short-term rhGH administration may be consistent with an inhibitory feedback of GH and/or IGF-I on ghrelin release. [ABSTRACT FROM AUTHOR]

Recombinant hGH treatment may alter thyroid hormone metabolism and we have recently reported that 50% of patients with GH deficiency (GHD) due to organic lesions, previously not treated with thyroxine, developed hypothyroidism during treatment with recombinant human GH (rhGH). These results prompted us to evaluate the impact of rhGH treatment on thyroid function in children with GHD. Open study of GH treatment up to 12 months. Investigations were performed at baseline, and after 6 and 12 months of GH therapy. Serum TSH, FT4, FT3, AbTg and AbTPO, IGF-I, height and weight, were evaluated in 20 euthyroid children (group A) with idiopathic isolated GHD and in six children (group B) with multiple pituitary hormone deficiencies (MPHD) due to organic lesions. Among the latter, four already had central hypothyroidism and were on adequate LT4 replacement therapy, while two were euthyroid at the beginning of the study. Serum IGF-I levels normalized in all patients. In both groups, a significant reduction in FT4 levels ( P < 0·01) occurred during rhGH therapy. No patient in group A had FT4 values into the hypothyroid range, while in four of six patients in group B, fell FT4 levels into the hypothyroid range during rhGH. In particular, the two euthyroid children developed central hypothyroidism during rhGH treatment, and their height velocities did not normalize until the achievement of euthyroidism through appropriate LT4 substitution. No variation in serum FT3 and TSH levels was recorded in either groups. Contrary to that observed in patients with MPHD, rhGH replacement therapy does not induce central hypothyroidism in children with idiopathic isolated GHD, further supporting the view that in children with MPHD, as in adults, GHD masks the presence of central hypothyroidism. Slow growth (in spite of adequate rhGH substitution and normal IGF-I levels) is an important clinical marker of central hypothyroidism, therefore a strict monitoring of thyroid function is mandatory in treated children with MPHD. [ABSTRACT FROM AUTHOR]