Search Results (101)

Background/Objectives: The endoscopic transsphenoidal approach constitutes an excellent technique for adrenocorticotropin hormone (ACTH)-producing pituitary tumours. It is associated with subnormal postoperative serum cortisol levels, which may guide decisions regarding immediate re-operation. Methods: The authors retrospectively reviewed patients with Cushing’s disease who had undergone endoscopic transsphenoidal surgery between 2013 and 2023. All operations were performed by neurosurgeons and skull-base otolaryngologists. Surgical outcomes were evaluated in combination with prognostic factors such as cortisol and ACTH levels in terms of long-term remission and late recurrence rates of Cushing’s disease. Results: Fifty patients aged between 15 and 69 (average 37.8) years were evaluated, having undergone 50 operations. The median follow-up was 76.5 months (range: 23–122 months). Major complications with a transient CSF leak resulting from the surgical approach occurred in three patients. Two patients in the series experienced minor complications, developing a deep vein thrombosis, and thirteen patients developed transient diabetes insipidus. The initial remission rate was 84% (n = 42/50). Initial non-remission occurred in eight (8) patients (16%), with three macro- and five microadenomas. A total of 3 of the 42 patients with initial remission had a late recurrence after 50 months follow-up and required repeat transsphenoidal surgery. Seven patients (16.6%) who did not exhibit early postoperative cortisol reduction subsequently achieved remission. Male gender was the only factor that was significantly associated with lower remission rates in either short- or long-term follow-up (p = 0.003 and 0.038, respectively). An immediate postoperative ACTH nadir of ≤5 pg/mL was significantly related to long-term remission (p = 0.004). In our study, a significant correlation was confirmed between remission of the disease and 24 h urinary cortisol values, both early and late (p = 0.019), and serum cortisol <138 nmol/L. In this retrospective study from a single institution specialising in pituitary tumour management, the endoscopic transsphenoidal approach was shown to be both safe and effective. Additionally, we found that the risk of relapse in patients with Cushing’s disease persisting for more than 5 years after surgery is real but low. Moreover, failure to achieve an early postoperative cortisol reduction does not preclude a subsequent remission. Conclusions: Our findings demonstrate that ACTH, postoperative serum cortisol, and urinary free cortisol are valuable predictors of relapse over a five-year period and are closely correlated to each other. Full article

Hirsutism, characterized by excessive terminal hair growth in androgen-sensitive areas, presents significant medical and psychosocial challenges in Gulf Cooperation Council (GCC) countries. This narrative review explores the epidemiology, endocrine factors, molecular basis of pathophysiology, cultural influences, and management approaches to hirsutism within the GCC. Regional factors such as consanguinity, rising obesity rates, and lifestyle habits contribute to a higher prevalence of hirsutism and related endocrine disorders, particularly polycystic ovary syndrome (PCOS). Cultural stigmas surrounding body hair further delay diagnosis and treatment, compounding psychological distress. The review examines the role of androgen excess, genetic susceptibility, and emerging molecular insights, including epigenetic dysregulations. Diagnostic limitations and the need for region-specific screening tools are discussed, alongside the current reliance on pharmacological, cosmetic, and traditional therapies. Public health initiatives targeting stigma reduction and early detection are emphasized. Future recommendations include culturally tailored research, enhanced public awareness, and the adoption of advanced diagnostic strategies to improve patient outcomes. This review aims to guide healthcare practices and inform policy development for the better management of hirsutism in the GCC context. Full article

Background: Adrenal incidentalomas are detected in various medical and surgical healthcare departments, including primary healthcare. One up to three out of ten individuals confirmed with nonfunctioning adrenal incidentalomas (NFAs) actually present a mild autonomous cortisol secretion (MACS), which is distinct from Cushing’s syndrome. Objective: We aimed to assess the cortisol secretion in newly detected adrenal incidentalomas in patients who were referred by their primary healthcare physician upon accidental detection of an adrenal tumor at abdominal computed tomography (CT) scan that was performed for unrelated (non-endocrine) purposes. Methods: This retrospective study included adults diagnosed with an adrenal incidentaloma via CT during the previous 3 months. Inclusion criteria: age ≥ 40 years (y). A triple stratification of exclusion criteria involved: (1) Clinical aspects and medical records such as active malignancies or malignancies under surveillance protocols, subjects under exogenous glucocorticoid exposure (current or during the previous year), or suggestive endocrine phenotypes for any hormonal ailment; (2) Radiological appearance of suspected/confirmed (primary or secondary) adrenal malignancy, adrenal cysts, or myelolipomas; (3) Endocrine assays consistent with active endocrine tumors. Protocol of assessment included baseline ACTH, morning plasma cortisol (C-B), cortisol at 6 p.m. (C-6 pm), and after 1 mg dexamethasone suppression testing (C-1 mg-DST), 24-h urinary free cortisol (UFC), and a second opinion for all CT scans. MACS were defined based on C-1 mg-DST ≥ 1.8 and <5 µg/dL (non-MACS: C-1 mg-DST < 1.8 µg/dL). Results: The cohort (N = 60, 78.33% female; 60.72 ± 10.62 y) associated high blood pressure (HBP) in 66.67%, respectively, type 2 diabetes (T2D) in 28.37% of the patients. Females were statistically significantly older than males (62.40 ± 10.47 vs. 54.62 ± 9.11 y, p = 0.018), while subjects with unilateral vs. bilateral tumors (affecting 26.67% of the individuals) and those with MACS-positive vs. MACS-negative profile had a similar age. Body mass index (BMI) was similar between patients with unilateral vs. bilateral incidentalomas, regardless of MACS. Patients were divided into five age groups (decades); most of them were found between 60 and 69 years (40%). Left-gland involvement was found in 43.33% of all cases. The mean largest tumor diameter was 26.08 ± 8.78 mm. The highest rate of bilateral tumors was 46.67% in the 50–59 y decade. The rate of unilateral/bilateral and tumor diameters was similar in females vs. males. The MACS-positive rate was similar in females vs. males (23.40% vs. 23.08%). A statistically significant negative correlation (N = 60) was found between BMI and C-B (r = −0.193, p = 0.03) and BMI and UFC (r = −0.185, p = 0.038), and a positive correlation was found between C-B and C-6 pm (r = 0.32, p < 0.001), C-B and UFC (r = 0.226, p = 0.011), and C-6 pm and C-1 mg-DST (r = 0.229, p = 0.010), and the largest tumor diameter and C-1 mg-DST (r = 0.241, p = 0.007). Conclusions: Adrenal incidentalomas belong to a complex scenario of detection in the modern medical era, requiring a multidisciplinary collaboration since the patients might be initially detected in different departments (as seen in the current study) and then referred to primary healthcare for further decision. In these consecutive patients, we found a higher female prevalence, a MACS rate of 23.33%, regardless of uni/bilateral involvement or gender distribution, and a relatively high rate (than expected from general data) of bilateral involvement of 26.67%. The MACS-positive profile adds to the disease burden and might require additional assessments during follow-up and a protocol of surveillance, including a tailored decision of tumor removal. The identification of an adrenal incidentaloma at CT and its hormonal characterization needs to be integrated into the panel of various chronic disorders of one patient. The collaboration between endocrinologists and primary healthcare physicians might improve the overall long-term outcomes. Full article

Background/Objectives: Cushing’s syndrome (CS), including Cushing’s disease (CD)—the most common type—has a substantial negative impact on morbidity, mortality, and patients’ quality of life. Medical management of CS is essential for controlling hypercortisolism as part of preoperative preparation for definitive surgical treatment and for managing residual or relapsed hypercortisolism post-surgery. Osilodrostat, a dual inhibitor of glucocorticoid and mineralocorticoid biosynthetic pathways, has been approved for the medical treatment of CS since early 2020. However, real-world data on its adverse effects remain limited. We mined the FAERS database and analyzed the reports associated with osilodrostat up to 1 October 2024. Methods: Descriptive and disproportionality methods based on Relative Odds Ratio (ROR), Chi-square (χ²), and Proportional Reporting Ratio (PRR), were used to discern potential safety signals and assess the significance of osilodrostat-associated adverse events. Results: This study identified 782 reports in which osilodrostat was the primary suspected drug, containing 593 preferred terms (PTs) and 2481 occurrences. The most frequently registered events belonged to the following SOCs: “General disorders and administration site conditions” (n = 457, 18.4%), “Injury, poisoning and procedural complications” (n = 311, 12.5%), “Gastrointestinal disorders” (n = 278, 11.2%), “Investigations” (n = 260, 10.5%), and “Nervous system disorders” (n = 184, 7.4%). Among PTs, off-label use was the most commonly reported, aligning with the fact that the vast majority of cases originated from the U.S. (84%), where osilodrostat is officially approved only for the treatment of CD. Disproportionality analysis confirmed previously known and new potential adverse drug reactions associated with osilodrostat treatment, including reports of cardiac flutter (n: 4; PRR: 19.42; χ²: 49.57), ventricular extrasystoles (n: 4; PRR: 11.85; χ²: 29.62), muscular weakness (n: 8; PRR: 2.25; χ²: 4.38), rib fracture (n: 4; PRR: 6.66; χ²: 13.99), spinal fracture (n: 3; PRR: 4.66; χ²: 5.35), sepsis (n: 9; PRR: 2.63; χ²: 7.56), fungal infections (n: 4; PRR: 3.67; χ²: 5.33), and COVID-19 (n: 32; PRR: 5.07; χ²: 101.16). Conclusions: This study highlights new risks and offers valuable insights into osilodrostat use; however, further research and validation are necessary, particularly for adverse reactions not yet explicitly documented in the summary of product characteristics. Full article

Cushing’s disease (CD) is a rare disorder caused by adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumors, which lead to chronic hypercortisolism and significant complications with increased mortality. These tumors are characterized by a substantial heterogeneity in their biological behavior, prognosis, and therapeutic response, making their management challenging. While transsphenoidal surgery remains the first-line treatment, recurrence rates remain high, and alternative therapeutic approaches, such as pharmacological therapy and radiotherapy, have a variable efficacy and are frequently limited due to side effects. Increasing evidence suggests that molecular biomarkers, both immunohistochemical and genetic, may play an important role in predicting a tumor’s aggressiveness, recurrence risk, and response to targeted therapies. The immunohistochemical evaluation of its granulation pattern, Ki-67 proliferation index, and E-cadherin expressions have been linked to a tumor’s invasiveness and surgical outcomes, while somatostatin and dopamine receptor expressions may influence its response to Pasireotide and cabergoline therapy. Genetic alterations such as USP8 mutations impact tumor growth and its response to targeted therapies, whereas CABLES1 and TP53 alterations may contribute to more aggressive tumor behavior. Despite these findings, the clinical applicability of many of these markers remains limited by inconsistent validation and lack of standardized cutoff values. This narrative review provides an update on the latest evidence regarding the roles of molecular biomarkers in corticotropinomas, emphasizing their role in prognosis, recurrence risk, and the response to different treatment options. A better understanding and integration of these biomarkers into clinical practice could lead to a better patient stratification, more efficient therapeutic strategies, and personalized treatment approaches for patients with CD. Full article

Background/Objectives: Pasireotide-LAR represents a novel therapeutic option for patients with Cushing’s disease (CD). Its efficacy and safety were assessed in clinical trials; however, the real-world evidence is still scarce. Methods: The study aimed to evaluate the impact of 12-month pasireotide-LAR therapy on disease control, glucose metabolism, lipid profiles, and adverse effects in a real-life setting. We retrospectively studied prospectively collected data of patients with persistent or recurrent CD administered with pasireotide-LAR in a single pituitary center. Results: Mean urinary free cortisol (mUFC) showed a sustained decrease from baseline, with the most pronounced decrease in the first 3 months of therapy (p = 0.007). The analysis of mean late-night salivary cortisol showed fluctuations over time, with the largest mean reduction in mLNSC at 3 months. During the therapy, an improvement in blood pressure control was observed, with a significant decrease in systolic blood pressure during the first 6 months of treatment (p = 0.005). Hyperglycemia was the most common adverse effect. Fasting plasma glucose and glycated hemoglobin (HbA1c) showed a gradual increase during pasireotide-LAR treatment, with the HbA1c significantly increasing at the last follow-up (p = 0.04). Conclusions: Pasireotide-LAR is an effective alternative treatment in selected patients with CD. Pasireotide-LAR is overall safe and well tolerated, with hyperglycemia being the most common but manageable adverse event. Full article

Ectopic adrenocorticotropic hormone syndrome (EAS) occurs when a tumor develops neuroendocrine differentiation with the secretion of ACTH resulting in hypercortisolism and possibly Cushing’s syndrome (CS). Only 5–10% of CS cases are attributed to EAS; of these, breast tumors comprise less than 1%. Two known variants of breast neuroendocrine tumors include neuroendocrine-differentiated carcinoma and ductal carcinoma with neuroendocrine features. Currently, guidelines for treatment are limited and EAS is associated with significant morbidity and mortality. A 39-year-old female presented with a rapidly enlarging breast mass. Biopsy demonstrated invasive poorly differentiated breast carcinoma with high-grade neuroendocrine features and necrosis. Staging at diagnosis confirmed metastatic disease of the liver and bone. First-line chemotherapy (Cisplatin/Etoposide/Durvalumab) was initiated with evidence of disease progression after four cycles. Given a poor response to therapy, a simple mastectomy was performed for local control and complete pathologic analysis, demonstrating high-grade neuroendocrine carcinoma with large-cell features. Second-line therapy (Adriamycin/Cyclophosphamide) was initiated for three cycles after which the patient required admission for severe and refractory hypokalemia. Workup confirmed elevated ACTH consistent with paraneoplastic EAS and further evidence of disease progression. Third-line therapy (Nab-Paclitaxel) was initiated, and genetic testing was completed, confirming the PIK3 mutation, for which access to Alpelisib therapy was requested. Given symptoms of progressive severe CS with significant liver disease limiting medical therapies, the patient underwent urgent bilateral laparoscopic adrenalectomy after which she was able to be discharged home while awaiting additional systemic therapy. EAS resulting in CS secondary to breast neuroendocrine carcinoma is a rare and challenging diagnosis. Further research is needed to inform treatment guidelines to improve outcomes. While patient survival is dependent upon the underlying disease process, laparoscopic bilateral adrenalectomy is an accepted, definitive treatment option. Full article

Double pituitary neuroendocrine tumors (double PitNETs) are two distinct tumors in the same gland and are infrequent in clinical practice. In typical double PitNETs, an MRI detects two separate tumors that are diagnosed by pathology; they could also appear as a single tumor, and pathology would then identify the two independent tumors. A literature review was conducted, and 142 cases were analyzed to determine the characteristics of double PitNETs. Of these cases, acromegaly (45.5%) was the most common clinical feature, followed by Cushing’s disease (35.1%) and prolactinoma (17.9%), indicating that double PitNETs are usually noticed by hormonal excess symptoms due to at least one functional tumor. The pathological analysis of 284 tumors showed that somatotroph (28.9%) and corticotroph (26.8%) tumors were predominant, with a recent increase in the proportion of gonadotroph tumors. Regarding transcription factors, 51.1% were of GH-PRL-TSH PIT1-lineage, 26.1% ACTH TPIT-lineage, and 17.9% LH-FSH SF1-lineage. The radiological analysis of 82 cases revealed that double tumors (45.1%) and single tumors (47.6%) were comparable, suggesting that double PitNETs are often detected as a single tumor, and attention should be paid to hidden micro-tumors during surgery. Double PitNETs are complicated by a wide variety of clinical, radiological, and pathological findings, but diagnostic and therapeutic approaches are advancing. Full article

Endogenous Cushing’s syndrome (CS) is a rare neuroendocrine disorder characterized by either secondary cortisol increases due to an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor (Cushing’s disease (CD)), an ACTH-secreting neuroendocrine tumor (NET) of non-pituitary origin (ectopic ACTH syndrome (EAS)), or by the primarily adrenal autonomous overproduction of cortisol [...] Full article

Trilostane is a drug able to block the synthesis of progesterone from pregnenolone, dependent on the enzyme 3β-hydroxysteroid dehydrogenase/Δ⁵⁻⁴ isomerase. As a consequence of this effect, it is used to treat endocrinological diseases such as Cushing’s syndrome, especially in dogs. Because of the modulatory effects of trilostane on the hypothalamic–pituitary–adrenal axis, trilostane administration causes an increase in brain levels of neurosteroids with anticonvulsant properties, as in the case of allopregnanolone. Allopregnanolone is also of interest in curing depression, suggesting that trilostane might represent a tool to address neurological and psychiatric disorders. In this review, we investigated the historical development of this drug and its current use, mechanisms, and possible developments. By searching the literature from 1978 to 2025, we identified 101 papers describing studies with trilostane. Precisely, 55 were about dogs and trilostane, 3 were on cats, and 23 were with other animals. Some studies (15) were also designed with human patients. The main disease treatment with trilostane was hyperadrenocorticism. However, we also found two preclinical papers on trilostane’s potential use in psychiatric diseases and three on trilostane’s potential use in neurological disorders. Moreover, few clinical and preclinical studies suggested the involvement of neurosteroids modulated by trilostane in different neurological disorders, thus opening a possible new perspective for the use of this drug. Full article

Cortisol, an essential glucocorticoid hormone, is crucial in regulating the stress response and maintaining physiological and behavioral homeostasis in mammals, including dogs. This review explores cortisol’s physiological and behavioral role in canines, focusing on its effects on stress, immune function, and metabolism. Various methods of measuring cortisol levels in dogs, invasive (blood, saliva, urine) and non-invasive (hair, fecal assays), are discussed regarding their accuracy and practical applications. The review also highlights the influence of different environmental factors, such as shelter conditions, human interaction, and music, on cortisol levels in dogs. Furthermore, the clinical and behavioral implications of abnormal cortisol levels are examined, with particular attention to conditions like Cushing’s disease and stress-related behavioral issues. The findings emphasize the importance of cortisol monitoring in veterinary practice and animal welfare, proposing future research directions to improve canine health and stress management. Full article

In the current work, we aimed to evaluate the association of clinical data of Cushing’s disease (CD) patients with USP8 mutation status and to study USP8-related molecular mechanisms connected to the regulation of corticotropinoma growth and activity. 35 CD patients were enrolled; the sequencing of exon 14 in USP8 revealed variants in eighteen adenomas, two of which were described for the first time in CD. USP8 variants were more common in women (94% vs. 76%; p = 0.001), and microadenomas and tumor recurrence were prevalent in the USP8-mutant group (44% vs. 29%; p = 0.04 and 44% vs. 22%; p = 0.0015). Preoperative ACTH and serum cortisol did not differ in the USP8-WT and USP8-mutant patients. All USP8-mutant adenomas were SST5-positive, and 73% of them were double-positive (SST5+/SST2+). A total of 50% of USP8-WT adenomas were double-negative (SST5−/SST2−), and 40% of them were SST5-positive. Analysis of transcriptome was performed for nine USP8-mutant and six USP8-WT adenomas and revealed the that the bidirectional dysregulation of Wnt signaling, including both the agonist RSPO2 and antagonist SFRP1, in the USP8-mutant corticotropinomas was downregulated. These alterations may indicate the existence of regulatory connections between USP8 enzyme activity, Wnt signaling, EGFR signaling and somatostatin receptors’ trafficking, which can explain, at least in part, the clinical manifestations of CD in patients with corticotropinomas harboring USP8 variants. Full article

The adenomas in Cushing’s disease frequently exhibit mutations in exon 14, within a binding motif for the regulatory protein 14-3-3 located between the catalytic domain (DUB), responsible for ubiquitin hydrolysis, and the WW-like domain that mediates autoinhibition, resulting in constantly active USP8. The exact molecular mechanism of deubiquitinase activity disruption in Cushing’s disease remains unclear. To address this, Sanger sequencing of USP8 was performed to identify mutations in corticotropinomas. These mutations were subjected to computational screening, followed by molecular dynamics simulations to assess the structural alterations that might change the biological activity of USP8. Eight different variants of the USP8 gene were identified both within and outside the “hotspot” region. Six of these had previously been reported in Cushing’s disease, while two were detected for the first time in our patients with CD. One of the two new variants, initially classified as benign during screening, was found in the neighboring SH3 binding motif at a distance of 20 amino acids. This variant demonstrated pathogenicity patterns similar to those of known pathogenic variants. All USP8 variants identified in our patients caused conformational changes in the USP8 protein in a similar manner. The identified mutations, despite differences in annotation results—including evolutionary conservation assessments, automated predictor data, and variations in localization within exon 14—exhibit similar patterns of protein conformational change. This suggests a pathogenic effect that contributes to the development of CD. Full article

In veterinary medicine, the significance of high-density lipoprotein (HDL) measurements is not as well documented as it is in humans. The HDL level can be measured in dogs as well and, through referring to the normal range, it is possible to find out what this means in relation to various endocrine diseases and hyperlipidemia diseases. The aim of this study is to measure the HDL levels in dogs with various conditions and to evaluate whether the total cholesterol (TC)-to-HDL ratio is effective as a prognostic indicator in various hyperlipidemia and endocrine diseases, which is significant since it is the first trial in dogs. Through a retrospective study design, sixteen client-owned dogs and cats visiting a local private practice were divided into three groups: five dogs without hyperlipidemia or metabolic disease (Group 1), eight dogs with Cushing’s, hypothyroidism, and gallbladder sludge (Group 2), and three cats, including one with diabetes, one with a urinary disorder, and one healthy cat (Group 3). In two dogs, the TC/HDL values were between 2 and 3; in two dogs, the values were between 3 and 4; and in two dogs, the values were between 4 and 5. In three dogs, the TC/HDL values were between 5 and 6 and in three dogs the ratio values were between 6 and 7. The other value was higher than 8. Except for two dogs that showed lower values than 3, all dogs in Group 1 and Group 2 had concurrent endocrine disease. This means that TC/HDL values can be an excellent indicator of endocrine disease in dogs as well. In cats, although it is a very small batch of samples, a high TC/HDL value of 9 points was shown in the cat that had diabetes mellitus. However, for more statistically significant results, a larger sample group for further investigation is needed. Full article

A distinct myotonia is a muscle disorder that may occur secondary to excess corticosteroids (hyperadrenocorticism, HAC, or Cushing’s disease) and is associated with electrodiagnostic abnormalities on electromyography (EMG). Clinically these disorders cause muscle stiffness, weakness, atrophy, and/or contractures, which can severely limit the quality of life of those affected. To date, there are very few published data regarding the onset, development, and treatment of hyperadrenocorticism-associated myotonia/pseudomyotonia. This is a multi-institutional retrospective study describing the clinical signs, diagnosis, and treatment of HAC-associated myotonia/pseudomyotonia. We found that this disorder was and continues to be rare. It most commonly occurs in adult dogs with chronic steroid exposure secondary to pituitary-dependent HAC. No cases of adrenal dependent HAC were identified in this population. In addition to muscle stiffness, dermatologic disease and liver enzyme abnormalities were common. A wide variety of therapeutic strategies, including polypharmacy and physical rehabilitation, were implemented, with little success. Analgesics were the most frequently administered type of medication. Full article