Search Results (176)

Background/Objective: One third of “non-functioning adrenal tumours” (NFAs) have mild autonomous cortisol secretion (MACS). An updated analysis of the hormonal biomarkers profile, including risk factors and the rate of post-surgery adrenal insufficiency (PSAI), the duration of restoring the normal adrenocortical function in MACS/NFA and potential impacts on clinical comorbidities. Methods: Comprehensive review based on PubMed search (January 2020–January 2025). Results: The studies (n = 14) included 2623 patients (N = 1158 underwent unilateral adrenalectomy), aged 18–93 (mean = 57.49 years), with a female-to-male ratio = 1.54. Post-adrenalectomy (n = 9, N = 753) analysis: the PSAI risk correlated with the severity of baseline hypercortisolism. PSAI incidence: 50% of MAC. The rate after 4–6 weeks follow-up was 71.9% (adrenal Cushing’s syndrome) vs. 50% (MACS) vs. 14.4% (NFA). PSAI duration was up to 35 months. Early PSAI diagnosis was reflected by post-operative cortisol assay on day 1 (cut-off ≤ 5 µg/dL) and an ACTH (Cosyntropin) stimulation test (CST) (cortisol cut-off ≤ 14 µg/dL). Pre-operatory PSAI predictors: higher serum cortisol-DST (1 mg dexamethasone testing) and lower baseline plasma ACTH (not all studies agreed). Conclusions: A stratified strategy is encouraged following a unilateral adrenalectomy in MACS; PSAI is expected in almost half of patients, with a potential improvement of hypertension. Serum cortisol assays serve as most useful biomarker as pre-operatory PSAI predictor (after DST) and, potentially, in addition with baseline ACTH. Post-surgery basal cortisol measurement (± CST) helps the decision of glucocorticoids replacement since first post-operative day and during follow-up, serial testing at 3 months is a useful tool. Full article

We present a novel method to estimate blood cortisol concentration from sweat cortisol measurements, incorporating a kinetic model to simulate cortisol transport dynamics. Cortisol dysregulation is observed in conditions like Cushing’s syndrome, characterized by excessive cortisol production, and stress-related disorders, which can lead to metabolic disturbances, anxiety, and impaired overall health. Sweat-sensing technology offers a non-invasive and continuous alternative to blood sampling. However, the limited research exploring the sweat–blood cortisol relationship in patients shows a moderate correlation ($R<0.6$), hindering its clinical application for long-term monitoring. In this paper, we propose a novel kinetic model describing cortisol transport from blood to sweat. The model was validated using data from 44 patients before and after cardiac surgery. A high Pearson correlation coefficient of 0.95 (95% CI: 0.92–0.97) was observed between our model’s estimated and experimental blood cortisol concentrations. Moreover, the method enables personalized estimation of physiological parameters, accurately reflecting patients’ status under varying clinical conditions. The method paves the way for the clinical application of long-term, non-invasive monitoring of cortisol using sweat-sensing technology. Enabling the personalized estimation of physiological parameters could potentially support clinical decision-making, helping doctors diagnose and monitor patients with health conditions involving cortisol dysregulation. Full article

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

Background/Objectives: Ectopic Cushing’s syndrome (ECS) is a rare, life-threatening condition caused by uncontrolled ACTH secretion from tumors, most commonly small-cell lung cancer (SCLC). ECS is traditionally reported in 1–6% of SCLC cases; however, recent data suggest it may be much higher. This study compares the clinical presentation of SCLC-related ECS (ECS-SCLC) with other ECS etiologies and analyzes the diagnosis, treatment, and outcomes of ECS-SCLC. Methods: We retrospectively analyzed the records of 39 ECS patients diagnosed between 2000 and 2024 at a tertiary endocrinology center. Seven cases (18%) were due to SCLC. Diagnosis was based on clinical signs, biochemical testing, imaging, and histopathology. Results: ECS-SCLC patients (five men, two women; median age 61), compared to other ECS etiologies, had a shorter time to diagnosis (median 1 vs. 2 months; p = 0.03), worse general condition (ECOG 4 vs. 3; p = 0.01), greater muscle weakness (Lovett scale median 2[IQR 1–2] vs. 2[IQR 2–3]; p = 0.04), more severe hypokalemia (2.12 vs. 2.7 mmol/L; p = 0.03), and required higher potassium supplementation (200 vs. 120 mEq/day; p = 0.001). All ECS-SCLC patients experienced weight loss (median 5 kg). Cortisol-lowering therapy (metyrapone or osilodrostat) was initiated in six patients (mean initiation time 3.7 days), leading to clinical improvement. Oncological treatment (chemotherapy or radiotherapy) was administered in five patients after stabilization. The median follow-up time was 3 months. Conclusions: Early recognition of ECS-SCLC and a multidisciplinary approach are critical. Severe hypokalemia and muscle weakness should prompt timely evaluation for hypercortisolism. Cortisol-lowering therapy may improve clinical status and facilitate oncological treatment. 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

Craniopharyngiomas (CPs) are rare intracranial tumors arising from remnants of Rathke’s pouch. Despite their benign histology, CPs present considerable clinical challenges due to their tendency to exert mass effect and adherence to critical neurovascular structures. There remains no clear consensus on the most effective management of CPs. We explore the latest developments in targeted treatment approaches, examining how innovations in surgery, radiation therapy, and emerging therapies are improving outcomes and management for these challenging tumors. In addition to providing our experience, we reviewed previously reported case series and reviews relevant to CPs. Studies show a bimodal age distribution for CP diagnosis, with peak incidence occurring in children aged 5–14 years and in adults aged 50–74 years. Surgical resection is the typical initial treatment for CPs, and adjuncts, including radiation therapy and intracavitary treatments, have been proven effective for tumor control. Additionally, genetic mutations associated with CPs offer an opportunity for novel strategies that address the underlying molecular mechanisms driving tumor growth through targeting the Wnt/β-catenin and/or MAPK/ERK pathways to disrupt the aberrant signaling that promotes tumor proliferation and survival. Survival rates for CPs are generally favorable (five-year survival of 80%), with recent studies showing improved outcomes and higher survival rates in children. CPs remain rare and challenging tumors. Although surgical resection is the main treatment, surgeons must weigh the benefits of achieving a gross total resection with the risks of iatrogenic injury. Adjuncts, including intracavitary and radiation treatments, may assist with subtotal resections and recurrences, as well as approved BRAF inhibitor therapy for the papillary variant. Many improvements in diagnostic and therapeutic methods were made after Dr. Cushing coined the term “craniopharyngioma”. Ongoing experiments, investigations, and advances in radiation techniques and molecular targeted therapies will provide patients with promise for safer and more effective treatments. 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

Background: Hypercalcemia is a frequently encountered laboratory finding in endocrinology, warranting accurate clinical and laboratory evaluation to identify its cause. While primary hyperparathyroidism and malignancies represent the most common causes, many other etiologies have been described, including some reports of hypercalcemia secondary to adrenal insufficiency. On the contrary, hypoparathyroidism is a relatively common cause of hypocalcemia, often arising as a complication of thyroid surgery. In real-world clinical practice, however, many challenges come into play, and a comprehensive approach may not be enough to establish a diagnosis. Case presentation: we describe a peculiar case of severe hypercalcemia occurring in a 47-year-old woman with a previous history of post-surgical permanent hypoparathyroidism treated with calcitriol (0.5 µg bid) and calcium carbonate (1 g qd), which persisted after withdrawal of these drugs. During her follow-up, an ACTH-independent Cushing syndrome was diagnosed, leading to a unilateral right adrenalectomy. In the two months following surgery, she was admitted to the emergency ward on three occasions because of severe, persistent, idiopathic hypercalcemia. On each occasion, parathyroid hormone levels were confirmed to be undetectable, with low vitamin D levels. Common and rare causes of hypercalcemia were excluded, and the persistence of severely elevated calcium levels led to the empirical use of intravenous clodronate, achieving remission of both hypercalcemia and, unexpectedly, hypoparathyroidism. After 8 months, due to borderline-reduced calcium, calcitriol at 0.5 µg qd was restarted. After 18 months of follow-up, the patient is well and normocalcemic, with low-dose calcitriol. Notably, the patient had no acute adrenal insufficiency, distinguishing this case from other post-adrenalectomy hypercalcemia reports. Conclusions: the history of hypoparathyroidism makes this case even more unusual, and it encourages careful follow-up of hypoparathyroid patients with Cushing syndrome. Ongoing observation, as well as new research on the physiopathology of cortisol and calcium metabolism, are needed to clarify the pathogenesis of this case. Full article