Elevated Adrenocorticotropic Hormone Levels Research Articles

7372 Anti-Corticotropin-Releasing Hormone (CRH) Monoclonal Antibody HBM9013 For The Treatment Of Congenital Adrenal Hyperplasia (CAH) And Polycystic Ovarian Syndrome (PCOS)

Abstract Disclosure: H. Pan: None. L.L. Liu: None. Q. Lv: None. F.G. Grosveld: None. D. Drabek: None. R.V. Haperen: None. X. Wang: None. Y. He: None. Y. Wang: None. J. Huang: None. J. Lee: None. G. Zhang: None. J.J. Rong: None. H.V. Chen: None. J.A. Majzoub: Advisory Board Member; Self; Chair of SAB of Harbour BioMed Alpha Therapeutics, which owns the rights of HBM9013.. Stock Owner; Self; Equity Owner of Harbour BioMed Alpha Therapeutics, which owns the rights of HBM9013.. J.J. Zhao: None. Anti-Corticotropin-Releasing Hormone (CRH) Monoclonal Antibody HBM9013 for the Treatment of Congenital Adrenal Hyperplasia (CAH) and Polycystic Ovarian Syndrome (PCOS). Abstract Congenital Adrenal Hyperplasia (CAH) is a rare autosomal recessive genetic disease due to mutation of CYP21A2 which leads to deficiency of 21-Hydroxylase enzymatic activity. Classical CAH patients are born with life-threatening deficiency of glucocorticoid (GC) and mineralocorticoid. Due to this enzymatic block and the lack of negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis by GC, the adrenal gland produces excessive amounts of androgen which result in masculinized genitalia and virilization. The current standard care is supraphysiological doses of GC, which are difficult to balance between excess GC exposure and excess androgen secretion. Too little GC does not suppress production of androgen sufficiently and too much GC leads to Cushing Syndrome (CS). Previous work found that corticotropin-releasing hormone (CRH) is absolutely required for activation of the HPA axis during loss of GC negative feedback, via adrenocorticotropic hormone (ACTH) (1), which is necessary for production of adrenal androgens (2). We report here the development of Anti-CRH humanized monoclonal antibody HBM9013 (PR302334-24) for the treatment of CAH. HBM9013 binds to CRH with high affinity and neutralizes its signaling through both CRH Receptor 1 (CRHR1) and CRH Receptor 2 (CRHR2) in vitro. HBM9013 shows in vivo activities in two preclinical models. It blocks restraint stress-induced increases in plasma ACTH and corticosterone in mouse and rat. Mouse ACTH and Corticosterone were reduced from 210 ± 63 pg/ml to 27 ± 8 pg/ml (Mean ± SD, p = 5.2*10-6; IgG1 Control Group = 6 mice; HBM9013 Group = 8 mice) and from 303 ± 28 ng/ml to 57 ± 15 ng/ml (Mean ± SD, p = 6.2*10-[1][1]; IgG1 Control Group = 6 mice; HBM9013 Group = 8 mice), respectively. It also markedly reduces the constitutive, extremely elevated plasma ACTH levels in Mrap-knockout mice from 3847 ± 240 pg/mL to 1080 ± 302 pg/mL (Mean ± SD, n = 5 independent experiments, p = 2.3*10-7). HBM9013 has excellent CMC characteristics with ∼5 g/L titer and ∼80% yield. HBM9013 also has an excellent safety profile with no-observed-adverse-effect-level (NOAEL) of 150 mg/kg in weekly dosing for five doses in both rat and cynomolgus dose-ranging-finding (DRF) toxicology studies. HBM9013 is formulated up to 150 mg/ml as a weekly to monthly subcutaneous injection for ease of administration and compliance for CAH patient. HBM9013 could be a next generation therapy for CAH, in combination with a low physiological dose of GC that would avoid CS. Since ∼50% of Polycystic Ovarian Syndrome (PCOS) androgens may be of adrenal origin, we believe that HBM9013 could also be indicated for PCOS. References(1)Muglia LJ et al. J Clin Invest. 2000. 105:1269-77.(2)Weber A et al. Clin Endocrinol. 1997. 46:431-7. Presentation: 6/1/2024

9375 Acth-Producing Pituitary Carcinoma in the Falx Cerebri and Other Unusual Locations

Abstract Disclosure: J.E. Esquivel Vargas: None. A. Cob Guillén: None. A.B. Santos Rojo: None. A. Hong Lo: None. ACTH-producing Pituitary Carcinoma in the Falx Cerebri and other unusual locations Background: Pituitary carcinoma is a condition defined by metastasis of a pituitary tumor to a distant location. Pituitary carcinomas are very rare and account for approximately 0.12% of adenohypophyseal tumors (1). Clinical case: We present a case of a 29-year-old female who was followed up in our Endocrinology Department. Past medical history included the diagnosis of Cushing Disease and transsphenoidal tumor resection at 12 years of age, followed by transcranial resection two years later because of persistently elevated adrenocorticotropic hormone (ACTH). Despite the surgical management, the patient persisted with increased ACTH and hypercortisolism, so bilateral adrenalectomy was performed a year later. Two years after the procedure, the patient presented with a newly diagnosed pituitary macroadenoma, so the diagnosis of Nelson Syndrome was made. Linear accelerator radiotherapy was given, which reduced the size of the tumor. Later, multiple imaging studies showed multiple lesions on the falx cerebri, posterior clinoid process, retroclival region, cerebellopontine angle, pterygopalatine fossa, infratentorial region, and posterior ethmoidal cells. Biopsy and immunohistochemistry of the falx cerebri lesions described ACTH-producing pituitary adenocarcinoma. Treatment was given with intramuscular octreotide, dabrafenib, and trametinib. Despite persistently elevated ACTH levels, the patient has since remained clinically stable, without new development or worsening of symptoms. Conclusion: There are 3 unique aspects of our case. First, we reported an unusual presentation of this disease, because the patient in our case was a female with an early age of onset, in contrast with the reported literature. Second, this is the first reported case demonstrating pituitary carcinoma in the falx cerebri. Third, the prognosis of pituitary carcinoma is very poor, and mortality is extremely high, however, the patient in our case has been followed up for 7 years since the diagnosis of the metastatic lesions and has remained clinically stable.

Early Adverse Family Experiences and Elevated Adrenocorticotropic Hormone Predict Non-Suicidal Self-Injury in Females with Non-Psychotic Mental Disorders and Suicidal Ideation.

Nonsuicidal self-injurious behavior (NSSI), prevalent in patients with non-psychotic mental disorders (NPMD), is associated with numerous adverse outcomes. Despite active research into the clinical and psychological aspects of NSSI, the underlying biological mechanisms remain obscure. Early adverse experiences are believed to induce long-lasting changes in neuroendocrine mechanisms of stress control playing a key role in NSSI development. The aim of the study was to evaluate parameters potentially predicting development of NSSI in female patients with NPMD and suicidal ideation. Eighty female patients over 18 years with NPMD and suicidal ideation (40 with and 40 without NSSI) and 48 age matching women without evidence of mental illness (healthy controls) were enrolled. Diagnostic interviews and self-report measures were used to assess childhood maltreatment, presence, frequency, and characteristics of suicidal and self-injurious thoughts and behaviors, the Beck Depression Inventory scale to assess severity of depression. Hypothalamic-pituitary-adrenal axis markers, hormones, and neurotrophic factors were measured in blood serum. The likelihood of developing NSSI in patients with NPMD and suicidal ideation was associated with early adverse family history and elevated adrenocorticotropic hormone levels. Dysregulation of hypothalamic-pituitary-adrenal axis as a result of early chronic stress experiences may represent critical biological mechanism promoting the development of NSSI behaviors in patients with NPMD.

Association of Metabolic and Endocrine Disorders with Bovine Ovarian Follicular Cysts.

After estrus, when mature follicles fail to ovulate, they may further develop to form follicular cysts, affecting the normal function of ovaries, reducing the reproductive efficiency of dairy cows and causing economic losses to cattle farms. However, the key points of ovarian follicular cysts pathogenesis remain largely unclear. The purpose of the current research was to analyze the formation mechanism of ovarian follicular cysts from hormone and gene expression profiles. The concentrations of progesterone (P4), estradiol (E2), insulin, insulin-like growth factor 1 (IGF1), leptin, adrenocorticotropic hormone (ACTH) and ghrelin in follicle fluid from bovine follicular cysts and normal follicles were examined using enzyme-linked immunosorbent assay (ELISA) or 125I-labeled radioimmunoassay (RIA); the corresponding receptors' expression of theca interna cells was tested via quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the mRNA expression profiling was analyzed via RNA sequencing (RNA-seq). The results showed that the follicular cysts were characterized by significant lower E2, insulin, IGF1 and leptin levels but elevated ACTH and ghrelin levels compared with normal follicles (p < 0.05). The mRNA expressions of corresponding receptors, PGR, ESR1, ESR2, IGF1R, LEPR, IGFBP6 and GHSR, were similarly altered significantly (p < 0.05). RNA-seq identified 2514 differential expressed genes between normal follicles and follicular cysts. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis linked the ovarian steroidogenesis pathway, especially the STAR, 3β-HSD, CYP11A1 and CYP17A1 genes, to the formation of follicular cysts (p < 0.01). These results indicated that hormone metabolic disorders and abnormal expression levels of hormone synthesis pathway genes are associated with the formation of bovine ovarian follicular cysts.

Adrenal Hemorrhaging in a Patient with Severe Obstructive Sleep Apnea Syndrome with Elevated Plasma ACTH Levels.

Adrenal hemorrhaging (AH) is a rare condition characterized by bleeding into the suprarenal glands. A 62-year-old man with untreated obstructive sleep apnea syndrome (OSAS) was admitted to our hospital complaining of abdominal stiffness. He was diagnosed with left-sided AH and underwent adrenalectomy. Pre- and post-surgery, elevated plasma adrenocorticotropic hormone (ACTH) levels were observed. However, Cushing's syndrome and adrenal insufficiency were negative, and nasal continuous positive airway pressure (CPAP) normalized the plasma ACTH levels. Elevated ACTH levels are reportedly present in patients with OSAS. ACTH may be associated with the development of AH through the change in blood supply and other mechanisms.

The Association of the Hypothalamic-Pituitary-Adrenal Axis with Appetite Regulation in Children with Fetal Alcohol Spectrum Disorders (FASDs)

Prenatal alcohol exposure causes growth impairment and a wide range of developmental, physical, and cognitive disorders in children, collectively referred to as fetal alcohol spectrum disorders (FASDs). In the course of FASDs, abnormalities can also affect eating behavior and nutritional status, but these problems have received little attention. Therefore, the aim of our study was to determine the levels of hormones involved in the action of the hypothalamic-pituitary-adrenal axis: proopiomelanocortin (POMC), cortisol, and adrenocorticotropic hormone (ACTH), in the serum of patients with FASDs. To our knowledge, none of these hormones studied have yet been evaluated in FASDs to date. We investigated 62 FASD patients and 23 healthy controls by applying an enzyme-linked immunosorbent method (ELISA). Fasting POMC levels were significantly lower in patients with FASDs (10.97 vs. 18,57 ng/mL, p = 0.039) compared to controls. However, there were no differences in cortisol concentrations. Additionally, the sex and subgroup status (fetal alcohol syndrome (FAS), neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE), and FASD risk) did not affect hormone levels. POMC was positively correlated with some clinical parameters such as age, BMI percentile, carbohydrate biomarkers, and ACTH. A positive correlation was observed between ACTH and cortisol levels, as well as ACTH and cholesterol levels. Data analysis showed no HPA axis abnormalities in the form of elevated serum cortisol and ACTH levels. Differences in POMC concentration may indicate the involvement and/or impairment of central nervous system structures in hormonal alterations in FASD individuals, caused by prenatal alcohol exposure. Hormonal dysregulation in FASDs can contribute to reduced growth and development, as well as many other disturbed processes, including neurological/neurodevelopmental dysfunctions. Further insightful studies involving a larger group of patients are needed to determine the potential impact of the measured hormones.

Clinical and StAR genetic characteristics of 33 children with congenital lipoid adrenal hyperplasia

Objective: To analyze the clinical and genetic characteristics of 33 children with congenital lipoid adrenal hyperplasia (CLAH) caused by StAR gene defects. Methods: The clinical, biochemical, genetic, and follow-up (until December 2021) data of 33 children diagnosed with CLAH from 2006 to 2021 were retrospectively analyzed in Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Results: Of the 33 children with CLAH, 17 had a karyotype of 46, XX and 16 had a karyotype of 46, XY; 31 were female and 2 were male by social gender. Classic type and non-classic type were found in 30 and 3 children respectively. The age at diagnosis was 9.0 (3.0, 34.5) months. All the 30 cases with classic CLAH presented within the first year of life with skin hyperpigmentation (28 cases, 93%), vomiting and(or) diarrhea (19 cases, 63%), no increase in body weight (8 cases, 27%), elevated adrenocorticotropic hormone levels (21cases (70%)>275 pmol/L), decreased cortisol levels (47 (31,126) nmol/L), hyponatremia ((126±13) mmol/L), hyperkalemia ((5.7±1.1) mmol/L), and normal 17α-hydroxyprogesterone levels (30 cases, 100%). All these with classic CLAH exhibited female external genitalia. Three children with non-classic CLAH (including 2 cases of 46, XY and 1 case of 46, XX) also showed signs and symptoms of adrenal insufficiency, but 2 of them had an age of onset later than 1 year of age, including 1 case of 46, XY with male external genitalia and 1 case of 46, XX with female external genitalia. The other 46, XY patient with non-classic CLAH presented with adrenal insufficiency at 2 months of age, showing micropenis and hypospadias. In the 17 females with 46, XX, 4 older than 10 years of age showed spontaneous pubertal development. A total of 25 StAR gene pathogenic variants were identified in 33 patients, with p.Q258* (18/66, 27%), p.K236Tfs*47 (8/66, 12%) and p.Q77* (6/66, 9%) being the common variantion. Six novel variants were found, including c.358T>G, c.713_714del, c.125del, c.745-1G>A, c.179-2A>C, and exon 1 deletion. Conclusions: Patients with classic CLAH typically present with signs and symptoms of primary adrenal insufficiency in the early infancy period and female external genitalia. p.Q258*, p.K236Tfs*47 and p.Q77* are common variants in CLAH patients.

Prevalence and clinical characteristics of Crooke's cell adenomas in 101 patients with T-PIT-positive pituitary adenomas: Case series and literature review.

PurposeWe aimed to perform a retrospective analysis of a rare subtype of corticotroph adenoma, Crooke’s cell adenoma, to better understand its clinical features.MethodsWe 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.ResultsA 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.ConclusionCrooke’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.

The role of histamine in anterior pituitary secretion

Objectives: The aim of the present study was to determine the effects of histamine on the anterior pituitary secretion in rats. Materials and Methods: In the first experiments rats were injected with histamine 5 mg/kg i.p., and blood samples were collected to determine the effect of histamine on serum level of adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), prolactin, FSH, and luteinizing hormone (LH) after 10, 20, and 30 min of histamine injection. In the second experiments, rats were treated with (H 1 blocker), chlorphenramine 10 mg/kg, i.p. or (H 2 blocker), cimetidine 80 mg/kg, i.p. respectively, and after 30 min they were injected with histamine and blood samples were taken 30 min after the injection of histamine to determine the same hormones. Results: Histamine significantly elevated serum ACTH and LH level, and these stimulatory effects were inhibited by both H1 and H2 receptor blockers. However, histamine significantly inhibited the serum level of thyroid-stimulating hormone and this inhibitory effect was blocked by H2 receptor blocker, while it showed no effect on the secretion of both prolactin and FSH, although H2 blocker significantly decreased prolactin level and H1 blocker significantly elevated FSH level. Conclusion: The results clearly indicated that histaminergic pathways were involved in the anterior pituitary secretion.

Prevalence of testicular adrenal rest tumor and factors associated with its development in 6 month to 18 years-old patients with congenital adrenal hyperplasia

Introduction: Congenital adrenal hyperplasia (CAH) is a potentially life-threatening form of primary adrenal insufficiency characterized by cortisol, aldosterone, and epinephrine deficiencies, as well as overproduction of androgen. Infertility is one of the most important complications in male patients with CAH, and testicular adrenal rest tumors (TARTs) are known to be the most important caause of infertility in these patients. In the present study, the prevalence of TART and factors associated with its development were evaluated in patients with CAH. Methods & Materials: This is a descriptive cross-sectional study evaluating 30 males (6 month -18 years) with the classical 21-hydroxylase deficiency (21-OHD) through testicular ultrasonography. Data including age, bone age, puberty, 21-OHD phenotype (salt wasting (SW) or simple virilizing (SV)) and serum levels of 17- hydroxyprogesterone (17-OHP), androstenedione and adrenocorticotropic hormone (ACTH) were records. Results: The prevalence of TART was determined 56.7%, which increased with age with higher prevalence in children >12 (52.9%) year old. The mean age in patients with TART was 12.4 ± 4.18 years. No association was found between TART and 21-OHD phenotype, androstenedione, or 17OHP levels, but an association was found between TART and elevated levels of ACTH (p= 0.049), advanced bone age (p= 0.030) and puberty (p= 0.003). Conclusion: According to the results, TART is very common and can occur in pre-pubertal and young patients, and the disease control could be a factor associated with its development. Therefore, it is suggested to investigate the TART development early in childhood, mainly in poorly controlled 21-OHD patients.

Diagnostic Challenges of an Extremely Large Testicular Adrenal Rest Tumor - a Case Report

Background: Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder characterized by elevated levels of adrenocorticotropic hormone (ACTH) and overproduction of adrenal sex steroids. It is speculated that the correlation between CAH and testicular adrenal rest tumors (TARTs) is caused through ACTH-triggered progression of aberrant adrenal cells in testes. Case Presentation: Here, we present a case of a nine-year-old boy with bilateral testicular masses referred to Ghaem hospital (Mashhad, Iran), in the summer of 2019. Laboratory studies revealed elevated ACTH and 17-hydroxyprogesterone confirming the diagnosis of CAH. Radiologic assessment showed bilateral multiple heterogeneous masses that had replaced the normal testicular tissue. Conclusions: Due to the rare nature of TARTs and their manifestations, many of these patients, like ours don’t get prompt detection. It seems crucial for urologists and radiologists to be familiar with this condition as a benign differential diagnosis of bilateral testicular tumors

PTH-Independent Hypercalcemia in Undiagnosed Adrenal Insufficiency

In contrast to PTH-dependent hypercalcemia, the differential diagnosis of PTH-independent hypercalcemia is extensive. Thorough history and physical examination can help direct the clinician in the right direction and avoid extensive and unnecessary work up.A 27-year-old-female with a medical history significant only for untreated subclinical hypothyroidism was admitted to the hospital for hypercalcemia and acute kidney injury after presenting with dizziness, nausea, vomiting, dyspnea, and multiple syncopal episodes prior to admission. Serum calcium on presentation was elevated to 15.9 (8.5–10.2 mg/dL) with an intact parathyroid hormone level of 3.6 (8.5–75 pg/mL). On initial presentation, she was hypotensive, tachycardic, and was noted to be underweight with a body mass index of 17 kg/m2. The patient’s skin was diffusely hyperpigmented, with increased pigmentation in the creases of her hands and on the sides of her fingers. Further lab evaluation was remarkable for hyponatremia and hyperkalemia as well as an undetectable 8 AM cortisol of <1.0 (7–25 µg/dL), adrenocorticotropic hormone (ACTH) level significantly elevated to >1,250 (6–58 pg/mL), aldosterone <4 (<21 ng/dL), and plasma renin activity elevated to 18 (<0.6–3 ng/mL/h). Antibodies to 21-alpha hydroxylase were positive, confirming a diagnosis of Addison’s disease. Prior to the workup confirming an elevated ACTH and low cortisol levels, the patient was treated with aggressive intravenous fluid repletion and calcitonin with overnight improvement in calcium to 11.4 mg/dL. After the diagnosis of primary adrenal insufficiency was confirmed, she was treated with stress doses of intravenous hydrocortisone then gradually tapered to physiologic doses of oral hydrocortisone and fludrocortisone with resolution of her hypercalcemia by the fourth day of hospitalization.Adrenal insufficiency is a known but uncommon cause of PTH-independent hypercalcemia, but the exact mechanism is unknown. Hypercalcemia is thought to result from a combination of a hypovolemic state seen in adrenal insufficiency which leads to decreased urinary calcium excretion as well as increased bone resorption, which may result from increased serum sclerostin concentrations.Adrenal insufficiency should be considered in the differential of PTH-independent hypercalcemia. This case highlights the improvement in hypercalcemia that is seen with correction of glucocorticoid deficiency, and supports delaying additional work up for other PTH-independent causes until appropriate treatment has been given.

ADRENOCORTICOTROPIC HORMONE IMMUNOASSAY INTERFERENCE IN A PATIENT WITH SUBCLINICAL HYPERCORTISOLISM.

Immunoassays are vulnerable to occasional analytical errors despite their sensitivity and specificity. Adrenocorticotropic hormone (ACTH) is among hormones which are vulnerable to assay interference. In this case report, we aimed to present a case of ACTH interference in a patient with subclinical hypercortisolism. We present a case of subclinical hypercortisolism with unexpectedly elevated levels of ACTH in whom interference was shown by different biochemical methods.It is important for the clinician to keep in mind the possibility of interference when clinical and laboratory results are discordant. The communication between the clinician and laboratory staff is important while interpreting results. This case report shows that ACTH interference should be considered in patients with subclinical hypercortisolism who have unexpectedly high levels of adrenocorticotropic hormone.

Hypothesis: does adrenalitis caused by immune checkpoint-inhibitors put melanoma patients at an elevated risk for recurrence?

Primary adrenal failure (Addison’s disease) is a rare complication of immune checkpoint inhibitor (ICI) therapy. Untreated – and also sometimes under adequate hydrocortisone replacement therapy – the levels of ACTH (Adrenocorticotropic hormone) and MSH (Melanocyte stimulating hormone) are elevated. This may be a reason for concern in patients with malignant melanoma (MM): Melanocortin receptors bind to ACTH and the different isoforms of MSH. For example, the melanocortin 1 receptor (MC1R) is overexpressed in many human melanoma cells. Since it is also involved in the proliferation of melanoma cells, the elevated levels of ACTH and its proteolytic cleavage product α-MSH typical for primary failure may lead to an activation of the receptor and, thus, put MM patients that suffered from primary adrenal failure after ICI therapy at an elevated risk for recurrence or an unfavorable course of the disease. Novel dual-release hydrocortisone therapy results in lower ACTH (and most probably lower α-MSH) levels due to the more physiological mode of hydrocortisone release. Given that the concern raised in this hypothesis is confirmed in future investigations, patients who suffer from primary adrenal failure after ICI therapy may benefit from a dual-release hydrocortisone replacement regimen.

MON-317 Ectopic Cushing's Syndrome Due to Prostate Cancer: A Case Series

Background: The introduction of chemotherapy and androgen receptor signaling inhibitors to patients with newly diagnosed metastatic or castration resistant prostate cancer has resulted in longevity and improved quality of life. However, as the disease transitions to a more resistant clinical state despite multiple agents, there has been, in some patients, the emergence of a more aggressive form of the disease with adrenocorticotropic hormone (ACTH) production due to either small cell or neuroendocrine features. These subtypes of prostate cancer are behaviorally unique and can manifest with clinical symptoms and laboratory abnormalities due to severe hypercortisolemia that portend rapid clinical decline if not death. In order to facilitate early recognition and treatment of this rare clinical syndrome, we describe several cases of ectopic ACTH-dependent Cushing’s syndrome that were associated with this histologic entity and were not easily identified despite refractory hypokalemia and hypertension. Methods: Through a dataline search we identified 10 cases of prostate cancer with ectopic ACTH-dependent Cushing’s syndrome treated at MSKCC over the past 20 years. Data were abstracted from patients' medical records, including clinical course, histopathology and response to therapy. Results: Mean age at presentation was 66 years (range 58 to 80). 9 of 10 patients reported prior tobacco use. 7 of 10 patients had prostate adenocarcinoma prior to diagnosis of ectopic Cushing’s, and 9 of 10 patients had a Gleason score >7. When available, tumor pathology showed small cell or high grade neuroendocrine carcinoma, but despite elevated plasma ACTH levels, not all tumors had immunohistochemistry that was positive for ACTH. Spontaneous hypokalemia was present in all 10 patients, and presenting signs of Cushing’s syndrome were most commonly hypokalemia or resistant hypertension. One patient had hypertensive urgency and two developed psychosis. Median survival was ~2.5 months after the development of Cushing’s syndrome. Four patients died of complications from progressive tumor growth, and three died of complications due to infections, including PCP, aspergillus lung infection, mold lung infection, cellulitis/fasciitis, and mastoiditis. Three died of unclear causes. Conclusions: Prostate cancer that evolves into an ACTH-secreting neuroendocrine phenotype is a rare entity that is associated with high risk for infections, refractory hypokalemia, and poor survival. Further clinical and pathological characterization is needed to ensure early recognition and appropriate treatment interventions for these patients.

Metastatic Adrenocorticotropic Hormone-Secreting Breast Cancer Treated with Bilateral Adrenalectomy

Objective: Endogenous Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion occurs most commonly from small-cell lung carcinoma. Ectopic ACTH secretion from a neuroendocrine tumor of the breast is very rare, with only 7 previously reported cases in the literature. Methods: We describe a rare case of a metastatic ACTH-producing neuroendocrine carcinoma of the breast causing Cushing syndrome that was managed with bilateral simultaneous retroperitoneoscopic adrenalectomy. Results: A 51-year-old female with a history of bilateral mastectomy for ACTH-secreting neuroendocrine carcinoma of the breast presented with medically intractable Cushing syndrome. Elevated 24-hour urine free cortisol and ACTH levels and clinical findings of diabetes, vertebral compression fractures, and venous thromboembolism were present. Computed tomography scan of the abdomen demonstrated bilateral adrenal hyperplasia. The patient underwent simultaneous retroperitoneoscopic bilateral adrenalectomy. Histopathology...

Thymic Carcinoid with Adrenocorticotropic Hormone-Producing Ectopic Cushing Syndrome and Empty Sella

Ectopic Cushing's syndrome secondary to thymic carcinoid is a rare disorder that may be difficult to diagnose and manage. We describe a case of severe Cushing's syndrome secondary to a large adrenocorticotropic hormone (ACTH) producing thymic carcinoid in a patient with history of primary hyperaldosteronism. A 43-year-old female with a 20-year history of an aldosterone-secreting adrenocortical adenoma status post right adrenalectomy presented with acute onset of proximal muscle weakness, swelling, facial hirsutism, and severe hypokalemia. Ectopic Cushing's Syndrome was suspected based on the sudden symptom onset and markedly elevated 24-hr urine cortisol and ACTH levels. MRI revealed an empty pituitary sella and a large (7.3 cm) mediastinal mass visible on chest CT. The mass was resected by video-assisted thoracoscopic surgery, resulting in resolution of symptoms and cortisol levels. Pathology assessment confirmed well-differentiated thymic carcinoid with positive ACTH staining. The case highlights clinical features, challenges in diagnostic work up, treatment modalities, and associated endocrine findings in a thymic carcinoid abutting the heart and presenting with ectopic ACTH secretion.

Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: a case report

BackgroundPulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians.Case presentationA 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing’s syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing’s syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH.ConclusionsWe highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing’s symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

THYMIC CARCINOID WITH ACTH-PRODUCING ECTOPIC CUSHING'S SYNDROME AND EMPTY SELLA.

Abstract Objective: Ectopic Cushing's syndrome secondary to thymic carcinoid is a rare disorder that may be difficult to diagnose and manage. Methods: We describe a case of severe Cushing's syndrome secondary to a large adrenocorticotropic hormone (ACTH) producing thymic carcinoid in a patient with history of primary hyperaldosteronism. Results: A 43-year-old female with a 20 year history of an aldosterone-secreting adrenocortical adenoma status post right adrenalectomy presented with acute onset of proximal muscle weakness, swelling, facial hirsutism, and severe hypokalemia. Ectopic Cushing's Syndrome was suspected based on the sudden symptom onset and markedly elevated 24-hr urine cortisol and ACTH levels. MRI revealed an empty pituitary sella and a large (7.3 cm) mediastinal mass visible on chest CT. The mass was resected by video-assisted thoracoscopic surgery, resulting in resolution of symptoms and cortisol levels. Pathology assessment confirmed well-differentiated thymic carcinoid with positive ACT...

ALD1613, a Novel Long-Acting Monoclonal Antibody to Control ACTH-Driven Pharmacology.

Adrenocorticotropic hormone (ACTH) is the primary regulator of adrenal glucocorticoid production. Elevated levels of ACTH play a critical role in disease progression in several indications, including congenital adrenal hyperplasia and Cushing disease. We have generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1613) to ACTH. In vitro, ALD1613 neutralizes ACTH-induced signaling via all 5 melanocortin receptors and inhibited ACTH-induced cyclic adenosine monophosphate accumulation in a mouse adrenal cell line (Y1). ALD1613 administration to wild-type rats significantly reduced plasma corticosterone levels in a dose-dependent manner. In rodent models with either chronic infusion of ACTH or acute restraint stress-induced ACTH, corticosterone levels were significantly reduced by ALD1613. Administration of ALD1613 to nonhuman primates on days 1 and 7 stably reduced plasma cortisol levels >50% for 57 days. ALD1613 demonstrates the potential of a monoclonal antibody to be an effective therapeutic for conditions with elevated ACTH levels.