Retrospective Analysis of Nivolumab-Induced Isolated Adrenocorticotropin Deficiency.

Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare disorder, characterized by secondary adrenal insufficiency. We experienced a case of isolated ACTH deficiency presented with prolonged QT intervals which was helpful in diagnosis. Hereby we report our case and review the previous cases. We describe a 77 year-old female whose major complaints were general malaise, anorexia, and depression. On admission, QT intervals of ECG were prolonged. Endocrine tests indicated that she was suffering from isolated ACTH deficiency. After hydrocortisone replacement therapy was started, QT intervals were shortened and all of her complaints were resolved. There are only six reports about isolated ACTH deficiency associated with prolonged QT intervals until now. Prolongation of QT intervals is known to be a risk factor for cardiovascular events such as ventricular fibrillation, but interestingly prolonged QT intervals associated with isolated ACTH deficiency infrequently cause lethal arrhythmia. The initial symptoms of adrenal deficiency in elderly patients are obscure and adrenal deficiency is often misdiagnosed as unidentified clinical syndrome. It is important to consider isolated ACTH deficiency when recognizing unexplained prolonged QT intervals.

ISOLATED ADRENOCORTICOTROPIC HORMONE (ACTH) deficiency is a rare pituitary disorder characterized by decreased secretion of ACTH, but not of the other hormones of the anterior pituitary and causes secondary adrenal insufficiency.1 Since isolated ACTH deficiency gradually and latently develops and shows non-specific symptoms, it is easily misdiagnosed. We report a case of middle-aged-onset isolated ACTH deficiency that showed a severe major depressive episode. A 62-year-old man was admitted to our hospital due to suicidal behavior. He did not have any previous history of neuropsychiatric or endocrine disorders. From 6 months before the admission, he complained of mild general fatigue, depressed mood, loss of pleasure, psychomotor retardation, insomnia, decrease in appetite, and weight loss. He was diagnosed as having major depressive disorder. A dose of 100 mg/day of sertraline did not relieve him of his depressive symptoms at all. At the time of admission, he was fully conscious and showed a severe major depressive episode with suicidal ideas. He did not show any symptoms suggestive of atypical depression or chronic fatigue syndrome, such as hypersomnia, lead paralysis, mood reactivity, rejection sensitivity, muscle pain, lymph node swelling, and fever. Magnetic resonance imaging of his brain did not show any structural abnormality, including an empty sella. Blood test revealed anemia (red blood cell count, 3.24 × 106/µL; hemoglobin, 10.0 mg/dL) and hyponatremia (117 mEq/L). Thyroid function studies were consistent with hypothyroidism: thyroid-stimulating hormone (TSH), 49.8 µIU/mL (normal range, 0.6–5.1); fT3, 2.45 pg/mL (2.47–4.34); and fT4, 0.71 ng/dL (0.97–1.79). Rheumatoid factor and antinuclear, antithyroglobulin, anti-thyroid peroxidase, TSH-receptor, and antipituitary antibodies were negative. Both serum ACTH (<2.0 pg/mL; normal range, 7.2–63.3) and cortisol (0.2 µg; 3.7–19.4) were extremely low, whereas aldosterone (61.6 pg/mL; 38.9–307.0) was within normal range. Neither ACTH nor cortisol responded to corticotrophin-releasing hormone stimulation test, showing that he suffered from secondary adrenocortical insufficiency. Thyrotropin-releasing hormone test, gonadotrophin-releasing hormone test, and growth hormone-releasing hormone test showed normal responses, revealing that his secondary adrenocortical insufficiency was caused by isolated ACTH insufficiency. We discontinued sertraline and started to administer him 5 mg/day of hydrocortisone. Three days later, his symptoms mimicking major depressive episode were dramatically resolved. As in our case, isolated ACTH deficiency may be comorbid with primary hypothyroidism although the mechanism of the coexistence is unknown.2 However, the comorbid hypothyroidism did not seem to induce his depressive state as hypothyroidism was recovered 4 months after rapid relief of his psychiatric state. Relationships between glucocorticoid function and symptoms mimicking major depressive episodes are complex but might reflect insufficient glucocorticoid signaling. Some major depressive episodes might be associated with the insufficient glucocorticoid signaling by decrease of glucocorticoid production or decrease of sensitivity of glucocorticoid receptors.3 Our case suggests that isolated ACTH deficiency should be added into a differential diagnostic list of major depressive disorder. The patient gave the authors informed consent to publish this letter.

BackgroundWith the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events.MethodsA retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month.Results28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18–39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up.ConclusionsIAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

Immunotherapy with immune checkpoint inhibitor (ICI) monoclonal antibodies has shown to be an effective therapeutic alternative in several malignant tumors. However, adverse effects related to an activation of the immune system may accompany ICI therapy. Among the immune-related adverse events (irAEs) are autoimmune endocrine adverse effects, such as thyroiditis, and hypophysitis. Secondary adrenal insufficiency due to isolated ACTH deficiency (IAD) has also been recently reported to be associated with ICI antibodies. We carried out a systematic review of IAD cases induced by cancer immunotherapy published to date using PubMed's database. We selected 35 articles that reported 60 cancer patients diagnosed with IAD induced by ICI therapy. The prevalence was higher in men (ratio 1.6/1). Mean age at diagnosis was 63.2 ± 11.6 (range,30-87). Melanoma was the tumor most commonly reported (35%) followed by lung (28.3%) and kidney cancer (18.3%). The ICI monoclonal antibody most frequently associated was nivolumab in monotherapy (60%), followed by pembrolizumab (18.3%). Median (IQR) time to develop IAD after starting ICI therapy was 6 (4-8) months. The main symptoms at IAD diagnosis were fatigue (82.8%) and anorexia (67.2%). Hyponatremia (68%) and eosinophilia (31.8%) were the laboratory abnormalities most frequently associated with IAD. Pituitary magnetic resonance imaging (MRI) was normal in most patients (93%). Thyroiditis was the most prevalent (35%) endocrine irAE associated with IAD. In conclusion, ICI-induced IAD is a rare and potentially life-threatening condition that must be taken into account whenever treatment with immunotherapy in cancer patients is starteddue to their potential serious prognostic implications.

Patient: Female, 67-year-oldFinal Diagnosis: Isolated adrenocorticotropic hormone deficiencySymptoms: Anorexia • fatigue • vomiting • muscle weaknessMedication: —Clinical Procedure: Dynamic endocrine testingSpecialty: Endocrinology and metabolicObjective:Rare co-existance of disease or pathologyBackground:Isolated adrenocorticotropic hormone deficiency (IAD) is a rare disorder characterized by central adrenal insufficiency (AI) but normal secretion of pituitary hormones other than adrenocorticotropic hormone. IAD usually presents with unspecific symptoms of AI, such as anorexia and fatigue, but some patients present with a variety of atypical manifestations. Rhabdomyolysis is a potentially life-threatening clinical syndrome caused by skeletal muscle injury with the release of muscle cell contents into the circulation. A wide variety of disorders can cause rhabdomyolysis. Herein, we report an unusual case of IAD presenting with hyponatremia and rhabdomyolysis.Case Report:A 67-year-old Japanese woman with a 2-month history of anorexia and fatigue was diagnosed with severe hyponatremia (serum sodium, 118 mEq/L) and rhabdomyolysis (serum creatine phosphokinase, 6968 IU/L), after 2 days of vomiting and muscle weakness. Physical and laboratory findings did not show dehydration or peripheral edema. Her rhabdomyolysis resolved with normalization of serum sodium levels during administration of sodium chloride. However, her anorexia and fatigue remained unresolved. After reducing the amount of sodium chloride administered, the patient still had hyponatremia. Detailed endocrinological examinations indicated IAD; her hyponatremia was associated with inappropriately high plasma arginine vasopressin levels. The patient received corticosteroid replacement therapy, which resolved her anorexia, fatigue, excessive arginine vasopressin, and hyponatremia.Conclusions:This case highlights the importance of considering the possibility of central AI in patients with hyponatremia and excessive arginine vasopressin levels. In addition, rhabdomyolysis associated with hyponatremia can be an important manifestation of IAD.

A case of isolated ACTH deficiency accompanying transient primary hypothyroidism was reported along with a review of literature on isolated ACTH deficiency in Japan with special reference to its association with thyroid function. Our case, a 56-year-old woman, developed somnolence and hypoglycemia due to isolated ACTH deficiency. She also had the features of hypothyroidism, namely mounding phenomenon, muscle rigidity, increased plasma myogenic enzymes and cold intolerance. Both free T3 and free T4 were decreased, and basal as well as TRH-stimulated TSH levels were abnormally high. Plasma thyroglobulin was increased and no anti-thyroid antibodies were detected. All thyroid related physical and biochemical abnormalities disappeared after hydrocortisone replacement. A review of the literature on 103 cases disclosed that more than half the cases with isolated ACTH deficiency had a high plasma level of TSH, basal and/or TRH-induced, while the antithyroid antibodies were reported to be positive in only 13 cases. In more than 70% of such cases, the abnormality in the pituitary-thyroid axis was transient and was reversed by glucocorticoid replacement. Our case and cases in the literature indicate that the interference of thyroid hormone synthesis and/or secretion by glucocorticoid deficiency per se is the major cause of thyroid dysfunction rather than associated autoimmune thyroid disease.

To investigate the clinical characteristics of isolated adrenocorticotropic hormone deficiency (IAD) induced by pembrolizumab, and to provide reference for diagnosis and treatment. Clinical reports of pembrolizumab-induced IAD before February 28, 2025 were collected for retrospective analysis. Twenty (51.3%) women and 19 (48.7%) men entered the study, with a median age of 66 years (range: 38-85). The median time for the onset of IAD was 7.3 months (range: 2-30) after initial administration, and the median cycle was 7 cycles (range: 2-40). Fatigue (65.8%) and anorexia (52.6%) were the most common complaints. Hyponatremia (92.3%) and eosinophilia (33.3%) were the laboratory abnormalities most commonly associated with IAD. Pituitary magnetic resonance imaging (MRI) was normal in most patients (88.2%). After receiving glucocorticoid therapy, patients' symptoms improved significantly with or without pembrolizumab. Pembrolizumab-induced IAD is a rare disease that needs to be paid sufficient attention to. IAD patients have nonspecific manifestations and may be delayed in diagnosis. Further studies are needed to confirm the risk factors and prognosis of pembrolizumab-induced IAD.

An acquired partial pituitary insufficiency with selective ACTH and GH deficiency was demonstrated in two men aged 47 and 54, for which the clinical course over many years corresponds to Addison's disease. In one of the 2 cases, antibodies to anterior pituitary cell membrane, assayed by an immunofluorescence method with GH3 cells (rat GH and prolactin secreting cell) and AtT-20 cells (mouse ACTH secreting cell) as antigens, were positive. We also present a 55-year-old man with isolated ACTH deficiency associated with transient GH deficiency. In this case, hydrocortisone replacement corrected his subnormal, pre-therapy GH response to insulin tolerance and glucagon propranolol tests, although there was no response of serum GH to L-dops and arginine stimulation test before therapy. Selective ACTH and GH deficiency are very rare and the finding of transient GH insufficiency in a patient with isolated ACTH deficiency suggests that repeated testing while on hydrocortisone replacement therapy is of great diagnostic importance in order to distinguish between selective ACTH and GH deficiency and isolated ACTH deficiency accompanied by transient GH insufficiency.

Non-specific symptoms such as asthenia, anorexia, unintentional weight loss, nausea/vomiting particularly in the elderly population are often overlooked both by caretakers and physicians. Deteriorating general health and neuro-psychiatric symptoms are often attributed to depression in the elderly population. The most common electrolyte abnormality, hyponatremia is again more common in the elderly population. Often neglected chronic hyponatremia remains asymptomatic in many cases. Once hyponatremia is detected clinicians should establish a proper diagnosis before supplementation. Failure to diagnose such cases will lead to repeated hospitalization, poor quality of life, wastage of resources and even death. Isolated ACTH deficiency (IAD) is a rare disorder and potentially fatal. IAD can present rarely as hyponatremia and diagnosis can easily be missed if not suspected. IAD may not be as rare as earlier thought as more and more such cases are been reported. Here we report two cases of generalized weakness and nausea; they were repeatedly hospitalized and treated for hyponatremia and ultimately diagnosed as IAD in our hospital.

Disclosure: J. Poncelet: None. Q. Wang: None. A.J. Montero: Advisory Board Member; Self; AstraZeneca, Gilead. Other; Self; Medical Advisor for Paragon Infusion Services. L. Tranchito: None. Isolated Adrenocorticotropic Hormone Deficiency in the Setting of Anti-PD1 Immunotherapy Introduction: Immune checkpoint inhibitors have been associated with endocrine immune-related adverse events, such as secondary adrenal insufficiency with isolated ACTH deficiency in rare instances. Case Presentations: We present two different cases of isolated ACTH deficiency (IAD) while on anti-PD1 therapy with pembrolizumab. Patient A is a 66-year-old woman with history of tobacco use, hypertension, and COPD diagnosed with stage IV lung adenocarcinoma. After completing 15 cycles of pembrolizumab, she reported symptoms of fatigue, weakness, lightheadedness, and was subsequently admitted to the hospital for symptomatic hyponatremia. Lab workup revealed a morning cortisol level of 0.6 ug/dL (n2.5-20 ug/dL) and ACTH &amp;lt;1.5 pg/mL (n7.2-63.3 pg/mL), both of which had previously been normal. Her TSH was mildly elevated with a normal free T4. Her FSH, LH, prolactin, and IGF levels were normal as was MRI of the pituitary. She therefore was diagnosed with IAD and started physiologic steroid replacement therapy with hydrocortisone with subsequent symptomatic improvement and normalization of her serum sodium. Patient B is a 60-year-old woman with a history of osteoporosis, aortic stenosis, and stage II triple negative breast cancer treated with neoadjuvant chemotherapy and pembrolizumab. Two months after starting immunotherapy, she presented to her oncology office with symptoms of fatigue, poor appetite, body aches, and dizziness. Her labs revealed mild hyponatremia, cortisol of 0.9 ug/dL (n2.5-20 ug/dL) and ACTH &amp;lt;1.5 pg/mL (n7.2-63.3 pg/mL). TSH, LH, FSH, and prolactin levels were normal. She started physiologic steroid replacement therapy with hydrocortisone for IAD, which led to improvement in her symptoms. Both patients continue pembrolizumab. Conclusions: Immune-related adverse events affecting endocrine pathways have been reported with immune checkpoint inhibitors. There is no method to predict which patients may be affected, and no guidelines exist on when or how often to monitor hormone levels in these patients. Importantly, patients can continue immune checkpoint inhibitors despite IAD if controlled by hormone replacement, though ACTH recovery should not be expected[1]. Recognition of symptoms can prompt earlier evaluation for secondary adrenal insufficiency and provide greater benefit to patients. 1.Schneider BJ, Naidoo J, Santomasso BD, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update [published correction appears in J Clin Oncol. 2022 Jan 20;40(3):315]. J Clin Oncol. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440 Presentation: 6/1/2024

[Introduction] Immune checkpoint inhibitors (ICIs) are widely used for the treatment of several malignancies. Despite their effectiveness, they may cause immune-related adverse effects on endocrine organs. Here we describe three cases of isolated ACTH deficiency (IAD) that has occurred after ICI therapy. [Case presentation] Case 1: An 80-year-old female patient with advanced melanoma received nivolumab (NIVO) (3 mg/kg intravenously (IV) every two weeks) for 16 weeks, followed by ipilimumab (3 mg/kg IV every three weeks). After the third injection of ipilimumab, she was alert but complained of general fatigue and anorexia. Her laboratory tests revealed hyponatremia (Na 126 mEq/l), hypoglycemia (Glu 65 mg/dl), low ACTH (ACTH <2.1 pg/ml), hypocortisolemia (cortisol (F) 3.6 µg/dl), and inflammation (white blood cell (WBC) 9,000/µl and C-reactive protein 12.87 mg/dl). Case 2: A 52-year-old diabetic male patient on sulfonylurea for the past two years was given 13 courses of NIVO (3 mg/kg IV every two weeks) for the treatment of recurrent lung cancer but could not proceed with the 14th treatment because of general malaise, appetite loss, and slight fever (37ºC). About three weeks after the 13th injection, he went into hypoglycemic coma (Glu 32 mg/dl) and received intravenous glucose. On admission, his Glasgow Coma Scale score was 14 (E4V4M6). Laboratory tests showed hyponatremia (Na 133 mEq/l), low ACTH (ACTH <2.1 pg/ml), and hypocortisolemia (F 0.2 µg/dl), but no leukocytosis (WBC 6,000/µl). Case 3: A 67-year-old male patient received NIVO (3 mg/kg IV every two weeks) as third-line therapy for advanced gastric cancer. After the seventh course of treatment, he complained of general fatigue, anorexia, joint pain, and palpitations. His blood laboratory test was unremarkable with normal serum sodium (Na 140 mEq/l). Six days later, he returned due to persistent symptoms. Laboratory investigation revealed hyponatremia (Na 135 mEq/l), normoglycemia (Glu 88 mg/dl), low ACTH (2.7 pg/ml), and hypocortisolemia (F 0.8 µg/dl), but no inflammation (WBC 3,200/µl). In all three cases, magnetic resonance imaging showed no abnormalities and endocrinological tests confirmed the clinical diagnosis of IAD. All of them were discharged on a physiological replacement dose of hydrocortisone. [Discussion] A recent report suggested that hyponatremia can be an early manifestation of ICI-induced IAD. Indeed, in Cases 1 and 2, adrenal insufficiency was suspected due to hyponatremia and hypoglycemia, although in Case 2, sulfonylurea presumably also contributed to the development of hypoglycemia. In Case 3, however, serum sodium and glucose levels were normal when he initially became symptomatic. This case illustrates the importance of suspecting IAD in ICI-treated patients who present with non-specific symptoms, such as malaise, even in the absence of hyponatremia or hypoglycemia.

We found symptomatic hyponatremia in four elderly patients in which serum sodium (Na) levels ranged from 101 to 122 mEq/l. All 4 patients had low levels of plasma adrenocorticotropic hormone (ACTH), serum cortisol, and urinary excretion of 17-OHCS, and poor responses of ACTH to exogenous insulin and antidiuretic hormone (ADH). Other pituitary hormones were all normal. They were therefore diagnosed as having isolated ACTH deficiency. Plasma ADH was relatively high despite hypoosmolality which was associated with the hyponatremia. Water loading test revealed impaired water excretion and poor suppression of plasma ADH. Replacement with 20-30 mg hydrocortisone completely restored the serum Na level and restored the plasma ADH level to the normal range in all 4 patients. Other factors such as decreased glomerular filtration, enhanced urinary Na loss and decreased Na intake were also included. These results indicate that there is marked hyponatremia and that in the presence of hypoosmolality the sustained secretion of ADH is the key factor in causing the impaired water excretion and hyponatremia in isolated ACTH deficiency.

A 60-year-old man was hospitalized with complaints of general malaise and weight loss. On admission, ACTH and cortisol levels were low, and thyroid function tests revealed hyperthyroidism. These findings and further examination led to a diagnosis of isolated ACTH deficiency (IAD) with Graves' disease. It is known that IAD is frequently associated with thyroid disease, but its association with Graves' disease is rare. The present case is worth noting, because some reports indicate that aggravation of associated Graves' disease may concomitantly aggravate adrenal insufficiency in patients with IAD.

Intractable Nausea Attributable to Isolated Deficiency of Adrenocorticotropic Hormone: Prompt Resolution after Administration of Glucocorticoid

Isolated ACTH deficiency (IAD) is a rare disorder, characterized by secondary adrenal insufficiency (AI) with low or absent cortisol production, normal secretion of pituitary hormones other than ACTH and the absence of structural pituitary defects. In adults, IAD may appear after a traumatic injury or a lymphocytic hypophysitis, the latter possibly due to autoimmune etiology. Conversely, a genetic origin may come into play in neonatal or childhood IAD. Patients with IAD usually fare relatively well during unstressed periods until intervening events spark off an acute adrenal crisis presenting with non specific symptoms, such as asthenia, anorexia, unintentional weight loss and tendency towards hypoglycemia. Blood chemistry may reveal mild hypoglycemia, hyponatremia and normal-high potassium levels, mild anemia, lymphocytosis and eosinophilia. Morning serum cortisol below 3 microg/dl are virtually diagnostic for adrenal insufficiency. whereas cortisol values comprised between 5-18 microg/dl require additional investigations: insulin tolerance test (ITT) is considered the gold standard but-when contraindicated-high or low dose-ACTH stimulation test with serum cortisol determination provides a viable alternative. Plasma ACTH concentration and prolonged ACTH infusion test are useful in differential diagnosis between primary and secondary adrenal insufficiency. For some patients with mild, near-to-asymptomatic disease, glucocorticoid replacement therapy may not be required except during stressful events; for symptomatic patients, replacement doses i.e., mean daily dose 20 mg (0.30 mg/kg) hydrocortisone or 25 mg (0.35 mg/kg) cortisone acetate, are usually sufficient. Administration of mineralocorticoids is generally not necessary as their production is maintained.