Evidence Of Pituitary Adenoma Research Articles

OR11-03 A Novel Mutation In The Ligand-binding Domain Of The NR3C1 Gene Associated With Fluctuating Resistance To Glucocorticoids

Abstract Disclosure: M. Laulhé: None. E. Kuhn: None. J. Bouligand: None. L. Amazit: None. J. Perrot: None. P. Kamenicky: None. M. Lombes: None. J. Fagart: None. S. Viengchareun: None. L. Martinerie: None. Introduction: Constitutive glucocorticoid resistance is associated with mutations in the NR3C1 gene, encoding the Glucocorticoid Receptor (GR). We identified a novel heterozygous point mutation causing fluctuating resistance to glucocorticoid depending on ligand concentrations. Initially, the propositus, a 45-year-old man, was diagnosed with a right adrenal incidentaloma and an ACTH-independent biological hypercortisolism. Shortly after adrenal surgery, plasma cortisol increased again (612 nmol/L) associated with inadequate ACTH levels (122 pg/mL) without any evidence of pituitary adenoma or ectopic ACTH-secreting tumor, suggesting a glucocorticoid resistance syndrome. Methods: We sequenced NR3C1 gene and performed in vitro analysis to assess contribution of this variant to the patient’s phenotype and how it affects biological activity of GR. Results: Exon sequencing of the NR3C1 gene identified a novel missense variant located on exon 5 (NM_000176.3, c.1706 G>A) resulting in substitution of arginine to glutamine at amino acid 569 (GR R569Q) in the Ligand-Binding Domain (LBD) of GR. We characterized transcriptional activity of GR R569Q in HEK 293T cells transiently co-transfected with either GR WT or GR R569Q, together with a luciferase reporter gene construct placed under control of a promoter containing two glucocorticoid responsive elements. We observed a decreased transcriptional activity of GR R569Q (EC50 4.55 nM [3.8;5.3]) compared to GR WT (EC50 0.19 nM [0.15; 0.24]), in response to dexamethasone. Interestingly, GR R569Q exerted a dominant negative effect on GR WT, with a decrease in transcriptional activity of 80% when stimulated with 1 nM dexamethasone (2-way ANOVA test, P<0.0001), which was blunted when stimulated with a 100-fold higher concentration of dexamethasone. As the variant is located within the second nuclear localization signal, we studied nuclear translocation in response to 1 nM cortisol for 1 h. As expected, nuclear-cytoplasmic ratio was lower in patients’ fibroblasts (2.3 ± 0.14 vs 3.0 ± 0.98, ANOVA 2-Way, P < 0.0001) compared with control fibroblasts, as quantified by automated high-throughput microscopy. Three-dimensional modeling revealed that arginine substitution leads to loss of a hydrogen bond stabilizing the LBD structure. This may result in a lower ligand affinity that can be bypassed by high concentrations of agonist. We are currently testing receptor affinity and reversibility of phenotype after hydrogen bond restoration by directed mutagenesis (c.1705 C>A, p.Q569K). Conclusion: Overall, we identified a novel variant of the NR3C1 gene associated with fluctuating GR sensitivity depending on ligand concentration. This finding may provide new insights into mechanisms involved in GR sensitivity. Presentation: Friday, June 16, 2023

PSAT044 Management of Severe Cushing's Syndrome in a Patient with Cyclical Ectopic ACTH Production Treated with Osilodrostat.

Abstract Introduction We are presenting a case of severe Cushing's syndrome with multiple complications treated medically with osilodrostat. Clinical Case A 71-year- old female with severe chronic obstructive pulmonary disease was noted to have episodes of hypokalemia, hyperglycemia, and hypertension lasting for several weeks. At the time of presentation to the clinic, she had normal vital signs and no physical exam findings suggestive of hypercortisolism except for mild proximal muscle weakness. Between 2019 and 2021, she had multiple episodes of the presenting symptoms along with elevated morning serum cortisol of 57 to 119 mcg/dl (normal 7-22 mcg/dl), 24-hour urine free cortisol 1343 to 2464 mcg/24 hours (normal 4.5-45 mcg/24 hours), midnight saliva cortisol 509 to 8870 ng/dl (normal <100 ng/dl), and ACTH 105 to 150 pg/ml (normal 5-52 pg/ml). Between episodes labs were normal. A diagnosis of cyclic ACTH-dependent Cushing's syndrome was made. Pituitary MRI was normal, with no evidence of pituitary adenoma. Inferior petrosal sinus sampling was done while cortisol level was elevated, and it showed petrosal sinus to peripheral ACTH ratio of 1.2 following stimulation, a ratio <3.0 suggests ectopic ACTH-dependent Cushing's syndrome. A Ga-65 DOTATATE scan did not localize the tumor. As she was considered a poor surgical candidate for bilateral adrenalectomy, she was started on osilodrostat 10 mg twice daily and hydrocortisone 10 mg twice daily for a block and replace strategy. She was admitted to the hospital 5 days later for increasing fatigue and severe hyperglycemia. Potassium level was 2.2 mmol/L (normal 3.5-5 mmol/L), blood glucose >500 mg/dl, Hemoglobin A1c 8.2%, and random cortisol level was 96 mcg/dl. She was hypertensive and had new acute rib fractures, right lower lobe pulmonary embolism, and deep vein thrombosis. She was given potassium supplements, insulin, anticoagulation, and spironolactone 100 mg bid. The dose of Osilodrostat was increased to 20 mg twice daily. Over 12 days, her cortisol level decreased gradually to 6.3 mcg/dl on the day of discharge. Spironolactone, insulin, and potassium were discontinued and hydrocortisone was prescribed for physiologic replacement. As an outpatient, she continues both osilodrostat and hydrocortisone and is doing quite well. Conclusion Osilodrostat can rapidly and effectively decrease cortisol levels in patients with severe Cushing's syndrome. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Recurrence of a neuroendocrine tumor of adrenal origin: a case report with more than a decade follow-up

BackgroundNeuroendocrine tumor (NET) with adrenocorticotropic hormone (ACTH) secretion are very rare. To our knowledge, no follow-up study is published for ACTH-secreting NET, regardless of the primary site, to show second occurrence of tumor after a long follow-up, following resection of primary tumor.Case presentationHere, we describe a 49-year-old-man with cushingoid feature, drowsiness and quadriparesis came to emergency department at December 2005. Laboratory tests revealed hyperglycemia, metabolic alkalosis, severe hypokalemia, and chemical evidence of an ACTH-dependent hypercortisolism as morning serum cortisol of 57 μg /dL without suppression after 8 mg dexamethasone suppression test, serum ACTH level of 256 pg/mL, and urine free cortisol of > 1000 μg /24 h. Imaging showed only bilateral adrenal hyperplasia, without evidence of pituitary adenoma or ectopic ACTH producing tumors. Importantly, other diagnostic tests for differentiating Cushing disease (CD) from ectopic ACTH producing tumor, such as inferior petrosal sinus sampling (IPSS), corticotropin releasing hormone (CRH) stimulation test, octreotide scan or fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan were not available in our country at that time. Therefore, bilateral adrenalectomy was performed that led to clinical and biochemical remission of hypercortisolism and decreased ACTH level to < 50 pg/mL, findings suggestive of a primary focus of NET in adrenal glands. After 11 years uncomplicated follow up, the ACTH level elevated up to 341 pg/mL and re-evaluation showed a 2 cm nodule in the middle lobe of the right lung. Surgical excision of the pulmonary nodule yielded a carcinoid tumor with positive immunostaining for ACTH; leading to decrease in serum ACTH level to 98 pg/mL. Subsequently after 7 months, serum ACHT levels rose again. More investigation showed multiple lung nodules with metastatic bone lesions accompanied by high serum chromogranin level (2062 ng/mL), and the patient managed as a metastatic NET, with bisphosphonate and somatostatin receptor analogues.ConclusionThis case of surgically-treated NET showing a secondary focus of carcinoid tumor after one decade of disease-free follow-up emphasizes on the importance of long-term follow-up of ACTH-secreting adrenal NET.

SUN-436 Severe Hyponatremia as the Presenting Feature of Partially Empty Sella

Introduction: We report a case of severe acute on chronic hyponatremia meeting the laboratory diagnostic criteria of SIADH. Subsequent evaluation showed secondary adrenal insufficiency due to partially empty sella. Hyponatremia completely resolved following hydrocortisone treatment. Clinical Case: A 76-year-old man with history of hypothyroidism and SIADH was admitted with weakness, fatigue, and leg cramps for the past 3 months. He was staying in a cabin with a broken air conditioner during the summer when his symptoms started. Physical exam revealed mild dry mucus membranes, normal skin turgor, capillary refill less than 2 sec., bradycardia, and no skin hyperpigmentation. He was found to have acute-on-chronic hyponatremia with a serum sodium of 115 mEq/L (baseline 124 mEq/L-130 mEq/L), which worsened with initial volume resuscitation. Lasix and salt tablets were not effective treatment. Other labs showed a low serum osmolality (241 mOsm/kg), high urine osmolality (598 mOsm/kg), high urine sodium (121 mmol/L), low serum uric acid (2.7 mg/dL, n 3.3-8.5 mg/dL), normal TSH, and a low normal AM cortisol (5.7 ug/dL, n 4.0-17.0 ug/dL). A subsequent cosyntropin stimulation test confirmed adrenal insufficiency with a 60 min cortisol of 10.3 ug/dL. ACTH was inappropriately normal (23 pg/mL, n 7-69 pg/mL) indicating a central etiology. In addition, he had a mildly elevated prolactin (23 ng/mL, n 4-15 ng/mL), inappropriately normal TSH (2.83 uIU/mL, n 0.30-4.50 uIU/mL), low normal total T4 (5 ug/dL, n 4.9-11.7 ug/dL), and a mildly low total T3 (52.3 ng/dL, n 58.0-159.0 ng/dL) suggesting a possible secondary hypothyroidism. A pituitary MRI revealed partially empty sella without evidence of pituitary adenoma. The patient was started on stress-dose hydrocortisone with subsequent increased urine output (4 L within 8 h of initial treatment) and increased serum sodium as well. To prevent rapid sodium correction, one dose of desmopressin was given with a low rate hypertonic saline to equilibrate the desmopressin effect. Hydrocortisone was tapered to maintenance dose, and the fluid restriction was discontinued to prevent dehydration. His home Levothyroxine dose was increased, and he was discharged with a serum sodium of 133 mEq/L. As an outpatient, his sodium has normalized with continued treatment. Discussion: Secondary adrenal insufficiency is characterized by euvolemic hyponatremia with biochemical features of SIADH without hyperkalemia. ADH increases due to the lack of cortisol negative feedback loop and the reduction in systemic blood pressure and cardiac output from cortisol deficiency. Hyponatremia corrects rapidly with steroid treatment, which turns off ADH and causes free water excretion. Desmopressin and hypertonic saline can be effectively used to prevent or stop rapid sodium correction. An interesting feature about this case is that partially empty sella is the cause for hypopituitarism.

SAT-483 A Rare Case of Pituitary Adenoma: The Mysterious Crooke's Cell Adenoma

Cushing's disease is caused by an excess of cortisol. In a cushingoid state, excess cortisol leads to a cytoplasmic accumulation of cytokeratin filaments. This accumulation of cytokeratin filaments and hyalinization characterizes a Crooke cell tumor which is an interesting variant of corticotroph adenoma (1) This transformation is known as Crooke’s cell transformation. Crooke’s cell tumors are very rare (largest case series of 36) reported by George et al. (2), aggressive, and prone to recurrence after resection which makes identification and distinction from adenomas important for treatment and patient management. A 42-year-old Caucasian male, with a PMH of obesity, HTN, DM2, and refractory hypokalemia presented to the hospital, with symptoms of headache, eye pressure, bilateral pedal edema, and weight gain x 4 weeks. admitted for evaluation with suspicion for Cushing's syndrome. The patient appeared cushingoid with positive parinaud sign (limited upward eye deviation) suggestive of a pituitary mass. CT head revealed a 1.2cm right pituitary macroadenoma with remodeling of sella turcica. Random cortisol 39.6 and ACTH 140. Dexamethasone suppression testing, low and high dose, failed to suppress cortisol production which suggested hypercortisolism from an ectopic source. Inferior petrosal sinus sampling confirmed pituitary Cushing's with lateralization to the right pituitary, as the source of hypercortisolemia. The patient underwent endoscopic endonasal transsphenoidal (EET) resection of pituitary macroadenoma, Postoperatively cortisol levels initially decreased, plateaued and then began rising again with suspicion for a residual tumor in the sella. The patient underwent repeat EET mass resection. Cortisol levels dropped and reached a nadir of 3.0 with ACTH 13 upon discharge. Pathology results revealed Crooke cell adenoma. Discussion: Crooke’s cell tumors are a rare variant of pituitary adenoma and are important to distinguish from other types of adenomas due to their unique cellular behavior. There isn’t a good explanation as to why these tumors cause hyalinization and despite this hyalinization and microfilament deposition, which would be expected to suppress functionality, result in increased production of ACTH. There have been cases reported multiple recurrences in patients requiring repeat surgical removal. Prompt and complete resection may limit the risk for recurrence, and the increase in morbidity and mortality that are inherent to tumor regrowth and continued invasive resection. Additionally, nonsuppressable serum cotrisol with high dexamethasone dose in the presence of pituitary tumor , should raise possibility of Crook cell tumor in addition to paraneoplastic syndromes . conclusion: this case highlights the importance of suspecting Crooke’s tumor in patients with evidence of pituitary adenoma and Cushing’s syndrome.

Acromegaly with No Evidence of Pituitary Adenoma or Ectopic Source

Acromegaly with No Evidence of Pituitary Adenoma or Ectopic Source

Lymphocytic Hypophysitis in a Dog with Diabetes Insipidus

An 8-year-old male German longhaired pointer was referred for diabetes insipidus responsive to treatment with desmopressin. The dog had polyuria and polydipsia, exercise intolerance and a dull hair coat. Plasma concentrations of thyroid-stimulating hormone, thyroxine, growth hormone (GH) and insulin-like growth factor-1 were decreased; plasma adrenocorticotropic hormone (ACTH) was slightly elevated and plasma α-melanocyte-stimulating hormone (MSH) was within the reference range. Computed tomography revealed a heterogeneously contrast-enhancing pituitary mass compressing the hypothalamus. Transsphenoidal hypophysectomy was performed and microscopical examination of the surgical biopsy samples revealed hypophysitis without evidence of pituitary adenoma. The hypophysitis was characterized by marked lymphocytic infiltration of the adenohypophysis that contained a mixed population of neuroendocrine cells expressing GH, ACTH or α-MSH. The lymphocytes were identified as T cells, resulting in a final diagnosis of lymphocytic hypophysitis strongly resembling human primary lymphocytic hypophysitis.

Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds.

Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds.

The Value of Adrenal Autotransplantation with Attached Blood Vessels for the Treatment of Cushing’s Disease: A Preliminary Report

We treated 5 patients with Cushing’s disease by total adrenalectomy and left adrenal autotransplantation with attached blood vessels. An end-to-end vascular anastomosis was made between the adrenal central vein and the inferior epigastric artery, and the saphenous vein and adrenal middle artery were anastomosed by intussuscepting the artery into the vein in 4 patients. Steroid replacement was withdrawn 7 to 90 days after bilateral total adrenalectomy. The patients were followed for 1 to 4 years. Repeated measurement of plasma cortisol, 24-hour urinary 17-hydroxycorticosteroid and 17-ketosteroid levels in all cases was normal. As soon as the adrenal central vein and inferior epigastric artery were anastomosed part of the adrenal gland was then excised. Oozing of blood from the cut surface was retained and the adrenal gland was then embedded into the inguinal muscle in 1 patient. Small doses of steroid replacement (12.5mg. cortisone per day) were still necessary 1 year postoperatively. The result thus indicates that this procedure is feasible and valuable for the treatment of patients with Cushing’s disease and no evidence of pituitary adenoma on magnetic resonance imaging or computerized tomography.

Failure of nomifensine administration to discriminate between tumorous and nontumorous hyperprolactinemia.

It has recently been claimed that the PRL-lowering response to nomifensine administration (200 mg, orally) reliably discriminates patients with PRL-secreting tumors from those with so-called functional hyperprolactinemia. In the present study, this test was performed in 15 healthy controls, 7 hyperprolactinemic subjects without evidence of pituitary tumor, and 16 patients with prolactinoma. A decrease of serum PRL to below 65% of basal levels, which seemed to be the cut-off point in the previous study, was obtained in 11 subjects of the first group, in 4 subjects of the second group, and in 4 subjects of the third group. The decrease of mean serum PRL concentration after nomifensine was only significant in the first and second groups. Analysis of variance showed a significant difference in the PRL inhibition by nomifensine between the tumor group and the two groups without evidence of pituitary adenoma. Nevertheless, this study shows that the nomifensine test is unable to discriminate in the individual patient the tumorous or nontumorous origin of excessive PRL secretion.

Serum Levels of Prolactin in Basal Conditions and after Administration of 2-Bromo-5α-Ergocryptine in Normal and Galactorrheic Subjects

Serum levels of prolactin were measured basally and after the oral administration of 2.5 mg of 2-bromo-5α-ergocryptine to healthy male (n = 4) and female (n = 5) subjects; to women with spontaneous galactorrhea and normal, biphasic cycles (n = 3); to galactorrheic women with spontaneous bleeding but no indirect signs of ovulation (n = 9); to galactorrheic-amenorrheic women with no evidence of pituitary adenoma (n = 19); and to galactorrheic-amenorrheic women with roentgenologic signs of pituitary adenoma (n = 4). The drug was given between 8:00 and 9:00 A.M.; blood samples were obtained before and 60, 120, 180, and 240 minutes and 24 hours after the administration of 2-bromo-5α-ergocryptine. Serum levels of prolactin were measured by radioimmunoassay with a double-antibody technique. The mean basal prolactin level in normal men was 12.5 ± 1.0 ng/ml; in normal women (7th to 9th days of the cycle) it was 16.2 ± 4.0 ng/ml. After drug administration serum levels of prolactin decreased progressively and systematically; minimal values were found at 180 to 240 minutes. The lowest maximal percentage of inhibition in normal subjects was 56%. Basal prolactin levels in galactorrheic women tended to be higher in relation to the severity of the pathophysiologic involvement. The highest levels were found in patients with demonstrable tumors. The drug-induced percentage reduction of these prolactin levels was lower in galactorrheic women than in normal women; paradoxical increases in prolactin levels occurred in some cases. The wide variability of the results obtained in the galactorrheic groups would restrict the practical application of this testing procedure.

Chlorpromazine-Induced Changes in Serum Prolactin in Women with Oligomenorrhea, Amenorrhea, and Pituitary Adenoma

Chlorpromazine (CPZ, Thorazine) administration has been found to result in an increase in peripheral serum levels of prolactin (hPRL) in both men and women. Normal menstruating women were found to have at least a doubling of serum hPRL (100% increase) over basal values within 150 minutes of the intramuscular administration of CPZ (0.7 mg/kg). Thirty-nine women with oligomenorrhea or amenorrhea with normal or elevated basal levels of serum hPRL were evaluated by this testing modality. Their responses were compared with those of normal women as well as those of 18 women with elevated serum hPRL levels and roentgenographic evidence of pituitary microadenoma. Women with oligomenorrhea or amenorrhea and normal serum hPRL levels generally had a normal response to CPZ (9 of 16 [56.3%]). A smaller percentage of normal responses was found in women with elevated hPRL levels but no overt evidence of pituitary microadenoma (7 of 21 [33%]). Women with elevated hPRL levels and evidence of pituitary microadenoma uniformly failed to have a normal hPRL response following CPZ administration. Although the group with microadenomas did not show a significant hPRL response to CPZ, this test does not unequivocally differentiate between women who have evidence of pituitary adenoma and those who do not. Suggestive, but not conclusive, evidence of hypothalamic dysfunction as the cause of the oligomenorrhea or amenorrhea is presented.

Use of brom-ergocryptine in treating amenorrhea/galactorrhea.

Seven women with amenorrhea and galactorrhea, and no evidence of pituitary adenoma, were treated with brom-ergocryptine for two to 24 weeks. All seven patients had the resumption of regular menses within eight weeks, but six patients required 24 weeks of therapy to completely cease lacting. Two of the five women attempting to conceive became pregnant. Four of the five nonpregnant patients had a total recurrence of their symptoms after discontinuing the drug. Brom-ergocryptine appears to be very effective in inhibiting prolactin secretion and thus reestablishing normal ovulatory menstrual cycles and fertility.