Pituitary Disease Research Articles

MON-122 Introduction of an Ambulatory Curriculum in Endocrinology Diabetes and Metabolism for Internal Medicine Trainees

Internal Medicine (IM) training programs are disproportionately weighted to inpatient learning opportunities. IM residents‘ exposure to outpatient internal medicine subspecialties, such as Endocrinology, Diabetes and Metabolism (EDM), is limited. This may contribute to gaps in medical knowledge in these content areas in spite of the frequent occurrence of EDM disorders. Further, reduced exposure during training may adversely impact interest in pursuing fellowship training in these fields, in spite of increased societal need.In July 2015 the IM residency program at the University of Pennsylvania switched to a “6 + 2” training model. In this training module, trainees are grouped into four cohorts, each of which have 6 weeks of inpatient rotations, followed by 2 weeks of an ambulatory experience. This model allowed the introduction of an organized ambulatory curriculum during the 2-week outpatient blocks, which was named the Interactive Learning Module (ILM). This creates the opportunity to deliver a standardized curriculum to all residents. Through this module we coordinate an immersive experience in five distinct outpatient themes: General Internal Medicine, Infectious Disease, EDM, Nephrology, and Rheumatology. The EDM ILM is co-led by a core faculty member and senior endocrinology fellow with interest in pursuing a career in medical education.During the EDM ILM, IM interns receive 12 hours of interactive didactics in high yield content areas including: Diabetes Workshop, Adrenal and Pituitary Diseases, Osteoporosis, Thyroid Diseases, Women’s Health, Calcium Disorders, Obesity and Endocrine Emergencies.Interns are given 3-4 opportunities to work with an EDM faculty member in the outpatient setting. Interns are also asked to read and review three publications within the field, which are discussed as a group.The EDM ILM has been consistently praised by IM interns, and feedback for the curriculum has been overwhelmingly positive. 97% of interns agreed the breadth of content was comprehensive and 94% agreed that the content was applicable to their delivery of ambulatory primary care. The quality of the teaching was rated high among 96% of interns. 89% reported improved understanding of EDM. Four years after the institution of the curriculum, we have not yet noted an increase in graduating IM residents choosing fellowship in EDM. However, all three of our IM residents who have matched into EDM fellowship over the past four years have chosen to stay at our institution.Faculty have thrived with these teaching opportunities: their consistently high evaluations have been an important criterion for academic promotion.Co-leading this course has been an important opportunity for senior EDM fellows to build expertise in medical education; three out of four participating fellows accepted academic positions with GME support.

SAT-142 Periodic Cushing Syndrome in a Patient with an Intestinal Neuroendocrine Tumor (NET). A Novel Case Report

Introduction A major diagnostic enigma regarding ACTH-dependent Cushing syndrome is the distinction between the source of ACTH, which may have either a pituitary or ectopic origin. We present the first described patient with cyclic Cushing syndrome caused by an intestinal neuroendocrine tumour (NET) detected by 68GA-DOTATATE PET-CT, despite functional tests that were indicative of pituitary Cushing disease. Clinical Case A 53-year old man was admitted to outpatient clinic because of muscle weakness. His phenotype and clinical findings (progressively worsening upper and lower limb weakness, emotional disturbances, easy bruising, a Buffalo hump, prediabetes and leucocytosis) led to the diagnosis of Cushing syndrome. Initial laboratory tests established the diagnosis with an abnormal diurnal cortisol and ACTH secretion (night cortisol F: 22.1μg / dl), absence of suppression with dexamethasone 1mg and increased free urinary free cortisol 24h (243.5μg /24h). Abdominal CT scanning revealed a left-sided adrenal adrenocortical adenoma 1.5 mm in max diameter. Pituitary MRI and somatostatin scintigraphy were normal. Low dexamethasone suppression test was indicative of Cushing (F: 14μg / dl) followed by a combined CRH stimulation test during bilateral inferior petrosal sinus sampling. Pituitary / peripheral ACTH ratio pre-infusion of CRH and 3 min after CRH infusion was compatible with right-sided pituitary origin of ACTH hypersecretion. Pending the results of the laboratory, the patient showed a remission of his symptoms along with a laboratory-confirmed recession of active hypercortisolaemia (LDDST test), and this led to the suspicion of periodic Cushing syndrome. The patient was followed with clinical and laboratory examinations weekly, with recurrence of symptoms 2 months later followed by a new remission 3 months later. A PETGA CT SCAN with 68GA-HA-DOTATATE was performed, which showed an increased uptake of the radioisotope in the small intestine. A surgical excision of the affected small bowel region was performed according to the guidelines for intestinal NETs. Histology confirmed the existence of a well-differentiated neuroendocrine neoplasm of the small intestine of 1.1 cm diameter, grade 1 (WHO 2010). Immunophenotype was positive for serotonin and ACTH. Postoperatively, the patient showed a complete remission of symptomatology and regression of hypercortisolaemia over a 18-month period. Follow-up abdominal MRI and 68GA-HA-DOTATATE revealed no pathological findings. Conclusion: Our patient is the first case of ectopic Cushing disease caused by intestinal NET. The differential diagnosis between pituitary and ectopic Cushing syndrome due to ACTH or CRH hypersecretion is not easy and frequently complicated by the periodicity of the disease. In patients with no visible pituitary lesions on MRI we suggest further investigation for ectopic ACTH- driven Cushing syndrome.

MON-723 Identification of Thyrotrope Signature Genes and Regulatory Elements

Recent genome wide association studies have begun to identify loci that are risk factors for sporadic pituitary adenomas, but the genes associated with these loci are unknown. In general, ~90% of GWAS hits are in noncoding regions, making it difficult to transition from genetic mapping to a biological understanding of risk factors. Recent studies that identify enhancer regions by undertaking large scale functional genomic annotation of non-coding elements like Encyclopedia of DNA Elements (ENCODE) have begun to yield a better understanding of some complex diseases. Dense molecular profiling maps of the transcriptome and epigenome have been generated for more than 250 cell lines and 150 tissues, but pituitary cell lines or tissues were not included. Epigenetic and gene expression data are emerging for somatotropes, gonadotropes and corticotropes, but there is very little available data on thyrotropes. We identified the transcription factors and epigenetic changes in chromatin that are associated with differentiation of POU1F1-expressing progenitors into thyrotropes using cell lines that represent an early, undifferentiated Pou1f1 lineage progenitor (GHF-T1) and a committed thyrotrope (TαT1). TαT1 is an excellent cell line for this purpose because it responds to TRH, retinoids, and secretes TSH in response to diurnal cues. We have also used genetic labeling and fluorescence activated cell sorting to purify thyrotropes from pituitaries of young mice and analyzed gene expression using single cell transcriptomics. We used the Assay for TransposaseAccessible Chromatin with sequencing (ATACseq) and Cleavage Under Target and Release Using Nuclease (CUT&RUN) to identify POU1F1 binding sites and histone marks associated with active enhancers, H3K27Ac and H3K4Me1, or inactive regions, H3K27Me3, in GHF-T1 and TαT1 cells. We integrated DNA accessibility, histone modification patterns, transcription factor binding and RNA expression data to identify regulatory elements and candidate transcriptional regulators. We identified POU1F1 binding sites that were unique to each cell line. For example, POU1F1 binds sites in and around Cga and Tshb only in TαT1 cells and Twist1 and Gli3 only in GHFT1 cells. POU1F1 binding sites are commonly associated with bZIP factor consensus binding sites in GHFT1 cells and Helix-Turn-Helix or basic Helix-Loop-Helix in TαT1 cells, suggesting classes of transcription factors that may recruit POU1F1 to unique sites. We validated enhancer function of novel elements we mapped near Tshb, Gata2, and Pitx1 by transfection in TαT1 cells. Finally, we confirmed that an enhancer element near Tshb can drive expression in thyrotropes of transgenic mice. These data extend the ENCODE analysis to an organ that is critical for growth and metabolism. This information could be valuable for understanding pituitary development and disease pathogenesis.

SAT-127 Localization and Treatment of the Ectopic ACTH Syndrome Using Somatostatin Analogues

Ectopic ACTH syndrome (EAS) is a rare disorder with a high morbidity and mortality due to the sequelae of severe hypercortisolism and possible underlying carcinoma. It is caused by various tumors, some originating from neuroendocrine cells. Optimal management includes localization and removal of the ectopic ACTH source. About 80% of these tumors have somatostatin (SS) receptors, so that SS analogues may be useful in the localization and treatment. This case demonstrates the use of SS analogues in localization and treatment of EAS.A 49-year-old female presented with 7 months of worsening Cushingoid features including rounded plethoric face, full supraclavicular fat pads, facial hair growth, multiple bruises, violaceous abdominal striae, kyphoscoliosis, 4+ peripheral edema, weight gain, hypertension (190/110 mmHg) and thoracic compression fractures. AM plasma ACTH concentration was 333 pg/mL (nl = 6 - 58 pg/mL); serum concentration cortisol was 71.4 mcg/dL (nl = 7 - 23 mcg/dL) and serum potassium concentration was 1.2 mmol/L (nl = 3.6 - 5.1 mmol/L). A 24-hour urine cortisol could not accurately be obtained. High dose 8 mg overnight dexamethasone testing demonstrated suppression of serum cortisol concentration from 71.4 to 6.3 mcg/dL, suggesting pituitary Cushing disease. Pituitary MRI scan revealed a 2.5 mm disc shaped cystic focus suggesting a Rathke’s cleft cyst. No central-to-peripheral ACTH gradient was present on bilateral inferior petrosal sinus sampling suggesting an ectopic ACTH source. There was a 1.2 x 1.0 cm nodule in the left lower lung lobe on CT chest. A gallium-68 dotatate PET/CT scan demonstrated enhancement of this same lung lesion and mild uptake in the left inferior hilum, suggesting a neuroendocrine lung tumor with possible metastases to lymph nodes. Biopsy and resection of the lesion was deferred until after control of her hypercortisolism. 30mg of Sandostatin LAR was started every 4 weeks to control the ectopic ACTH secretion and to confirm that the SS analogue positive lung lesion was the cause of the EAS. Sandsostatin LAR therapy over the next 12 weeks resulted in a steady clinical and biochemical improvement with a decrease in serum cortisol to 9.7 mcg/dL, control of hypertension (108/64 mmHg), weight loss of 6 pounds, and resolution of supraclavicular fat pads, hypokalemia, and peripheral edema. This confirmed our impression that the neuroendocrine lung tumor was the ACTH source.In summary, this patient with EAS had severe clinical manifestations of hypercortisolism and could not safely undergo surgical intervention. This case demonstrates the value of SS analogues (gallium-68 dotatate PET/CT and Sandostatin LAR) in localizing and confirming the source of ectopic ACTH production and markedly improving the clinical and biochemical features of the EAS.

SUN-312 Strikingly Low Prevalence of Pituitary Incidentalomas in Our Hospital

Introduction: Pituitary incidentalomas (PIs) have been reported in 10.6% of autopsies, 4-20% in computed tomography scans (CT) and 10-38% in magnetic resonance imaging (MRI), most of them microincidentalomas(<1cm). They may be have autonomous hormonal activity or impair normal gland function. The frequency of PIs in Uruguay is unknown. We aimed to investigate the prevalence of pituitary incidentalomas in our Hospital. Methods: We retrospectively identified all patients who underwent brain CT and MRI at our hospital over a 1-year period for disorders other than known or suspected pituitary disease. The period covered was from January 1 to December 31, 2017. We reviewed all scans; anamnesis and biochemical evaluation was performed on patients who presented PIs. Results: During this period 3894 patients underwent imaging studies. MRI was performed in 1146 patients, and CT in 2748 of them. Mean age was 53,1 ± 19 years, with similar gender distribution (50.6% women). Most imaging studies where ordered in the emergency department (43%), followed by the outpatient clinics (29%) and inpatient wards (28%). Most common reasons that led to request the image were trauma (20.4%), headaches (11.3%) and stroke (10.9%). We detected two PIs, which accounts for a prevalence of 5 cases per 10,000 individuals per year (0.05%). Both where detected by CT, with a MRI done later to further evaluate them. Final diagnosis was of a vascular aneurysm and a sellar meningioma. Work-up showed a secondary hypothyroidism in the patient with the sellar meningioma. No cases of pituitary adenomas were found. Discussion: We observed a strikingly lower prevalence of PIs than that reported in the literature. In addition, no PIs where found in MRI. Moreover, no pituitary adenoma was discovered. The reasons for these findings are unknown. In our study scans were not focused to the pituitary fossa so small lesions may have been missed. However, Esteves et al(1) reported a prevalence of PIs 5.8% in 1232 patients who had head MRI/CT, not pituitary MRI. In addition, the majority were pituitary adenomas, almost 40% of them microadenomas. Slices of 2-mm thickness were obtained in the scans, similar to imaging techniques used in other studies. Most reports have longer study duration (3-5 years).Our hospital is a teaching hospital where fellows evaluate scans initially, which are then reevaluated by neuroradiologists. This may account for the prevalence found, as sensitivity may be lower when professionals in training evaluate scans. In addition, frequency of pituitary hipointensity areas may decrease as the number of reviewers increase. Furthermore, this low prevalence could be related to difference in population characteristics.Conclusions: We found a very low prevalence of PIs in our hospital. More studies are warranted to further investigate frequency of PIs in our country. (1)Esteves et al. Pituitary. 2015;18(6):777-81.

SAT-288 Pituitary Developmental Defects Caused by Haploinsufficiency for the Transcription Factor SIX3 Are Worsened by POU1F1 Deficiency

Advances in genomic technologies are revolutionizing the practice of medicine by delivering molecular diagnoses that can be informative for prognosis and treatment of genetic disorders. Most of the known genetic causes of multiple pituitary hormone deficiency have been investigated as monogenic disorders. It can be challenging to predict clinical features from genetic data, as loss of function mutations in some genes can present with a spectrum of phenotypes ranging from craniofacial abnormalities, intellectual disability, and neurosensory and neuroendocrine defects to pituitary hormone deficiency with no other abnormalities. Although maternal exposures could be contributing factors, the contribution of rare, deleterious variation in other genes is a likely contributor. In humans, loss of function mutations in the transcription factor SIX3 cause variable, autosomal dominant holoprosencephaly with incomplete penetrance, and mouse models recapitulate some of the clinical features. Because Six3 and Pou1f1 gene expression patterns overlap in pituitary development, we hypothesized that doubly heterozygous mice (Six3+/-; Pou1f1+/dw) might have pituitary anomalies not present in singly heterozygous mice. We intercrossed Six3+/- and Pou1f1+/dw mice to produce doubly heterozygous animals. At e11.5, both Six3+/- and Six3+/-; Pou1f1+/dw exhibited abnormal morphology of the developing infundibulum and Rathke’s pouch, although ventral diencephalon expression of Tle4, Fgf10, and Nkx2.1 appeared normal. Both newborn Six3+/- and Six3+/-; Pou1f1+/dw littermates had abnormal pituitary gland morphology that resembled that of Aes-/-. AES is a co-repressor that interacts with SIX3. Specification of vasopressin neurons and anterior lobe hormone cell types appeared normal. Mice of all genotypes were born in expected Mendelian ratios (N=144, p=0.49), and there were no significant differences in body weight at 3 wks. A portion of the Six3+/- and doubly heterozygous mice developed hydrocephalus, exhibited failure to thrive, and died (6-9% of N=82, 85, respectively). At 6 wks, 25% (N=61) of the Six3+/-; Pou1f1+/dw animals exhibited striking pituitary dysmorphology in which the rostral aspect of the pituitary penetrated the palate. This was not observed in single heterozygotes. These results reveal that haploinsufficiency for Six3 affects Rathke’s pouch formation, resulting in pituitary gland dysmorphology in and around the stem cell niche. A significant portion of the Six3+/-; Pou1f1+/dw doubly heterozygous mice have a more pronounced pituitary phenotype than Six3+/-, supporting the possibility of digenic pituitary disease and highlighting phenotypic variability. Genetically engineered mice provide an excellent tool for assessing the possibility of gene-gene interactions that could enhance the severity of hypopituitarism and associated craniofacial development.

SAT-289 Evidence That Combined Pituitary Hormone Deficiency Frequently Has a Digenic/Oligogenic Etiology

Congenital hypopituitarism usually occurs in a child without a family history of pituitary disease. Explanations for such sporadic occurrence include: 1) monogenic inheritance (recessive or de novo), 2) digenic/oligogenic inheritance, and/or 3) nongenetic factors. To help distinguish these possibilities, we studied 9 children with hypopituitarism (HP)(small anterior pituitary gland, ectopic posterior pituitary, and either isolated GH deficiency (n=1) or combined with other pituitary hormone deficiencies(n=8)), with non-consanguineous parents and no family history of pituitary disease. SNP array analyses confirmed paternity and non-consanguinity and excluded significant copy-number variation. Exome sequencing was performed in probands and parents. Candidate variants (coverage >10, confirmed by examining BAM files, population frequency <1%, <2 homozygous subjects in gnomAD, and pathogenic prediction by at least 2 out of 3 prediction algorithms (SIFT, MutationTaster, PolyPhen2)) were identified. Children with non-familial non-endocrine idiopathic short stature (ISS) (n=19, sequenced at the same laboratory followed by simultaneous data processing with HP patients), served as a control group. To assess the frequency of genetic (mono-, di-, or oligogenic) HP cases, we identified heterozygous variants (regardless of inheritance) in 42 genes previously reported to be associated with pituitary development. The average number of variants per proband was greater in HP than in ISS (1.1 vs 0.26, P = 0.04). Similarly, the number of probands with at least 1 variant in a pituitary-associated gene was greater in HP than in ISS (67% vs 21%, P = 0.035). These data suggest that sporadic hypopituitarism is frequently genetic. To assess the number of monogenic cases, we counted the number of candidate variants (in any gene in the genome, to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence with a monogenic etiology (de novo mutation, autosomal recessive, X-linked recessive). There were fewer monogenic candidates in subjects with HP than ISS (1.6 vs 2.6 candidates/proband, P = 0.03). These data are consistent with approximately 1.6 non-causative variants/proband in both groups plus approximately 1 causative monogenic variant in ISS vs approximately 0 causative monogenic variants in HP. Candidate variants in genes previously reported to explain the phenotype were identified in 0 out of 9 trios with HP and in 8 of 19 trios with ISS (42%). These findings suggest that a monogenic inheritance is less common in HP than in ISS. In conclusion, the findings suggest that sporadic congenital hypopituitarism is frequently genetic but infrequently monogenic, implying a likely digenic/oligogenic etiology.

SAT-242 Isolated Adrenocorticotropic Hormone Deficiency Secondary to the PD-1 Inhibitor Pembrolizumab

Background: Immune checkpoint inhibitors (ICI’s) are now indicated in the treatment of several solid tumors and have improved the prognosis of patients with advanced malignancy. The expanded use of ICI’s has led to the rise of otherwise rare autoimmune sequelae. The overall incidence of ICI-induced autoimmune hypophysitis has increased to approximately 10%, but is only estimated to be 0.4% with PD-1 inhibitors specifically (1). Isolated ACTH deficiency from immune checkpoint inhibitors is rare, and very few cases secondary to the PD-1 inhibitor pembrolizumab have thus far been reported. Clinical Case: A 75-year old woman with history of Stage IV lung adenocarcinoma presented to oncology clinic in July 2019 with progressive weakness, weight loss, and confusion for several weeks. She was found to be hypotensive and dehydrated in the clinic and subsequently was admitted to the hospital. A comprehensive infectious work-up was non-contributory. History revealed that after treatment failure with carboplatin, she was treated with pembrolizumab from January 2017 to June 2019 with excellent response. Laboratory evaluation on admission demonstrated an undetectable AM cortisol level of < 1 ug/dL (n 5-25 ug/dL) with concomitant ACTH < 5pg/mL (Roche cobas, n 7.2-63 pg/mL), consistent with central adrenal insufficiency. Testing of the remainder of the pituitary axis, including TSH (0.83uU/mL, n 0.4-4.6 uU/mL), FSH (34.7 mIU/mL, n <150mIU/mL), LH (12.6mIU/mL, n <60 mIU/mL), and IGF-1 (33ng/mL, n 34-245ng/mL), all returned within normal limits. Further chart review verified that she had not been exposed to any form of glucocorticoids within the past 6 months. MRI brain with contrast demonstrated no obvious pituitary disease. The patient was started on 5mg of prednisone daily, with significant improvement in mental status, appetite, and blood pressure. She was discharged home on maintenance prednisone for adrenal insufficiency due to presumed isolated corticotroph destruction. Conclusions: Isolated ACTH deficiency is a very rare but potential consequence of pembrolizumab use. It can be especially difficult to diagnose in patients on chemotherapy who are at higher risk for dehydration and failure to thrive. Duration of pembrolizumab therapy should not preclude the diagnosis of isolated ACTH deficiency, as it can occur even as late as 2.5 years into therapy. Reference: (1) Chang, L., Barroso-Sousa, R., Tolaney S., Hodi F.S., Kaiser, U.B., Min, L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints, Endocr Rev. 2019;40;17–65.

SAT-723 Effects of Organohalogenated Endocrine Disrupting Chemicals on Cell Proliferation and Gene Expression in GH3 Somatolactotropes

Endocrine Disrupting Chemicals (EDCs) are substances that have been increasingly implicated in many serious pathologies, such as tumor formation, metabolic, growth and reproductive disorders. The economic and health burden of exposure to these compounds has an annual predicted cost in excess of €150 billion, across the EU regions alone. Of the growing list of compounds that act as EDCs, the organohalogenated compounds (OHCs), polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) have been associated with an increased risk of pituitary disease. We have previously reported that feline patients with hypersomatotropism (acromegaly) are exposed to elevated levels of PBDEs and PCBs in their environment. However, the mechanisms by which these compounds might directly influence somatotroph function have yet to be established. In this study, we use the GH3 rat somatolactotrope cell line to investigate how two PCB congeners - 138 and 153 - influence cell proliferation (using a Crystal Violet assay) and somatotrope gene expression (using a multiplex RT-qPCR approach to examine expression of Esr1, Esr2, Sstr1, Sstr2, Sstr3, Sstr4, Sstr5, Insr, Tshr, Pou1f1, Ghrhr2, Gh). GH3 cells were treated with Phenol Red-free media in the absence or presence of either PCB138 or 153 (-10 to -6 M), or in combination (-10 to -6M) for up to 72h. Treatment with either PCB alone, or in combination, caused significant concentration-dependent, biphasic changes in cell proliferation at each time point, but with a different profile of response on each day (significantly increased at high pM/low nM concentrations); there was no evidence of toxicity at maximum concentrations (-6M). Gene expression changes were determined in GH3 cells treated in the absence or presence of either -8M or -6M PCB138 or 153 for 24h. Differential effects of these compounds were seen on the expression of Sstr3, Sstr4, Sstr5 and Insr; all other gene transcripts were unaffected. These findings reveal that GH3 cells exposed to physiologically relevant concentrations of PCB138 and 153, alone or in combination, show concentration-dependent increases in cell proliferation; furthermore, the expression of genes associated with therapeutic targets for the treatment of acromegaly (i.e. SSTRs) are differentially affected by exposure to PCB138 and 153. Our data indicate a potential mechanism for EDCs in the onset of acromegaly, that require further, in vivo, investigations.

MON-269 FGFR-4 Expression in Pituitary Adenomas Is Associated with Aggressive Tumor Features

Biomarkers predicting tumor aggressiveness in pituitary adenomas have been largely investigated, albeit, with inconsistent results. We investigated the relationship of Fibroblast Growth Factor Receptor-4 (FGFR-4) expression and determined its relationship with radiological, pathological, and clinical parameters.In our study, 650 patients who were followed up for pituitary disease were reviewed from medical charts retrospectively. Of the 307 patients who underwent pituitary surgery for a pituitary adenoma between 2000 and 2015, we selected 161 cases on the basis of availability of pathology specimen of hypophysis tissue in our center. Patients’ radiological, pathological, and clinical parameters were obtained from medical charts. FGFR-4 immunostaining was evaluated using a semiquantitative Histologic score (H score).The mean age of the patients was 56.02 ± 14.80 years. Ninety-two (57.1%) were male and 69 (42.9%) were female. The mean follow-up period was 68.94 ± 44.15 months. Pathological examination revealed the following subtypes; 53 nonfunctioning pituitary adenomas, 26 corticotroph adenomas, 25 hormone receptor negative adenomas, 22 mammotroph adenomas, 13 somatotroph adenomas, 8 combined hormone secreting adenomas, 7 somatomammotroph, and 7 PIT-1 positive adenomas. The mean tumor size was 26.83 ± 14.92 mm. In patients with cavernous sinus invasion, the mean adenoma size was significantly higher than those without (p <0.001). Mean H-score and Ki-67 levels were not different between patients with and without cavernous sinus invasion (p>0.05 for all). The mean H-score, Ki-67, and adenoma size were significantly higher in patients without remission than those with remission (p <0.001, p = 0.014, p <0.001, respectively). The mean H score and adenoma size were significantly higher in patients with residual lesions than those without (p = 0.002, p <0.001; respectively); there was no significant difference in Ki-67 levels (p>0.05). When the H-score and Ki-67 levels were assessed in terms of gender, sellar-dural invasion, tumor function or presence of poor subtype, no significant difference was detected (p>0.05 for all). The mean H score and adenoma size were significantly higher in patients with Ki-67≥ 3 than those with <3 (p = 0.002, p = 0.004; respectively). There was a weak positive correlation between H-score and Ki-67 (p = 0.005; r = 0.218); on the other hand, Ki-67 was not correlated with mitosis grade, p53 staining, and age, respectively (p>0.05 for all).In our study, we demonstrated that patients with residual lesion and those without remission had high expression of FGFR-4. Also FGFR-4 levels were positively correlated with Ki-67 which itself correlated with lack of remission. Taken together, our results indicate that higher levels of FGFR-4 and Ki-67 in pituitary adenomas might indicate a more aggressive tumor phenotype.

Androgen Treatment in Adolescent Males With Hypogonadism.

During adolescence, androgens are responsible for the development of secondary sexual characteristics, pubertal growth, and the anabolic effects on bone and muscle mass. Testosterone is the most abundant testicular androgen, but some effects are mediated by its conversion to the more potent androgen dihydrotestosterone (DHT) or to estradiol. Androgen deficiency, requiring replacement therapy, may occur due to a primary testicular failure or secondary to a hypothalamic–pituitary disorder. A very frequent condition characterized by a late activation of the gonadal axis that may also need androgen treatment is constitutional delay of puberty. Of the several testosterone or DHT formulations commercially available, very few are employed, and none is marketed for its use in adolescents. The most frequently used androgen therapy is based on the intramuscular administration of testosterone enanthate or cypionate every 3 to 4 weeks, with initially low doses. These are progressively increased during several months or years, in order to mimic the physiology of puberty, until adult doses are attained. Scarce experience exists with oral or transdermal formulations. Preparations containing DHT, which are not widely available, are preferred in specific conditions. Oxandrolone, a non-aromatizable drug with higher anabolic than androgenic effects, has been used in adolescents with preserved testosterone production, like Klinefelter syndrome, with positive effects on cardiometabolic health and visual, motor, and psychosocial functions. The usual protocols applied for androgen therapy in boys and adolescents are discussed.

Pregnancy-related reference intervals for serum thyrotropin based on real-life clinical data

Aim During pregnancy, thyroid homeostasis is physiologically modified, leading to altered levels of thyrotropin (TSH): hence, the adoption of pregnancy-related, population- and method-specific reference ranges is recommended. This monocentric and retrospective study was conducted to establish local pregnancy-related reference intervals for serum TSH in singleton pregnant women using real-life clinical data. Methods We included women who measured serum TSH during pregnancy at our Laboratory over six years, excluding pregnant women with current or past history of thyroid disease, pituitary or autoimmune diseases, use of medications known to influence thyroid function, multiple and/or pathological pregnancies, BMI >30 Kg/m2. Results We retrieved a total of 3744 TSH results. Reference limits (90% confidence intervals) for TSH (in mIU/L) are: first trimester 0.09 (0.06–0.12) − 3.16 (3.05–3.29); second trimester 0.25 (0.11–0.30) − 3.55 (3.34–3.73); third trimester 0.42 (0.15–0.48) − 3.93 (3.80–4.08). Conclusion In conclusion, real-life clinical data could be used to establish or verify local reference intervals for TSH in pregnant women: this may reduce the risk of misclassification of pregnant women undergoing thyroid function testing.

Development and Study of Semi-Solid Preparations Containing the Model Substance Corticotropin (ACTH): Convenience Application in Neurodegenerative Diseases.

Corticotropin (ACTH, previously an adrenocorticotropic hormone) is used in the diagnosis and treatment of pituitary gland disorders, adrenal cortex disorders, and other diseases, including autoimmune polymyositis, systemic lupus erythematosus, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. So far, the ointment dosage form containing ACTH for use on the skin is unknown. Therefore, it seems appropriate to develop a semi-solid formulation with corticotropin. Emulsion ointments were prepared using an Unguator based on the cream base Lekobaza® containing corticotropin in different concentrations, and then the physical and chemical parameters of the ointment formulations, such as pH, spreadability, rheological properties, and texture analysis, were evaluated. In addition, a USP apparatus 2 with enhancer cells was utilized to study the in vitro drug release characteristics of the selected formulations. All the ointments obtained were characterized by good spreadability and viscosity. An analysis of the ointment texture was performed and the dependence of the tested parameters on the ACTH content in the ointment was demonstrated. Examination of the structure of the ointment showed that a high concentration of ACTH increases the hardness and adhesiveness of the ointment. In turn, it adversely affects the cohesiveness and elasticity of the ointments tested. The results of the release study showed that ACTH is released the fastest from the formulation with the lowest concentration, while the slowest from the ointment with the highest concentration of ACTH.

P37 Erdheim-Chester disease: an ultra-rare mimic of IgG4-related disease

Abstract Background A 56 year old female was hospitalised in July 2019 with abdominal pain and significant weight loss, but little in the way of bone pain. Examination showed no evidence of xanthelasma. A large pericardial effusion was detected, requiring pericardiocentesis. The pericardial fluid contained numerous macrophages staining with CD68. Methods CT scans were reported as consistent with metastatic carcinoma. There were multiple sclerotic bone lesions in the manubrium, T7, T11, L2 and L4. She also had a periaortitis with soft tissue infiltrate around the ascending aorta and aortic arch, in the mediastinum, posterior paravertebral region, and in the retroperitoneum, obscuring both adrenal glands and surrounding both kidneys. Bone marrow aspirate and trephine demonstrated reactive appearances only. Results She required re-admission with breathlessness due to recurrence of the pericardial effusion. Biopsy from the left perinephric region was performed. Histopathology revealed a fibroinflammatory disorder. Some histiocytes were seen. There was no evidence of the typical features of IgG4-RD such as storiform fibrosis or obliterative phlebitis, which had been the working diagnosis thus far. Serum IgG4 level was normal. The classical histological features of Erdheim-Chester disease (ECD, an ultra-rare non-Langerhans cell Histiocytosis) in terms of foamy macrophages and Touton cells, were not obvious, but in the literature, it is not uncommon for the typical histological appearances of ECD to be absent. Further investigation demonstrated the classical radiographic findings of ECD with symmetrical sclerotic lesions in the long bones of the lower limbs. Radionuclide bone scan showed multifocal symmetrical increase in isotope uptake, predominately in the distal femora, proximal and distal tibiae, mandible and maxillae with multiple lesions in the thoracic and lumbar spine. Endocrine failure is frequently seen in ECD. Fortunately, our patient had neither pituitary disease nor hypoadrenalism. Furthermore, CNS involvement, ataxia and retro-orbital disease have all been reported in ECD. Our patient has experienced daily episodes of right retro-orbital pain, dizziness on upward gaze without diplopia, and occasional staggering. An MRI of brain, orbits and whole spine is scheduled, as are a whole body FDG-PET scan and cardiac MRI (to exclude myocardial infiltration). BRAF V600E mutation analysis is in progress since around 50% of ECD patients with this mutation may respond to vemurafenib treatment. Conclusion In this illustrative case, the combination of a fibroinflammatory disorder surrounding both kidneys, along with recurrent pericardial effusion and sclerotic bone lesions, was clinically and radiologically diagnostic of Erdheim-Chester disease. ECD is a recognised mimic of IgG4-RD, which itself is a mimic of multiple other conditions, including metastatic carcinoma. We present this case to highlight this little-known condition. Rheumatologists and Physicians should consider ECD in the differential diagnosis of IgG4-RD, periaortitis, pericardial effusion, symmetrical sclerotic bone lesions, endocrine failure and neurological features. Disclosures J.S. McLaren None. V. Campbell None. M. Rahilly None. J.M. Rehman None. R. Cargill None.

Immune checkpoint inhibitor-associated pituitary adverse events: an observational, retrospective, disproportionality study.

The aim of this study was to identify and characterize immune checkpoint inhibitors (ICIs)-associated pituitary adverse events (AEs). This is a retrospective disproportionality study based on VigiBase, the World Health Organization (WHO) global database of individual case safety reports (ICSRs), with a study period from January 1, 2011 to March 6, 2019. Information component (IC) and reporting odds ratio (ROR) are measures of disproportionate analysis. IC was used to evaluate the association between ICIs and pituitary AEs, while ROR was used to evaluate the differences in reporting of pituitary AEs between different ICI subgroups. The following ICI-associated pituitary diseases have been increasingly reported: hypophysitis (835 reports; information component 6.74 [95% CI 6.63-6.83]), hypopituitarism (268; 6.12 [95% CI 5.92-6.27]), pituitary enlargement (28; 5.19 [95% CI 4.57-5.63]). The anti-CTLA-4 subgroup had a stronger association with hypophysitis/hypopituitarism than the anti-PD(anti-PD-1 or anti-PD-L1) subgroup (ROR 8.0 [95% CI 6.7-9.6]). Among ICI-associated hypophysitis/hypopituitarism cases, the proportion of male was higher than female (630 [63.9%] vs 356 [36.1%]). Anti-CTLA-4 subgroup and ICI combination (nivolumab plus ipilimumab) subgroup both had a significantly earlier onset time than anti-PD subgroup (67days [IQR 48-87]; 90 [IQR 34-155]; 140 [IQR 62-218], both p < 0.05). Other endocrinopathies that co-occurred with hypophysitis/hypopituitarism were adrenal insufficiency, thyroid dysfunction, diabetes mellitus and diabetes insipidus. Gastrointestinal disorder was the most common concurrent disease except for endocrinopathies. ICI-associated pituitary adverse events have significantly increased, and their clinical characteristics should be kept in mind by oncologists and endocrinologists who manage patients treated by immunotherapy.

Presence of CD3+ and CD79a+ Lymphocytes in the Pituitary Gland of Dogs at Post-mortem Examination

Hypophysitis has been reported occasionally in dogs, with most cases resembling primary lymphocytic hypophysitis in man. Although it is generally assumed that lymphocytes are not present normally in the canine pituitary gland, few studies have investigated this hypothesis. However, lymphocytes are recognized in the pituitary gland of people and horses without signs of pituitary disease. It is unknown to what degree lymphocyte infiltration of the pituitary gland might occur as an incidental finding in dogs. The aim of the present study was to investigate the presence and distribution of lymphocytes in the pituitary gland of dogs without clinical suspicion of pituitary disease. Twenty dogs were subjected to routine necropsy examination. Formalin-fixed and paraffin wax-embedded sections of pituitary were stained with haematoxylin and eosin (HE) or subjected to immunohistochemistry (IHC) using primary antibodies specific for the T-cell marker CD3 and the B-cell marker CD79a. The number of CD3+ and CD79a+cells per area unit (CPA) was determined for different pituitary regions. Two dogs had extensive neoplastic lesions in the pituitary gland and were excluded from analysis. In the remaining 18 dogs, occasional scattered CD3+cells were found in the pituitary gland. There was a significant difference in CD3+ CPA between pituitary regions (P=0.001). The highest CD3+ CPA was found in the pars tuberalis (median 41.3cells/mm2, interquartile range 20.9-50.5cells/mm2). In six of the 18 dogs (33%), CD79a+cells were detected in small number (median total cell number 0cells/section, interquartile range 0-1.0cells/section). This study shows that T cell, and fewer B cells, may be found in the pituitary gland of dogs without clinical suspicion of pituitary disease. Regional difference in T-cell density, with the highest CD3+ CPA in the pars tuberalis, may imply regional immunoregulatory functions in the canine pituitary gland.

Pituitary metastases: presentation and outcomes from a pituitary center over the last decade

PurposeHighlight and characterize manifestations, diagnostic/management approaches and outcomes in a contemporary cohort of patients with pituitary metastases (PM) from a large European pituitary center—over 10 years.MethodsRetrospective review of PM cases between 1/2009 and 12/2018. Clinical, laboratory, imaging data at PM detection and during follow-up were analysed.Results18 cases were identified (14 females; median age at diagnosis 61.5 years). Most common primary malignancies were lung (39%) and breast (32%). Most frequent presenting manifestation was visual dysfunction (50%). Gonadotrophin, ACTH, TSH deficiency were diagnosed in 85%, 67%, 46% of cases, respectively; diabetes insipidus (DI) was present in 17%. 33% of cases were detected during investigation for symptoms unrelated to PM. PM management included radiotherapy (44%), transsphenoidal surgery (17%), transsphenoidal surgery and radiotherapy (6%) or monitoring only (33%). One-year survival was 49% with median survival from PM detection 11 months (range 2–47).ConclusionsIn our contemporary series, clinical presentation of PM has evolved; we found increased prevalence of anterior hypopituitarism, decreased rates of DI and longer survival compared with older literature. Increased availability of diagnostic imaging, improvements in screening and recognition of pituitary disease and longer survival of patients with metastatic cancer may be contributing factors.

Mensuration of the rabbit pituitary gland from computed tomography.

The aim of this retrospective reference interval observational study was to determine the mensuration of the pituitary gland (hypophysis cerebri) by analyzing CT studies in rabbits without clinical evidence of pituitary disease or central neurologic signs. Though diseases of the rabbit pituitary gland are uncommon, the pituitary gland is essential in regulation of the rabbit's endocrine system, as in other species. Currently, there are minimal published studies that detail the rabbit head anatomy on cross-sectional imaging, and even less specifically examining the pituitary gland. The pituitary gland was measured by one observer at a single time point from transverse and reconstructed sagittal CT images in a soft-tissue algorithm in 62 rabbits for a total of 66 rabbit head CT studies. The rabbits ranged from 0.84 to 14 years in age (mean±SD: 5.46±3.05 years) and 0.92 to 4.95kg in weight (2.21±0.83kg). Linear pituitary measurements were performed using electronic calipers. The mean ± SD pituitary height was 4.22 ± 0.57mm, width was 4.48 ± 0.71mm, and length was 6.02 ± 0.70mm. The pituitary gland height-to-brain area ratio was 1.10 ± 0.16mm-1 , which is much higher than the values reported in normal dogs and cats. The age, weight, and sex of the rabbits were not found to have a significant impact on pituitary gland mensuration. These measurements could be useful as a reference range for future rabbit head CT studies and to rule out pituitary enlargement or disease when evaluating rabbit pituitary glands.

Postoperative management of patients with pituitary tumors submitted to pituitary surgery. Experience of a Spanish Pituitary Tumor Center of Excellence.

There is a lack of evidence on timing, frequency, and duration of postoperative endocrine, radiologic, and ophthalmologic assessments that should be performed after pituitary surgery (PS). However, it is known that careful optimization of treatment and follow-up strategies as well as a multidisciplinary approach may have a significant impact on long-term outcomes, improving surgical results, minimize complications and facilitate their correct treatment if occurring, and optimize the hormonal, ophthalmological, and radiological reassessment throughout the follow-up. Considering that there are no specific guidelines on the postoperative management of patients with pituitary tumors (PT), we present our protocol for the postoperative management of patients with PT. It has been elaborated by the multidisciplinary team of a Spanish Pituitary Tumor Center of Excellence (PTCE) that includes at least one neurosurgeon, ENT, neuroradiologist, neuro-ophthalmologist, endocrine pathologist and endocrinologist specialized in pituitary diseases. We elaborated this guideline with the aim of sharing our experience with other centers involved in the management of PT thereby facilitating the postoperative management of patients submitted to PS.

Diagnosis and Management of pituitary disease with focus on the role of Magnetic Resonance Imaging.

Magnetic resonance (MR) imaging is an essential tool in the diagnosis and management of pituitary diseases, indispensable for making correct treatment decisions. Successful management and follow-up of pituitary pathology requires an understanding of the MR appearance of normal and abnormal structures in the sellar region. This review will describe the MR appearance of the normal and abnormal pituitary gland and proposes an algorithm for the management strategy of some of the most common abnormalities in or around the sella.