Hypopituitarism Research Articles

Baseline Clinical Factors Associated with Cessation of Growth Hormone Therapy in Patients with Severe Growth Hormone Deficiency - Real World Evidence

Background: Growth hormone replacement is indicated in adults with severe growth hormone (GH) deficiency, adult growth hormone deficiency assessment (AGHDA) score of at least 11 and are receiving treatment for other pituitary hormone deficiencies. There are no data looking at the cessation of GH replacement in adult patients with severe GH deficiency and the factors that predict the likelihood of patients continuing or stopping growth hormone replacement. Methods: We audited patients on the GH register between January 2006 and January 2023 in Hull University Teaching Hospitals NHS foundation Trust, a UK tertiary hospital. Baseline characteristics, the cause of GH deficiency, AGHDA score at diagnosis and the reason for stopping GH were collected. Proportions were compared between patients adhering to GH replacement and those who had ceased it. Logistic regression analysis was used to identify factors independently associated with cessation of GH. Results: The study comprised 141 adult patients with a mean age of 52 years, of which 75 (53%) were female. 54 (38%) individuals had discontinued GH replacement therapy. Predominant reasons for discontinuation were lack of therapeutic benefit (46%) and a change in clinical indication (26%). Among patients who discontinued GH therapy, the most frequent cause of GH deficiency was idiopathic (57%), while for those on GH replacement, pituitary surgery was the leading cause of GH deficiency (53%). Logistic regression analysis showed no baseline factor was statistically significantly associated with GH cessation, except female gender which had a borderline significance (P = 0.05). Conclusions: In this real-world investigation of patients with severe GH deficiency, over two in five individuals who discontinued GH therapy cited the absence of perceived benefits. We show a borderline association of female gender with GH cessation and large population-based studies will be needed to investigate this and other causes of GH cessation.

The Enigma That Is ROHHAD Syndrome: Challenges and Future Strategies

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare syndrome presenting in early childhood associated with a high risk of mortality between 50 and 60%. It is characterised by rapid, early onset of obesity between 1.5–7 years, along with central hypoventilation and hypothalamic dysfunction, such as central hypothyroidism, hyperprolactinemia, disorders of sodium and water balance, growth hormone deficiency, adrenocortical insufficiency, or disorders of puberty and features of autonomic dysregulation. Up to half of cases have neural crest tumours, most commonly ganglioneuromas or ganglioneuroblastomas. The incidence of ROHHAD syndrome in any population is unknown. Currently, there is no specific diagnostic or genetic biomarker for ROHHAD, and diagnosis is based on clinical signs and symptoms, which is often challenging, and consequently may be delayed or unrecognised. Early diagnosis is important, as without intervention, ROHHAD is associated with high morbidity and mortality. Aetiology remains unclear; an autoimmune origin has been postulated, with immunosuppressive agents being used with variable benefit. With no cure, multidisciplinary management is largely supportive. Therefore, there are many unanswered questions in ROHHAD syndrome. In this review article, we outline the challenges posed by ROHHAD syndrome, including aetiology, genetics, diagnosis, screening, management, and prognosis. We present research priorities to tackle these issues to improve outcomes.

The molecular basis of hypoprolactinaemia.

Hypoprolactinaemia is an endocrinopathy which is typically encountered as part of a combined pituitary hormone deficiency picture. The vast majority of genetic causes identified to date have been in the context of congenital hypopituitarism with multiple co-existent endocrinopathies. This is primarily with its closest hormonal relation, namely growth hormone. Acquired hypoprolactinaemia is generally rare in paediatric patients, and usually occurs together with other hormonal deficiencies. Congenital hypopituitarism occurs with an incidence of 1:4,000-10,000 cases and mutations in the following transcription factors account for the majority of documented genetic causes: PROP-1, POU1F1, LHX3/4 as well as documented case reports for a smaller subset of transcription factors and other molecules implicated in lactotroph development and prolactin secretion. Isolated prolactin deficiency has been described in a number of sporadic case reports in the literature, but no cases of mutations in the gene have been described to date. A range of genetic polymorphisms affecting multiple components of the prolactin signalling pathway have been identified in the literature, ranging from RNA spliceosome mutations (RNPC3) to loss of function mutations in IGSF-1. As paediatricians gain a greater understanding of the long-term ramifications of hypoprolactinaemia in terms of metabolic syndrome, type 2 diabetes mellitus and impaired fertility, the expectation is that clinicians will measure prolactin more frequently over time. Ultimately, we will encounter further reports of hypoprolactinaemia-related clinical presentations with further genetic mutations, in turn leading to a greater insight into the molecular basis of hypoprolactinaemia in terms of signalling pathways and downstream mediators. In the interim, the greatest untapped reserve of genetic causes remains within the phenotypic spectrum of congenital hypopituitarism.

An Update on Advances in Hypopituitarism: Etiology, Diagnosis, and Current Management.

This article provides an updated review of hypopituitarism (HP), an endocrine disorder characterized by a deficiency of one or more pituitary hormones. The various etiologies are reviewed, including pituitary neuroendocrine tumors (PitNETs), hypothalamic lesions, genetic mutations, and acquired factors such as head trauma, medications, neoplasms, and infiltrative diseases. It is noted that PitNETs are responsible for approximately half of the cases in adults, whereas in children the causes are predominantly congenital. Diagnosis is based on clinical evaluation and hormonal testing, with identification of the specific hormonal deficiencies essential for effective treatment. Laboratory tests present challenges and limitations that must be understood and addressed. Hormone replacement therapy is the mainstay of treatment, significantly improving patients' quality of life. It is important to know the possible interactions between hormone replacement therapies in HP. Recent advances in understanding the pathophysiology of HP and the importance of a multidisciplinary approach to the management of associated complications are discussed. This article emphasizes the need for comprehensive evaluation and continuous follow-up to optimize outcomes in patients with HP and highlights the importance of ongoing research to improve diagnostic and treatment strategies.

OPTIC PATHWAY GLIOMAS AFTER TRANSITIONING INTO ADULTHOOD – AN INSTITUTIONAL EXPERIENCE

Abstract AIMS Optic pathway gliomas (OPG) are rare tumors affecting the optic nerve and the chiasm that occur predominantly during childhood and are generally managed by pediatric neurosurgeons/ pediatric oncologists. Prognosis is quite good for these benign tumors, and many patients survive into adulthood. While clinical care for these patients in childhood is well-standardized, the clinical course of patients with OPG after transitioning into adulthood is not well studied.We herein aimed to characterize patients with OPG diagnosed in childhood after transitioning into adult neurosurgical care in order in order to ellucidate the clinical course of OPG in adulthood and to identify potential problems with clinical care of these special patients in adult neurosurgery or neuro-oncology services. METHOD Clinical and radiographical data from adult patients (> 16 years of age) with OPG diagnosed in childhood and treated in our institution were collected from patient charts. Descriptive statistics and outcome analysis were performed using commercial statistical software. RESULTS Of 124 patients with OPG diagnosed in childhood, 35 patients transitioned into adulthood. The population included equal distribution of male (18, 51.4%) vs female (17, 48.6%) patients. Median age at diagnosis was 8.0 years (range 0.5 – 15.0) and median age at last follow up was 20.8 years (range 17.1 – 38.6). 12 patients were positive for NF (34.3%). 9 patients had undergone surgery for the OPG (25.7%), 11 had chemotherapy (31.4%) and 15 (42.8%) had received radiotherapy. 8 patients showed an endocrine deficiency (22.9%), 4 hypothalamic dysfunction (11.4%) and 8 cognitive/behavioral difficulties (22.9%). Visual acuity impairment was detected in 12 patients (34.3%). 9 patients experienced recurrence (25.7%). CONCLUSION Patients with OPG transition into adulthood frequently and experience a wide range of clinical problems. Close neurosurgical/neuro-oncology specialist follow-up is recommendable.

6610 Emphasizing the evaluation of autonomic dysfunctioncontributes to the diagnosis of ROHHAD Syndrome -- Based on a comparative analysis of two center ROHHAD Syndrome case reports and reported literature

Abstract Disclosure: Y. Wang: None. L. Chen: None. C. Gong: None. Background: ROHHAD is the acronym of rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysfunction, it is an extremely rare and potentially fatal disease.The purpose of this study is to describe the clinical symptoms and timelines of ROHHAD syndrome. Methods: All patients with ROHHAD syndrome were included. Patients from 2007 to2019 published previously was regarded as group 1. We searched for the keyword "ROHHAD" in the PUMBED database, and included all literature describing theclinical symptoms of ROHHAD patients (group 2, from October 2019 to August 2023).We compared and analyzed the above two sets of data with our data (group 3). Results: In the past 2 years, we diagnosed 16 cases of ROHHAD syndrome totally, with a male to female ratio of 8:8. Mean BMI z score was 4.23 ± 1.70, and the age of rapid obesity was 3.17 (1.67, 7.92) years old, ranging from 3 to 22.5 kg/year. The age at which hypoventilation, hypothalamic dysfunction, and autonomic dysfunction occurred was 5.55 (3.61, 8.25) years old, 4.46 (1.83, 9.25) years old, 3.42 (1.83, 8.00) years old, respectively. The most common autonomic dysfunction were cardiovascular manifestations (13 cases), thermal dysregulation and excessive sweating (each with 11 cases). Totally 13 cases had emotional, cognitive and behavioral abnormalities, 7 cases had neurogenic tumors. Case 2 had neurogenic tumors more than 5 years before rapid obesity, cognitive and behavioral abnormalities more than 2 years ago. Case 10 had abnormal pain sensation shortly after birth, and following polyuria in 2 years before rapid obesity. A total of 116 patients including 100 cases previously reported and 16 cases in this study were analyzed. Compared with the incidence rates of rapid obesity, central hypoventilation and hypothalamic dysfunction in patients in this study, there was no statistically significant difference between three groups. Among patients who had autonomic dysfunction (group 1 vs group 2 vs group 3), thermal dysregulation was 65.7% vs 17.0% vs 68.8%, cardiovascular manifestations was NA vs 12.8% vs 81.2%, excessive sweating was 28.6% vs 10.6% vs 68.8%, gastrointestinal disturbances was 11.4% vs 8.5% vs 62.5%, strabismus was 25.7% vs 12.8% vs 62.5%, and sleep disturbance was NA vs 6.4% vs 50.0%, all p< 0.05. The incidence of abnormal emotion, cognition and behavior was NA vs 29.8% vs 81.2% (p<0.05). Conclusion: The incidence of autonomic dysfunction in 16 patients of this study is100%, with multiple manifestations of autonomic dysfunction coexisting. The incidenceof autonomic dysfunction and abnormal emotion, cognition and behavior in reportedcases from different eras were significantly lower than those of our study, indicating theimportance of fully evaluating the autonomic dysfunction and limbic system. Fewpatients may occur tumors or autonomic dysfunction before rapid obesity. Presentation: 6/3/2024

7704 Generating pituitary cells from iPSCs of patients with child onset congenital hypopituitarism harboring PROP1 pathogenic allelic variants

Abstract Disclosure: J.M. Marques: None. F. Fattahi: None. L.R. Carvalho: None. Introduction: Reduced or absent levels of pituitary hormones due to genetic or organic causes is known as combined pituitary hormone deficiency (CPHD) and PROP1 is the most frequent cause of CPHD, but more than 85% of the cases are without molecular diagnosis. Novel Techniques such as induced pluripotent stem cells (iPSC), can be used to generate patient’s specific pituitary cells for disease modeling. Aim: To generate iPSC from CO-CH patients’ peripheral blood mononuclear cells (PBMC) and differentiate them into pituitary cells. Methods: Peripheral blood was collected from 2 siblings (HC1 and HC2) harboring compound heterozygous PROP1 allelic variants and their parents (HC3 and HC4). PBMCs were isolated and expanded with MNC medium prior to nucleoporation and transfection with plasmids containing pluripotency genes (OCT4 and SOX2; cMYC and KLF). After 48h, transfected cells were transferred to Geltrex coated plates and fed with E8, NaB and βFGF until pluripotent colonies were formed. iPSCs were differentiated into cranial placode cells using pituitary placode conditioned medium (PPCM) until day 15. For pituitary cell maturation, pituitary conditioned medium (PPCM without SB431542) was used until day 30. qPCR and flow cytometry using the Kit BD Stemflow - Human Pluripotent Stem Cell Transcription Factor Analysis (BD Biosciences) for stem cells and the eBioscience™ Foxp3 / Transcription Factor Fixation/Permeabilization (Thermo Fisher Scientific) for the placode and pituitary markers were used. Pituitary hormonal levels from cell supernatant were measured at the Laboratory of Hormones and Molecular Genetics - HCFMUSP. Results: we generated iPSCs from patient and control blood cells. iPSCs were more than 90% positive for the pluripotency markers SOX2, NANOG, OCT3/4. Pituitary cells were generated with positivity for the placode marker SIX1 (58%) and pituitary markers, as LHX3 (56%) and PROP1 (59%), at day 15. Control cell lineages expressed higher levels of pituitary hormones at days 15 and 30 at RNA and protein levels while patient cells failed to induce hormone-producing cells properly. Pituitary hormonal release was impaired in patients pituitary cells. Conclusion: CO-CH patients’ PBMC were dedifferentiated to a pluripotent state, being able to generate pituitary hormone producing cells. Patient cells were able to mimic human phenotype. These cells can be used, in the future, to study CO-CH basis in patients specific background, to develop pituitary disease modeling as well as test possible new treatments. Presentation: 6/3/2024

7280 Pituitary Dysfunction Following Mild Traumatic Brain Injury in Female Athletes: Neuropsychological and Psychological Functioning

Abstract Disclosure: L.Ó. Eggertsdóttir Claessen: None. M.K. Jónsdóttir: None. H. Kristjánsdóttir: None. S.H. Lund: None. I. Unnsteinsdóttir Kristensen: None. H.Á. Sigurjónsdóttir: None. Background: Pituitary dysfunction (PD), as well as neuropsychological and psychological symptoms, have been reported following mild traumatic brain injury (mTBI). These symptoms may be due to the brain injury itself or PD as hypopituitarism (HP) can have neuropsychological and psychological effects. To the best of our knowledge, this study is the first to report neuropsychological and psychological outcomes in female athletes with PD following sport-related mTBI. Subjects: Female athletes aged 18 to 45 years currently active in or retired from soccer, team handball, basketball, ice hockey, and martial arts who answered an online questionnaire regarding mTBI history and mental health were included (n = 508). Of the 308 women who reported one or more mTBI, 166 (53.8%) accepted to participate in a further interview and neuropsychological tests. All 166 women were subsequently invited to participate in a medical interview. Of those 151 accepted (90.9%) and 131 (86.7%) of them participated in pituitary hormone screening blood tests (SBT). Methods: The online questionnaire included a post-concussion symptom scale, and mental health scales evaluating symptoms of anxiety, depression, stress, and quality of life. Sleep disturbances were evaluated, and neuropsychological tests were performed in the psychological interview. The Sustained Attention to Response Task (SART). Executive functioning, visual search, motor and processing speed, divided attention, working memory, and intellectual abilities were also measured. The SBT were taken at 8 a.m. and included S-IGF1 (age dependant reference range), S-cortisol (values < 350 nmol/L were considered abnormal), S-prolactin (reference range 4.79 - 23.3 μg/L), S-TSH (reference range 0.270 - 4.20 mIU/L), S-fT4 (reference range 12 - 22 pmol/L), S-FSH, S-oestrogen, and S-progesterone measurements. If SBT were repeatedly O-RV, detailed endocrinological tests were performed for each axis as indicated. Results: Following a detailed endocrinological evaluation, 16 women were diagnosed with PD (HP n = 6, hyperprolactinemia n = 10) following mTBI. Women with PD had a significantly higher mean SART error score than women with normal pituitary function (PF) (16.7 and 12.8 respectively; p = 0.04). No other significant differences in neuropsychological outcome were found between the two groups. Moreover, there was not a significant difference with regards to mTBI symptoms, anxiety, depression, stress, QOL or insomnia between women with PD and those with normal PF. Conclusions: Sustained attention or inhibitory performance may be affected in women with PD following mTBI as they had a higher mean SART error score than women with normal PF. No other significant difference in neuropsychological or psychological outcome was demonstrated. Presentation: 6/3/2024

8138 Pituitary Stalk Interruption Syndrome (PSIS) in a patient with Isolated Hypogonadotropic Hypogonadism

Abstract Disclosure: A. Thomson: None. R. Osman: None. Pituitary Stalk Interruption Syndrome in a Patient with Isolated Hypogonadotropic Hypogonadism Pituitary Stalk Interruption syndrome (PSIS) is a rare cause of hypopituitarism, characterized by a radiologic constellation of thin or interrupted pituitary stalk, hypoplasia, or aplasia of the anterior lobe and with the presence of an ectopic posterior pituitary (EPP). It is most commonly associated with isolated growth hormone deficiency (IGHD) and is often diagnosed in childhood. We present one case of a patient with isolated hypogonadotropic hypogonadism in adulthood, subsequently found to have an PSIS on MRI. A 45 year old male patient presented to our clinic with hypogonadism. He gradually started developing decreasing libido, fatigue, and loss of erections. He had normal puberty and childhood growth, and has fathered one child. He denied history of anosmia or visual symptoms. Subsequent hormonal testing showed: morning Total Testosterone: 145 ng/dl (normal 264-916 ng/dl), Free testosterone 1.5 pg/ml (normal 6.8-21.5 pg/ml), LH 1.1 mIU/ml (normal 1.7-8.6 mIU/ml) and FSH of 3.6 mIU/ml (normal 1.5-12.4 mIU/ml). Prolactin was minimally elevated at 21 ng/ml (normal 4.0 - 15.2 ng/ml). Thyroid, IGF-1, cortisol, and ferritin levels were within normal limits. Repeat levels showed similar findings. He denied ever taking any form of exogenous testosterone. His pituitary MRI revealed a small volume of anterior pituitary tissue, measuring 0.2cm x 0.7cm x 0.7cm, without discrete pituitary adenoma, a hypoplastic midline stalk measuring 1.3 mm in AP diameter (nl 2-3 mm), with a T1 hyperintense nodularity measuring 0.6cm x 0.4cm along the posterior aspect of the sella turcica consistent with EPP. No additional structural abnormality or any mass lesions were identified. He was subsequently started on replacement testosterone therapy and his symptoms resolved. PSIS usually presents in childhood with IGHD. Patients may have other pituitary hormone deficiencies and congenital central nervous system defects, although panhypopituitarism is rare. There have been reports in children with delayed puberty and isolated hypogonadotropic hypogonadism who have been found to have PSIS. Only one othercase of an adult female patient exhibiting hypogonadotropic hypogonadism as the only manifestation of PSIS has been documented in the literature. Our case highlights the potential for an adult male to present later in life with hypogonadotropic hypogonadism as a manifestation of PSIS. The marginally elevated prolactin level may be due to lack of inhibition of hypothalamic dopamine on lactotroph cells within the pituitary caused by the EPP, although it is doubtful that this has clinical significance. This is a rare presentation of PSIS, clinicians should be mindful ofthis radiological constellation and the potential for isolated hypogonadotropic hypogonadism presenting unusually in the adulthood. Presentation: 6/3/2024

9194 Generation of a Human-Induced Pluripotent Stem Cell Line From a Patient With Hypopituitarism and a Novel Nonsense Variant in FOXA2

Abstract Disclosure: M.A. Camilletti: None. G.T. Chirino Felker: None. G. Amin: None. S. Castañeda: None. F. Zabalegui: None. C. Romano Florit: None. A. Waisman: None. M. Ciaccio: None. M.I. Di Palma: None. E. Vaiani: None. A. Belgorosky: None. S.G. Miriuka: None. L.N. Moro: None. M.I. Perez-Millan: None. Congenital Hypopituitarism (CH) is a genetically complex disease characterized by one or more pituitary hormone deficiencies. Forkhead Box A2 (FOXA2, 600288) is a pioneer transcription factor associated with development of multiple tissues in humans and mice. Heterozygous loss of function mutations in FOXA2 were recently shown to cause CH with hyperinsulinemic hypoglycemia, but little is known about the molecular mechanism of FOXA2 action during pituitary development. We identified a novel, heterozygous nonsense variant in FOXA2 (c.686C<A; p.S229X) in a patient diagnosed with GH deficiency at 1.7 years of age, with anterior lobe hypoplasia and absent pituitary stalk, asymptomatic hypoglycemia, and craniofacial malformations. To discover the mechanism of FOXA2 regulation of pituitary development we generated an induced pluripotent stem cell line (FOXA2mut-iPSC) from the patient’s polymorphonuclear blood cells (PBMCs) using an EF1a-hSTEMCCA-loxP vector containing the pluripotency genes OCT-4, SOX-2, c-MYC and KLF4. FOXA2mut-iPSC clone R1 had a normal karyotype and embryonic stem cell-like morphology. These cells express endogenous pluripotency-associated markers NANOG, SOX2, and OCT4, have alkaline phosphatase activity, and can differentiate into all three developmental layers, indicating that these cells are pluripotent. Short tandem repeat (STR) analysis confirmed that FOXA2mut-iPSC R1 clone profiles matched those of the donor PBMCs. Next, we compared pituitary differentiation of FOXA2mut-iPSC vs. control-iPSCs in vitro. Cells were cultured in a differentiation medium containing BMP4, the smoothened agonist SAG, and fibroblast growth factor (FGF), as described in Zimmer et al., 2016 (1). Gene expression analysis (by qRT-PCR) of samples collected on days 0, 4, 7, and 15 of the differentiation protocol showed an increased expression of genes associated with anterior pituitary development including OTX2, PITX1/2, and SIX1 in both cell lines (n=2). These preliminary data suggest that pituitary cell fate can be induced in the heterozygous FOXA2mut-iPSC clone. Ongoing studies will assess pituitary hormone-producing cell differentiation after longer periods of FOXA2mut-iPSC cell culture. In sum, patient iPSC differentiation is a promising tool for assessment of normal and variant FOXA2 function in human pituitary development, and for enlightening the mechanisms of FOXA2 action in human pituitary development. (1) Zimmer et al., Stem Cell Reports. 2016 Jun 14;6(6):858-872. Presentation: 6/1/2024

7151 Generation of a Human-Induced Pluripotent Stem Cell Line From a Patient With Hypopituitarism and a Novel Nonsense Variant in FOXA2

Abstract Disclosure: M.A. Camilletti: None. G.T. Chirino Felker: None. G. Amin: None. S. Castañeda: None. F. Zabalegui: None. C. Romano Florit: None. A. Waisman: None. M. Ciaccio: None. M.I. Di Palma: None. E. Vaiani: None. A. Belgorosky: None. S.G. Miriuka: None. L.N. Moro: None. M.I. Perez-Millan: None. Congenital Hypopituitarism (CH) is a genetically complex disease characterized by one or more pituitary hormone deficiencies. Forkhead Box A2 (FOXA2, 600288) is a pioneer transcription factor associated with development of multiple tissues in humans and mice. Heterozygous loss of function mutations in FOXA2 were recently shown to cause CH with hyperinsulinemic hypoglycemia, but little is known about the molecular mechanism of FOXA2 action during pituitary development. We identified a novel, heterozygous nonsense variant in FOXA2 (c.686C<A; p.S229X) in a patient diagnosed with GH deficiency at 1.7 years of age, with anterior lobe hypoplasia and absent pituitary stalk, asymptomatic hypoglycemia, and craniofacial malformations. To discover the mechanism of FOXA2 regulation of pituitary development we generated an induced pluripotent stem cell line (FOXA2mut-iPSC) from the patient’s polymorphonuclear blood cells (PBMCs) using an EF1a-hSTEMCCA-loxP vector containing the pluripotency genes OCT-4, SOX-2, c-MYC and KLF4. FOXA2mut-iPSC clone R1 had a normal karyotype and embryonic stem cell-like morphology. These cells express endogenous pluripotency-associated markers NANOG, SOX2, and OCT4, have alkaline phosphatase activity, and can differentiate into all three developmental layers, indicating that these cells are pluripotent. Short tandem repeat (STR) analysis confirmed that FOXA2mut-iPSC R1 clone profiles matched those of the donor PBMCs. Next, we compared pituitary differentiation of FOXA2mut-iPSC vs. control-iPSCs in vitro. Cells were cultured in a differentiation medium containing BMP4, the smoothened agonist SAG, and fibroblast growth factor (FGF), as described in Zimmer et al., 2016 (1). Gene expression analysis (by qRT-PCR) of samples collected on days 0, 4, 7, and 15 of the differentiation protocol showed an increased expression of genes associated with anterior pituitary development including OTX2, PITX1/2, and SIX1 in both cell lines (n=2). These preliminary data suggest that pituitary cell fate can be induced in the heterozygous FOXA2mut-iPSC clone. Ongoing studies will assess pituitary hormone-producing cell differentiation after longer periods of FOXA2mut-iPSC cell culture. In sum, patient iPSC differentiation is a promising tool for assessment of normal and variant FOXA2 function in human pituitary development, and for enlightening the mechanisms of FOXA2 action in human pituitary development. (1) Zimmer et al., Stem Cell Reports. 2016 Jun 14;6(6):858-872. Presentation: 6/1/2024

7102 Pituitary Apoplexy with Eventual Complete Tumour Involution

Abstract Disclosure: A. Ng: None. R. Lai: None. Pituitary apoplexy is an endocrinological emergency resulting from infarction or haemorrhage of the pituitary gland. We present a case of pituitary apoplexy from a non-functioning pituitary macroadenoma, complicated by pituitary insufficiency and subsequent tumour involution. An 80-year-old gentleman presented to the Emergency Department with sudden severe headaches and persistent vomiting and admitted for further evaluation. Computed tomography (CT) imaging of the brain showed a prominent pituitary gland and magnetic resonance imaging (MRI) confirmed a large sellar hyperintense lesion containing blood and proteinaceous material. It measured 1.6 cm by 1.2 cm by 1 cm and indented the optic chiasm. CT angiography did not reveal any aneurysms or intracranial haemorrhage. There were no neurological or visual field deficits at presentation. There was no indication for surgery upon neurosurgical consultation. Initial evaluation of the pituitary axis was consistent with central hypocortisolism (cortisol 75 nmol/L, adrenocorticotropic hormone 1.4 pmol/L [reference range (RR) 1.6-13.9]) and hypoprolactinaemia (prolactin 56 mIU/L, RR 73-351). Luteinising hormone levels were < 1 IU/L (RR 1-9); follicle stimulating hormone levels were 3 IU/L (RR 1-19) and testosterone levels were < 1 nmol/L (RR 5 to 30) as the patient was on androgen deprivation therapy for prostate cancer. Hydrocortisone was started and he was monitored for development of frank diabetes insipidus. He did not require regular desmopressin. He later developed anti-diuretic hormone mediated hyponatraemia (serum sodium nadir of 125 mmol/L, serum osmolality 275 mmol/kg, urine osmolality 390 mmol/kg) that was managed with fluid restriction and solute loading. He also developed central hypothyroidism on day 19 of admission (free thyroxine 11 pmol/L, thyroid stimulating hormone 0.49 mIU/L, RR 0.45-4.5) and oral levothyroxine was started. He was discharged with oral hydrocortisone and levothyroxine replacement. A repeat MRI of the pituitary 2 months later showed complete resolution of the mass and resolution of the mass effects. He was kept on oral hydrocortisone and levothyroxine replacement with regular follow-up.Most pituitary macroadenomas are non-functional, and can present with complications of apoplexy, mass effects or hormonal disturbances. However, the natural history of non-functional macroadenomas is not well known as most are operated on. Spontaneous regression of the tumour can rarely occur, notably in the setting of apoplexy and lymphocytic hypophysitis. Recovery of the pituitary axis may also accompany tumour regression. As spontaneous remission of pituitary macroadenomas may occur, close observation of tumours without visual field defects or significant mass effects may be an alternative to surgery. Presentation: 6/1/2024 12:15:00 PM

7839 Assess Management of Adrenal Insufficiency in Melanoma Patients Treated with Cancer Immunotherapy

Abstract Disclosure: W. Lin: None. L. Min: None. Despite high prevalent of adrenal insufficiency in melanoma patients treated with cancer immunotherapy, no study has examined the management of adrenal insufficiency in these patients. We performed this retrospective, longitudinal cohort study at Mass General Brigham, Boston, aims to characterize the management of adrenal insufficiency in melanoma patients. Patients were identified through our RPDR search tool, and medical record reviews were conducted. Three patient groups were analyzed: Melanoma with secondary adrenal insufficiency group (Mel_SAI, n=74), Melanoma matched control group (Mel_Con, n=69), and Pituitary macroadenoma-related adrenal insufficiency matched control group (Pit_Con, n=37). We compared self-perceived quality of life, glucocorticoid replacement dose, and clinic visit. Mel_SAI patients exhibited significantly higher incidences of anxiety (43.1%, 95%CI: 32.3-54.6), fatigue (73.6%, 95%CI: 62.4-82.4), pain (58.3%, 95%CI: 46.8-69.0), and insomnia (36.1%, 95%CI: 26.0-47.6), as compared to Pit_Con group (21.6%, 11.4-37.2; 24.3, 13.4-40.1; 29.7%, 17.5-45.8; 5.4%, 1.5-17.7, respectively). The initial hydrocortisone dose was higher for Mel_SAI (30mg qd, 95%CI: 20.5-25.1) compared to Pit_Con (15mg qd, 95%CI: 12.8-18.3). Additionally, the Mel_SAI group had fewer endocrinology clinic visits (3, 95%CI: 3.40-5.04) than the Pit_Con group (9, 95%CI: 7.35-10.9). Subgroup analysis indicated a higher mortality risk (HR 2.61, 95% CI 1.11-6.13) in Mel_SAI patients with fewer than three endocrinology visits over five years. Compared to the Mel_Con group, Mel_SAI patients also showed higher incidences of fatigue (71.6%, 95%CI: 60.5-80.6; Mel_Con: 55.1%, 95%CI: 43.4%-66.2%), but lower rates of depression (25.7%, 95%CI: 17.1-36.7; Mel_Con: 43.5%, 95%CI: 32.4-55.2) and appetite loss (24.3%, 95%CI: 16.0-35.2; Mel_Con: 47.8%, 95%CI: 36.4-59.4). No significant difference in other self-perspective symptoms. Furthermore, Mel-SAI patients had more oncological clinic visits (71, 95%CI: 74.0-109.2) than those in the Mel_Con group (41, 95%CI: 42.1-64.1). Our study suggests that most self-perceived quality of life in the Mel_SAI group is related to melanoma rather than adrenal insufficiency. Therefore, a higher initiating dose of hydrocortisone in melanoma patients with adrenal insufficiency may not be necessary. However, increasing endocrine clinic visits in cancer patients with cancer immunotherapy-related adrenal insufficiency may improve their survival outcomes. Presentation: 6/3/2024

8263 Long-term Imaging Follow-up of Non-functioning Pituitary Adenomas

Abstract Disclosure: N. Mehrotra: None. M.M. Ross: None. A.S. Chilukuri: None. S. Eljamri: None. C. Ewing: None. S. Patel: None. V. Patel: None. L.B. Siegel: None. D. Sistla: None. R.K. Shariff: None. P.K. Fazeli: None. Pituitary adenomas are common, affecting ∼15% of the population. Once a pituitary adenoma has been identified on imaging, an evaluation is undertaken for pituitary hormone excess and for pituitary hormone deficiency in the setting of larger adenomas (typically 1cm in size or greater). Hormone-producing or functioning pituitary adenomas are typically treated with medical or surgical therapy, but non-functioning pituitary adenomas can be followed conservatively if they are not contributing to morbidity. The natural history of non-functioning pituitary adenomas has not been well characterized and therefore although guidelines recommend follow-up pituitary imaging, there are no specific guidelines addressing how frequently or for how long these lesions should be followed. Our aim was to describe the clinical history of non-functioning pituitary adenomas using long-term clinical data from a large academic health system. We identified 791 patients who met our inclusion criteria of having more than one brain/pituitary MRI performed at least 3 months apart with a suspected non-functioning adenoma identified on the initial MRI. Each medical record was individually reviewed to confirm whether the adenoma was non-functioning based on clinical/biochemical evaluation. Patients were a median [interquartile range] of 48.3 [34.4, 63.6] years of age at the time of first MRI and 65% (n=517) were women. At presentation, 66% (n=523) of the pituitary adenomas were microadenomas (< 1 cm in size) and 34% were macroadenomas (> 1 cm). All patients had an MRI repeated at least 3 months after the initial MRI with median time of total imaging follow-up of 39.8 [17.0, 75.6] months. During follow-up, 658 patients were noted to have a stable lesion or a decrease in size of the adenoma. Patients whose lesion was noted to grow on MRI were slightly older than those who did not have growth (growth: 57.1 [41.9, 70.3] years versus no growth: 46.8 [33.7, 62.3] years, p< 0.0001). There were no differences with respect to BMI, hypopituitarism, smoking history or alcohol use between those with growth versus those without growth. Seventy-eight patients (9.9%) had surgical resection of their adenoma during follow-up. The most common indication for surgery was growth of the lesion (n=27), followed by visual changes (n=22). In the patients with a microadenoma at presentation, 90.8% remained stable in size or decreased in size during a median follow-up of 43.2 [20.5, 78.6] months. Only 2.3% of patients with a microadenoma at presentation underwent surgical resection during follow-up. In conclusion, the majority of non-functioning pituitary adenomas remain stable during prolonged imaging follow-up. Further study is needed to determine predictors of growth of non-functioning pituitary adenomas. Presentation: 6/2/2024

6529 The Risk of Hypophysitis Following Treatment With Relatlimab+Nivolumab Appears Higher Than Expected

Abstract Disclosure: N. Chamorro-Pareja: None. A.T. Faje: None. K.K. Miller: Stock Owner; Self; Bristol-Myers Squibb. Hypophysitis is a recognized complication of immune checkpoint inhibitor therapy; the risk of developing hypophysitis in patients receiving nivolumab (an anti-programmed death-ligand 1 [anti-PD-1]) is estimated to be < 1%. Relatlimab is a human monoclonal antibody targeting lymphocyte activation gene 3 (LAG-3) recently approved in combination with nivolumab for the treatment of unresectable or metastatic melanoma. The risk of hypophysitis as a complication of relatlimab therapy is not well-defined. Objective: To examine the prevalence, identify risk factors, and characterize the clinical presentation of hypophysitis in patients receiving relatlimab+nivolumab. Methods: 159 patients received relatlimab+nivolumab at the Mass General Brigham health care system between 6/2015 and 11/2023. Twenty-seven patients were excluded because they were either diagnosed with adrenal insufficiency (AI) before receiving relatlimab+nivolumab or AI was secondary to other factors, primarily exogenous glucocorticoid administration, leaving a total of 122 patients. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were reviewed. Data are presented as mean ± SD. Results: Central AI was diagnosed in 10 patients (7.5% of the cohort) after relatlimab+nivolumab administration. The mean age was 64.5±13.8 vs. 67.1±14.4 in patients with AI vs. patients without AI (p= 0.58). Sixty percent of patients in the AI group were male compared to 53% of patients without AI (p= 0.68). The development of AI was not related to the cumulative dose of relatlimab+nivolumab (mean number of cycles 6.4±3.2 vs. 4.9±5.0, p=0.35). The most common presenting symptoms of AI were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies, though not all patients were evaluated for these diagnoses; none had diabetes insipidus. Nine patients had MRIs performed after the diagnosis of central AI; 7 of these patients had pre-treatment MRIs for comparison. Diffuse pituitary enlargement was seen on MRI after initiation of relatlimab+nivolumab in 3 patients up to 8 weeks prior to the diagnosis of hypopituitarism. All patients had persistent hypopituitarism at the most recent evaluation. Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab+nivolumab. A significant portion of patients were diagnosed with central AI, presumptively due to hypophysitis given the lack of an identifiable alternative etiology. Although the clinical phenotype of these patients paralleled published studies analyzing anti-PD-1 monotherapy, combination treatment with relatlimab+nivolumab appeared to confer a significantly higher risk of developing hypophysitis. Presentation: 6/3/2024

8454 Iron deficiency as a cause of euthyroid syndrome

Abstract Disclosure: O.V. Samburskaya: None. S. Kalinchenko: None. L. Vorslov: None. Annotation: The prevalence of euthyroid pathology syndrome is increasing, and the cause of its occurrence remains unknown, despite the decrease in the quality of life of these patients, there is no treatment for this pathology. One of the reasons may be iron deficiency, which not only reduces the activity of thyroid enzymes, but also disrupts the feedback between a decrease in triiodothyronine and the level of thyroid-stimulating hormone (TSH). Materials and methods: There are 6 patients under observation, aged from 25 to 55 years, average age 38.4±12.67 years, gender distribution: 4 women 67% and 2 men 33%, who are undergoing treatment to compensate for iron deficiency and simultaneously control thyroid function. The analysis of iron deficiency is performed according to blood test parameters: total blood count, total serum iron binding capacity, transferrin, ferritin, serum iron. The function of the thyroid gland is determined by blood test parameters: T4 free, T3 free, TSH.The received data. According to the results of the data obtained, latent iron deficiency was found in all 6 patients. All patients have a decrease in thyroid hormone levels: T3 free 3.87±0.45 pmol/l (reference range 3.69-8.46 pmol/L) and T4 free 14.17±1.23 pmol/L (reference range 12.3-22.8 pmol/L) is closer to the lower limit of normal, but TSH is also closer to the lower limit of the norm is 1.46±0.33 µm/ml (reference range 0.70-5.9 µm/ml). Discussion: The existing iron deficiency leads to the development of chronic hypoxia, which leads to a violation of the functioning of many endocrine glands, including a violation of the work of thyroid enzymes: thyroid peroxidase and deiodinases, with a decrease in the synthesis of thyroid hormones (T4 and T3), and according to the feedback principle, an decrease in the level of thyroxine and triiodothyronine is expected raising the level of TSH. However, with chronic hypoxia, iron deficiency, hypoxic dysfunction develops not only of the peripheral endocrine glands, but also hypoxic hypothalamic-pituitary dysfunction, which leads to an inadequate response of the pituitary gland, i.e. the absence of an increase in TSH in response to a decrease in thyroid hormones. Conclusion: All patients with euthyroid syndrome need to evaluate the biochemical parameters of the body's iron supply, and the elimination of deficiency of which may be the necessary treatment for patients with euthyroid pathology. Presentation: 6/2/2024

8800 A Case of Hypopituitarism Due to Sheehan Syndrome

Abstract Disclosure: N. Akabogu: None. S. Dejhansathit: None. F. Marium: None. B. Stanley: None. E.M. Bazuaye: None. L.S. Krusniak: None. L.G. Kurukulasuriya: None. U.Z. Khan: None. Background: Sheehan syndrome, which is also known as postpartum pituitary infarction, refers to the necrosis of the anterior pituitary gland due to postpartum hypovolemia, hemorrhage, shock, resulting in various degrees of hypopituitarism. The pituitary gland enlarges during pregnancy due to estrogen stimulation and becomes hyper-vascular, making it prone to infarction with postpartum hemorrhage. The initial symptoms include hyponatremia, weakness, weight loss, but the most prominent specific symptoms are inability to nurse and postpartum amenorrhea. Depending on the severity of hypopituitarism, symptoms may develop within the first few days to weeks after delivery or may take months to years to develop. Case presentation: 35year-old Caucasian female with a medical history of gestational diabetes, hyperlipidemia, and hypertension, who presented to the hospital with flu-like symptoms, leg pain, abdominal pain, and proximal muscle weakness. The evaluating hospitalist observed that patient appeared sluggish and spoke with a deep coarse voice, which concerned him for hypothyroidism. Thyroid function test revealed undetectable free T4 with inappropriately normal TSH of 1.38 – consistent with secondary hypothyroidism. Additional history from patient uncovered 9 months history of constant fatigue, weight gain, dry skin, hair loss, cold intolerance, and intermittent ankle swelling. There is no history of brain irradiation or head trauma. She has 4 biological children, and her last childbirth 3years ago was complicated by severe bleeding from her incision site, requiring transfusion of 6 units of blood. She has been amenorrheic since and is neither on birth control nor had hysterectomy. Physical exam showed mildly enlarged tongue, diffuse pallor, dry scaly skin on upper arms, scanty eyebrows, and slowed speech. Further work-up for pituitary insufficiency showed secondary adrenal insufficiency, secondary hypogonadism, low prolactin, and growth hormone deficiency. There was no evidence of AVP deficiency. Other lab and clinical findings were hypoglycemia, hyperlipidemia, elevated CK, elevated Cr, pericardial effusion, and diastolic hypertension. Pituitary MRI showed markedly attenuated and flattened pituitary gland with no focal mass. Patient was given stress dose hydrocortisone and thyroid hormone replacement, initially IV then oral. Following hydrocortisone and thyroid hormone replacement, her diastolic BP, hypoglycemia, CK, and Cr improved. Further management plans include initiating estrogen (plus progesterone) for bone health. Conclusion: Although Sheehan syndrome is rare in developed countries, it does occur. This case emphasizes the importance of detailed history taking, to discover the root of patients’ presentation. Even though TSH is the screening test for thyroid disease, when pituitary etiology is suspected, it is important to also check a free T4. Presentation: 6/1/2024

6672 Pituicytomas and Spindle Cell Oncocytomas: Rare Posterior Pituitary Tumors

Abstract Disclosure: Y. Park: None. A. Shen: None. M. Christie: None. J. Wentworth: None. C.J. Yates: None. J. King: None. Background: Pituicytomas and spindle cell oncocytomas (SCO) are rare non-functioning benign posterior pituitary tumors that can present as suprasellar or sellar-suprasellar masses.[1] Pituicytomas originate from the pituicytes in the neurohypophysis and infundibulum of the pituitary gland.2 SCO were previously thought to derive from the adenohypophysis,3 however, are now classified as a tumor of the neurohypophysis characterized by immunohistochemical reactivity to thyroid transcription factor 1 (TTF1).4 According to the World Health Organization 2021 classifications, pituicytomas, granular cell tumors and SCO may represent morphologic variations of the same tumor expressing TTF1.5 Due to their rarity, their clinical characteristics are not yet well-defined and can be mistaken as non-functioning pituitary adenomas. Methods: We retrospectively reviewed the clinical data of two patients with pituicytomas and two patients with SCO confirmed on histopathology at our institution, evaluating their clinical characteristics and management outcomes. Results: Two male patients, aged 59 and 79, were diagnosed with pituicytoma, and two male patients, aged 33 and 55 were diagnosed with SCO. Three presented with visual impairment from mass effects and three patients had hypogonadotropic hypogonadism. None had pre-operative arginine vasopressin (AVP) deficiency. All lesions were isointense on T1-weighted, and most were hyperintense on T2-weighted magnetic resonance imaging. Three cases had non-gross total resection due to hypervascularity. Postoperatively, two patients developed AVP deficiency and three developed persistent anterior pituitary insufficiency (Table 1). Pituicytomas had a Ki67 of 1-3%, and SCO had a Topoisomerase labelling index of <1%. In one case of pituicytoma, due to tumor recurrence 2 years after initial surgery, adjuvant radiotherapy was considered. However, the patient developed a severe peri-tumoral subarachnoid hemorrhage and died prior to receiving radiotherapy. In contrast, the progression of the residual SCO occurred at a slower rate. Discussions: Posterior pituitary tumor differentials are broad, including pituicytoma, SCO, granular cell tumor, craniopharyngioma, meningioma and germinoma;6 hence, histopathological diagnosis is crucial. Although benign, pituicytomas and SCO can result in increased morbidity and postoperative complications, such as AVP deficiency and hypopituitarism. Recurrence and progression are common.7, 8 Gross total resection is optimal, but this is difficult due to hypervascularity.9 Our case of peri-tumoral subarachnoid hemorrhage resulting in death emphasizes the hypervascular nature of pituicytomas. Patients with pituicytomas and SCO should be monitored for tumor progression or recurrence and hemorrhagic complications. Adjuvant radiotherapy may be considered for the management of tumor recurrence. Presentation: 6/3/2024

8342 A Rare Case of a Corticotropic and Gonadotropic Pituitary Double Adenoma

Abstract Disclosure: S. Gruber: None. D. Kirschenbaum: None. T. Hortobagyi: None. C. Serra: None. A. Bink: None. F. Beuschlein: None. Z. Erlic: None. Background: Pituitary adenomas account for about 15% of all intracranial neoplasms and typically arise from monoclonal proliferation of anterior pituitary cells. While lactotropic and clinically hormone-inactive adenomas make up by far the largest proportion, somatotropic and corticotropic adenomas have a significantly lower prevalence. This case describes the very rare finding of a corticotropic and gonadotropic double adenoma. Clinical Case: A 63-year-old Caucasian man (BMI 36.7 kg/m2) presented in the obesity clinic. Hypercortisolism was suspected by repeated lack of cortisol suppression in low-dose dexamethasone suppression tests [minimal 87 nmol/l] and disrupted circadian rhythm of cortisol secretion according to salivary cortisol profile. Cortisol levels in a 24-hour sample of urine were normal. ACTH levels were elevated [73 ng/l; n<61 ng/l] leading to suspicion of Morbus Cushing. Concomitant diseases include sleep apnea, arterial hypertension and newly diagnosed type 2 diabetes mellitus. Medical history was notable for deep vein thrombosis and pulmonary embolism. Other stigmata of hypercortisolism were not evident. The rest of endocrine work up confirmed partial secondary hypothyroidism and hypogondotropic hypogonadism. An MRI of the pituitary gland revealed a pituitary macroadenoma with a maximum dimension of 20 mm. The patient underwent an endoscopic transnasal adenomectomy with post-operative corticotropic insufficiency. Contrary to our expectations, the histological examination of the surgical resection revealed a gonadotrophic pituitary adenoma with SF1 and focal FSH expression. The discrepancy between clinical, biochemical and histological findings led to subsequent examinations of the specimen with detection of an small fragment accounting for less than 5% of the total sample with expression of T-Pit and ACTH but neither SF1 nor Pit-1, corresponding to an additional corticotropic adenoma with densely granulated pattern. The tumor cells did not show overlapping expression patterns of transcription factors or hormones, which indicates the coincidence of two distinct adenomas. Three months postoperatively, the patient is biochemically cured. Partial anterior pituitary insufficiency remained. Conclusion: Pituitary double adenomas are found in 0.5-1.5% of all surgical specimens. They are characterized by their origin from different cell lines, which distinguishes them from plurihormonal adenomas, which originate from one single cell line. Here we demonstrate a SF1-T-Pit lineage combination resulting in a neighboring ACTH and FSH-adenoma. In this particular case, the clinically relevant corticotropic adenoma was comparatively tiny, making it easy to miss. This illustrates well the importance of careful correlation of clinical, laboratory and histologic findings as correct diagnosis is crucial for postoperative patient management. Presentation: 6/2/2024

6367 Growth gone Awry: A Rare Case of Acromegaly in a 16-Year-Old Female with Panhypopituitarism Secondary to Craniopharyngioma on Low Doses of Growth Hormone with Low IGF-1 levels

Abstract Disclosure: L.M. Ayala Castro: None. J. Ye Tay: None. A. Diaz: None. This report highlights a rare case of a 16-year-old female with panhypopituitarism due to craniopharyngioma, where GH replacement therapy triggered acromegaly features despite having low IGF-1 levels. Background: Craniopharyngiomas are the most common tumors causing acquired pituitary deficiencies in children. Various mechanisms contribute to acromegaly, and hypersensitivity to hormonal treatment in this benign tumor emerges as a plausible avenue for investigation. Case Presentation: A 16-year-old female diagnosed with craniopharyngioma at age 5 developed secondary panhypopituitarism. Baseline hormonal profiles indicated markedly reduced levels of IGF-1 and insulin growth factor–binding protein 3 (IGF-BP3). Despite the established condition, GH treatment was initiated at age 8 for potential growth and development benefits. Before commencing GH therapy, a bone age assessment revealed normal skeletal development. However, GH replacement therapy led to an unexpectedly robust response, resulting in physical changes consistent with acromegaly. Paradoxically, laboratory evaluations showed low IGF-1 levels. Imaging studies, including pituitary MRI, ruled out new abnormalities or tumors. As the patient approached peak adult height at 16, having been on adult GH therapy since age 13, a decision was made to discontinue GH replacement therapy and address acromegaly symptoms. Frequent follow-up visits were planned to assess growth velocity, monitor hormonal levels, and evaluate potential adverse effects. Discussion: This case demonstrates an unusual sensitivity to exogenous GH, resulting in an exaggerated response contrary to expected IGF-1 elevation. Atypical IGF-1 levels may suggest alterations in liver physiology, GH receptor signaling pathways (e.g., Laron Syndrome), or downstream defects in IGF-1 synthesis. Further research is crucial to elucidate the underlying mechanisms. Conclusion: Only 3 cases of acromegaly as a side effect of GH replacement therapy have been reported in the literature. We report a further case that underscores the complexity of managing hormonal imbalances, especially in unique patient populations with panhypopituitarism secondary to craniopharyngioma. The unexpected response to GH treatment emphasizes the need for individualized approaches and vigilant monitoring.