bluuebunny/crossref_metadata_2025 huggingface dataset:
Prenatal Androgen Excess Impairs Sexual Behavior in Adult Female Mice: Perspective on Sexual Dysfunction in PCOS
Authors: Donaldson Nina , Prescott Melanie , Campbell Rebecca Elaine , Desroziers Elodie
Published: May 2021

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders worldwide, affecting 5-20% of reproductive aged women [1]. PCOS is characterised by androgen excess, oligo- or anovulation, and polycystic ovarian morphology [1]. PCOS patients also experience sexual dysfunction, including decreased sexual desire, increased sexual dissatisfaction and gender dysphoria [2-4]. The origins of PCOS-related sexual difficulties remain unidentified, but may be related to impaired central mechanisms regulating sexual behaviours. Prenatally androgenized (PNA) mice recapitulate the PCOS phenotype and exhibit alterations in the neuronal network regulating reproductive function [5], providing a powerful, pathology-based model to unravel the biological origins of sexual dysfunction in PCOS. Here, we aimed to determine whether female sexual behaviours are impaired in the PNA mouse model of PCOS. To model PCOS, female dams received injections of dihydrotestosterone (PNA) or oil vehicle (VEH) daily from gestational day 16-18. Adult female offspring were ovariectomized and implanted with a silastic capsule of estradiol to examine the female-typical sexual behaviour: lordosis as well as partner preference. We also examined a potential masculinisation of the brain by replacing the estradiol implant by a testosterone implant then testing the female for male-like sexual behaviours. PNA females exhibited significantly reduced lordosis behaviour compared to VEH females (p<0.01). In contrast, partner preference and male-like sexual behaviour were not different between PNA and VEH females. In addition, using Open-field test and elevated-plus maze, we observed no effect of prenatal androgen exposure on locomotion and anxiety. These results highlight, for the first time, that prenatal exposure to the non-aromatisable androgen, DHT, impairs female receptivity only without masculinisation. These findings support the use of the PNA mouse model of PCOS to identify the neuronal targets of prenatal androgen action and to determine the mechanisms by which prenatal androgen excess impairs lordosis. Taken together, this study introduce a novel perspective on the origins of sexual dysfunction in women with PCOS and indicate the need for further investigation into the mechanisms of androgen excess on the female brain and sexual function. [1] Lizneva D et al, Fertil Steril. 2016;106:6-15. [2] Fliegner M et al, Geburtshilfe Frauenheilkd. 2019;79:498-509.[3] Kowalczyk R et al, Acta Obstet Gynecol Scand. 2012;91:710-4.[4] Mansson M et al, Eur J Obstet Gynecol Reprod Biol. 2011;155:161-5. [5] Ruddenklau A, Campbell RE. Endocrinology. 2019 Oct 1;160(10):2230-2242.
Role of FOXO1 in Glucocorticoid-Induced Somatotrope Maturation
Authors: Das Pratyusa , Stallings Caitlin E , Ellsworth Buffy Sue
Published: May 2021

Growth hormone (GH) is a well-known metabolic factor secreted by pituitary somatotropes. Transcription factors such as POU1F1 and NEUROD4 promote somatotrope differentiation, maturation, and function. The forkhead transcription factor, FOXO1, is necessary for the proper timing of somatotrope differentiation and function, but the underlying mechanisms behind it have yet to be unraveled. Pituitary gland development also depends on regulation by signaling factors and hormones. Glucocorticoids have mixed effects on growth hormone production. However, when the effects of glucocorticoid signaling on the hypothalamus and pituitary gland are uncoupled, the direct effects of glucocorticoid signaling on pituitary somatotropes are not only stimulatory, but necessary for initiation of somatotrope maturation and for maintenance of somatotrope function. We find that FOXO1 is necessary for glucocorticoid induction of important somatotrope genes. Activation of glucocorticoid signaling in the somatotrope-derived MtT/S cell line induces transient expression of the bZIP transcription factor, Crebl2 within 2 hours. Interestingly, glucocorticoid induction of Crebl2 as well as the somatotrope genes Ghrhr and Gh1, is impaired in the presence of the FOXO1 inhibitor (AS1842856). There are several possible mechanisms underlying the requirement of FOXO1 in glucocorticoid induction of somatotrope maturation. One possible mechanism is that glucocorticoid signaling upregulates expression of Foxo1 and ultimately FOXO1 targets. Consistent with this possibility, Foxo1 expression is induced 8 hours after activation of glucocorticoid signaling. This does not appear to be the only mechanism underlying the role for FOXO1 in mediating glucocorticoid-induced somatotrope maturation, however, because many FOXO1 target genes, such as Neurod4 and Fosl2 are not affected by glucocorticoid signaling. We are currently investigating whether cooperative binding between FOXO1 and the glucocorticoid receptor contributes to transcriptional regulation of common targets genes. Together these data demonstrate that FOXO1 is a key factor mediating glucocorticoid induction of somatotrope maturation.
Role of Growth Hormone in Ghrelin’s Metabolic Actions
Authors: Gupta Deepali , Varshney Salil , Shankar Kripa , Osborne-Lawrence Sherri , Metzger Nathan P , Zigman Jeffrey Marc
Published: May 2021

Objective: Ghrelin regulates eating, body weight, and blood glucose. Upon binding to its receptor (growth hormone secretagogue receptor; GHSR), administered ghrelin increases food intake, body weight, and blood glucose. In contrast, blocking ghrelin lowers body weight and food intake. Also, mice that lack ghrelin or GHSR develop life-threatening hypoglycemia when submitted to a prolonged caloric restriction protocol providing only 40% of usual daily calories. Although GHSR was first identified in the pituitary, ghrelin was first defined by its ability to stimulate GH secretion via GHSRs, GH replacement prevents hypoglycemia in ghrelin-KO mice undergoing prolonged caloric restriction, and GH is known to modulate body composition, relatively little attention has been devoted to the role of GH-secreting pituitary somatotrophs (“GH cells”) in ghrelin action. The objective here was to determine the requirement for GHSR-expressing GH cells in mediating ghrelin’s metabolic actions. Methods: Mice with GH cell-selective GHSR deletion were generated by crossing novel GH-IRES-Cre mice to novel floxed-GHSR mice. GH cell-selective GHSR knockout mice and three control littermate groups were studied. Plasma GH, food intake, and blood glucose were measured after ip or sc ghrelin administration. Blood glucose and plasma GH were measured over the course of a 15-d calorie restriction protocol providing only 40% of usual daily calories. Results: In mice with GH cell-selective GHSR deletion, ghrelin-induced GH secretion and food intake were attenuated (by 84.1% at 15 min and by 35.3% at 45 min, respectively) as compared to controls; ghrelin-induced blood glucose elevation was unchanged. Mice with GH cell-selective GHSR deletion exhibited an attenuated GH rise (by 76.8%) over the 15-d calorie restriction period, yet they nonetheless resisted life-threatening hypoglycemia which is observed in similarly-treated ghrelin-KO mice, GHSR-null mice, and mice with hepatocyte-selective GH receptor deletion. Conclusions: These results suggest that GH cell-expressed GHSRs are required for ghrelin’s acute orexigenic and GH secretory actions but are dispensable for ghrelin’s glucoregulatory actions, at least in the settings assessed here. Although GH cell-expressed GHSRs are required for the progressive GH elevations associated with prolonged calorie restriction, they are not required for ghrelin’s overall protective effects to block prolonged calorie restriction-associated hypoglycemia.
The Cell Fate Determinant Musashi Is Controlled Through Dynamic Protein:Protein Interactions
Authors: Bronson Katherine , Balasubramaniam Meenakshisundaram , Hardy Linda , Childs Gwen V , MacNicol Melanie C , MacNicol Angus M
Published: May 2021

The Musashi RNA-binding protein functions as a gatekeeper of cell maturation and plasticity through the control of target mRNA translation. It is understood that Musashi promotes stem cell self-renewal and opposes differentiation. While Musashi is best characterized as a repressor of target mRNA translation, we have shown that Musashi can activate target mRNA translation in a cell context specific manner via regulatory phosphorylation on two evolutionarily conserved C-terminal serine residues. Our recent work has found that Musashi is expressed in pituitary stem cells as well as in differentiated hormone producing cell lineages in the adult pituitary. We hypothesize that Musashi maintains cell fate plasticity in the adult pituitary to allow the gland to modulate hormone production in response to changing organismal needs. Here, we seek to understand the regulation of Musashi function. Both Musashi isoforms (Musashi1 and Musashi2) contain two RNA-recognition motifs (RRMs) that bind to specific sequences in the 3’-UTR of target mRNA transcripts; however, neither isoform has enzymatic properties and thus functions through interactions with other proteins to regulate translational outcomes, but the identity and role of Musashi partner proteins is largely unknown. In this study, we have identified co-associated partner proteins that functionally contribute to Musashi-dependent mRNA translational activation during the maturation of Xenopus oocytes. Using mass spectrometry, we identified 29 co-associated proteins that interact specifically with Musashi1 during oocyte maturation and determined that the Musashi co-associated proteins ePABP, PABP4, LSM14A/B, CELF2, PUM1, ELAV1, ELAV2, and DDX6 attenuated oocyte maturation through individual antisense DNA oligo knockdowns. An assessment of the role of these cofactors in the control of Musashi-dependent target mRNA translation is in progress. In addition to studying co-associated proteins, we have created a computational 3D model of the Musashi1 molecule to assist in our investigation Musashi dimerization. This model has indicated that both Musashi1 dimerization and Musashi1:Musashi2 heterodimerization are energetically favorable, and co-pulldown studies have verified both Musashi1 homo-dimerization and Musashi1:Musashi2 heterodimerization in vivo. Computational modeling of Musashi dimer complexes has also identified the key amino acids necessary for these interactions. The contribution of each co-associated protein’s influence on Musashi-dependent translation, relative to the requirement for Musashi:Musashi dimerization, is expected to provide unparalleled insight into regulation of Musashi action. Moreover, cell type specific regulation of association of Musashi co-factors would directly influence Musashi target mRNA translation in oocyte maturation and during pituitary cell plasticity.
A Case of Silent Corticotroph Adenoma
Authors: Ibekwe Usonwanne U , Zwagerman Nathan , Kidambi Srividya , Marifke Jerald Peter
Published: May 2021

Background: Silent Corticotroph Adenomas (SCAs) are tumors with no biochemical or clinical features consistent with hypercortisolism but have positive immunostaining for ACTH. They account for approximately 1.1-6% of all pituitary adenomas and 5.5% of nonfunctioning adenomas. Clinical Case: A 49-year-old woman presented to clinic with a 6-month history of headache, vision changes, fatigue, hair thinning, brittle nails, lightheadedness, polydipsia, easy bruising, increased appetite, and weight gain of 178 pounds in 2 years. Labs obtained: morning cortisol 10 mcg/dl(7-25 mcg/dl), ACTH 59 pg/ml(7.2-63 pg/ml), IGF-1 96 ng/ml(52-328 ng/ml), LH 0.2 mIU/ml(1.9-12.5 mIU/ml), FSH 0.8 mIU/ml(2.5-10.2mIU/ml), alpha subunit <0.1 ng/ml(52-328 ng/ml), TSH 0.991 uIU/ml(0.358-3.74 uIU/ml), free T4 1.12 ng/dl(0.76-1.46 ng/dl), salivary cortisol 66 ng/dl(<100 ng/dl), 24-hour urine cortisol 10 mcg/24hr(3.5-45 mcg/24hr) and prolactin 64.3 ng/ml(2.8-29.2 ng/ml). No hook effect noted with serial dilution. MRI brain showed a 22 x 29 x 26 mm sellar mass extending into the suprasellar cistern displacing and compressing the optic nerves and chiasm superiorly with partial invasion into the right cavernous sinus. She had an endoscopic resection of the sellar mass. She developed diabetes insipidus post-operatively and required desmopressin transiently. In the immediate post-operative period, morning cortisol and ACTH were 16.9 ug/dl(6.2-19.4 ug/dL) 24.8 pg/ml(7.2-63.3 pg/ml) respectively. She was sent home without steroids. Pathology showed a staining pattern consistent with pituitary adenoma with positive staining for ACTH. One month after her surgery she was admitted with symptoms of orthostatic hypotension. Cortisol at 5pm was 3 ug/dl(2.3-11.9 ug/dl), ACTH 31.7 pg/ml(7.2-63.3pg/ml). She had a cosyntropin stimulation test done with peak cortisol of 19.3 ug/dl at 60 minutes. Due to her symptoms, she was started on oral hydrocortisone (HC) for secondary adrenal insufficiency (AI), but was eventually tapered off the steroids. Six months after her surgery, she developed worsening headaches. Repeat MRI obtained showed significant growth of the residual adenoma on the right side of the sella, invading the cavernous sinus. Morning cortisol level of 5.3 mcg/dl(4.3-22.4 mcg/dl) and ACTH level was 11 pg/ml(6-50 pg/ml). She had a repeat endoscopic resection of the pituitary tumor. Her post-surgery cortisol at 2 PM was 3 mcg/dl at which time patient reported symptoms of AI. She was discharged on HC. Pathology again showed a staining pattern consistent with pituitary adenoma with positive staining for ACTH. MIB-1 proliferative index was 5.6%. P53 immunostaining showed a moderate density of moderately intense nuclei in the adenoma. Conclusion: This case illustrates aggressive nature of SCAs with higher risk of recurrence compared to other non-functioning adenomas and therefore requires close follow up.
A Challenging Case of Pituitary Macroprolactinoma During Pregnancy
Authors: Zainal Abir , Adderley Elaina , Torres Mira
Published: May 2021

Introduction: Prolactinoma is the most common secreting pituitary adenoma diagnosed in women of reproductive age. The mainstay of treatment is pharmacotherapy with dopamine agonists. Management during pregnancy poses a considerable challenge to physicians. We describe a case of a patient who developed significant symptoms of pituitary enlargement following cessation of Cabergoline in pregnancy. Case Description: A 28-year-old female presented at age 16 with galactorrhea and oligomenorrhea. She was treated with Cabergoline for 12 years. Her peak prolactin was 191ng/ml (normal range, non-pregnant: 2.8-29.2ng/ml, pregnant: 9.7- 208.5ng/ml). On MRI, she had a 1cm tumor that was stable from 2016 to 2019. Prior to recent pregnancy, she remained compliant with Cabergoline 1.5mg twice weekly with prolactin levels that ranged between 30-44 ng/ml. After becoming pregnant in August 2019, Cabergoline was discontinued. During pregnancy, she did not initially schedule follow up with endocrinology. She developed blurred vision at 12 weeks gestation but did not seek medical care until 24 weeks gestation, at which time she was found by Ophthalmology to have bitemporal field cuts. MRI pituitary at 26 weeks showed marked enlargement and evidence of a left sided pituitary macroadenoma measuring 2cm with hemorrhagic component, suprasellar extension compressing the optic chiasm and subtle extension into the left cavernous sinus. She was recommenced on Cabergoline 1.5mg twice weekly but had no improvement in visual changes or MRI findings after two weeks. Her prolactin level at 30 weeks gestation was 170ng/ml. Neurosurgical evaluation resulted in urgent endoscopic transsphenoidal surgery at 30 weeks and pathology was consistent with prolactinoma. Post-operative outcomes were favorable with no evidence of pituitary hormonal deficiencies. Her visual abnormalities resolved, and she underwent delivery via C-section at 38 weeks gestation. She had intermittent breast milk production and her baby is in good health. She remains off Cabergoline with a prolactin level of 2.38ng/ml and no residual disease on MRI done 6 months postop. Conclusion: Tumor growth causing significant symptoms requiring intervention has been reported in 2.4% of microadenomas and 21% of macroadenomas. It is essential to periodically assess visual fields during pregnancy particularly in patients with macroadenomas. Dopamine agonists are discontinued during pregnancy unless symptomatic enlargement of prolactinoma occurs. In such cases, reinstitution of dopamine agonists usually results in positive outcomes and delivery can be considered if appropriate for gestational age. Further deterioration or lack of improvement necessitates urgent neurosurgical intervention in cases such as our patient.
A Rare Event: Pituitary Apoplexy 6 Weeks After Gamma Knife Radiosurgery for a Non-Functioning Pituitary Macroadenoma
Authors: Sach Gabrielle , Wu Yu-Fang , Fuller John , Davidson Andrew , Champion Bernard , Preda Veronica Angela
Published: May 2021

Background: Pituitary apoplexy is a very uncommon side effect of gamma-knife radiosurgery, with only one other case to our knowledge. We report an acute presentation of pituitary apoplexy within 6 weeks of single fraction gamma-knife stereotactic radiosurgery for a non-functioning pituitary macroadenoma. Clinical Case: An 84-year-old male presented initially to his GP with lethargy. He was found to have a non-functioning pituitary macroadenoma 23Tx17APx12CC mm, with right cavernous sinus invasion causing cranial nerve IV palsy and panhypopituitarism. He declined transsphenoidal surgery. He was managed with pituitary hormone replacement therapy, including full anterior hormone replacement. Approximately 6 months after his initial diagnosis, he underwent single fraction stereotactic gamma knife radiosurgery aimed at local control. One month after single fraction gamma knife radiosurgery the patient presented to another hospital with a new two-day history of nausea, vomiting and persistent bilateral retro-orbital headache. On examination, he was afebrile and alert, with a new third nerve palsy of the right eye. The initial diagnosis was presumed steroid-underdosing by the non-treating team. An MRI of the brain and pituitary gland was performed. Review by the patient’s usual multidisciplinary pituitary care team confirmed acute pituitary apoplexy, with new haemorrhage on imaging in the gland post-gamma knife radiosurgery, with the additional clinical relevant development of a right cranial nerve III palsy. Review of the biochemistry showed to the patient to have a cortisol of <28nmol/L (despite Cortate ingestion), TSH <0.005mIU/L (RI: 0.40-5.00), T4 10.6 pmol/L (RI: 10.0-20.0) and T3 4.1 pmol/L (RI: 2.3-5.7). The patient was commenced on dexamethasone to aid reduction of swelling in the pituitary fossa, and there was resolution of the third nerve palsy. Pituitary apoplexy usually occurs spontaneously without any known precipitant. It has been reported to occur in association with other conditions including fractionated radiotherapy, head trauma, estrogen, anticoagulants1. Gamma knife radiosurgery is a form of stereotactic radiosurgery for intracerebral lesions, with lower overall dose and usually complications. Conclusion: To our knowledge, this is the second case of gamma-knife associated pituitary apoplexy. It raises the importance of recognising an acute clinical deterioration in our patients. References: 1. Briet C, Salenave S, Bonneville JF, Laws ER, Chanson P. Pituitary apoplexy. Endocrine reviews. 2015 Dec 1;36(6):622-45.
Acute Myeloid Leukemia Leading to Central Diabetes Insipidus
Authors: Wojeck Brian , Gossmann Mona , Zeidan Amer , Inzucchi Silvio E
Published: May 2021

Background: Central diabetes insipidus (CDI) as a complication of acute myeloid leukemia (AML) is rare, occurring in less than 0.6% of AML cases. The mechanism is thought to involve leukemic infiltration in or around the pituitary gland, not always seen on imaging. In one study, as many as 61.4% of patients with CDI due to AML had no abnormalities on MRI, and at autopsy 46% of AML patients had perihypohyseal leukemic infiltration in the absence of overt CDI. CDI is also associated with AML in cases that involve monosomy 7 and inversion 3q21q26, both of which result in ectopic viral integration site 1 (EVI-1) overexpression. It is postulated that EVI-1 overexpression interferes with hypothalamic secretion of antidiuretic hormone (ADH) or may lead to its inactivation. We present a case of adipsic CDI due to AML in a patient with monosomy 7.

Case: A 70-year-old female presented for routine follow-up and was found to have a white blood cell count of 2.6 K/µL with 29% blasts, anemia (Hgb 10.3 g/dL) and normal platelets (300 K/µL). She was diagnosed with AML and molecular evaluation showed del (3)(q21),-7,add(17(p13) consistent with monosomy 7. She was admitted for induction chemotherapy with cytarabine, daunorubicin and intrathecal methotrexate. She denied thirst. On physical exam she was euvolemic and visual fields were full on confrontation. Her admission sodium was 146 mmol/L, urine osmolality was 149 mOsm/kg H2O, urine sodium 14 mmol/L. Urine output was 5.1 L over the first 24 hours. She underwent a 6 hour water deprivation test, during which her urine output averaged 250 cc/hr. Her sodium increased to 158 mmol/L, serum osmolality 331 mOsm/kg H2O, urine osmolality 146 mOsm/kg H2O. She was then administered 100 µg of DDAVP PO and her serum sodium and osmolality decreased to 155 mmol/L and 326 mOsm/kg H2O, respectively, while her urine osmolality nearly doubled to 292 mOsm/kg H2O. Urine output decreased to 50-100 cc/hr. At no point during her testing did she report thirst. The patient’s pituitary laboratory profile did not show any other abnormalities. Her pituitary MRI revealed subtle thickening of the proximal infundibulum and hypothalamus but no definitive intra-sellar pathology. She was discharged on twice daily DDAVP with a sodium of 142. Unfortunately, her AML was refractory to treatment. She was transitioned to comfort care and died peacefully.

Conclusion: CDI as a complication of AML is very rare and is a poor prognostic marker. Based on her MRI findings, the most likely mechanism in this case was infundibular/hypothalamic infiltration. Her adypsia is interesting and may point to more generalized hypothalamic involvement including thirst center. Her monosomy 7 mutation may have also played a role. We present this case to bring awareness to this etiology of DI and its proposed mechanisms.
Corticosteroids Replacement in a Patient With Panhypopituitarism and COVID-19 Infection
Authors: Karuppasamy Gowri , Alamer Zaina Abdelhalim , Rose Samman , Al-Janahi Ibrahim Abdulla
Published: May 2021

Background: Hypopituitarism refers to complete or partial insufficiency of pituitary hormone secretion and patients require lifelong hormone replacement. Those with ACTH deficiency rely on exogenous glucocorticoids and at times of intercurrent illness require stress doses to prevent an adrenal crisis. The benefits and adverse effects of corticosteroids for treatment of COVID-19 pneumonia are currently under investigation. We report our experience in a patient with COVID-19 pneumonia who received high dose corticosteroids for panhypopituitarism. Clinical Case: A 51-year-old man presented with one-week history of fever and generalized weakness. He had been diagnosed with a non-functional pituitary macro-adenoma causing panhypopituitarism 1 year ago when he developed generalized tonic-clonic seizures. He underwent trans-sphenoidal resection of the pituitary adenoma. However, he then discontinued his hormonal therapy and was lost to follow up. He had postural hypotension but was not tachypneic or hypoxemic. He tested positive for COVID-19 and chest x-ray showed prominent bilateral broncho-vascular markings; he was hospitalized as mild COVID-19 pneumonia. Laboratory investigations revealed secondary adrenal insufficiency, secondary hypothyroidism and hypogonadotropic hypogonadism. MRI of the pituitary now showed persistence of the pituitary macroadenoma, measuring 3.5 x 3.7 x 2.4 cm in dimensions, causing sellar obliteration and left cavernous sinus invasion. Treatment with stress dose steroids, Hydrocortisone 50 mg 4 times daily was initiated, followed by thyroid hormone replacement with Levothyroxine 125 mcg daily. He also received antivirals and

supportive care for COVID-19, guided by local hospital protocol. After significant clinical improvement, steroids were tapered down and he was discharged on a maintenance dose of 20 mg hydrocortisone per day in divided doses. The patient was stable at outpatient follow up after one month. He was started on testosterone replacement for erectile dysfunction due to hypogonadotropic hypogonadism. He was offered surgery for complete resection of the residual pituitary adenoma, but he declined and preferred to continue medical therapy. Conclusion: Hypopituitarism is associated with significant morbidity and premature mortality, a key risk factor being cortisol deficiency. Adrenal crisis is a life-threatening medical emergency and remains an important cause of death in patients with adrenal insufficiency. These patients are also vulnerable to develop severe complications from COVID-19 infection due to the absence of normal cortisol responses to stress. Despite receiving stress dose corticosteroids, this high-risk patient recovered from COVID-19 pneumonia without complications. These findings support the use of corticosteroids when necessary for treatment of coexisting conditions in patients with COVID-19.
Cushing’s Disease Presenting With Severe Weight Loss, Anorexia and Refractory Psychotic Depression
Authors: McDonnell Tara Muire , Lockhart Michael , Kennedy Carmel , Cussen Leanne , Roberts Graham , Smith Diarmuid , Javadpour Mohsen , Agha Amar
Published: May 2021

Introduction: In this paper we report an unusual case of Cushing’s disease presenting with psychotic depression, paranoia, anorexia leading to severe weight loss culminating in 18% of her body weight. Case: A 22 year old female admitted with first episode psychosis to her local hospital displaying psychotic depressive symptoms, low mood, severe anorexia and mood congruent delusions regarding food contamination. Clinical manifestations of Cushing’s were recognised: cushingoid facies, facial plethora, hirsutism with striae and proximal myopathy. The degree of weight loss (70kg to 57kg) and paranoid ideation surrounding food necessitated caloric supplementation parenterally. Laboratory indices notable for hypokalaemia of 2.7nmol/l, male range testosterone level of 10.7nmol/l, DHEAS>27.1umol and suppressed gonadotrophins. Urine Free Cortisol was >25 times normal. Late night salivary cortisol was 13.4nmol/L(<2.6nmol/L). ACTH was raised at 74.0pg/ml in keeping ACTH dependent Cushing’s. MRI pituitary showed a bulky pituitary. CRF testing and Inferior Petrosal Sinus Sampling both indicated pituitary dependent Cushing’s disease. Following Metyrapone therapy and nutritional treatment the patient condition improved. She proceeded to transphenoidal pituitary exploration. Intraoperatively a very soft central lesion was excised and neuropathology confirmed a corticotroph adenoma. Post-operative morning cortisol at day 3 was 31nmol/l indicating early remission. 3 months post-operative there was remarkable improvement in mood, weight, cessation of anti-psychotics with normal diet and return of menses. She remained severely hypocortisolaemic 6 months post-op Conclusion: Cushing’s disease may present with severe psychiatric manifestation and significant weight loss. Clinicians need to be vigilant of psychosis as the primary presentation of Cushing’s disease.
Diagnosis of a Rare Case of Acromegaly Secondary to Pituitary Macroadenoma Debuting as Sudden DKA
Authors: Rivera Nazario Ivan Augusto , Moya Kyomara Hernandez , Ortiz Arnaldo Nieves , Rivera Jose Ayala , Figueroa Arnaldo Rojas , Cintron-Colon Hector R , Miranda Maria De Lourdes
Published: May 2021

Acromegaly is an uncommon clinical syndrome that results from excessive secretion of growth hormone with an annual incidence of 6 to 8 cases per 1 million of individuals with a mean age of diagnosis between 40-45 years. Pituitary adenomas can be the principal reason for an overgrowth of the anterior pituitary somatotroph cells, and account for approximately one-third of all hormone-secreting pituitary adenomas with a prevalence of about 38-69 cases per 1 million and an incidence of 3-4 cases per 1 million individuals. The onset of acromegaly is insidious, and its progression is usually very slow. At the moment of diagnosis, approximately 75% of patients have presence of macro adenomas, but most cases are diagnosed after several laboratory workups and incidental brain imaging. A characteristic clinical presentation of pituitary adenomas could be secondary to mass effect. Metabolic presentation such as diabetes is one of the most common related conditions preceding the diagnosis of acromegaly. Clinical presentation with abrupt onset of DKA could be a determining factor on disease progression due to higher GH levels correlating with an increased prevalence of insulin resistance. We present a rare case of a 28y/o female G5P3A2 without previous PMHx who presented to ER with abdominal pain, general malaise, slurred speech, headache and gait difficulty of 3 days of evolution. Upon initial evaluation at ER patient was found with hyperglycemia of 317mg/dL, low central bicarbonate, high anion gap and positive serum ketones suggestive of DKA de novo. Based on neurological complaints, head CT performed showed an incidental parasellar/suprasellar/temporal hyperdense mass measuring 2.5cm x 2.6cm with optic chiasm compression features. Upon further specific questioning patient referred amenorrhea for the past 3 years, bitemporal hemianopsia, galactorrhea and marked facial feature changes, frontal bossing, weight gain, and acanthosis nigricans, for the past year. Pituitary adenoma workup revealed low prolactin levels (1.38), markedly increased growth hormone (501) and IGF-1 (893) suggesting diagnosis of acromegaly, most likely secondary to a functioning macroadenoma. Patient initially treated with Cabergoline, uncontrolled diabetes was managed and was referred to Neurosurgery service for further evaluation and tumor removal. Based on current literature, the incidence of acromegaly cases is low, more specifically when presenting with new onset diabetic ketoacidosis, insulin resistance and secondary to functioning macroadenomas. Medical awareness should be promoted to assess for careful consideration of signs and symptoms, workup, management and treatment to assess and minimize further health complications and physical burdens acromegaly and pituitary adenomas could pose for affected individuals.
Does Pituitary Dysfunction Always Occur Following Penetrating Head Trauma?
Authors: Agarwal Shubham , Patel Sabah , Hammad Faiza , Gilden Janice L
Published: May 2021

Background: Pituitary dysfunction and panhypopituitarism remain underdiagnosed in penetrating and blunt head trauma and can occur in both acute and chronic settings. Case: A 56 years old male with no significant PMH was admitted with a gunshot wound to the left T9 rib paraspinally with bullet deflection cranially along the left lung, left sternocleidomastoid, and resting anterior to the suprasellar cistern just above the midline of the sphenoid sinus close to the pituitary gland. Moderate volume pneumocephalus, chest hemopneumothorax, and sudden loss of right-sided vision required neurosurgical and pulmonary intervention. Endocrinology was consulted to evaluate pituitary function in the context of the bullet within the cranium. Physical examination showed intact mental status, non-focal exam, right-sided blindness, and foley catheter with normal urine output. Laboratory hormonal assessment for hypothalamic-pituitary axis (HPA) was performed consistent with normal sodium, potassium, FSH of 14.2 mIU/ml (1.0-13.0 mIU/ml), LH of 4.5 mIU/ml (1.0-9.0 mIU/ml), AM cortisol of 13.6 ug/dl (5-25 ug/dl), free cortisol of 2.06, ACTH of 10 pg/ml (10-60 pg/ml), IGF-1 of 80 ng/ml (78-220 ng/ml), TSH 1.93 mIU/L (0.5-5.0 mIU/L), FT4 1.05 ng/dl (0.8-1.8 ng/dl), Prolactin of 14.2 ng/ml (4-23 ng/ml) and HbA1c 5.1%. He reported no symptoms of adrenal insufficiency and remained hemodynamically stable. He was monitored for symptoms of pituitary insufficiency and suppression of the HPA axis along with urine output which remained normal and reassuring for the absence of central DI. The patient will continue outpatient endocrine surveillance. Discussion: The development of hormone deficiencies is directly related to the severity of head trauma. Mild traumatic brain injury (TBI) patients discharged from the ED, without loss of consciousness or post-traumatic amnesia less than 30 minutes do not require endocrine surveillance. Pituitary dysfunction occurs in 20-40% of patients with moderate to severe TBI. Pituitary ischemia leads to pituitary injury, due to changes in cerebral blood flow, cerebral hypoxia, and increased intracranial pressure. Compressive effects on the stalk from increased intracranial pressure is another indirect mechanism for pituitary dysfunction. Hospitalizations longer than 48 hours following TBI, require pituitary screening at 3-6 months. Chronic hypopituitarism develops in 15-20% of patients within 2-3 years with ACTH and GH deficiencies. Other changes in LH, FSH, TSH, and development of central diabetes insipidus can occur. However, despite severe TBI, acute pituitary hormonal involvement may not always occur, as in our patient. References: Tan CL, Alavi SA, Baldeweg SE, et al. The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance. J Neurol Neurosurg Psychiatry. 2017 Nov;88(11):971-981.
Growth Hormone (GH) and Thyroid Stimulating Hormone (TSH) Co-Secreting Pituitary Macroadenoma
Authors: Maliakal Alvin , Antony McAnto , Jackson Bethany Ann , Mathew Anu Alvin
Published: May 2021

Background: TSH secreting pituitary adenomas are rare and accounts for 0.5-3% of all pituitary adenomas. Only 20-25% of those adenomas co-secrete other hormones like growth hormone or prolactin. Mixed GH and TSH secreting adenomas present with symptoms from tumor growth and features of both acromegaly and hyperthyroidism.

Clinical Case: A 57 years old woman with a past medical history of chronic joint pains and bilateral knee swelling presented to her PCP with complaints of chronic fatigue. Evaluation revealed a normal TSH level and MNG and patient did not have any further work-up. She reported undergoing periodic knee arthrocentesis which gave her only temporary pain relief. Two years later, patient presented with complaints of unintentional weight loss, tremors and palpitations. She also reported enlargement in the size of hands, feet and forehead and no improvement in the knee swelling after multiple arthrocentesis. Lab evaluation revealed high free T4 2.31ng/dl (0.58-1.64), high free T3 6.44pg/ml (2.50-4.30), non-suppressed TSH 1.32mU/L (0.34-5.00), elevated IGF-1 415ng/ml (47-236), GH 7.76ng/ml (0.01-3.61) and prolactin 6.69ng/mL (2.74-26.72). Neck USG showed multiple nodules and 24hr radioactive iodine uptake scan showed increased uptake at 43%. 75gm OGTT showed non-suppression of GH level. MRI of brain showed 1.8 cm pituitary macroadenoma. Patient underwent transsphenoidal pituitary resection in January 2018 and the final pathology showed positive tumor staining for GH and TSH. Following surgery, patient reported improvement in symptoms. Lab work-up from October 2018 showed normal IGF 189 ng/ml (47-236), normal GH 0.35(0.01-3.61), Free T4 0.80(0.58-1.64), Free T3 2.41(2.50-4.30), TSH 0.06(0.34-5.00) and MRI from August 2020 showed no evidence of residual pituitary tumor.

Conclusion: This is a rare case of a GH and TSH co-secreting pituitary macroadenoma. This case highlights the importance of considering acromegaly early in the differential diagnosis of patients presenting with chronic musculoskeletal symptoms and to pursue work up for central hyperthyroidism in a hyperthyroid patient presenting with a non-suppressed TSH level.
Hyponatremia and Isolated Free T4 Elevation in a Patient With Acute Intermittent Porphyria
Authors: Gandhi Anand , Mortensen Michael , Alsayed Mahmoud , Kumar Aditi , Targovnik Jerome H
Published: May 2021

Background: Porphyrias represent a spectrum of diseases that stem from dysfunction within the heme biosynthetic pathway. Acute intermittent porphyria (AIP) is the most common type of porphyria due to a genetic deficiency of porphobilinogen deaminase which results in a wide range of neurovisceral symptoms. Hyponatremia and abnormalities with thyroid function have been found in AIP but the mechanisms behind these processes are unclear. Clinical Case: A 26-year-old male with a history of chronic, recurrent abdominal pain presented with 10 days of progressively worsening periumbilical abdominal pain and constipation. He describes that preceding the onset of symptoms he had been binging 5-10 standard alcoholic drinks each day for a few days. Initial laboratory workup demonstrated hyponatremia with Na 114 mmol/L (n: 134 – 137 mmol/L), hypochloremia with Cl 76 mmol/L (n: 95 – 108 mmol/L), and hyperbilirubinemia with total bilirubin 2.5 mg/dL (n: 0.2 – 1.3 mg/dL). CT abdomen/pelvis was negative for any concerning pathology. Further studies showed low serum osmolality at 243 mOsm/kg (n: 275 – 295 mOsm/kg), urine Na 62 mmol/L (n > 20mmol/L), and urine osmolality at 394 mOsm/kg (n: 300 – 900 mOsm/kg) consistent with SIADH. The patient was treated with 3% NaCl and free water restriction to 1.2L/day with improvement in Na levels. Further laboratory workup demonstrated normal TSH, but persistently elevated free T4 with maximum free T4 of 2.77 ng/dL (n: 0.80 – 1.70 ng/dL) which downtrended to 1.99 ng/dL by discharge. Thyroid ultrasound was unremarkable. Pituitary evaluation via hormonal workup and MRI brain was negative for any abnormalities. Given the symptomatology and laboratory findings, the patient was evaluated for porphyria. Laboratory evaluation demonstrated severe elevations in urine porphyrins, urine delta aminolevulinic acid (56.8 mg/24h, n < 4.5 mg/24h), and urine porphobilinogen (82.5 mg/g, n < 2.3 mg/g) consistent with AIP. The patient was treated with four days of hematin infusions which resolved his abdominal pain and was discharged in an improved state. Conclusion: AIP is a rare entity brought out by a deficiency in porphobilinogen deaminase, a key enzyme in the heme biosynthesis pathway. Various metabolic disturbances have been described in AIP including hyponatremia and alterations in thyroid function tests suggestive of thyrotoxicosis. Hyponatremia in our patient was likely due to SIADH from neurovisceral pain. Our patient displayed isolated free T4 elevation as well. We hypothesize this developed due to his acute illness causing a greater decrease in D2 deiodinase activity compared to any concomitant increase in D3 deiodinase activity. This was supported by his free T4 level downtrending following treatment of his AIP attack. More research is needed to further elucidate the mechanism behind these derangements in biochemical markers and their impact on patient prognosis.
Intrasellar Cavernous Hemangioma, a Rare Condition Causing Both Radiological And Clinical Difficulties- a Case Report
Authors: Nowak Andrzej Jerzy , Grochowska Anna , Adamek Dariusz , Godlewska Magdalena , Motyka Marcin , Gilis-Januszewska Aleksandra , Hubalewska-Dydejczyk Alicja
Published: May 2021

Introduction: Intrasellar cavernous hemangiomas constitute an extremely rare group of findings in endocrinological practice. Diagnosis remains challenging due to non-characteristic symptoms and neuroradiological features which may resemble those of pituitary adenomas.

Presentation of the Case: We present a case of female born in 1941, diagnosed with a hemangioma cavernosum located in the Sella turcica. In 2004 our patient presented with uncharacteristic symptoms: syncopes and chronic headaches. Computed tomography (CT) of the head revealed an intrasellar hyperdense tumor mass with radiological features suggesting a pituitary adenoma. In 2005 the patient underwent transcranial resection of the sellar mass, with subsequent oculomotor nerve palsy. In histopathological examination, diagnosis of cavernous hemangioma was determined. Between 2005 and 2020 patient was asymptomatic, with multiple follow-up head MRIs scans, showing gradual progression in size of the intrasellar tumor. The patient was consulted by a neurosurgeon, with no direct indications for surgical approach found. Furthermore, due to suprasellar expansion into the direct proximity of the right optic nerve, the patient was disqualified for Gamma-Knife radiotherapy.

The last MRI of the hypothalamic-pituitary area in 2020 revealed a polycyclic, homogeneous, 33x31x29 mm mass, filling in the space of the Sella turcica, with strong enhancement after contrast administration. Invasion of the surrounding structures, including the clivus, right cavernous sinus and right trigeminal cave were described. Bilaterally, internal carotid arteries and right optic nerve adhered directly to the lesion. Pituitary gland was compressed by the tumor mass. In July 2020, in order to verify the ambiguous radiological and clinical characteristics of the lesion including tumor regrowth and its invasiveness, a transsphenoidal partial resection was performed. Tissue samples were collected for the histopathological examination, which confirmed the initial diagnosis of cavernous hemangioma originating from the cavernous sinus. During a multidisciplinary tumor board, having taken into consideration relatively stable clinical condition and high risk possible surgical complications, the patient was currently disqualified from neurosurgical re-operation nor radiotherapy. Surprisingly, during whole follow up, patients pituitary function remained unimpaired. A watchful waiting approach, with radiological and endocrinological follow up were scheduled. Conclusion: To date, only few cases of intrasellar cavernous hemangiomas have been reported. Intrasellar hemangiomas may originate from the vascular tissue of the cavernous sinus. Surgical removal remains the recommended treatment modality, but radiosurgery could be a therapeutic option as well. Stable patients with no clinical symptoms may remain in observation.
Macroprolactinoma in a Patient With Schizophrenia: A Therapeutic Challenge
Authors: Voelz Eduardo , Matias Luiz Fernando , Student Medicine , Medeiros Mateus , Student Medicine , Pimentel Murilo D
Published: May 2021

Introduction: The most common pituitary tumors are prolactinomas and they are treated with dopamine agonists. In schizophrenia, antipsychotics (dopamine receptor blockers) are used, which can result in hyperprolactinemia. The association of Schizophrenia and prolactinoma represents a clinical challenge, once the treatment of one disease can exacerbate the symptoms of the other.

Clinical Case: A 39-year-old man diagnosed with schizophrenia about 20 years ago, sought medical attention in January 2015, due to frequent headache that worsened in the last 3 years and loss of visual field, with bitemporal hemianopsia. The MRI revealed a pituitary macroadenoma (22x15x27mm) with cavernous sinus invasion and displacement of the optic chiasm. In laboratory tests, the serum prolactin level was 223 ng/ml (reference value up to 20 ng/ml in men), while the others pituitary hormones were normal. Therefore, diagnosed with macroprolactinoma. Surgical resection was suggested, but due to the risks, it was decided to start drug treatment. As an initial treatment, the use of 1 mg/ week cabergoline was chosen. Four months after the first visit, prolactin remained high (203 ng/ml) and the dose was readjusted to 1.5 mg/week. In September, there was a reduction in prolactin (97 ng/ml) and a further increase (2.5 mg/week). Ten months after the first medical appointment, a new MRI was performed with a reduction of the macroadenoma (15x08x16mm), without compression of adjacent structures and prolactin of 68.5 ng/ml. In 2016, the patient had episodes of hallucination and depression, quetiapine 100 mg/day was started and his prolactin was 49,2. In February of the following year, he presented an increase in prolactin (203 ng/ml), due to the possible action of quetiapine and haloperidol parenterally 15/15 days, associated with the irregular use of cabergoline. There was no increase in volume in the MRI. In September, he presented a reduction in prolactin (65.76 ng/ml) and it was chosen to maintain the dosage of cabergoline (2.5 mg/week), injectable haloperidol in 15-15 days and quetiapine 200 mg/day. In 2018, there was an increase in prolactin (200 ng/ml), possibly linked to the increase in doses of antipsychotics. At this time the MRI has not been performed due to financial problems. The following year, MRI showed no progression of the macroadenoma. In 2020, the patient presented central hypothyroidism, (TSH: 1.2 mU/L and free T4: 0.44 ng/dl), starting Levothyroxine 50 mcg. The prolactin was 104 ng/ml in this year.

Conclusion: It is necessary to analyze prolactin levels, imaging tests and the prescription of antipsychotic medications for correct analysis and evaluation of prolactinomas in schizophrenic patients.
Paraganglioma
Authors: Aluko Oluwatomisin A , Ruby Edward
Published: May 2021

Introduction: Paragangliomas are rare neuroendocrine tumors arising from extra-adrenal medullary neural crest derivatives. The terms pheochromocytoma and paraganglioma are often used interchangeably because morphologically and functionally these entities are almost the same. However, paragangliomas that arise in the adrenal medulla are called pheochromocytomas and those outside the adrenal gland are called paragangliomas. Paragangliomas are often discovered incidentally during imaging studies performed for other reasons. We report a case of a patient who had incidental finding of retroperitoneal paraganglioma on imaging done for evaluation of thigh and gluteal cellulitis.

Clinical Case: A 24-year-old female presented with chief complaints of episodic headaches, multiple skin abscesses, fever and malaise. She has a history of Type 1DM and had been non-compliant on insulin. Vitals on presentation was significant for tachycardia with heart rate of 124, blood pressure of 119/81, respiratory rate of 16. Initial labs were consistent with DKA. CT abdomen and pelvis done for further evaluation of gluteal and thigh abscess showed incidental finding of a 3.4 cm retroperitoneal/para-aortic well-circumscribed rim-enhancing mass with central hypoenhancing component, suspicious for neoplasm such as paraganglioma. Biochemical testing was performed. 24-hour urine catecholamine levels obtained showed elevated urine norepinephrine level of 1008μg/day (reference range 15-100μg/day), urine dopamine 410μg/day (reference range 65- 400μg/day), urine epinephrine less than 2μg/day (reference range 0-20μg/day). Total urine catecholamines was elevated 1008μg/day (reference range 15-100μg/day). These results confirmed diagnosis of paraganglioma. Treatment options were discussed with the patient including surgery for removal of paraganglioma which she has currently declined.

Conclusion: Diagnosis of a paraganglioma can usually be made using biochemical and radiographic testing. All patients with paraganglioma should be tested for hypersecretion of catecholamines in a 24-hour urine or serum collection, even if they do not present with a clinical picture of catecholamine hypersecretion. Importantly these extra-adrenal tumors do not have the enzymatic capacity to form epinephrine from norepinephrine as was exemplified by our case. For catecholamine-secreting tumors, biochemical diagnosis should be followed by radiological evaluation (typically either CT or MRI of the abdomen and pelvis) to locate the tumor. Treatment options are dependent on location of tumor, size, presence of symptoms and if there is metastatic disease present.