bluuebunny/crossref_metadata_2025_split 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

Abstract
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&lt;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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt;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(&lt;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

Abstract
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

Abstract
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 &lt;28nmol/L (despite Cortate ingestion), TSH &lt;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

Abstract
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.