bluuebunny/crossref_metadata_2025_split huggingface dataset:
6731 Initial therapeutic effects of weekly growth hormone replacement therapy: somapacitan
Authors: Fujio S , Makino R , Sugata J , Hanada T , Hanaya R 
Published: October 2024

Abstract
Disclosure: S. Fujio: None. R. Makino: None. J. Sugata: None. T. Hanada: None. R. Hanaya: None.
Introduction: In Japan, the restriction on the administration of somapacitan, a long-acting growth hormone (GH) analogue, was lifted in December 2022, allowing the drug to be administered to many patients with severe growth hormone deficiency (sGHD). [Patients and methods] We have 10 patients for whom somapacitan was started as a new drug regime and 26 patients who switched from their daily GH replacement therapy. Among these 36 patients, 21 patients (5 new cases and 16 switched cases) who were followed for more than 6 months after the start of treatment were included in the present study. We compared lipid metabolism, glucose tolerance, liver function, and quality-of-life before and after treatment with somapacitan. [Result] The study population included 12 men and 9 women with a median age of 65 years. Cases included 15 NF-PitNET, 2 Lactotroph PitNET, 2 germ cell tumor, 1 craniopharyngioma, and 1 granuloma. Starting doses of somapacitan were 1.5 mg/week for adults to 60 years of age and 1.0 mg/week for patients aged &gt;60 years. In the switched cases, the median levels of T-chol dropped from 214.5 to 198.5 mg (p&lt;0.05). The median levels of HbA1c dropped from 5.9 to 5.8% (p&lt;0.05). In the newly prescribed cases, the median levels of γ-GTP dramatically improved from 53 to 34I U/L, but this was not statistically significant. In the newly prescribed cases, quality-of-life assessment by Adult Hypopituitarism Questionnaire; AHQ showed improvement in both psychological/social aspects and physical function, but the number of cases was small and no significant difference was obtained. Body fat percentage measured by the impedance method showed no significant change in either the switched or newly prescribed groups. There were no adverse events, but some participants commented that it was easier to forget weekly injections of somapacitan than the daily GH. [Discussion] We were able to introduce somapacitan without any major problems. In newly prescribed cases, somapacitan resulted in a significant improvement in liver function. Improvements in lipid metabolism and glucose tolerance were observed in the switched patients. Compared to the daily GH replacement therapy, somapacitan may have a higher GH replacement effect.
Presentation: 6/3/2024
9228 Insulin-Like Growth Factor-1 Modulates Arcuate Kisspeptin Neuron Activity
Authors: Silva Josiane Nascimento , Frazao Renata 
Published: October 2024

Abstract
Disclosure: J.N. Silva: None. R. Frazao: None.
The kisspeptin-producing cells located at the arcuate nucleus of the hypothalamus (ARHKisspeptin) are considered the GnRH pulse generator necessary for fertility. In addition, ARHKisspeptin cells act as a metabolic sensor to control the hypothalamic-pituitary-gonadal (HPG) axis. The insulin-like growth factor-1 (IGF-1) is considered a component contributing to puberty onset and fertility. Peripherical or intracerebroventricular IGF-1 administration is sufficient to increase hypothalamic Kiss1 expression. However, whether IGF-1 acts directly on ARHKisspeptin cells to modulate the HPG axis is not known. To determine whether IGF-1 modulates ARHKisspeptin neuron activity, we used mice expressing the green fluorescent protein “humanized renilla” under the transcriptional control of the Kiss1 gene (8-10 weeks old). Fura-2 fluorescent probe was used to evaluate the state coupled or uncoupled to calcium in the face of IGF- 1 administration (0.5 μg/ml). Furthermore, whole-cell patch-clamp was employed to determine IGF-1 effects on ARHKisspeptin neuron's resting membrane potential (RMP). FURA-2 was incorporated by 64 ARHKisspeptin neurons out of 424 cells in the ARH. IGF-1 administration to the bath led to a significant increase of the intracellular calcium levels ([Ca2+]i) in 53% of ARHKisspeptin cells evaluated in male mice (34 out of 64 cells; IGF-1, 203.0 ± 26.1 nM; baseline period, 68.8 ± 9.6 nM; P&lt; 0.0001). Non-responsive cells (30 out of 64 ARHKisspeptin neurons) exhibited average [Ca2+]i of 53.2 ± 6.3 nM after IGF-1 application vs 46.2 ± 5.6 nM in the baseline period (P= 0.3). Of note, IGF-1 also increased [Ca2+]i in 25% of non-kisspeptin cells in the ARH (93 out of 364 cells, IGF-1, 193.8 ± 12.4 nM; vs baseline period, 73.0 ± 5.6 nM, P&lt; 0.0001). By evaluating the IGF-1 effects on ARHKisspeptin neuron’s RMP, we observed that IGF-1 tends to depolarize the RMP of 18% of cells recorded from males (4 out of 22 cells, IGF-1, -58.0 ± 3.0 mV; baseline, -64.1 ± 4.4 mV; P= 0.05), and depolarized the RMP of 44% of cells recorded from female mice (7 out of 16 cells, IGF-1, -61.1 ± 3.3 mV; baseline, -66.3 ± 2.7 mV; P= 0.002). Importantly, IGF-1-induced depolarization of ARHKisspeptin cells RMP was blocked when the recordings were performed in the presence of tetrodotoxin and ionotropic amino acid antagonists. Therefore, IGF-1-induced effects on ARHKisspeptin cells RMP depend on action potentials mediated by synaptic transmission. Our results suggest that IGF-1 indirectly modulates the activity of a large number of ARHKisspeptin neurons. Thus, situations of metabolic stress that induce changes in growth hormone secretion and, consequently, IGF-1 circulating levels, (e.g., fasting), can modulate the HPG axis through the indirect modulation of the activity of ARHKisspeptin cells.
Presentation: 6/2/2024
8388 Insulin-Like Growth Factor-1 Modulates Arcuate Kisspeptin Neuron Activity
Authors: Silva Josiane Nascimento , Frazao Renata 
Published: October 2024

Abstract
Disclosure: J.N. Silva: None. R. Frazao: None.
The kisspeptin-producing cells located at the arcuate nucleus of the hypothalamus (ARHKisspeptin) are considered the GnRH pulse generator necessary for fertility. In addition, ARHKisspeptin cells act as a metabolic sensor to control the hypothalamic-pituitary-gonadal (HPG) axis. The insulin-like growth factor-1 (IGF-1) is considered a component contributing to puberty onset and fertility. Peripherical or intracerebroventricular IGF-1 administration is sufficient to increase hypothalamic Kiss1 expression. However, whether IGF-1 acts directly on ARHKisspeptin cells to modulate the HPG axis is not known. To determine whether IGF-1 modulates ARHKisspeptin neuron activity, we used mice expressing the green fluorescent protein “humanized renilla” under the transcriptional control of the Kiss1 gene (8-10 weeks old). Fura-2 fluorescent probe was used to evaluate the state coupled or uncoupled to calcium in the face of IGF- 1 administration (0.5 μg/ml). Furthermore, whole-cell patch-clamp was employed to determine IGF-1 effects on ARHKisspeptin neuron's resting membrane potential (RMP). FURA-2 was incorporated by 64 ARHKisspeptin neurons out of 424 cells in the ARH. IGF-1 administration to the bath led to a significant increase of the intracellular calcium levels ([Ca2+]i) in 53% of ARHKisspeptin cells evaluated in male mice (34 out of 64 cells; IGF-1, 203.0 ± 26.1 nM; baseline period, 68.8 ± 9.6 nM; P&lt; 0.0001). Non-responsive cells (30 out of 64 ARHKisspeptin neurons) exhibited average [Ca2+]i of 53.2 ± 6.3 nM after IGF-1 application vs 46.2 ± 5.6 nM in the baseline period (P= 0.3). Of note, IGF-1 also increased [Ca2+]i in 25% of non-kisspeptin cells in the ARH (93 out of 364 cells, IGF-1, 193.8 ± 12.4 nM; vs baseline period, 73.0 ± 5.6 nM, P&lt; 0.0001). By evaluating the IGF-1 effects on ARHKisspeptin neuron’s RMP, we observed that IGF-1 tends to depolarize the RMP of 18% of cells recorded from males (4 out of 22 cells, IGF-1, -58.0 ± 3.0 mV; baseline, -64.1 ± 4.4 mV; P= 0.05), and depolarized the RMP of 44% of cells recorded from female mice (7 out of 16 cells, IGF-1, -61.1 ± 3.3 mV; baseline, -66.3 ± 2.7 mV; P= 0.002). Importantly, IGF-1-induced depolarization of ARHKisspeptin cells RMP was blocked when the recordings were performed in the presence of tetrodotoxin and ionotropic amino acid antagonists. Therefore, IGF-1-induced effects on ARHKisspeptin cells RMP depend on action potentials mediated by synaptic transmission. Our results suggest that IGF-1 indirectly modulates the activity of a large number of ARHKisspeptin neurons. Thus, situations of metabolic stress that induce changes in growth hormone secretion and, consequently, IGF-1 circulating levels, (e.g., fasting), can modulate the HPG axis through the indirect modulation of the activity of ARHKisspeptin cells.
Presentation: 6/2/2024
7940 Is Urocortin 2 A Mediator Of Stress-induced Suppression Of The Luteinizing Hormone Surge?
Authors: Bell Helen F , Carrasco Rodrigo A , Kreisman Michael J , McCosh Richard B , Breen Church Kellie M 
Published: October 2024

Abstract
Disclosure: H.F. Bell: None. R.A. Carrasco: None. M.J. Kreisman: None. R.B. McCosh: None. K.M. Breen Church: None.
Stress is thought to be a contributing factor to the reduction of reproductive function and infertility observed in many different species. Although this is a well-documented phenomenon, the neural mechanisms mediating the suppression of reproductive neuroendocrine activity in response to stress are not yet fully understood. The paraventricular nucleus (PVN) of the hypothalamus is an integral part of the neural response to stress. The PVN initiates activation of Corticotropin Releasing Hormone (CRH) neurons and, in addition to CRH, the PVN contains a population of neurons expressing Urocortin 2 (UCN2), a CRH-like family member, with high affinity for CRH receptor 2. In females, stress has been shown to inhibit both the pulse and surge modes of Luteinizing Hormone (LH) secretion. We have preliminary evidence that kisspeptin neurons, controlling either type of LH secretion, contain CRH receptor 2. In this study we tested the sufficiency of UCN2 to disrupt the estradiol-induced LH surge. Female mice were ovariectomized and given a high estradiol treatment to induce a circadian-timed LH surge. Two days later, UCN2 or Vehicle was administered into the lateral ventricle via ICV injection on the morning of the expected surge (10 AM). Blood and brains were collected in the evening (6 PM), at the time of the expected surge. Whole blood from the tail tip was measured by LH ELISA and a surge was defined as &gt; 0.5 ng/mL. A majority of saline-treated animals expressed an LH surge (8 of 9 females). In contrast, 0% of UCN2-treated animals surged (n=7), suggesting that UCN2 impaired the positive feedback response to estradiol. Additionally, immunohistochemistry was performed to observe colocalization of c-Fos within Kisspeptin neurons in the rostral periventricular region of the third ventricle (RP3V) which are responsible for surge generation. Lower Kisspeptin/C-Fos co-expression in animals treated with UCN2 demonstrated the efficacy of UCN2 to impair estradiol-induced activation of RP3V Kisspeptin neurons which are critical for LH surge generation. These results support the hypothesis that UCN2 signaling plays a mediatory role in the stress-induced reduction of ovulatory function in the female mouse.
Presentation: 6/1/2024
12265 Isolated Adrenocorticotropic Hormone Deficiency In The Setting Of Anti-PD1 Immunotherapy
Authors: Poncelet Jennifer , Wang Qian , Montero Alberto J , Tranchito Lily 
Published: October 2024

Abstract
Disclosure: J. Poncelet: None. Q. Wang: None. A.J. Montero: Advisory Board Member; Self; AstraZeneca, Gilead. Other; Self; Medical Advisor for Paragon Infusion Services. L. Tranchito: None.
Isolated Adrenocorticotropic Hormone Deficiency in the Setting of Anti-PD1 Immunotherapy Introduction: Immune checkpoint inhibitors have been associated with endocrine immune-related adverse events, such as secondary adrenal insufficiency with isolated ACTH deficiency in rare instances. Case Presentations: We present two different cases of isolated ACTH deficiency (IAD) while on anti-PD1 therapy with pembrolizumab. Patient A is a 66-year-old woman with history of tobacco use, hypertension, and COPD diagnosed with stage IV lung adenocarcinoma. After completing 15 cycles of pembrolizumab, she reported symptoms of fatigue, weakness, lightheadedness, and was subsequently admitted to the hospital for symptomatic hyponatremia. Lab workup revealed a morning cortisol level of 0.6 ug/dL (n2.5-20 ug/dL) and ACTH &lt;1.5 pg/mL (n7.2-63.3 pg/mL), both of which had previously been normal. Her TSH was mildly elevated with a normal free T4. Her FSH, LH, prolactin, and IGF levels were normal as was MRI of the pituitary. She therefore was diagnosed with IAD and started physiologic steroid replacement therapy with hydrocortisone with subsequent symptomatic improvement and normalization of her serum sodium. Patient B is a 60-year-old woman with a history of osteoporosis, aortic stenosis, and stage II triple negative breast cancer treated with neoadjuvant chemotherapy and pembrolizumab. Two months after starting immunotherapy, she presented to her oncology office with symptoms of fatigue, poor appetite, body aches, and dizziness. Her labs revealed mild hyponatremia, cortisol of 0.9 ug/dL (n2.5-20 ug/dL) and ACTH &lt;1.5 pg/mL (n7.2-63.3 pg/mL). TSH, LH, FSH, and prolactin levels were normal. She started physiologic steroid replacement therapy with hydrocortisone for IAD, which led to improvement in her symptoms. Both patients continue pembrolizumab. Conclusions: Immune-related adverse events affecting endocrine pathways have been reported with immune checkpoint inhibitors. There is no method to predict which patients may be affected, and no guidelines exist on when or how often to monitor hormone levels in these patients. Importantly, patients can continue immune checkpoint inhibitors despite IAD if controlled by hormone replacement, though ACTH recovery should not be expected[1]. Recognition of symptoms can prompt earlier evaluation for secondary adrenal insufficiency and provide greater benefit to patients. 1.Schneider BJ, Naidoo J, Santomasso BD, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update [published correction appears in J Clin Oncol. 2022 Jan 20;40(3):315]. J Clin Oncol. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440
Presentation: 6/1/2024
8155 Isolated Hypothalamic-Pituitary Langerhans' Cell Histiocytosis in Adult Patients
Authors: Vu A , Aguilera M , Shakil J , Al-Ward R 
Published: October 2024

Abstract
Disclosure: A. Vu: None. M. Aguilera: None. J. Shakil: None. R. Al-Ward: None.
Introduction: Langerhans cell histiocytosis (LCH) is an infiltrative disease due to clonal proliferation of immature dendritic cells mainly affecting children and seen in adults in less than 30% of cases. It can present as localized or with systemic manifestations, with isolated hypothalamic-pituitary lesions being exceptionally rare. Our report adds to the limited published literature by presenting two cases of isolated hypothalamic-pituitary LCH diagnosed in adults. Furthermore, one of the cases reveals a rare association with papillary thyroid cancer (PTC). Case 1: 35-year-old woman with no past medical history presented with 4 year history of amenorrhea and weight gain and more recently, polyuria and polydipsia. Further investigations showed hypogonadotropic hypogonadism, central hypothyroidism, and mildly elevated prolactin. She couldn’t complete water deprivation test due to extreme thirst. A dedicated pituitary MRI showed marked infundibular enlargement, concerning for hypophysitis. An extensive workup including assessments for autoimmune etiology, sarcoidosis, infections, and low-grade tumors, did not identify a definitive etiology. A PET scan was obtained (to rule out LCH and Erdheim Chester disease), which showed increased uptake in the pituitary stalk. Due to otherwise negative workup, transsphenoidal biopsy of the pituitary lesion was done. Post-procedure, diabetes insipidus (DI) was diagnosed due to elevated sodium while fasting for the procedure. Tissue examination revealed increased histiocytes and lymphocytes, and a positive BRAF V600E mutation confirming LCH as the underlying diagnosis. Case 2: 26-year-old male with history of LCH limited to the skull, in remission for 8 years after chemotherapy, presented with 4-week history of polyuria, polydipsia and weight loss. A 24-hour urine collection resulted in 6.5L of urine. During water deprivation test, there was notable increase in serum sodium, serum osmolarity, and urine osmolarity. Initial pituitary MRI was normal, but subsequent imaging revealed the loss of the posterior pituitary bright spot. PET scan showed focal FDG avidity in the right lower thyroid lobe, confirmed on fine needle aspiration as PTC with BRAF mutation. He underwent total thyroidectomy and is currently receiving chemotherapy for LCH recurrence. Discussion: LCH is infrequent in adults, presenting with variable manifestations based on affected organs. In the multifocal form, the hypothalamic-pituitary axis is involved in 5-50% of cases. Our report describes two unique cases with only four other reported cases of isolated hypothalamic-pituitary axis LCH in adults. Central diabetes insipidus can be seen before the diagnosis or as the disease progresses. Pituitary biopsy, although invasive, should be considered when the diagnosis is not clear. The association of PTC with a BRAF mutation is extremely rare and has been reported.
Presentation: 6/2/2024
6612 Both Overt And Mild Hypercortisolism Accelerate Biological Aging
Authors: Yu K , Saini J , Farr J N , Vanessa F , Khosla S , Bancos I 
Published: October 2024

Abstract
Disclosure: K. Yu: None. J. Saini: None. J.N. Farr: None. F. Vanessa: None. S. Khosla: None. I. Bancos: Advisory Board Member; Self; AstraZeneca, Adrenas, Neurocrine, Spruce, Recordati, Xeris, Novo Nordisk, HRA Pharmaceuticals, Sparrow, Diurnal, Corcept. Research Investigator; Self; HRA Pharmaceuticals, Recordati.
Importance: Patients with both mild autonomous cortisol secretion (MACS) and overt Cushing syndrome (CS) demonstrated high prevalence of aging-related morbidity and an increased mortality. Objective: To determine whether p16INK4a in T cell, a cell cycle enzyme that associated with chronological aging and cell senescence, is associated with hypercortisolism and hypercortisolism-related comorbidities. Design, Setting, and Participants: In this single-center cross-sectional study, we prospectively recruited consecutive patients with hypercortisolism between July 1, 2020 and August 24 2022. Patients were included if they were diagnosed with Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS). Age- (± 2 years) and sex-matched referent subjects without known adrenal disorders were included if abdominal imaging was available. Participants on exogenous glucocorticoids within 3 months prior were excluded. Exposure: Presence of hypercortisolism (MACS and CS). Main Outcomes and Measures: Primary outcomes included p16INK4a, advanced glycation end products (AGE) reader result, Frailty Index score, frailty (defined as frailty index&gt;0.31), and physical performances in patients and matched referents at index date. Secondary outcomes included correlation between biological age markers, hormonal workup and the risk of comorbidities. p16INK4a expression analysis was adjusted for age, sex, smoking, and alcohol use for all analyses except for associations with CVD and frailty. Results: Of 85 patients (87% women, mean age 53 years), 51 (60%) had MACS (34 had matched referents), 34 (40%) had overt CS (16 had matched referents). Patients with CS demonstrated a median 1.9-fold higher p16INK4a expression (P&lt;.001), and patients with MACS showed a median of 1.70-fold p16INK4a expression (P=.013), when compared to referent subjects. Age- and sex-adjusted p16INK4a expression was associated with frailty index score (r=0.23, P=.035), time-up-and-go test (r=0.28, P=.048), gait speed (r=-0.36, P=.035), but not with AGE reader result, 6-minute walk test, or hand grip measurement. The p16INK4a expression was associated with history of cardiovascular disease (age-adjusted odds ratio (aOR)=3.70, 95% confidence interval (CI), 1.20-11.43) and frailty (aOR=2.27, 95%CI, 1.04-4.98). Conclusion and relevance: We demonstrated evidence of cell senescence in both patients with CS and patients with MACS. Further studies need to determine the impact of surgical, cortisol-lowering, and senolytic medical therapies in MACS on cell senescence and associated aging-related comorbidities.
Presentation: 6/1/2024
7441 KNDy Neurons and the Control of the Gonadotropic Axis in Midgestation Fetal Sheep
Authors: Amodei R , Jonker S S , Gribbin K , Lazen E , Estill C T , Roselli C E 
Published: October 2024

Abstract
Disclosure: R. Amodei: None. S.S. Jonker: None. K. Gribbin: None. E. Lazen: None. C.T. Estill: None. C.E. Roselli: None.
Recent evidence suggests that the neuropeptide kisspeptin (Kiss) plays a role to activate and regulate the male reproductive axis to secrete LH and testosterone during a time in gestation critical for brain sexual differentiation. KNDy neurons, an acronym for Kiss neurons that co-express neurokinin B (NKB) and dynorphin (Dyn), regulate pulsatile GnRH/LH secretion and are present in the hypothalamic arcuate nucleus of midgestation sheep fetuses. Notably, KNDy neurons are more abundant in female than in male fetuses. We hypothesize that KNDy-GnRH signaling is established during midgestation and that negative feedback mediated through KNDy neurons serves to regulate levels of testosterone needed for brain masculinization. In the current study, we used immunofluorescence histochemistry to assess the effect of testosterone manipulations on the number of arcuate Kiss neurons in male and female fetuses. In addition, we employed unanesthetized cannulated midgestation fetal sheep to test the effects of KNDy peptides on LH secretion and characterize receptor specificity in a real-time physiological context. We found that biweekly administration of testosterone propionate to the dam from Day 30–58 of gestation significantly increased (P &lt; 0.05) plasma testosterone concentrations, which resulted in a significant decrease (P &lt; 0.05) in both mean plasma LH concentrations and the number of arcuate Kiss neurons in female lamb fetuses. Conversely, chemical castration of midgestation male fetuses by treatment with the GnRH antagonist degarelix from day 60 – 90 of gestation resulted in a significant decrease (P &lt; 0.05) in mean plasma LH and testosterone concentrations that was accompanied by a significant increase (P &lt; 0.05) in the number of arcuate Kiss neurons. In unanesthetized fetuses, we found that bolus administration of both KP-10 (Kiss agonist) and senktide (NKB agonist) elicited a robust release of LH within 15 min. Treatment with the NK3 receptor antagonist SB222200 effectively blocked the senktide response, whereas the Kiss1 receptor antagonist P271 appeared to have an effect in males only. Blocking κ-opiate receptor (KOR) with a bolus injection of the KOR antagonist PF4455242 resulted in a significant increase in LH release and enhanced the stimulatory effect of senktide. These results support the hypothesis that KNDy neurons play a regulatory role in GnRH and hence gonadotropin secretion in sheep fetuses and serve as targets for negative feedback in males for maintaining a stable androgen environment crucial for brain masculinization. Supported by NIH Grant OD11047 to CER.
Presentation: 6/1/2024