bluuebunny/crossref_metadata_2025 huggingface dataset:
7295 Giant Pituitary Adenoma with Rapid Symptomatic Progression and Postoperative Mortality
Authors: Kennedy R D , Nicholson M
Published: October 2024

Disclosure: R.D. Kennedy: None. M. Nicholson: None.

Introduction: Giant pituitary adenomas, defined as pituitary adenomas measuring greater than 4 cm, present a therapeutic challenge because of their size, clinical features, and increased potential for complications following surgical intervention. Early detection and intervention to prevent growth and progression is paramount. We present a case of a patient with a giant 6.3 cm pituitary adenoma who had significant neurologic compromise, requiring surgical intervention, with resultant postoperative complications and death. Case:Patient is a 41 year old male with known history of pituitary adenoma who presented on 11/1/2023, from outside hospital, to the Neuroendocrine clinic with complaints of excessive truncal obesity, impotence, fatigue, and apathy. Vital signs were within normal limits. Physical exam revealed clouding of consciousness, grossly intact cranial nerve function, truncal obesity, and diminished power, tone, and bulk of the extremities. Formal visual field testing revealed bitemporal hemianopsia. A head CT scan revealed a 6.3 cm sellar mass with expansion of the sella, invasion of soft tissue into the sphenoid sinus, and extension of soft tissue cranially to the level of the third ventricle eccentric to the left. There was no evidence of apoplexy. Lab results revealed Prolactin of 924 ng/mL. The patient had been taking Bromocriptine, 2.5 mg daily, for at least three weeks. Less than three weeks after his initial evaluation, he returned to the hospital with complaint of acute ataxia. Pituitary MRI revealed 6.3 cm sellar mass with evidence of acute and subacute blood products, stretching of the optic chiasm from mass effect, extension into the bilateral cavernous sinuses, superior left MCA displacement, posterior left PCA displacement, 5 mm midline shift, uncal herniation and descending transtentorial herniation. The patient underwent endoscopic transsphenoidal resection with subsequent craniotomy for debulking. Postoperatively, he developed new right sided hemiplegia with aphasia with subsequent MRI finding of watershed infarct at the left MCA/PCA lateral posterior border zone territories with increasing mass effect over a 30 day hospital stay. He developed progressive global edema with worsening uncal and tonsillar herniations. Brain death was pronounced on 11/30/23. Discussion:This case highlights the importance of early intervention in patients with giant pituitary adenomas. Our patient had been experiencing right sided weakness for at least one year prior to his admission to our facility. In this case, earlier treatment with a dopamine agonist may have decreased the size of the adenoma or prevented rapid growth. This may have precluded the need for surgical intervention on an adenoma of this size, which carries increased risk for postoperative complications.

Presentation: 6/2/2024
12218 Gnrh Pulse Frequency And Irregularity Play A Role In Depression
Authors: Choi J , Kim M
Published: October 2024

Disclosure: J. Choi: None. M. Kim: None.

Gonadotropin-releasing hormone (GnRH) has a role in hypothalamic control of depression, but the underlying patterns and relationship with downstream reproductive hormones are still unclear. Here we report that hypothalamic GnRH pulse frequency and irregularity increase before GnRH pulse amplitude slowly decreases during social defeated stress models (SDS). While mice castrated and testosterone inhibited induced depression by conducting SDS, these mice led to anti-depression effects and affected by GnRH signaling, indicating that high-frequency GnRH pulses. Regramming the endogenous GnRH pulses of depressed male mice via an optogenetic approach revealed that increasing GnRH pulses frequency causes depression acceleration, while lowering the frequency of and stabilizing GnRH pulses can slow down depression. In conclusion, GnRH pulses are important for depression in male mice.

Presentation: 6/1/2024
7541 Growth Hormone Secreting Pituitary Macroadenoma Presenting as Intractable Headache, Right Eye Epiphora and Ptosis
Authors: Niedzialkowska Ewelina Marta , Aljaloudy Mustafa , Banka Ajaz Ahamad
Published: October 2024

Disclosure: E.M. Niedzialkowska: None. M. Aljaloudy: None. A.A. Banka: None.

Introduction: Headache is not an uncommon feature in patients with pituitary tumors. It is present in up to 70% of cases and is irrespective of tumor volume or cavernous sinus invasion. Intractable headache is common in patients with GH secreting tumors. Unilateral ptosis and epiphora (excessive tearing) is an extremely rare phenomenon in this patient population. Case:44 y.o. male with a history of chronic occipital headaches and pituitary mass (diagnosed 2 years prior) was referred to our hospital for worsening right eyelid ptosis with inability to open his eye, photophobia and worsening occipital headache. The patient was diagnosed with occipital neuralgia in the past and received nerve blocks without improvement of symptoms. On admission, physical examination was positive for right eyelid ptosis, brisk and symmetric pupils, negative for features of acromegaly. Imaging revealed normal CT orbits but was concerning for pituitary mass. Pituitary MRI confirmed a mass within the right aspect of the pituitary gland measuring 9x12x12 mm with mild impression into the right cavernous sinus and stalk deviation to the left, without optic nerve chiasm impression. Laboratory results showed IGF-1 514 ng/ml (N <215), testosterone 232 ng/dl (N 240-890), LH 1.8 mIU/ml (N 0.6- 12.1), FSH 3.1 mIU/ml (1-12), normal alfa subunit, prolactin, ACTH, cortisol, TSH and ft4. The patient underwent endonasal transsphenoidal resection of pituitary mass with complete resolution of headaches, and photophobia as well as improvement of ptosis and lacrimation. Repeat IGF-1 postoperatively was mildly elevated at 239 ng/ml. 6 months after surgery IGF-1 remained elevated at 299 ng/ml, GH 5.1 ng/ml (N 0.1-3), repeat brain MRI was concerning for residual tumor tissue within the left superior aspect of the gland. The patient was started on lanreotide 60 mg monthly. The patient also reported recurrence of intractable occipital headaches and recurrence of right eye lacrimation at that time. Repeat lab studies showed IGF-1 464 ng/ml, LH 0.5 ng/ml, testosterone 155 ng/dl consistent with central hypogonadism and residual GH secreting tumor. The patient is currently awaiting Neurosurgery evaluation. Conclusion: Headache is present in up to 12.5% of patients with acromegaly. It is commonly persistent, severe, unrelieved by the surgery and irrespective of biochemical markers. Lacrimal gland volume is higher in patients in this population and shows positive correlation with IGF-1 and GH levels. GH and IGF-1 independently induce features of hypersomatotropism that may stimulate exocrine glands. Epiphora in the setting of acromegaly is exceptionally infrequent in patients with acromegaly and usually presents bilaterally. GH secreting pituitary tumor presenting with unilateral ptosis and unilateral epiphora is an extremely rare phenomenon.

Presentation: 6/3/2024
7251 Heterozygous Sox2 Knockout Mice have Delayed Puberty, Fertility Deficiencies, and a Decreased Number of GnRH Neurons
Authors: Cassin Jessica , Nguyen Ryan D , Tonsfeldt Karen J , Dunn Geneva A , Chen Vivian , Yeo Seung E , Mellon Pamela L
Published: October 2024

Disclosure: J. Cassin: None. R.D. Nguyen: None. K.J. Tonsfeldt: None. G.A. Dunn: None. V. Chen: None. S.E. Yeo: None. P.L. Mellon: None.

Mutations in the SOX2 gene have been previously linked to a syndromic form of Isolated Hypogonadotropic Hypogonadism (IHH), with additional ocular and neurodevelopmental phenotypes. Recently, we published research detailing novel variants in SOX2, which demonstrated a functional role for SOX2 in Kisspeptin-expressing hypothalamic neurons, establishing a mechanistic relationship between SOX2 heterozygous variants and IHH. To further test the role of SOX2 in the hypothalamus, we utilized Sox2tm[1].[1]Lan/J mice to generate whole body heterozygous knockout (Sox2het) mice. We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2het mice compared to wild type (WT) controls (male WT: 29.7±0.7 days, Sox2het: 32.3±0.5 days and female WT: 28.8±0.9 days, Sox2het: 33.8±1 days). This difference is explained in part by a weight phenotype with Sox2het mice being significantly smaller at weaning and into adulthood despite observing no difference in weight at birth. We next examined the effect of Sox2het on fertility in both sexes. Sox2het male mice had a significant decrease in sperm motility compared to WT controls (WT: 40.4%±1.5, Sox2het: 29.5%±1.3); however, this decrease was insufficient to affect time to first litter or to decrease the number of pups per litter. In females, we observed a significant delay in time to first litter of Sox2het dams compared to WT controls (WT: 20.6±0.4 days, Sox2het: 26.5±1.7 days), which may arise from disrupted estrous cyclicity. Although Sox2het females did not spend an extended period of time in any one stage, they did not progress linearly through the stages as did their WT controls and therefore completed fewer cycles during our study (WT: 3.6±0.3 cycles, Sox2het: 2.5±0.2 cycles in 21 days). Finally, we assessed the number of GnRH neurons in the adult mouse and found that Sox2het mice have significantly fewer GnRH neurons (WT: 570.6±42.8 neurons, Sox2het: 228.4±32.8 neurons). Together these data further substantiate a role for SOX2 in the HPG axis by addressing the effects of Sox2 heterozygous knockout on the hypothalamus. Future studies will further define the role of SOX2 directly in the Kisspeptin and GnRH neurons.

Presentation: 6/3/2024
9270 Human loss-of-function variants in the TRPC5 associated with Postpartum Depression
Authors: Li Yongxiang , Farooqi Ismaa Sadaf , Xu Yong
Published: October 2024

Disclosure: Y. Li: None. I.S. Farooqi: None. Y. Xu: None.

Postpartum depression is a serious psychiatric disorder that is understudied and underdiagnosed. Postpartum depression, the most common complication of childbirth negatively impacts the mother, with suicide accounting for approximately 20% of postpartum deaths. Further, postpartum depression also has adverse effects on infant behavioral, emotional, and cognitive development. However, the neurobiological mechanisms underlying postpartum depression remain to be comprehensively elucidated. Transient receptor potential channel 5 (TRPC5/Trpc5), an ion channel that conducts calcium inward currents, as a critical regulator of many behaviors. Here, we found that microdeletions on chromosome Xq23 disrupting TRPC5 gene in humans and identified seven rare TRPC5 variants in mothers who exhibited postpartum depression and reduced bonding with their infants. Heterozygous females with TRPC5 deletions had postpartum depression and anxiety after delivery. We then generated a knock-in mouse model of a human severe loss-of-function mutation, K34del (Trpc5K34del). Our study showed that Trpc5K34del/+ heterozygous dams abandoned their pups after delivery. The Trpc5K34del/+ dams also showed inefficient retrieval and increased the time to retrieve pups, which is associated with abnormal pup care. Importantly, Trpc5K34del/+ dams exhibited severe depression-like and anxiety-like behaviors during the postpartum period. Oxytocin (OXT), a polypeptide comprised of 9 amino acids, is primarily synthesized by neurons in the paraventricular nucleus of the hypothalamus (PVH) and the supraoptic nucleus (SON). We found that endogenous Trpc5 protein is abundantly expressed by OXT neurons in PVH but not by SON. Further, the Trpc5K34del/+ dams reduced OXT expression in the PVH but does not affect OXT expression in the SON. Deletion of Trpc5 in OXTPVH neurons recapitulated phenotypes in Trpc5K34del/+ dams, including inefficient retrieval, abnormal pup care, depression-like and anxiety-like behaviors during the postpartum period. We then bilaterally injected AAV-DIO-Trpc5 into the PVH of virgin female Trpc5K34del/+/OXT-Cre mice to result in restoration of Trpc5 only in OXTPVH neurons in these mutant mice. Restoration of Trpc5 in OXTPVH neurons in Trpc5K34del/+/OXT-Cre mutant mice significantly improved pup retrieval behavior and indices of maternal care. After weaning, Trpc5K34del/+/OXT-Cre dams with Trpc5 restoration in OXTPVH neurons showed reduced depression-like and anxiety-like behaviors. Our study indicates that the postpartum depression and impaired maternal behavior of Trpc5 deficient female mice are mediated by impaired function of OXTPVH neurons. This revelation not only offers crucial insights into the pathogenesis of postpartum depression but also provides a foundation for potential therapeutic interventions.

Presentation: 6/2/2024
7926 Hypophysitis and Hypopituitarism Caused by Neurosyphilis in a Patient with Chronic HIV Infection
Authors: Malapur Bina , Jakoby Michael G
Published: October 2024

Disclosure: B. Malapur: None. M.G. Jakoby: None.

Introduction: Neurosyphilis is now mostly limited to individuals with HIV infections. We present a case of neurosyphilis complicated by hypophysitis and hypopituitarism in an HIV patient. Case: A 44-year-old male with chronic HIV and noncompliance with antiretroviral therapy presented for evaluation of a rash and photophobia. A copper-colored maculopapular rash was observed on the face, trunk, palms, and lower extremities. Neurosyphilis was diagnosed based on positive RPR (titer 1:64) and treponemal antibodies in cerebrospinal fluid. Mild hyponatremia, systolic blood pressure < 100 mm Hg, and plasma glucose 68 mg/dL raised concern for secondary adrenal insufficiency, and 8 AM cortisol was 2.7 mcg/dL. ACTH level was inappropriately low (16 mcg/dL), and the patient was also found to have secondary hypothyroidism (free T4 0.4 ng/dL [0.5-1.3], TSH 1.25 mIU/L [0.45-1.33]) and hypogonadism (testosterone < 10 ng/dL [270-1070]), LH 1.0 mIU/mL [1.2-8.6]). MRI revealed a non-enhancing, hypointense 12 x 4 x 4 mm mass in the anterior pituitary. The patient was started on treatment for T. pallidum, antiretroviral therapy, and hormone replacement with hydrocortisone and levothyroxine. On evaluation six months later, hypogonadism had resolved (testosterone 387 ng/dL, LH 6.3), and repeat MRI demonstrated resolution of the pituitary mass. Unfortunately, the patient was subsequently lost to follow up. Discussion: Hypophysitis complicating neurosyphilis in adults is rare and appears to be documented entirely in the case report literature. The first two cases were published in the 1950’s, prior to awareness of HIV, and hypopituitarism resolving after treatment with penicillin was documented for one patient. The first case in an HIV patient was published in 2013, and a case in a patient confirmed to be free of HIV was published in 2015. This patient’s presentation and course is similar to other cases published to date, with headache and/or photophobia, diffuse pituitary enlargement or focal pituitary mass, hypopituitarism, and resolution of hormonal and anatomic abnormalities after treatment for neurosyphilis. Though hypophysitis and hypopituitarism appear to occur rarely, they should be considered in patients with suspected or confirmed neurosyphilis presenting with headache or photophobia and clinical or laboratory findings that may be due to anterior pituitary deficits.

Presentation: 6/1/2024
12219 Hypothalamic Regucalcin Modulates Body Temperature Through Thyrotropin-releasing Hormone (trh)in Aging
Authors: Kim Min Soo , Jang Min Jun , Choi Jeongyoon
Published: October 2024

Disclosure: M. Kim: None. M. Jang: None. J. Choi: None.

Hypothalamic Regucalcin modulates body temperature through Thyrotropin-Releasing Hormone (TRH) in aging: Min Jun Jang[1],[2], Jeongyoon Choi[1] and Min Soo Kim[1],[3],[4]* [1] Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea, [2]Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, [3]Division of Bio-Medical Science & Technology, KIST School, Korea National University of Science and Technology (UST), Seoul 02792, Republic of Korea, [4]KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea

Regucalcin (RGN), recognized as a calcium-binding protein and aging marker, plays a pivotal role in maintaining cellular homeostasis and function by contributing synthesis ascorbic acid in liver. However, the role of RGN in hypothalamus utilizing peripheral homeostasis is not unclear even the expression levels of mRNA increased in aged brain. Interestingly, the levels of RGN were decreased in other organ, including liver and kidney in aging progression. We found that RGN expression was highly increased in Medio-basal Hypothalamus (MBH) in aged mice. When we down-regulated RGN expression by using AAV-shRNA in MBH of aged mice, thermogenic activities in cold chamber were decreased compared to scramble virus injected mice (control). In addition, we found that over-expression of RGN in MHB of young mice showed increase of body temperature levels. Investigation into genes associated with TRH neuron activation, known to be stimulated under low-temperature exposure, confirmed our hypothesis, demonstrating reduced expression in TRH-related genes in mice with decreased RGN. The results suggest a vital role for hypothalamus-specific RGNs in the regulation of temperature homeostasis through the modulation of TRH neurons. Keywords: Regucalcin, RGN, Body Temperature, Thermoregulation, Cold stress, Thyroid hormone, TRH

Presentation: 6/2/2024
6509 IGF-1 receptor and insulin receptor in LepRb neurons coordinates body growth, reproduction, and metabolism
Authors: Wang Mengjie , Hill Jennifer Wootton
Published: October 2024

Disclosure: M. Wang: None. J.W. Hill: None.

Growth and reproduction are tightly linked. Growth hormone (GH) deficiency results in a profound suppression of postnatal growth accompanied by severely delayed puberty and reproductive senescence, while GH excess is correlated with the reverse. The specific mechanism underlying this delay is undefined. Although leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, the role of insulin-like growth factor 1 receptor (IGF1R) signaling in LepRb neuron function is unknown. Previous studies have shown that IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1RLepRb mice) and mice simultaneously lacking IGF1R and IR in LepRb neurons (IGF1R/IRLepRb mice) to test if IGF1R and insulin receptor (IR) cooperatively regulate metabolic and reproductive functions. IGF1RLepRb and IGF1R/IRLepRb mice displayed delayed onset of puberty and impaired fertility in both sexes, which suggested that both IGF1R and IR in LepRb neurons are required for normal reproduction. Additionally, we found transient growth retardation in IGF1RLepRb and IGF1R/IRLepRb mice. Loss of IGF1R in LepRb neurons led to lower serum IGF-1 and GH levels in male mice and impaired trabecular and cortical bone development in mice of both sexes. Only transient and mild changes were noticed in the body weight. However, we found IGF1R and IR in LepRb neurons jointly regulate body mass composition, energy homeostasis and glucose homeostasis, as shown by elevated fat mass composition, low energy expenditure and low physical activity in IGF1R/IRLepRb mice. Taken together, these studies identify the unique and cooperative role of LepRb IGF1R and IRs in the regulation of body growth, reproduction, and metabolism.

Presentation: 6/3/2024
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

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 >60 years. In the switched cases, the median levels of T-chol dropped from 214.5 to 198.5 mg (p<0.05). The median levels of HbA1c dropped from 5.9 to 5.8% (p<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

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< 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< 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

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< 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< 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

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 > 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

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 <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 <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

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

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>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<.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

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 < 0.05) plasma testosterone concentrations, which resulted in a significant decrease (P < 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 < 0.05) in mean plasma LH and testosterone concentrations that was accompanied by a significant increase (P < 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
7503 Light Composition Alters Feline Stress in a Shelter Environment
Authors: Yaw Alexandra M , Gardella Mary E , Jacobs Jacquelyn , Hoffmann Hanne Mette
Published: October 2024

Disclosure: A.M. Yaw: None. M.E. Gardella: None. J. Jacobs: None. H.M. Hoffmann: None.

Millions of cats enter animal shelters each year. Unfortunately, due to high numbers of cats entering shelters and limited physical housing space, over 50% of healthy and adoptable cats with extended shelter stays are euthanized yearly. While animal shelters are essential for keeping cats safe from unfit living conditions, they are a stressful environment. High stress in cats increases health risks and undesirable behaviors and is associated with reduced adoptions. Given the role of light in regulating hormonal stress responses and behavior, we partnered with a Midwestern animal control and shelter to evaluate how light intensity and light composition impact feline behavior and urinary cortisol levels in 123 domestic cats (Felis catus; 65 male and 58 female). The impact of three lighting conditions, white, dim, and orange (blue-depleted) light, were evaluated for the first 5-6 days following admittance into the shelter. Individually housed adults (8 months-10 years) were outfitted with PetPace Smart Collars to evaluate locomotor activity, and cat stress was evaluated daily through urine samples and a behavioral approach test. All data were analyzed by experimenters who were blind to the groups and tested via one or two-way ANOVA or repeated measures mixed-effects model with Geisser-Greenhouse correction. Urinary cortisol levels were dependent on both light quality and day in shelter, where cats under orange light had reduced cortisol on days 4-5 in the shelter compared to cats in standard lighting. Light quality also altered cat hiding behavior, such that the percentage of cats hiding was increased on dim light compared to both standard and orange light. A novel behavioral approach task found reduced cat stress on days 4-5 in standard and orange light; however, dim light increased cat stress on day 5 in shelter. All cats exhibited circadian rhythms in locomotor activity with periods ranging from 21.33-35.67h independent of light condition and day in shelter, and locomotor activity increased on days 3-4 compared to day 2 in the shelter, with no effect of light condition. There were no sex differences in in hiding, PetPace activity, or cat stress scores under any light condition; however, females displayed increased urinary cortisol levels compared to males in standard, but not dim or orange, light. This shows for the first time that room light manipulation can help shelters enact easy and inexpensive changes that make the adjustment period shorter and less stressful for incoming cats which will improve animal wellbeing.

Presentation: 6/1/2024