Hormone Axis Research Articles

Enhancing gosling growth and secretion of somatotrophic and thyrotrophic axis hormones through egg turning during incubation

ABSTRACT 1. Growth performance of Yangzhou geese hatched from eggs with turning angles of 50° or 70° was evaluated in association with serum hormones and somatotrophic gene mRNA expression. 2. Egg turning at 70° significantly (P< 0.05) increased hatchability, gosling quality and hatching weight. Gosling post-hatch body weight, leg and breast muscle weight in the 70° turning group was significantly heavier until 50 d of age. 3. Serum concentrations of GH were significantly higher until 30 d of age in the 70° turning group goslings, and those of IGF-I and T3 were higher from hatching to 50 d of age. 4. The mRNA expression of GHRH, pituitary GH, liver and leg muscle IGF-I were all significantly higher at 1 and 30 d of age after hatch, but not at 70 d after hatch, in the 70° turning group. 5. Egg turning at 70° during incubation improves embryo and gosling quality and growth performance through up-regulation of gene expression and secretion of somatotrophic axis hormones, GHRH, GH and IGF-I, as well as T3.

Abstract 15472: Skeletal Muscle Sirt3 Deficiency Remotely Regulates Pulmonary Vascular Remodeling Via Loxl2-cnpy2-p53 Axis In Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

Background: Pulmonary hypertension in the context of heart failure with preserved ejection fraction (PH-HFpEF) is the most common cause of PH worldwide. However, major pathways involved in the regulation of PH-HFpEF are still not well understood. We have previously reported a role of skeletal muscle sirtuin-3 (SIRT3) in PH-HFpEF. In the present study, we aimed to investigate how skeletal muscle SIRT3 defects remotely affect pulmonary vascular health in PH-HFpEF. Methods and Results: Using global mass spectrometry-based comparative analysis, we found increased secretion of lysyl oxidase homolog 2 (LOXL2) in SIRT3-deficeint skeletal muscle. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3 skm-/- mice, rats with experimental PH-HFpEF (SU5416/Obese ZSF1, Ob-Su), and patients with PH-HFpEF. Additionally, expression levels of canopy fibroblast growth factor signaling regulator&amp;nbsp;2 (CNPY2), a known angiogenic and proliferative factor, were increased in PASMCs obtained from Sirt3 skm-/- mice and Ob-Su rats, suggesting a potential role of CNPY2 as a molecular target of skeletal muscle SIRT3-LOXL2 signaling in PASMCs. Treatment with LOXL2 recombinant protein resulted in increased levels of CNPY2, PCNA, and cellular proliferation in vitro in PASMCs. LOXL2 treatment, as well as CNPY2 overexpression, decreased the levels of tumor suppressor p53 in PASMCs. In addition, CNPY2 overexpression also decreased CNPY2 expression level in PASMCs. Media conditioned by SIRT3-deficient skeletal muscle cells increased CNPY2 expression in PASMCs, concomitant with decreased p53 and enhanced PCNA. Finally, knockdown of both SIRT3 and LOXL2 in skeletal muscle cells and/or suppression of LOXL2 with β-aminopropionitrile&amp;nbsp;(BAPN) restored CNPY2, p53, and PCNA levels in PASMCs. Conclusions: These studies reveal a new endocrine signaling axis that links skeletal muscle SIRT3 deficiency to remote CNPY2 -p53 regulation in the pulmonary vasculature through myokine LOXL2. Our data may also identify skeletal muscle SIRT3, myokine LOXL2, CNPY2, and p53 as potential targets for the treatment of PH-HFpEF.

Longitudinal patterns of neuroendocrinecoupling from middle childhood to early adolescence.

Recent scholarship has highlighted the importance of understanding relations between hormones, rather than studying hormones in isolation. Considering neuroendocrine coupling, or the coordination of hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-gonadal axis hormones over time, is one way to investigate how systems governing stress responsiveness and pubertal development covary during critical periods. To date, however, most work has considered hormone coupling cross-sectionally. The current study investigated neuroendocrine coupling in a longitudinal sample from the Northeastern United States. Youth (N=437, 53% male, 90% White) provided saliva samples for analysis of diurnal hormone activity at ages 9 (three samples per day across 3days) and 12 (one sample per day on the same weekday for 4weeks). At both timepoints, samples collected 30-min after waking were assayed for cortisol, dehydroepiandrosterone (DHEA), and testosterone. Multilevel growth modeling was used to determine how levels of morning cortisol changed in tandem with DHEA and testosterone. Morning cortisol-DHEA coupling varied by child sex, as males' cortisol-DHEA diminished over time, especially among pubertally advanced males. Females, in contrast, demonstrated strengthening cortisol-DHEA coupling over time, especially more pubertally advanced females. Morning cortisol-testosterone coupling did not vary by sex or pubertal status, demonstrating strengthening associations between ages 9 and 12. The current findings contribute to the literature on hormone coupling across development and expand this work into an earlier developmental phase than previously investigated.

New View on the Impact of the Low-Frequency Electromagnetic Field (50 Hz) on Stress Responses: Hormesis Effect

Introduction: Low-frequency electromagnetic field (50 Hz) (EMF) can modify crucial neuronal processes. Existing data indicate that exposure to EMF may represent a mild stressor and contribute to disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. The important regulatory pathways controlling HPA axis activity include two types of corticosteroid receptors: mineralocorticoid receptors (MRs) and glucocorticoid receptors. They are particularly abundant in the hippocampus, a key locus of HPA axis feedback control. The research aimed at determining whether (1) EMF exhibits hormesis, it means bidirectional action depending on EMF intensity (1 or 7 mT) and (2) repeated EMF exposure changes stress response to subsequent stress factors. Methods: The exposure (7 days, 1 h/day) of adult rats to EMF (1 mT and 7 mT) was repeated 3 times. HPA axis hormones and their receptors were analysed after each following exposure. Moreover, the impact of EMF exposure on hormonal and behavioural responses to subsequent stress factor – open-field test was evaluated. Results: Our data suggest that exposure to EMF can establish a new “set-point” for HPA axis activity. The direction and dynamics of this process depend on the intensity of EMF and the number of exposures. EMF of 1 mT induced an adaptive stress response, but 7 mT EMF caused sensitization. Consequently, EMF changed the vulnerability of the organism to a subsequent stress factor. We have also shown the increase in MR mRNA abundance in the hippocampus of 1 mT EMF-exposed rats, which can represent the possible neuroprotective response and suggest therapeutic properties of EMFs.

LBMON274 Total Osteocalcin Levels Are Independently Associated With Worse Testicular Function And A Higher Degree Of HPG Axis Activation In Klinefelter Syndrome

Abstract Context. Osteocalcin (OCN) is an osteoblast-produced polypeptide, emerging as the core element of the bone-testicular axis toghether with its undercarboxylated form (uOCN), proposed to increase testosterone (Te) levels in healthy men, by binding the Gpcr6a receptor on Leydig cells and modulating the GnRH pulse frequency and amplitude. However little is known with regards to its role in pubertal development and male hypogonadism. Objective and Design We investigated OCN concentrations in 47,XXY men affected by Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism, in a retrospective longitudinal study between 2007 and 2021 at an academic referral center. Patients and Methods 254 KS subjects, divided into the following groups: 1) pre-pubertal (n = 48, from 1 year of age until Tanner stage II), 2) pubertal (n = 46, Tanner stages II through V, &amp;lt;18 years), and 3) adults (n = 160, Tanner stage V, ≥18 years). All (pre-)pubertal patients were Te-naïve. Adult patients were categorized as: 1) eugonadal (total Te &amp;gt; 10.4 nmol/L; n = 47), 2) hypogonadal (Te &amp;lt; 10.4 nmol/L; n = 39), and 3) receiving testosterone replacement therapy (TRT) (n = 74). Data are presented as means ± SD, were tested with Brown-Forsythe and Welch ANOVA tests for unequal variances, corrected for multiple comparisons (Dunnett T3), and with partial correlations, after bootstrapping on 2000 samples. Main outcomes. Total serum OCN, hypothalamic-pituitary-gonadal (HPG) axis hormones (LH, FSH, total Te, 11β-estradiol, SHBG), and derived indexes. Results OCN levels varied throughout the life span, with a mean of 85.9±30.4 ng/mL in pre-pubertal infants, peaking at 130. 0±77.2 ng/mL in pubertal children (p = 0.243 vs pre-pubertal) and then declining to 22.9±9. 0 ng/mL in adults (p &amp;lt; 0. 001 vs pre-pubertal and pubertal). In (pre-)pubertal boys no correlation with HPG axis hormones was found. When comparing adult KS, OCN values were highest in eugonadal (26.5±10.4 ng/mL), slightly lower in hypogonadal (24.5±8.1 ng/mL, p = 0.268 vs eugonadal) and significantly lower in TRT subjects (20.4±8. 0 ng/mL, p = 0. 008 vs. eugonadal and = 0. 013 vs. hypogonadal). In adults, OCN correlated with both LH (r = 0.23, p = 0. 017) and FSH levels (r = 0.28, p = 0. 004). These significancies were maintained after the exclusion of subjects on TRT. Surprisingly, adjusting for age and BMI revealed significant inverse correlations with total Te (r = -0.44, p = 0. 004), calculated free Te (r = -0.37, p = 0. 016), the Te/LH (r = -0.40, p = 0. 010) and the calculated free Te/LH ratios (r = -0.33, p = 0. 031). These results were confirmed on a smaller sample with available uOCN levels. Conclusions In an experimental model of hypergonadotropic hypogonadism, OCN showed no association with gonadal function during normal pre-puberty and pubertal development. In adults, OCN levels were unexpectedly associated with worse testicular function and a higher degree of HPG stimulation. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

RF04 | PSUN135 Genetic Inactivation of Glutaminase Reduces Amino Acid Induced Alpha Cell Proliferation

Abstract Glucagon stimulates glycogenolysis and gluconeogenesis in liver resulting in increased hepatic glucose output. Thus, interrupting glucagon signaling in liver reduces blood glucose levels in animal models and individuals with diabetes. However, interrupting glucagon signaling also leads to hyperaminoacidemia and proliferation of glucagon secreting alpha cells, evidence of an endocrine liver-alpha cell axis. Among the high amino acids, we previously identified high glutamine levels are required for alpha cell proliferation. We recently found that glutaminase (GLS) is expressed in alpha cells at much higher levels than any other pancreatic endocrine cells. Additionally, mouse pancreatic islets cultured in high amino acid containing media and treated with the small molecule inhibitor of GLS (CB839) have reduced alpha cell proliferation (Vehicle: 7.6 ± 2.2%, 0.1µM CB839: 0.11 ± 0.05%**, 10µM: 0.02 ± 0.01%**; n=3-4, **p &amp;lt; 0.01). To further characterize the role of glutamine metabolism in glutamine-induced alpha cell proliferation, GLS activity was specifically knocked out in mouse alpha cells by breeding Gcg-CRE ERT2 with Glsflox mice (aGlsKO). Targeted deletion of Gls expression in most alpha cells was confirmed by staining for GLS and glucagon (aGlsWT: 95% GLS+, aGlsKO: 18% GLS+). Mice were treated with a glucagon receptor monoclonal antibody (GCGR mAb/mAb-4) for 10 days or with isotype control IgG. aGlsWT mice treated with GCGR mAb have robust alpha cell proliferation while aGlsKO mice treated with GCGR mAb for 10 days showed a 4.5-fold decrease in alpha cell proliferation and were similar to mice treated with the control IgG (aGlsWT Ab: 15.7 ± 3.6% alpha cell proliferation, aGlsWT IgG: 1.0 ± 0.4%***, aGlsKO Ab: 3.4 ± 0.6%**; n=4-6, ***p &amp;lt; 0.001). In addition, aGlsWT mice treated with GCGR mAb showed a robust activation of mTOR in alpha cells as measured by phospho-S6 expression while this was lost in aGlsKO mice treated with GCGR mAb. Induced expression of the mTOR-dependent glutamine transporter SLC38A5 was also lost (aGlsWT Ab: 25.0 ± 4.8% alpha cell SLC38A5 expression, aGlsWT IgG: 0.40 ± 0.27%***, aGlsKO Ab: 3.7 ± 3.5%***, n= 2-4, ***p &amp;lt; 0.001). Similar results on proliferation and mTOR activation in alpha cells were observed after 4 weeks of GCGR mAb treatment. Together these data suggest a critical role for glutamine metabolism via glutaminase in alpha cell proliferation. Presentation: Saturday, June 11, 2022 1:36 p.m. - 1:41 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP319 IGF-1 and BMI are Associated in Obese Patients with Acromegaly

Abstract Regulation of the growth hormone (GH) axis is complex and influenced by factors including age and nutritional status. Studies of individuals across the weight spectrum demonstrate an inverted U-shaped correlation between BMI and total IGF-1 levels; in both individuals with anorexia nervosa-range BMIs and those who are severely obese, total IGF-1 levels are low. Acromegaly is a disorder of the GH/IGF-1 axis characterized by IGF-1 excess secondary to autonomous GH secretion. The relationship between BMI and IGF-1 levels has not been well studied in acromegaly and whether the association between BMI and IGF-1 observed in non-acromegalic individuals is also present in acromegaly is not known. Patients who underwent endoscopic endonasal resection of pituitary adenomas at our institution between 1/2015-6/1/2021 were studied to investigate the association between BMI and preoperative IGF-1 in acromegaly. Ninety-nine patients were identified who either had evidence of preop biochemical hormone excess [elevated IGF-1 level and/or GH &amp;gt;1ng/ml following 75g oral glucose tolerance test] (n=40) or who had a clinically non-functioning, non-staining (NF) pituitary adenoma, or non-functioning GH-staining adenomas (n=59). We excluded anyone with a prior history of surgery/radiation, those on medical therapy (including somatostatin analogues, cabergoline), and those on oral contraceptives in the 3-months preceding surgery (n=8 in each group). Median age of acromegaly patients (n=32) was 39.5 years [29.3, 51.8], mean BMI was 30.2 +5.3 (SD) kg/m 2 (range: 20.9-40.4 kg/m 2) and 50% were female. Preoperative IGF-1 levels were measured using a clinically available assay. To control for differences in IGF-1 levels based on age/sex, we calculated % upper limit of normal (ULN) for IGF-1 based on age/sex determined normal ranges (mean %ULN IGF-1: 219.7+74.8%). In the acromegalic group, univariate analysis demonstrated a significant positive association between both BMI and IGF-1 (R=0.44, p=0. 01) as well as BMI and IGF-1%ULN (R=0.35, p=0. 047). In contrast, in the NF group (n=51 with 49% female and mean age: 56.4+16.7 years), there was no significant association between BMI (mean: 31.3+6.5 kg/m 2; range: 19.1-47 kg/m 2) and %ULN IGF-1 (median: 38.9% [26.8, 61.4]) (rho=0.15, p=0.30). However, in the subgroup of NF patients with severe obesity (BMI &amp;gt;35 kg/m 2; n=17), a significant inverse association between BMI and %ULN IGF-1 was observed (rho: -0.54; p=0. 03) . These data demonstrate that in contrast to the inverse relationship that is typically observed between total IGF-1 and BMI in obese individuals, which is preserved in a NF adenoma group, there is a significant positive association between %ULN IGF-1 and BMI in patients with acromegaly, including those with severe obesity. Further study is necessary to determine whether obese patients with acromegaly exhibit more severe symptoms related to their disease due to this positive association between BMI and IGF-1 or whether obesity is a secondary effect of their acromegaly. Presentation: No date and time listed

PMON214 Kisspeptin Restores Sexual and Attraction Brain Processing in Women with Hypoactive Sexual Desire Disorder

Abstract Introduction Sexual desire is a key component of the sexual response model. Absence or deficiency of sexual desire can lead to marked distress or interpersonal difficulty, termed 'hypoactive sexual desire disorder' (HSDD). HSDD is the most common female sexual health complaint worldwide, affecting 10% of women. Despite its detrimental impact on psychological well-being and quality of life, treatment options are currently limited. The hormone kisspeptin is a key endogenous activator of the reproductive endocrine axis, with emerging roles in sexual and emotional behaviour, and thus could serve as a novel treatment option in women with HSDD. Hypothesis Kisspeptin restores sexual brain processing in women with HSDD. Methods To test our hypothesis, we performed a randomized, double-blind, two-way crossover, placebo-controlled study in 32 (mean age ± SEM 29.2±1.2 years; BMI 23.1±0.5 kg/m2) premenopausal women with HSDD using psychometric assessments, functional neuroimaging, and hormonal assessments to investigate the effects of kisspeptin administration on brain activity, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Study visits were undertaken in the early follicular phase of the menstrual cycle. Results Kisspeptin administration resulted in an increase in self-reported ratings of feeling 'sexy', compared to placebo, measured using the Sexual Arousal and Desire Inventory (t [32] =2.27, P=0.03). On functional MRI, kisspeptin administration deactivated the left inferior frontal gyrus and activated the postcentral and supramarginal gyrus in response to erotic videos (Z=2.3, P&amp;lt; 0.05). Kisspeptin administration deactivated the secondary somatosensory cortex (Z=2.3, P&amp;lt;0.05) and enhanced activation in the posterior cingulate cortex on viewing male faces, which correlated with a reduction in self-reported sexual aversion (r=0.476, P=0.005). Kisspeptin resulted in a mean increase in LH of 2.75 iU/L (F(1, 62) = 6.084, P=0.02) and FSH of 0.37 iU/L (F(1, 62) = 4.030, P=0.05) across the 75-minute duration of the study, with no effect observed on downstream circulating estradiol, progesterone or testosterone levels. Interpretation of results and conclusionsDeactivation of the left inferior frontal gyrus by kisspeptin administration likely serves to reduce the internal monologue and response inhibition. Furthermore, kisspeptin's deactivation of the secondary somatosensory cortex can reduce a woman's focus on herself, her body image, and related negative thoughts, thus augmenting her judgement of male facial attractiveness. Finally, kisspeptin's actions in the posterior cingulate cortex can serve to increase feelings of romantic love and reward processing, thereby reducing sexual aversion and increasing sexual desire. Collectively these brain changes provide mechanistic insights for the observed increase in sexual desire and attraction during kisspeptin administration in women with HSDD. These behavioural and mechanistic findings in women with HSDD lay the foundations for clinical applications for kisspeptin in psychosexual disorders. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Impulsive time series modeling with application to luteinizing hormone data.

This work considers the estimation of impulsive time series pertaining to biomedical systems and, in particular, to endocrine ones. We assume a signal model in the form of the output of a continuous linear time-invariant system driven by a sequence of instantaneous impulses, which concept is utilized here, in particular, for modeling of the male reproductive hormone axis. An estimation method to identify the impulsive sequence and the continuous system dynamics from sampled measurements of the output is proposed. Hinging on thorough mathematical analysis, the method improves upon a previously developed least-squares algorithm by resolving the trade-off between model fit and input sparsity, thus removing the need for manual tuning of user-defined estimation algorithm parameters. Experiments with synthetic data and Markov chain Monte-Carlo estimation demonstrate the viability of the proposed method, but also indicate that measurement noise renders the estimation problem ill-posed, as multiple estimates along a curve in the parameter space yield similar fits to data. The method is furthermore applied to clinical luteinizing hormone data collected from healthy males and, for comparability, one female, with similar results. Comparison between the estimated and theoretical elimination rates, as well as simulation of the estimated models, demonstrate the efficacy of the method. The sensitivity of the impulse distribution to the estimated elimination rates is investigated on a subject-specific data subset, revealing that the input sequence and elimination rate estimates can be interdependent. The dose-dependent effect of a selective gonadotropin releasing hormone receptor antagonist on the frequency and weights of the estimated impulses is also analyzed; a significant impact of the medication on the impulse weights is confirmed. To demonstrate the feasibility of the estimation approach for other hormones with pulsatile secretion, the modeling of cortisol data sets collected from three female adolescents was performed.

ODP334 Must we Wait for the Development of Metastasis to be Able to Distinguish Dopamine Resistant Aggressive Prolactinoma from Prolactin Producing Pituitary Carcinomas? Case Report and Literature Review

Abstract Background Prolactinomas, the most prevalent type of neuroendocrine disease, account for approximately 40% of all pituitary adenomas. In the vast majority of cases, these are benign tumors with excellent clinical response to medical therapy with dopamine agonist agents such as bromocriptine and cabergoline. Rarely medical treatment fails to normalize prolactin levels and/or decrease the size of the tumor, posing a challenge to the clinician. Case presentation 40-year-old man who underwent resection of a 7.4 cm pituitary prolactinoma via frontal craniotomy followed by radiotherapy. He developed panhypopituitarism and was placed on chronic hormonal replacement therapy plus high dose cabergoline. Two years later he presented with recurrence of his disease and was diagnosed with an unresectable 4.9 cm pituitary adenoma showing cortical breakthrough of the sellar floor, invasion into the optic chiasm, erosion of the posterior sphenoid walls, extension into the sphenoid sinuses and posteriorly into the pons, midbrain and third ventricle, as well as complete encasement of the distal, superior cerebellar and posterior cerebral arteries. The patient underwent endoscopic trans sphenoidal partial tumor resection and CSF leak repair. Pathology revealed a pituitary prolactinoma with Ki-67 of up to 8% and positive p53 immunostaining. His cabergoline dose was adjusted to 0.5 mg PO daily and he was also started on Sandostatin 20 mg IM monthly as well as appropriate hormonal replacement of the other deficient pituitary hormonal axes. Follow up imaging revealed stability of the lesion. The patient continues to do clinically well and actively follows with endocrinology and neurosurgery with serial brain MRIs and laboratory workup. Discussion The histological and biochemical characteristics of aggressive prolactin secreting tumors has been reported to be of minimal utility in distinguishing benign from malignant lesions. Tumors can only be diagnosed as carcinomas after they have metastasized and they can only be classified as aggressive after treatment failure or unusual growth, which creates a disadvantage for the prognosis and management of these patients. Clinicians are in need of better guidelines that can help them identify the rare cases that might warrant more aggressive clinical interventions beyond dopamine agonists such as surgery, radiation, temozolomide, somatostatin receptor agonists and others, with the hope of delaying or preventing the development of metastasis. Case reports of atypical presentations of aggressive prolactinomas such as the one here presented, can help broaden our understanding of the predictable signs of poor prognosis. Presentation: No date and time listed

ODP339 Nonfunctioning Giant Adenomas

Abstract Introduction Giant pituitary tumors (GA), those with 4 cm or more on the largest axis, exhibit extension beyond the sella turcica and invade structures adjacent to it. Objectives To evaluate demographic, clinical, and imaging variables in a cohort of nonfunctioning GA(NGA) patients. Methods We conducted a retrospective and observational study of patients with NGA followed in our tertiary center between 2005 and 2021. We evaluated variables related to diagnosis, treatment, and follow-up. Results We found 48 patients diagnosed with NGA. Most patients were men (n=35, 73%), and meanage at diagnosis 55.5 ± 11.8 years (35-83). Symptoms such as headache and visual alteration were present within 13 years of diagnosis. The BMI was higher than 30 in 10 cases, two with morbid obesity. Among the comorbidities, 10 patients had diabetes mellitus and one glucose intolerance; hypertension was present in 20 cases and depression in 7. Polymedication was verified in 20 patients. Pituitary MRI revealed the largest tumor axis between 4-4.9 cm in 33 patients, 5-5.9 cm in 9, and equal or greater than 6 cm in 6. In 14 cases, there was intraventricular extension, invasion of the sphenoid sinus in 11, cavernous sinus in 21, frontal lobe in 1, temporal region in 6, clivus in 3, retroclivus in 3, and rhinopharynx in one. Hyperprolactinemia was detected in 17 cases (maximum value: 70.8 ng/mL). Only three patients presented all hormonal axes intact. Respectively, 9, 15, 11, and 8 patients presented 1, 2, 3, or 4 deficient axes. Hypocortisolism was present in 18 cases, GH deficiency in 16, hypothyroidism in 32, hypogonadism in 35, and hypoprolactinemia in 3. Four patients had diabetes insipidus. Ten cases of the 44 who underwent surgery underwent two interventions and 4 cases, 3. Nine patients underwent radiotherapy. After the first surgery, 26 patients had follow-up greater than 12 months (13 to 214 months). The last image showed a giant lesion in 7 cases, macroadenoma with a larger axis less than 4 cm in 15 cases, a lesion restricted to the sella in 3 cases, and 1 case without lesion. Conclusion In our cohort, the results show the handling difficulty of NGA, determined by the complex removal of the lesion, high degree of invasion to adjacent structures, and tumor regrowth. Sequential therapeutic decisions in this group of patients require a qualified multidisciplinary team to maximize the patients’ life expectancy and quality of life while working on sharing experiences and investing in the tumor molecular characterization and new molecules that add to the poor therapeutic arsenal available. Presentation: No date and time listed

ODP299 Cabergoline Administration Markedly Improves Cognitive Impairment Associated with Macroprolactinoma

Abstract Introduction Prolactinomas classically present with galactorrhea, infertility, or hypogonadal symptoms. However cognitive impairment is rare presentation. We describe a man with a macroprolactinoma presenting with significant cognitive dysfunction which improved remarkably with cabergoline treatment. Case History A 21-year-old man with no significant past medical history presented to the hospital for evaluation of seizure-like activity. His father noted him limping earlier in the day and witnessed him fall and hit his head, while his brother reported involuntary convulsions and decreased awareness earlier that week. The patient himself had been complaining of blurry vision for 3 months for which he was prescribed glasses. Initial head CT demonstrated a 3.4×4.3×3.4cm cystic mass in the sella, 3.9×3.2×2.6 cm mass in the right basal ganglia and 2.7×2.3×3cm mass in the right temporal lobe. His prolactin was elevated at 16326 ng/mL. He was empirically started on dexamethasone due to concern for cerebral edema and was admitted. Surgery was recommended given the severity of his presentation, but the patient declined and he was discharged on cabergoline 1.5mg/week, dexamethasone taper, hydrocortisone 15mg/day, and levetiracetam 1000mg twice daily. On initial outpatient endocrinology evaluation 3 weeks later, he required the use of a wheel chair. Examination was notably for markedly flat affect, slurred speech, decreased attention span requiring frequent re-direction during the interview but he was otherwise oriented to person, time, and place. Neurological examination was noted for 4/5 muscle weakness throughout, facial asymmetry, decreased facial sensation, and an antalgic gait. He was recommended for expedited neurosurgical evaluation but he again declined. Laboratory drawn at this time showed a prolactin of 1946 ng/mL and total testosterone of 45 ng/dL, but he had normal thyroid and growth hormone axis (adrenal axis was not assessed as he was on dexamethasone taper). Carbergoline was titrated with further improvement in his prolactin levels. Four months after initial presentation, he reported enrolling in college with resolution of any cognitive and neurological deficits. Fourteen months after presentation, serum prolactin was 34 ng/mL on 4mg cabergoline per week and he is active in college and regularly plays basketball. Discussion Prolactinomas are incidentally detected or found as a result of workup for galactorrhea, infertility, or low libido. Typically, goals for treatment are to relieve compressive effects along the optic chiasm or to restore gonadal function. Acute cognitive decline should also be considered when there is a macroprolactinoma, and serial monitoring for improvement may be considered a clinical marker along with MRI imaging and prolactin levels. In this case, the patient had marked cognitive dysfunction on initial presentation but after 3 months of treatment had almost complete recovery as evidenced by his re-enrolling in college classes successfully. Presentation: No date and time listed

PMON49 Checkpoint Inhibitor Induced Hypophysitis with Growth Hormone Deficiency and Implications for the Treatment of ACTH Deficiency

Abstract Background/Purpose Hypophysitis is a known complication of immune checkpoint inhibitor (ICI) therapies used in the treatment of malignant cancers. In general, central adrenal insufficiency (AI) and hypothyroidism are the most recognized deficiencies following a diagnosis of ICI induced hypophysitis. As a result, other hypothalamic-pituitary axes (HPAs) are either incompletely evaluated or are disregarded from a therapeutic standpoint. Of particular importance is the growth hormone axis which is well established to affect tissue level metabolism of cortisol and cortisone through its effect on 11 beta hydroxysteroid dehydrogenase in target tissues. Our hypothesis is that growth hormone deficiency is also present in ICI induced hypophysitis. Methods We queried current and legacy electronic medical records of patients who received ICI for clinical notes mentioning adrenal insufficiency and concern for hypophysitis using the EMERSE tool. Patients with ICI exposure were included if they had 2 of the following 3 criteria; new onset central AI as defined by a low ACTH and cortisol, pituitary imaging suggestive of hypophysitis, or clinical presentation concerning hypophysitis. Patients were excludedfrom the analysis if there was a history of brain irradiation or in whom the diagnosis was not clear due to high dose steroid exposure prior to biochemical evaluation. Results Twenty-nine patients met inclusion criteria. Out of 29 patients, 16 underwent testing of the growth hormone axis with IGF-1 (11) and/or random growth hormone level (5). Seventeen patients (59%) had biochemical evidence of deficiency of 3 or more HPAs. Twenty-six patients (90%) had biochemical evidence of 2 or more PHAs. Two patients only underwent evaluation of 2 pituitary axes so it is unknown if they indeed suffered from panhypopituitarism. Most patients (28/29) were prescribed hydrocortisone for AI with an average dose of 20 mg per day. Conclusions Our findings are suggestive that growth hormone deficiency may be present in ICI induced hypophysitis. This finding holds implications for cortisol replacement therapy for coexisting AI. When one considers the average adrenal cortisol production is 5.7–7.4 mg/m2/day or 9.5–9.9 mg/day, 20 mg of daily cortisol replacementmay be too high in the face of concomitant growth hormone deficiency. Practice changes may include lower doses ofhydrocortisone replacement or adjustment to cortisone acetate which has been shown to have more favorable effectson tissue level metabolic effects. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON251 Loss of Constitutive Androstane Receptor, CAR reduces the serum androgens levels and alters reproductive function

Abstract The nuclear receptor, Constitutive Androstane Receptor (CAR/NR1i3) is extensively known for its detoxification function in the liver. We have identified the role of CAR in regulating androgen levels and regulating testis function. Although the inactivation of CAR by the sex hormone axis via androstanol has been known for decades, its role in regulating reproduction has not been addressed. On examining the WT mice and the global CARKO mice, we found that CARKO mice have reduced serum testosterone and androstanol levels. Further, the levels of the steroidogenic gene, Srd5a1 was significantly reduced. This result correlated well with reduced anogenital distance in males, increased anxiety and subfertility. However, we did not find differences in the expression of detoxification genes in the CARKO testis. Histological analysis of the testis of the CARKO mice revealed abnormal Leydig cells and Oil Red O staining showed lipid accumulation in the Leydig cell island. We are currently examining the effect of the reduced androgens in the hypothalamic-pituitary-gonadal axis in the CARKO mice model. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Effects of selected light wavelengths on the transcript levels of photoreceptors and growth-related hormones and peptides in the Malabar grouper Epinephelus malabaricus

Fish growth is influenced by environmental cues, including light conditions. The duration of exposure (photoperiod), the intensity of exposure (illumination), and quality (light spectrum) play crucial roles in maximizing growth. This study aimed to clarify how selected light wavelengths are perceived and transduced as an internal signal to stimulate growth of the Malabar grouper Epinephelus malabaricus, an important aquaculture species in Asian countries. Four opsins (RH1, RH2, SWS2, and LWS) were selected from the database of photoreceptors of groupers, and reverse-transcription polymerase chain reaction revealed that these opsins were expressed in the eyes and brain. When fish were reared under conditions of long-day (light:dark = 14:10) with red (peak at 632 nm), green (519 nm), and blue (465 nm) LED and natural light, the specific growth rate was higher (P < 0.05) in fish exposed to blue LED light than to red LED light. Rearing fish under shorter light wavelengths (blue or green) resulted in high transcript levels (P < 0.05) of RH1 and RH2 in the eyes (retina) and of RH1 and SWS2 in the brain (diencephalon), suggesting that certain light wavelengths activate photoreceptors in light perceptive organs. The transcript levels of growth hormone (GH) and insulin-like growth factor (IGF-I) increased significantly (P < 0.05) in the pituitary and liver of fish reared under blue LED light, respectively. Moreover, similar increases (P < 0.05) in the transcripts of neuropeptide Y (NPY) and pro-opiomelanocortin were observed in the brain of fish reared under blue LED light. We concluded that blue light perceived by visual opsins in the eyes and brain activates the growth of the endocrine axis and its interaction with NPY. Consequently, rearing the Malabar grouper under specific light wavelengths helps maximize their growth.

Association between Thyroid Hormones and Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis in Obese Individuals Undergoing Bariatric Surgery.

Background: Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatic fibrosis have emerged as one of the leading causes of chronic liver disease. The prevalence of the NAFLD spectrum has increased, which can be attributed to the rise in obesity. As NAFLD can ultimately lead to liver cirrhosis, it is imperative to identify modifiable risk factors associated with its onset and progression to provide timely intervention to prevent potentially disastrous consequences. Considering the pivotal role of the endocrine axis in several metabolic pathways such as obesity and insulin resistance, thyroid hormones are crucial in the pathophysiology of NAFLD. The study is focused on the identification of an association between thyroid function and radiographic and histological parameters of NAFLD in patients with severe obesity. Methods: Ninety patients were recruited for this study and underwent initial assessments, including demographic profiles, anthropometric measurements, hepatic biopsy, and basic laboratory tests. Liver stiffness was evaluated using two-dimensional shear wave elastography (2D-SWE) at least 2 weeks before liver biopsy. Results: Among the 90 participants, 80% were women. The mean age was 38.5±11.1 years, and the mean body mass index (BMI) was 45.46±6.26 kg/m2. The mean levels of serum T3 and free T4 in patients with positive histology were not statistically significant compared with patients with negative histology. Furthermore, there was no statistical significance in the mean T3 and free T4 levels between patients diagnosed with hepatic steatosis or fibrosis (on ultrasonography and elastography) and those with negative hepatic imaging. Serum levels of thyroid-stimulating hormone (TSH) were negatively correlated with ultrasonography (P=0.007). Binary logistic regression analysis revealed that none of the thyroid hormones was a predictive factor for liver histology in both adjusted and crude models. Conclusion: The results from our analysis did not suggest an association between thyroid hormones and NAFLD, which is in line with several previously published studies. However, the authors note that there are published data that do propose a link between the two entities. Therefore, well-designed large-scale clinical studies are required to clarify this discrepancy.

Changes in the content of hormones of hypothalamic-pituitary-thyroid axis in growth of single and multiple primary tumors in the presence of comorbidity

Introduction. Thyroid dysfunction is known to be associated with higher risks of cancer development. The purpose of this study was to analyze levels of thyroid axis hormones in the hypothalamus, pituitary gland, thyroid, and blood serum of male and female Balb/c nude mice with B16/F10 melanoma and/or lewis lung carcinoma. Material and methods. Male and female Balb/c nude mice were divided into groups: 1 – intact mice (n=7), 2 – mice with b16/f10 melanoma (n=7), 3 – mice with lewis lung carcinoma (LLC) (n=7), 4 – mice with melanoma and LLC (n=7). Levels of thyroid-stimulating hormone (TSH), triiodothyronine (fT3), and thyroxine (fT4) were measured by ria in homogenates of the hypothalamus, pituitary gland, thyroid and blood serum of all animals, and TH-releasing was measured by ELISA. Statistical processing of results was performed using the Statistica 10.0 program. Results. TH-releasing was reduced in the hypothalamus of all tumor-bearing mice, compared to initial values. TSH levels in the pituitary gland and thyroid were changed only in males with the combination of tumors (increased by 2.8 and 1.5 times, respectively). Levels of free forms of hormones in the thyroid in animals of both genders sharply increased, together with the elevation of TSH in the blood serum and, as a result, the decrease of fТ3 and fТ4 levels. Conclusion. Female and male Balb/c nude mice of the studied groups demonstrated hypothalamic dysfunction manifested by the absence of regulation in the hypothalamus-pituitary-thyroid relationship, and by the hypothyroid status of animals.

Hydrogen peroxide suppresses excitability of gonadotropin-releasing hormone neurons in adult mouse.

It has been reported that reactive oxygen species (ROS) derived from oxygen molecule reduction can interfere with the cross-talk between the hypothalamic-pituitary-gonadal (HPG) axis and other endocrine axes, thus affecting fertility. Furthermore, ROS have been linked to GnRH receptor signaling in gonadotropes involved in gonadotropin release. There has been evidence that ROS can interfere with the HPG axis and gonadotropin release at various levels. However, the direct effect of ROS on gonadotropin-releasing hormone (GnRH) neuron remains unclear. Thus, the objective of this study was to determine the effect of hydrogen peroxide (H2O2), an ROS source, on GnRH neuronal excitabilities in transgenic GnRH-green fluorescent protein-tagged mice using the whole-cell patch-clamp electrophysiology. In adults, H2O2 at high concentrations (mM level) hyperpolarized most GnRH neurons tested, whereas low concentrations (pM to μM) caused slight depolarization. In immature GnRH neurons, H2O2 exposure induced excitation. The sensitivity of GnRH neurons to H2O2 was increased with postnatal development. The effect of H2O2 on adult female GnRH neurons was found to be estrous cycle-dependent. Hyperpolarization mediated by H2O2 persisted in the presence of tetrodotoxin, a voltage-gated Na+ channel blocker, and amino-acids receptor blocking cocktail containing blockers for the ionotropic glutamate receptors, glycine receptors, and GABAA receptors, indicating that H2O2 could act on GnRH neurons directly. Furthermore, glibenclamide, an ATP-sensitive K+ (KATP) channel blocker, completely blocked H2O2-mediated hyperpolarization. Increasing endogenous H2O2 by inhibiting glutathione peroxidase decreased spontaneous activities of most GnRH neurons. We conclude that ROS can act as signaling molecules for regulating GnRH neuron's excitability and that adult GnRH neurons are sensitive to increased ROS concentration. Results of this study demonstrate that ROS have direct modulatory effects on the HPG axis at the hypothalamic level to regulate GnRH neuron's excitabilities.

Endocrine hormone imbalance in heart failure with reduced ejection fraction: A cross-sectional study.

Sustained neurohormonal activation plays a central role in the progression of heart failure (HF). Other endocrine axes may also be affected. It was the aim of this study to examine the endocrine profile (thyroid, parathyroid, glucocorticoid, and sex hormones) in a contemporary sample of patients with HF and reduced ejection fraction (EF) on established disease-modifying therapy. This study prospectively measured morning fasting hormones in 52 ambulatory and stable HF patients with EF < 50% on disease-modifying therapy (mean age 63 ± 11 years, 29% female, mean LVEF 32 ± 9.6%) and compared them to 54 patients at elevated risk for HF (61 ± 12 years, 28% female) and 62 healthy controls (HC; 61 ± 13 years, 27% female). Main comparisons were performed using one-way analysis of variance. Associations with biomarkers were studied with linear regression. HF patients showed a reduced free triiodothyronine (fT3)/free thyroxine (fT4) ratio compared to HC (0.30 ± 0.06 vs. 0.33 ± 0.05, p = 0.046). Parathyroid hormone (PTH) and cortisol were increased in HF compared to both HC (median [IQR] 59 [50-84] vs. 46 [37-52] ng/L,p < 0.001 and 497 ± 150 vs. 436 ± 108 nmol/L, p = 0.03, respectively) and patients at risk (both p < 0.001). Total testosterone was reduced in male HF compared to HC (14.4 ± 6.6 vs. 18.6 ± 5.3 nmol/L; p = 0.01). No differences in TSH, estradiol, progesterone, and prolactin were found. Lower fT3 levels were found in HF with EF < 40% versus EF 40%-49% (4.6 ± 0.3 vs. 5.2 ± 0.7 pmol/L, p = 0.009). In HF patients, fT3 was an independent predictor of NT-proBNP and high-sensitivity troponin T in multiple regression analysis. PTH was positively associated with NT-proBNP. There is evidence of endocrine hormonal imbalance in HF with reduced EF beyond principal neurohormones and despite the use of disease-modifying therapy.

Effects of Kisspeptin Administration in Women With Hypoactive Sexual Desire Disorder

Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown. To test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD. This randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021. A 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion. Blood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli. Of the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects. These findings lay the foundations for clinical applications for kisspeptin in women with HSDD. ISRCTN trial registry identifier: ISRCTN17271094.