bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of PACAP-Expressing Neurons in the Hypothalamic Origins of Sympathetic Outflow Tracts Terminating in Brown Adipose Tissue of Mice
Authors: Filatov Ekaterina , Rudecki Alex P , Constantin Alina-Geta , Gray Sarah Louise
Published: May 2021

Adaptive thermogenesis in brown adipose tissue is stimulated by the sympathetic nervous system (SNS) in response to cold stress. Using retrograde viral transneuronal tract tracers, previous studies have identified that the paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), and median preoptic nucleus (MnPO) contain neurons that are part of sympathetic outflow tracts to brown adipose tissue, presumptively involved in SNS stimulation of interscapular brown adipose tissue (iBAT). Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a peptide hormone known to regulate energy homeostasis, acting in both the central (CNS) and peripheral nervous system (PNS). Mice lacking PACAP have impaired adrenergic-induced thermogenesis and a cold-sensitive phenotype. In the CNS, PACAP is highly expressed in the VMH, MnPO, and PVN of the hypothalamus. Injection of PACAP into the VMN increased core body temperature and sympathetic nerve activity to brown adipose tissue. While these studies show exogenous PACAP can activate sympathetic outflow tracts to brown adipose tissue, they do not confirm that endogenously expressed PACAP induces sympathetic nerve activity as an adaptive mechanism to cold stress, or if sympathetic outflow tracts originating in the hypothalamus express PACAP. We hypothesize that PACAP is expressed in neurons of sympathetic outflow tracts originating in the hypothalamus. To test this hypothesis, PACAP-eGFP transgenic mice were injected with the retrograde neural tracer, pseudorabies virus tagged with β-galactosidase (β-gal, PRV-BaBlu), in iBAT where postganglionic nerves innervate the tissue. Five-days post-infection, animals were culled, brains removed and cryosectioned. Neurons positive for green fluorescent protein (eGFP) and/or β-gal immunoreactivity (ir) were identified by immunohistochemistry in serial coronal and sagittal brain cryo-sections. Co-occurrence of eGFP-ir and β-gal-ir, inferred PACAP expressing neurons present in sympathetic outflow tracts (ImageJ). Co-occurrence was identified in several structures in the hypothalamus and thalamus. In conclusion, this study presents neuroanatomical evidence for populations of PACAPinergic neurons in the hypothalamus that are part of sympathetic outflow tracts to brown adipose tissue, providing further evidence of a central role for PACAP in regulating energy homeostasis.
Serotonin as a Regulator of Leptin-Mediated Food Intake Control Within a Novel Neuronal Circuit Between the Hypothalamus and Raphe Nuclei
Authors: Sadek Alia T , Cowan Hanson B , Jimenez Katie M , Crawford Jesseca N , Maxwell Nicholas D , Fadel Jim R , Reagan Lawrence P , Grillo Claudia A
Published: May 2021

The onset and exacerbation of obesity involves the overproduction of the adipocyte-derived hormone leptin, a key mediator of homeostatic appetite regulation and a signal for satiety. Although leptin’s hypothalamic regulation of food intake has been extensively investigated, its role in tandem with the anorectic neurotransmitter serotonin (5-HT) has been less characterized. 5-HT is synthesized in the dorsal raphe nucleus (DRN) where anatomical projections to many hypothalamic nuclei have previously been identified. Preliminary studies in our lab have: (1) identified serotonergic neurons responsive to leptin in the DRN that project to the arcuate nucleus (ARC) of the hypothalamus and (2) demonstrated leptin injected into the DRN significantly decreases food intake. The objective of the current study was to identify the role of 5-HT in leptin’s regulation of food intake first within the DRN, then between the DRN and the ARC. Adult male Sprague Dawley rats underwent stereotaxic surgery for guide cannula implantation in the DRN. After recovery, animals were administered 100 µg of p-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, in the DRN each day for four days. On the fourth day, leptin was also administered in the DRN (5 µg/rat) and food intake was measured over a 24-hour time course. ANOVA analysis revealed a significant difference in 24-hour food intake [F (3, 18) = 3.972; P = 0.0246] and post-hoc analysis showed that animals treated with leptin significantly decreased food intake (17.2 ± 2.0 g) compared to control rats (25.4 ± 0.9 g), whereas PCPA-treated rats did not differ from the control rats, suggesting that depletion of 5-HT attenuated leptin’s ability to regulate food intake within the DRN. To examine the role of 5-HT on leptin’s hypothalamic action, a subsequent experiment was conducted by implanting an additional cannula into the ARC for the administration of leptin or vehicle on the fourth day of treatment. ANOVA analysis revealed a significant difference in 24-hour food intake [F (3, 16) = 5.998; P = 0.0061] and post-hoc analysis showed that only rats treated with leptin in the ARC significantly decreased food intake (14.0 ± 1.5 g) compared to controls (21.8 ± 0.5 g). 5-HT depletion was assessed post-mortem using immunohistochemistry and was later quantified. Collectively, these results demonstrate that leptin’s ability to regulate food intake is dependent on 5-HT, regardless of the area of regulation (i.e. DRN or the hypothalamus).
Role and Mechanism of Chronic Restraint Stress in Regulating Energy Metabolism and Reproductive Function Through Hypothalamic Kisspeptin Neurons
Authors: Huang Yinqiong , Wen Junping , Chen Gang
Published: May 2021

Objectives: The purpose of this study was to investigate whether stress affected energy metabolism and reproductive function through the glucocorticoid receptor (GR) on Kisspeptin neurons in the hypothalamus. Methods: 1. The first part of this study focused on the effects of chronic restraint stress on energy metabolism and reproductive function in mice. 2. The second part of this study focused on the effects of chronic restraint stress on the expression of serum cortisol and prolactin and the expression of GR and Kiss1 genes in the hypothalamus.3. Based on the above research, we constructed Kisspeptin specific glucocorticoid receptor knock out (KGRKO) mice. The mice were subjected to restraint stress intervention, the body weight of the mice was monitored every day, and the vaginal smear was performed on the female mice to observe the estrous cycle. After 28 days of restraint stress, serum was collected to detect serum sex hormone levels, including LH, FSH and estrogen levels in female mice and testosterone level in male mice by ELISA. Results: 1.The body weight and energy intake of the restraint stress group were lower than those of the control. 2.After restraint stress, the female mice showed irregular estrous cycle. LH and FSH levels in the stress group were significantly decreased compared with the control group.3. After restraint stress, the levels of serum cortisol and prolactin in male and female mice were significantly higher than the control group, and the hypothalamus Kiss1 gene mRNA expression and Kisspeptin protein expression were significantly decreased.4. In female mice, compared with GRflox/flox/Kiss1Cre-control mice, the nadir serum cortisol increased significantly in the morning in GRflox/flox/Kiss1Cre+ KGRKO mice, however, there was no significant difference in the serum peak cortisol in the afternoon. Compared with the control group, the restraint stress group and the KGRKO + restraint stress group had a significant weight loss compared with the KGRKO group. Compared with the restraint stress group, the KGRKO+restraint stress group had a reduced weight loss, suggesting that restraint stress might partially affect the energy metabolism through GR on Kisspeptin neurons. Conclusions: Chronic restraint stress induced weight loss in mice and reversed body weight gain induced by high-fat diet. Chronic restraint stress played a negative role in regulating reproductive function. The effects of chronic restraint stress on energy metabolism and reproduction were partially mediated by GR on Kisspeptin neurons in the hypothalamus. This study provided a central mechanism for chronic restraint stress in affecting energy metabolism and reproductive function, and was of great significance in revealing the relationship between the HPA axis with energy metabolism and reproduction.
“An Unexpected Pit” - Ectopic Pituitary Adenoma
Authors: Aftab Hassaan B , Gunay Canan , Dermesropian Racha , Kantorovich Vitaly
Published: May 2021

Background: Ectopic pituitary adenomas (EPAs) are exceedingly rare neoplasms, comprising about 0.5% of all pituitary adenomas. These are often misdiagnosed radiologically, while the correct diagnosis requires high index of suspicion on pathology and immunohistochemistry analysis. Clinical Case: 62-year-old female presented to the ED with transient unilateral visual loss. She denied orbital pain, headache, or motor or sensory deficit. Following unremarkable ophthalmology evaluation, initial MRI brain was suggestive of pituitary adenoma. MRI of the pituitary with gadolinium contrast showed nonenhancing focus of about 1.5 cm within the posterior sphenoid sinus adjacent to a normal-appearing pituitary gland. Lab assessment showed no pituitary hormone excess or insufficiency. ENT evaluation with repeat MRI brain with contrast showed a T2 heterogeneously enhancing hyperintense lesion in the clivus measuring 2.1 x 1.9 x 1.3 cm (transverse, AP and CC, respectively) with bony thinning/erosion of the sellar floor, the posterior wall of sphenoid sinus and dorsal clivus. Patient underwent transnasal transsphenoidal resection of the tumor with sample submitted as clival chordoma. Pathology report showed a 3.3 x 2.7 x 0.9 cm tumor with immunohistochemistry positive for ACTH, FSH, synaptophysin, chromogranin, S100 and cytokeratin while staining negative for GH, LH, TSH, prolactin and epithelial membrane antigen (EMA). Reticulin stain showed loss of reticulin network and Ki-67 labeling index was 1%. Neurosurgery and ENT teams confirmed no gross manipulation of the pituitary gland had been performed and findings supported a diagnosis of ectopic pituitary adenoma. On 6-month follow-up patient continued to do well clinically and MRI showed normal-appearing pituitary gland with no residual or recurrent tumor. Conclusion: EPA is a rare entity with about 133 cases described in literature. EPAs are generally benign, however up to 79% are functionally active and more likely than their sellar counterparts to secrete multiple pituitary hormones. EPAs arise from remnants of embryonic pituitary tissue in the migratory part of the Rathke’s pouch during early fetal development. The most common locations for EPA are in the sphenoid sinus, clivus, nasopharynx, cavernous sinus and suprasellar space and these are often misdiagnosed on initial radiology as neuroendocrine tumors, sino-nasal carcinomas, clival chordomas or even fungal infections. It is vital to consider EPA in the differential diagnosis of tumors removed from the mentioned anatomic locations as establishing the correct diagnosis helps to avoid the significant morbidity associated with treatments employed for other tumors. Reference: Riccio, L., Donofrio, C.A., Tomacelli, G. et al. Ectopic GH-secreting pituitary adenoma of the clivus: systematic literature review of a challenging tumour. Pituitary 23, 457-466 (2020)
A Follicular Stimulating Hormone Secreting Adenoma
Authors: De Croos Mary , Vender John , Elshimy Ghada , Stachura Maximillian
Published: May 2021

A gonadotroph secreting pituitary adenoma, a rare endocrinopathy, is often overlooked due to ambiguous symptoms leading to other diagnoses, such as ovarian hyperstimulation syndrome (OHSS).

A 53 year old African American woman presented for evaluation of a 4 month history of right hemianopsia. Her past medical history included a total hysterectomy and bilateral oophorosalpingectomy for recurrent ovarian cysts 11 years prior. Initial MRI:4.1x3.6x3.9 cm pituitary macroadenoma with prechiasmtic optic nerve compression. Initial laboratory studies: follicular stimulating hormone (FSH) level 186.83 mIU/mL (RR:23.0-116.3 mIU/mL) and luteinizing hormone (LH) 14.44 mIU/mL (RR:15.9-54.0 mIU/mL). Other pituitary labs were unremarkable. Debulking surgery was performed to relieve mass effect; pathology showed an FSH immunoreactive adenoma. Postoperatively, FSH was 2.55 mIU/mL and LH was 0.75 mIU/mL.

The prevalence of pituitary adenomas is 80-100 per 100,000 persons; 15-30% are non-functional. The majority of gonadotroph adenomas are difficult to identify because they may not produce biologically active hormones. Clinically functioning gonadotroph adenomas are very rare, often macroadenomas when found, most often found in reproductive age women, and preferentially secrete FSH. In reproductive age women, a FSH secreting adenomas may present clinically with OHSS, with multiple large ovarian cysts found on ultrasound for menstrual or pelvic complaints as seen in our patient. While OHSS is a known complication of assisted reproductive procedures, spontaneous OHSS is atypical and suggests need for evaluation of a FSH-secreting adenoma. Men may present with macroorchidism. Children may present with precocious puberty.

The treatment of choice is surgical removal of the adenoma, normalizing FSH to an age appropriate level. When OHSS is present, this results in a rapid decline in estradiol level and regression of ovarian cysts. Medical treatment, if surgery is contraindicated, is limited to cabergoline, which can initially decrease FSH and estradiol levels. In patients with normal pituitary function, gonadotropin-releasing hormone agonists acutely stimulate LH and FSH, thereby desensitizing GnRH receptors and decreasing gonadotropin secretion. In patients with FSH-secreting adenomas, they may have a persistent stimulatory effect, and in rare cases, result in pituitary apoplexy. Tumors that cannot be completely surgically removed may be treated by adjuvant radiotherapy or radiosurgery.
Discordance Between Prolactinoma Size and Prolactin Level: An Unusual Laboratory Finding
Authors: Dawaher Wafa , Patel Sabah , Unjom Zubina , Moid Alvia , Gilden Janice L , Trendafilova Victoria
Published: May 2021

Background: Prolactinomas are a common cause of hyperprolactinemia. Prolactin (PRL) level higher than 250 mcg/L is associated with a prolactinoma and serum prolactin levels generally correlate with tumor size. It is unusual to find a PRL level that is markedly elevated out of proportion to prolactinoma size. We present the case of a 32-year-old man who was referred to Endocrinology Clinic with fatigue and low testosterone, found to have a PRL level of 1302 mcg/L with a 9 x 8 x 9 mm microprolactinoma.

Clinical Case: A 32-year-old man with past medical history of migraines reported fatigue, weight gain, low libido and erectile dysfunction and was referred to Endocrinology Clinic due to PRL elevation. His medications included a multivitamin and chasteberry herbal supplement. Physical exam was unremarkable and no visual field abnormalities were detected. Baseline lab results showed PRL: >1000 mcg/L and 1302 mcg/L after serial dilutions, FSH: 1.8 mIU/mL [0.7- 10.8 mIU/ml], LH:0.9 L [1.2- 10.6 mIU/ml], total testosterone 136 ng/dL [250-1100 ng/dl], free testosterone: 32 [35- 155 pg/ml], with normal cortisol, ACTH, IGF-1, TSH and Free T4 levels. MRI pituitary revealed a 9 mm x 8 mm x 9 mm microadenoma on the right side of the pituitary gland without optic chiasm compression. He was diagnosed with microprolactinoma, with very high PRL level causing secondary hypogonadism. Cabergoline 0.25 mg twice weekly resulted in significant improvement in PRL level. With dose increment to 0.5 mg twice weekly, PRL level improved further along with improvement in symptoms related to hypogonadism. Five months after initiation of treatment, total PRL was 58 ng/mL with monomeric PRL of 41 mcg/L, indicating only trace contribution of macroprolactin to the total PRL level.

Review of the Literature: In a retrospective study by Colao et al. (2003), men with hyperprolactinemia due to micro-prolactinoma had average pre-treatment PRL levels of 187.7 mcg/L (SD 51.8 mcg/L) and average pre-treatment diameter of 8.0 mm (SD 1.4 mm). A retrospective study of 1234 patients by Vilar et al. (2008) reported similar findings: microprolactinomas had average baseline PRL of 165.6 mcg/L (SD 255.1 mcg/L) and the highest reported level of PRL due to microprolactinoma was 525 mcg/L. Conclusion: Our case illustrates that assumptions about prolactinoma size should not be made based on laboratory findings alone. References: Melmed S. et al, Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 96: 273-288, 2011.Colao A. et al. Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia. European Journal of Endocrinology 148: 325-331.Vilar L. et al. Diagnosis and Management of Hyperprolactinemia: Results of a Brazilian Multicenter Study with 1234 Patients. J Endocrinol Invest 31:436-444.
Giant Pituitary Adenoma Presenting With Disinhibition: A Case Report of a 25-Year-Old Male
Authors: Nottingham Saleen , Boyle Veronica , Tamatea Jade , du Toit Stephen Andrew , Wolmarans Louise , Elston Marianne Susan
Published: May 2021

Background: Giant growth hormone secreting pituitary adenomas (defined by a diameter >4cm) are rare and difficult to treat (1). These typically invade surrounding structures, making surgery challenging or impossible (1). This report highlights a giant mammosomatotrophinoma with an unusual clinical presentation. Clinical Case: A 25-year-old male presented with personality changes, disinhibition and executive dysfunction progressing over a 3 to 4-year period. Further enquiry elicited a history of increasing headaches and significant visual loss, on the background of unilateral childhood visual loss in the contralateral eye. He was noted to have clinical features of acromegaly and complete temporal visual field loss in the left eye. On initial testing plasma IGF-1 was 137 nmol/L (reference interval [RI] 13-43nmol/L), GH >100 ug/L and prolactin 23,900 mIU/L (RI 0-400mIU/L). GH remained >100ug/L at 120 minutes after a 75g oral glucose load. He has hypogonadotropic hypogonadism, however thyrotropic and corticotropic function remained normal. MRI of the brain with contrast revealed an 8.0 x 7.1 x 7.4 cm mass arising from the pituitary fossa, extending into the suprasellar region and displacing both frontal lobes. The mass encased the basilar and right internal carotid arteries. It was deemed inoperable due to its exceptionally large size and encasement of vascular structures. Medical treatment was initiated with cabergoline (3.5mg per week in divided doses) and octreotide LAR, initially 30mg then increased to 60mg 4-weekly. A weaning course of steroids was initiated for oedema of his optic nerve. Within one month of treatment there was improvement of clinical symptoms of headaches, sweating, irritable mood and disinhibition with associated modest biochemical improvement (reduction of IGF-1 to 129 nmol/L and prolactin reduction to 2119 mIU/L). MRI of the brain revealed a reduction in the size of the adenoma to 7.8 x 7.1 x 6.3 cm, with a reduction in the mass effect on the frontal lobes. The patient continues medical management and close clinical monitoring with the aim of ongoing tumour shrinkage to allow reassessment for possible surgical debulking. Conclusion: This unique case of a GH and prolactin co-secreting giant pituitary adenoma posed a therapeutic challenge due to the significant surgical risk, limiting treatment to aggressive medical therapy. The cognitive and behavioral changes experienced due to tumour size and location added to the management complexity. Although early on in the treatment course, there is improvement of symptoms and tumour size on cabergoline and octreotide LAR injections. (1) Iglesias P, Rodríguez Berrocal V, Díez JJ. Giant pituitary adenoma: histological types, clinical features and therapeutic approaches. Endocrine. 2018 Sep;61(3):407-421.
Pituitary Macroadenoma: A Case of Balanced Deficiencies
Authors: Leimbach Robert , Shakir Mohamed K M , Hoang Thanh Duc
Published: May 2021

Introduction: Diabetes insipidus (DI) rarely occurs in pituitary tumors although some patients may develop DI following pituitary tumor resection. However DI is known to occur in patients with tumors metastatic to the pituitary or in infiltrative disorders of the pituitary gland. We are reporting a patient with a 2 cm pituitary macroadenoma whose DI was unmasked by glucocorticoid therapy. Case Presentation: A 61-year-old male with a history of non-functioning pituitary macroadenoma, incidentally discovered on imaging in 2015 and stable at 1.6cm for 4 years, was referred to endocrinology for interval enlargement of his macroadenoma. He had presented to primary care due to new headache during extreme physical exertion, but otherwise denied any symptoms such as vision loss, fatigue, decreased libido, weight loss, or urinary frequency. Repeat MRI indicated growth to 2.1cm in the suprasellar component, no cavernous sinus involvement, and abutting the optic chiasm. Laboratory results revealed new onset central hypothyroidism (FT4 0.21 ng/dL (ref 0.78-2.19) with triiodothyronine 68 ng/dL (ref 80-200) and TSH 1.61 mIU/L (ref 0.47-4.68), central hypogonadism (Testosterone Free 1.3 pg/mL (ref 6.6-18.1)) and concern for adrenal insufficiency with a cortisol of 4.4 mcg/dL. He was empirically started on hydrocortisone replacement until an ACTH stimulation test could be completed, and after 3 days instructed to begin low dose levothyroxine replacement. At close followup, patient revealed that he developed new hourly nocturia causing significant distress. An overnight water deprivation test yielded a serum sodium 152 mmol/L with a urine osmolality 191 mOsm/kg, both rapidly improving with intravenous desmopressin. Copeptin was 4.6 pmol/L. Discussion Diabetes insipidus occurring in pituitary tumors including macroadenomas is extremely rare. Secretion of AVP occurs in the hypothalamic osmoreceptors, supraoptic or paraventricular nuclei, and the superior portion of the supraopticohypophyseal tract. AVP deficiency is most commonly due to damage to these areas either through neurosurgery or trauma, and more rarely tumors or infiltrative disease. However, glucocorticoid and thyroid replacement each may precipitate the development of diabetes insipidus. Well described in literature, glucocorticoid deficiency and hypothyroidism each independently impairs free water excretion. Low cortisol stimulates release of antidiuretic hormone, but this secretion is then inhibited by exogenous steroid replacement. Cortisol interferes with AVP signaling through unclear mechanisms either at the V2 receptor or post-receptor level, decreasing translocation of type 2 aquaporins and therefore reducing free water reabsorption. It is important to recognize that CDI can be unmasked after glucocorticoid or thyroid hormone replacement.
Successful Treatment of Myxedema Coma Using Liothyronine in the Setting of Adrenal Crisis
Authors: Elghawy Omar , Hafey Alexander C , McCartney Christopher Rolland , Steinman Jeremy R
Published: May 2021

Background: Myxedema coma (MC) represents severe decompensated hypothyroidism and is associated with mortality rates up to 50%. It is precipitated by an acute event which disrupts compensatory mechanisms present in severe hypothyroidism. Treatment includes IV levothyroxine (LT4) with consideration of liothyronine (LT3) therapy and management of any underlying stressor. Here we present a case of MC and adrenal crisis due to pituitary dysfunction successfully treated with IV LT4 and LT3. Case: A 55-year-old female with no pertinent medical history presented with two weeks of shortness of breath, anorexia, fatigue, and unexplained falls. Her initial vital signs were notable for a blood pressure of 86/60, temperature of 36.3 °C, heart rate of 59, SpO2 of 86 on room air, and respiratory rate of 21. Exam was notable for altered mentation, respiratory distress, decreased bowel sounds, and edematous facies. Initial serum studies were notable for sodium of 133 mmol/L (135-145 mmol/L), blood glucose of 50 mg/dL (74-99 mg/dL), TSH of 2.1 mIU/L (0.45-4.50 mIU/L), and blood gas showed pH of 7.27 and PaCO2 of 84.7 mmHg. She was intubated, started on vasopressors, and IV hydrocortisone 100 mg was administered. Her pretreatment serum cortisol was unmeasurable (below 0.5 mcg/dL) and ACTH resulted at 2.0 pg/mL (7-63 pg/mL). Despite hydrocortisone 50 mg q8h, her vitals worsened with HR to 40 bpm and temperature to 34.4 °C. Given concerns for MC, free and total T4 tests were obtained and both were undetectable (below 0.4 ng/dL and 4.0 ug/dL, respectively), so 300 mcg IV LT4 was administered. The next day, the patient’s vasopressor requirement increased, so 5 mcg IV LT3 q8h was added and IV LT4 was maintained at 100 mcg/day. Total T4 and T3 were measured daily and increased into the reference range over the course of 8 days and 2 days, respectively. LT3 was discontinued after 8 days and LT4 was converted to oral regimen of 125 mcg LT4 (weight expected 115 mcg) on day 14 after extubation; her hydrocortisone was tapered to a daily total of 30 mg PO. An MRI of pituitary showed an empty sella with a thin rim of normal appearing tissue without other lesions. The patient later denied any history of post-partum hemorrhage, idiopathic intracranial hypertension, pituitary surgery, radiation, or trauma. She is currently doing well on LT4 and hydrocortisone replacement. Conclusion: This case highlights the successful use of combined LT4 and LT3 in the treatment of MC with concomitant adrenal crisis. LT3 therapy may have been particularly beneficial in this case as conversion of T4 to T3 may be limited in setting of severe illness and high-dose glucocorticoid administration. Limited observational literature suggests that LT3 use can have clinical benefit, although excessive LT3 dosing may be associated with increased mortality. Further research is required to elucidate the benefits of empiric LT3 use in MC with concurrent adrenal insufficiency.
Obesity Is Associated With Intensive Care Use and Duration of ICU Stay but Not Mortality Among 3246 Patients Hospitalized With COVID-19
Authors: Kang Yu Mi , Brancale Joseph , Athonvarangkul Diana , Alausa Jameel , Subair Labeebah , Lipska Kasia Joanna , Jastreboff Ania M
Published: May 2021

Obesity is associated with increased severity of viral illnesses, but its impact on outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is yet to be elucidated. We sought to determine the association of obesity and other clinical factors with outcomes among patients hospitalized for severe coronavirus disease (COVID-19). This study included patients hospitalized between March 1, 2020 and September 17, 2020 in a 5-hospital health care system in Northeast United States, who had a positive RT-PCR assay of nasopharyngeal swabs for SARS-CoV-2 performed during hospitalization. Body mass index (BMI) was calculated using admission weight and height, and the WHO classification was used to define obesity. Both bivariate and multivariate logistic regression analyses were performed to determine the association of obesity and other clinical parameters with mortality (defined as in-hospital death or transition to hospice care) and intensive care use (defined by transfer to intensive care unit [ICU]). Multivariate model was adjusted for demographics and 8 pertinent comorbidities. Among 3246 patients hospitalized with COVID-19, median age was 65 years (interquartile range, 51–78), 49.9% were female, 30.5% overweight, and 43.2% had obesity (20.8%, 12.1%, and 10.4% with class I, II, and III obesity, respectively). A total of 542 (16.7%) patients died or received hospice care, and 811 (25.0%) required ICU care. In unadjusted analyses, patients with obesity had lower mortality compared with normal weight adults (13.0% vs. 23.1%) but a higher risk of ICU care (26.5% vs. 22.5%) and longer duration of ICU stays (9.5±10.6 vs. 6.6±8.5 [days]; all p-values <0.05). Obesity was associated with a higher incidence of hypoxic respiratory failure requiring invasive (17.8% vs. 9.3%) and noninvasive (22.7% vs. 14.0%) ventilatory support. In multivariate analysis, older age, male sex, and diabetes were significantly associated with both mortality and ICU care. In contrast, obesity was not associated with a significantly higher mortality (adjusted odds ratio [OR] 1.14; 95% CI, 0.91–1.43) but was associated with a higher risk of ICU care (OR 1.27; 95% CI 1.07–1.51 for all obesity and OR 2.07; 95% CI 1.51–2.82 for class III obesity compared with normal weight). The association of underweight with mortality (OR 1.56; 95% CI 0.93 - 2.60) and ICU care (OR 1.20; 95% CI, 0.71–1.99) was not statistically significant. This retrospective study of hospitalized patients suggests that obesity is associated with intensive care use and longer duration of ICU stay but not with mortality due to COVID-19. These findings underscore the vulnerability of individuals with obesity during the current pandemic.
Unexpected but Not Uncommon - a Case of Adrenal Insufficiency
Authors: Ariyawansa Chanika , Zhang Rui , Lim Ee Mun , Beilin Jonathan
Published: May 2021

Background: Herbal remedies are widely available and whilst portrayed as generally harmless, they may contain a variety of potent medications that can cause unintended and potentially serious consequences. This danger is further amplified as their use is typically inadvertently not divulged to clinicians, such as in this case.

Clinical Case: A 65-year-old gentleman was referred to Endocrinology for assessment of adrenal insufficiency (AI) as a cause of his lethargy. He was found to have serum cortisol levels of 38 nmol/L and 68 nmol/L (150 – 700 nmol/L) on two separate mornings. No identified recent use of inhaled, topical, intra-articular or oral exogenous steroid therapy was noted. He had an inadequate response to Synacthen stimulation with peak serum cortisol of 150 pmol/L at 60-minutes (Adequate response – Post-Synacthen cortisol >430 pmol/L). Baseline plasma ACTH was low - 1.1 pmol/L(2.0 – 10 pmol/L) and secondary (pituitary) AI was suspected. He had normal thyroid function and prolactin. The patient subsequently admitted to taking an herbal medication, “Montalin” for a few months. It was obtained over-the-counter in Indonesia for symptomatic relief of “muscle pains”. The tablet underwent analysis to investigate for presence of corticosteroid components.

An intact Montalin capsule was partly dissolved and the soluble content was diluted and analysed via LCMS/MS. Presence of dexamethasone/betamethasone was confirmed at an approximate concentration of 69.8 nmol/L constituting 0.548mg and 0.81% of the tablet. At the time, betamethasone and dexamethasone could not be distinguished due to stereoisomerism, but since has been confirmed to be dexamethasone.

The patient likely had suppression of the hypothalamic-pituitary-adrenal axis from unintended exogenous corticosteroid use, causing a picture of secondary AI. He requires ongoing corticosteroid replacement pending recovery of endogenous production. Although Montalin is marketed as an herbal over-the-counter medication it was confirmed to be adulterated with a potent corticosteroid. An alert issued by the Singaporean government details two further cases of adverse effects from Montalin and warns against its use.

Conclusion: Herbal remedies with undisclosed potent ingredients may unknowingly cause serious adverse effects. With advances in LCMS/MS technology, laboratory analysis of either the tablets or the patient’s serum could be utilised to identify potential exogenous corticosteroid exposure.
Risk of Complications in Children With Type 1 Diabetes and Covid-19
Authors: Raisingani Manish Gope
Published: May 2021

Background: There is some data available in adults which suggests that Type 1 diabetes may be associated with higher risk with Covid-19 (1). Limited data has been available in pediatric Type 1 diabetes with Covid-19. Methods: We used TriNetX, with a large COVID-19 database, collecting real-time electronic medical records data. We compared children (0–18 years) who were diagnosed with Covid-19 with and without Type 1 diabetes. This database collected information from 54 health care organizations. Results: Mortality rate in children with Covid-19 and Type 1 diabetes was 0.618% (10/1618). Mortality rate in children with Covid-19 without Type 1 diabetes was 0.102% (257/251517). Relative risk of mortality for children with Covid-19 and Type 1 diabetes was 6.05 with a p value of < 0.0001. Endotracheal intubation rate in children with Covid-19 and Type 1 diabetes was 0.618% (10/1618). Endotracheal intubation rate in children with Covid-19 without Type 1 diabetes was 0.071% (178/251517). Relative risk of endotracheal intubation for children with Covid-19 and Type 1 diabetes was 8.73 with a p value of < 0.0001. Pneumonia rate in children with Covid-19 and Type 1 diabetes was 0.804% (13/1618). Pneumonia rate in children with Covid-19 without Type 1 diabetes was 0.562% (1414/251517). Relative risk of pneumonia for children with Covid-19 and Type 1 diabetes was 1.43 with a p value of < 0.1959. Septic shock rate in children with Covid-19 and Type 1 diabetes was 1.05% (17/1618). Septic shock rate in children with Covid-19 without Type 1 diabetes was 0.293% (737/251517). Relative risk of septic shock for children with Covid-19 and Type 1 diabetes was 3.59 with a p value of < 0.00001. Conclusion: Mortality rate, endotracheal and septic shock were increased in children with Type 1 diabetes and Covid-19 versus children with Covid-19 and no Type 1 diabetes. Further studies with larger sample size are needed to study complication rate of Covid-19 and Type 1 diabetes. References 1) Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol 2020 Oct;8(10):813–822. doi: 10.1016/S2213-8587(20)30272-2. Epub 2020 Aug 13.
What Does SGLT2 Inhibition Add in Managing Hyponatremia Secondary to Syndrome of Inappropriate Antidiuresis (SIAD)?
Authors: Jalal Fadzliana Hanum , Ibrahim Luqman , Lim Quan Hziung , Chooi Kheng Chiew , Rajendran Santhanaruben , Ratnasingam Jeyakantha , Paramasivam Sharmila Sunita , Vethakkan Shireene Ratna , Lim Lee-Ling
Published: May 2021

Background: Apart from treating the underlying causes, other treatment options for SIAD are of limited success. Drug repurposing of SGLT2 inhibitors for use in SIAD has been suggested. Clinical Case: A 72 years old gentleman with type 2 diabetes mellitus, hypertension, ischemic cardiomyopathy (ejection fraction 40%) and paranoid personality disorder presented with 3-day history of confusion, vomiting and reduced appetite. On examination, he was fully alert, afebrile, blood pressure 173/81 mmHg, heart rate 83 beats per minute and euvolemic. There were fine crackles in the lung bases bilaterally. Random capillary blood glucose level was 5.6 mmol/L (100 mg/dL) and there was no hypoxia. Laboratory results were suggestive of SIAD (serum sodium [Na] 115 mmol/L, serum osmolality 241 mmol/kg, urine osmolarity 458 mmol/kg, spot urine Na 56.7 mmol/L) with normal fT4 (17.6 pmol/L [1.37 ng/dL]), TSH (1.6 mIU/L) and cortisol (821 nmol/L [29.7 mcg/dL]) levels. Medications at admission were daily dosing of olanzapine 7.5 mg, sitagliptin/metformin 50/850 mg, losartan 50 mg, rosuvastatin 10 mg and aspirin 100 mg. Further investigations for causes of SIAD including magnetic resonance imaging of the brain and contrast-enhanced computed tomography of thorax, abdomen and pelvis were normal. He was treated with fluid restriction (1 liter/day) and furosemide (oral 20 mg daily for 2 doses, followed by intravenous 20 mg twice daily for 3 doses) on day 1-4, leading to negative fluid balance (total 3300 ml) with an increment in serum Na to 124 mmol/L on day 5. However, this was accompanied by a reduction in systolic blood pressure (148 to 118 mmHg) and serum potassium level (4.7 to 3.7 mmol/L), along with marked increases in urea (2.7 to 8.8 mmol/L) and creatinine levels (51 to 75 µmol/L) (eGFR from >90 to 87 mL/min/1.73m2). Hence, furosemide was stopped and empagliflozin 12.5 mg daily was initiated on day 5 with continuation of fluid restriction. Serum Na level increased by 2 mmol/L to 126 mmol/L after 12 hours and by 3 mmol/L (to 129 mmol/L) on subsequent day with negative fluid balance (950 ml per 24 hours). Urea and eGFR levels improved and losartan was reintroduced for blood pressure control. There was no euglycemic diabetic ketoacidosis episode. Patient was discharged on day 10 with a serum Na level of 131 mmol/L. Outpatient follow up 5 days after discharge showed further improvement in serum Na level to 134 mmol/L with serum osmolality 286 mmol/kg and urine osmolarity 672 mmol/kg. Clinical Lesson: SGLT2 inhibition can be considered as one of the treatment options of hyponatremia secondary to SIAD with good tolerability
Drug Induced Hyperprolactinemia
Authors: Venkatanarasu Ashok , Boddula Raman , Basavaraju Santosh , Chinte Chimutai , Tickoo Vidya
Published: May 2021

Introduction: Drugs are a common cause of hyperprolactinemia. It is essential to differentiate this cause from other pathological causes which avoids unnecessary investigations. Detailed history will help us in identifying the responsible drug and withdrawing the same will be rewarding. Here we are reporting a case series of drug induced hyperprolactinemia. Methods: It was a cross-sectional observational study. Subjects were recruited from our outpatient department. Hyperprolactinemia was defined as blood prolactin levels >30 ng/mL in females and >24 ng/mL in males, regardless of the presence of symptoms. Serum prolactin was repeated one week after holding the suspected drug(s). Drug induced hyperprolactinemia is defined as normalisation of serum prolactin on discontinuation of the offending drug. Demographics, clinical presentation and offending drug name were entered in pre designed proforma.

Results: Total of 32 subjects were studied in this study with age of 35.5±10.8years. Predominantly female subjects were present with female to male ratio 5.4. Basal prolactin was 132±68.7ng/mL and after holding the drug prolactin value was 16.9±8.2. Proton pump inhibitors in combination with prokinetics were the leading cause (71.8%) and followed by multiple drug combinations (15.6%), anti-psychiatric drugs(9.3%) and oral contraceptives(3.1%). Overall 86.75% of subjects were having symptomatic presentation. Commonest clinical presentation among the women was galactorrhea (88.9% of female subjects) followed by irregular menstrual cycles (59% of female subjects) and breast heaviness in 29.6%. Among the men erectile dysfunction was common presentation, noted among 80% of them. Asymptomatic presentation was there in 6.25% of subjects. All subjects were improved clinically after withdrawal of the the offending drug(s).

Conclusions: Most of the subjects were clinically symptomatic. Most common symptom in female was galactorrhea followed by irregular menses and breast heaviness, and erectile dysfunction in males. All subjects were improved clinically after withdrawal of the offending drug(s). A detailed drug history is rewarding and avoids unnecessary investigations for hyperprolactinemia
Pituitary Stalk Lesions - Single Center Long Term Observation
Authors: Kluczynski Lukasz , Godlewska Magdalena , Rogozinski Damian , Nowak Andrzej Jerzy , Zygmunt-Gorska Agata , Wojcik Malgorzata , Starzyk Jerzy , Hubalewska-Dydejczyk Alicja , Gilis-Januszewska Aleksandra
Published: May 2021

Background & Methods: Pituitary stalk lesions (PSL) are various changes located in the pituitary infundibulum. The underlying pathology and exact diagnosis are difficult to establish due to their unique anatomical locus. A retrospective observational analysis of 60 adult patients (34W/26M) with pituitary lesions was performed. The mean age of diagnosis was 33.8 years (SD 23.7). The etiologies were divided into 3 groups (congenital, inflammatory, neoplastic), classified as exact, probable or unknown and characterized hormonally. Aim: To present the etiological spectrum of pituitary stalk lesions and their clinical and hormonal characteristics on the basis of long term observation in the pediatric/adult endocrinology departments of our university. Results: The most common causes of PSL were neoplasms (20/60, 33.3%, 14W/6M); congenital malformations were detected in 17/60 (28.3%, 6W/11M), while inflammatory etiology was found in 15/60 (25.0%, 9W/6M) of patients. The exact diagnosis was established in 26/60 (43.3%) cases (16 congenital malformations, 6 adenomas, 1 pituitary cancer, 1 craniopharyngioma, 1 germinoma and 1 lymphocytic hypophysitis [LH]). The probable cause was suggested in 26/60 patients (43.3%) - 10 with the suspicion of LH, 4 with histiocytosis, 3 with a metastatic tumor from a disseminated cancer, 3 craniopharyngiomas, 1 posterior pituitary lobe ectopy, 1 prolactinoma, 1 granular cell tumor, 2 adenomas and 1 pituicytoma. The origin of 8/60 PSL (13.3%) remains unknown. During hormonal assessment the most common insufficiency concerned the gonadal axis found in 29/60 (48.3%) of patients, followed by thyroid (26/60, 43.4%), somatotropic (21/60, 35.0%) and adrenal axis (20/60, 33.3%) insufficiencies. Hyperprolactinemia was detected in 20/60 (33.3%) of patients, while diabetes insipidus was confirmed in 15/60 (25%) of cases. 45 patients presented at least 1 hormonal deficit, some of them were transient. In clinical aspect, symptoms associated with hormonal deficits led to the initiation of diagnostic work-up in 29 patients (48.3%; including 15 patients (25.0%) with growth retardation). Neurological symptoms such as headaches, visual disturbances and seizures were seen in 13 patients (21.7%). Polydipsia and polyuria were the primary presentation in 11 cases (18.3%), while 5 cases (8.3%) had a clinical manifestation of hormone overproduction. Incidental diagnosis was seen in 2 female patients (3.3%). Conclusions: The diagnosis, management and treatment of the pituitary stalk lesions remains challenging. Difficulties in establishing the exact diagnosis might also be related to the non-specific, transient characteristics of the symptoms and hormonal insufficiencies. Long term observations might help better the understanding of the disease and result in improvement of management.
Relationship Between 24-Hour Serum LH and Testosterone Concentrations and Their Interrelationships With Other Pituitary Hormones in Healthy Older Men
Authors: van der Spoel Evie , Roelfsema Ferdinand , van Heemst Diana
Published: May 2021

Background: With ageing, LH levels rise while T levels decline in men, although this decline in T levels could also be caused by a change in health status, including body composition, inflammation, and comorbidities. Not only levels of LH and T change with age, but levels of other pituitary hormones also change concomitantly with age. It could be hypothesized that these hormonal changes are synchronized with each other.

Objective: In this study, we aimed to determine the relationship between 24-h serum LH and T concentrations in healthy older men. Besides, we aimed to determine which health factors, including body composition, metabolic and inflammatory markers, and LH-T related markers are associated with the strength of this LH-T relationship. Furthermore, we explored the interrelationships between LH and T with 24-h serum concentrations of GH, TSH, cortisol, and ACTH.

Design: Hormones were measured in serum samples collected every 10 min during 24 h from 20 healthy men, comprising 10 offspring of long-lived families and 10 control subjects, with a mean (SD) age of 65.6 (5.3) years. We performed cross-correlation analyses to assess the relative strength between two 24-h hormone concentration series for all possible time shifts.

Results: A mean (95% confidence interval) maximal correlation coefficient of 0.21 (0.10 – 0.31) at lag time 60 min was found between LH and total T concentrations. Results were comparable for calculated free, bioavailable, or secretion rates of T. Men with strong LH-T cross-correlations had, compared to men with no LH-T relationship, lower fat mass (18.5 (14.9 – 19.7) vs. 22.3 (18.4 – 29.4) kg), waist circumference (93.6 (5.7) vs. 103.1 (12.0) cm), hsCRP levels (0.7 (0.4 – 1.3) vs. 1.8 (0.8 – 12.3) mg/L), IL-6 levels (0.8 (0.6 – 1.0) vs. 1.2 (0.9 – 3.0) pg/mL), and 24-h mean LH levels (4.3 (2.0) vs. 6.1 (1.5) U/L), and stronger LH-T feedforward synchrony (1.5 (0.3) vs. 1.9 (0.2)). Furthermore, T was positively cross-correlated with TSH (0.32 (0.21 – 0.43)), cortisol (0.26 (0.19 – 0.33)), and ACTH concentrations (0.26 (0.19 – 0.32)).

Conclusions: LH concentrations were followed by T concentrations/secretion with a delay of 60 min in healthy older men, which is in line with literature. Men with a strong LH-T relationship had more favorable body composition, inflammatory markers, 24-h mean LH levels, and LH-T feedforward synchrony. In contrast, chronological age and 24-h mean T levels were not associated with the strength of the LH-T relationship. This observation could indicate that LH and health markers play a bigger role in determining the strength of LH-T cross-correlations than T and chronological age. Furthermore, we observed positive correlations between T and TSH, cortisol, and ACTH concentrations. These exploratory analyses could indicate that T and other hormones are driven by a common regulator or that there is crosstalk between these hormones.