Integrating Basic Science into Endocrine Clinical Electives.

Practical and effective methods to integrate basic science material into clinical electives are lacking. We developed a primer for medical students participating in an ambulatory endocrinology elective highlighting pathophysiology, symptoms, diagnosis, and management of disorders. Students felt better prepared for the elective and mean scores on the endocrine knowledge test improved (7.5 (SD = 2.4) to 9.6 (SD = 2.2), p < 0.001). The endocrine primer required minimal faculty time and resources while integrating basic science information into a clinical elective, standardizing students' knowledge, and enhancing student satisfaction with the elective. This innovative primer lays the groundwork to expand to other specialty electives and institutions.

A National Survey of United States-Based Endocrinologists Who Prescribe Gender-Affirming Hormone Therapy.

OBJECTIVE: The World Professional Association for Transgender Health Standards of Care Version 7 recommended that before initiating gender-affirming hormone therapy (GAHT), patients should seek a psychosocial evaluation from a mental health professional documenting a diagnosis of persistent gender dysphoria. The Endocrine Society published guidelines in 2017 recommending against an obligatory psychosocial evaluation, which was affirmed in the recently published World Professional Association for Transgender Health Standards of Care Version 8 from 2022. Little is known about how endocrinologists ensure appropriate psychosocial assessment for their patients. This study assessed the protocols and characteristics of U.S.-based adult endocrinology clinics that prescribe GAHT. METHODS: An anonymous electronic survey sent to members of a professional organization and the "Endocrinologists" Facebook group was responded by 91 practicing board-certified adult endocrinologists who prescribe GAHT. RESULTS: Thirty-one states were represented by the respondents. Overall, 83.1% of GAHT-prescribing endocrinologists reported accepting Medicaid. They reported working in university practices (28.4%), community practices (22.7%), private practices (27.3%), and other practice settings (21.6%). Overall, 42.9% of the respondents reported that their practice required documentation of a psychosocial evaluation from a mental health professional before initiating GAHT. CONCLUSION: Endocrinologists who prescribe GAHT are divided about requiring a baseline psychosocial evaluation before prescribing GAHT. Further work is needed to understand the impact of psychosocial assessment on patient care and facilitate the uptake of new guidelines into clinical practice.

Radiology report language positively influences adrenal incidentaloma guideline adherence.

BACKGROUND: Adrenal incidentalomas are common radiographic findings. Guidelines recommend biochemical and radiographic surveillance of adrenal incidentalomas. We investigated if patients were appropriately referred for outpatient evaluation. METHODS: Retrospective chart review was performed to identify patients with adrenal masses on imaging between November 7, 2016 and November 7, 2017. Demographic information, medical history, and outpatient referral information was collected. RESULTS: 11,723 computed tomography (CT) scans of the chest and/or abdomen/pelvis were performed. 246 patients were noted to have adrenal incidentalomas and met inclusion criteria. The CT report recommended follow-up in 63/246 cases (25.6%). 38/246 (15.4%) patients were referred for evaluation. Age, adrenal nodule size, and type of evaluating provider did not affect referral. A radiology report recommending follow-up was associated with increased referral rate (OR 5.441, 95% CI: 2.491-11.887). CONCLUSION: There was low outpatient referral for adrenal incidentalomas. Language in the radiology report significantly influenced referral rates and may be an important resource for improving guideline adherence.

Symptomatic Cushing's syndrome and hyperandrogenemia in a steroid cell ovarian neoplasm: a case report.

BACKGROUND: Malignant steroid cell tumors of the ovary are rare and frequently associated with hormonal abnormalities. There are no guidelines on how to treat rapidly progressive Cushing's syndrome, a medical emergency. CASE PRESENTATION: A 67-year-old white woman presented to our hospital with rapidly developing signs and symptoms of Cushing's syndrome secondary to a steroid-secreting tumor. Her physical and biochemical manifestations of Cushing's syndrome progressed, and she was not amenable to undergoing conventional chemotherapy secondary to the debilitating effects of high cortisol. Her rapidly progressive Cushing's syndrome ultimately led to her death, despite aggressive medical management with spironolactone, ketoconazole, mitotane, and mifepristone. CONCLUSIONS: We report an unusual and rare case of Cushing's syndrome secondary to a malignant steroid cell tumor of the ovary. The case is highlighted to discuss the complications of rapidly progressive Cushing's syndrome, an underreported and often unrecognized endocrine emergency, and the best available evidence for treatment.

Disrupted Nitric Oxide Metabolism from Type II Diabetes and Acute Exposure to Particulate Air Pollution.

Type II diabetes is an established cause of vascular impairment. Particulate air pollution is known to exacerbate cardiovascular and respiratory conditions, particularly in susceptible populations. This study set out to determine the impact of exposure to traffic pollution, with and without particle filtration, on vascular endothelial function in Type II diabetes. Endothelial production of nitric oxide (NO) has previously been linked to vascular health. Reactive hyperemia induces a significant increase in plasma nitrite, the proximal metabolite of NO, in healthy subjects, while diabetics have a lower and more variable level of response. Twenty type II diabetics and 20 controls (ages 46-70 years) were taken on a 1.5 hr roadway traffic air pollution exposure as passengers. We analyzed plasma nitrite, as a measure of vascular function, using forearm ischemia to elicit a reactive hyperemic response before and after exposure to one ride with and one without filtration of the particle components of pollution. Control subjects displayed a significant increase in plasma nitrite levels during reactive hyperemia. This response was no longer present following exposure to traffic air pollution, but did not vary with whether or not the particle phase was filtered out. Diabetics did not display an increase in nitrite levels following reactive hyperemia. This response was not altered following pollution exposure. These data suggest that components of acute traffic pollution exposure diminish vascular reactivity in non-diabetic individuals. It also confirms that type II diabetics have a preexisting diminished ability to appropriately respond to a vascular challenge, and that traffic pollution exposure does not cause a further measureable acute change in plasma nitrite levels in Type II diabetics.

Proteolytic Cleavage of AMPKα and Intracellular MMP9 Expression Are Both Required for TLR4-Mediated mTORC1 Activation and HIF-1α Expression in Leukocytes.

LPS-induced TLR4 activation alters cellular bioenergetics and triggers proteolytic cleavage of AMPKα and HIF-1α expression in leukocytes. In human leukocytes, and more specifically neutrophils, AMPKα cleavage yields 55- and 35-kDa protein fragments. In this study, we address the mechanism by which AMPKα is cleaved and its relevance to human health. Our data indicate that AMPKα cleavage is linked to MMP9 expression and that both are required for mammalian target of rapamycin complex-1 and S6K1 activation and HIF-1α expression in LPS-stimulated human and mice leukocytes. Three key observations support this conclusion. First, no changes in AMPKα and TLR4 signaling intermediates (mammalian target of rapamycin complex-1/S6 kinase 1/HIF-1α) were detected in LPS-stimulated MMP9-deficient mice leukocytes. Second, rMMP9 cleaved human AMPKα ex vivo, producing degradation products similar in size to those detected following LPS stimulation. Third, MMP9 inhibitors prevented AMPKα degradation and HIF-1α expression in LPS-activated human leukocytes, whereas AMPK activators blocked MMP9 and HIF-1α expression. Significantly, AMPKα degradation, MMP9, and TLR4 signaling intermediates were all detected in leukocytes from patients with type 2 diabetes mellitus and patients following cardiopulmonary bypass surgery. Plasma from these two patient cohorts induced AMPKα cleavage and TLR4 signaling intermediates in healthy donor leukocytes and either a TLR4 inhibitor or polymyxin prevented these outcomes. Detection of AMPKα degradation, MMP9 expression, and TLR4 signaling intermediates described in this study in leukocytes, the most readily available human cells for clinical investigation, may provide a powerful tool for further exploring the role of TLR4 signaling in human diseases and lead to identification of new, context-specific therapeutic modalities for precision medicine.

Insulin-like growth factor-I inhibition with pasireotide decreases cell proliferation and increases apoptosis in pre-malignant lesions of the breast: a phase 1 proof of principle trial.

INTRODUCTION: Estrogen inhibition is effective in preventing breast cancer in only up to 50% of women with precancerous lesions and many experience side effects that are poorly tolerated. As insulin-like growth factor I (IGF-I) underlies both estrogen and progesterone actions and has other direct effects on mammary development and carcinogenesis, we hypothesized that IGF-I inhibition might provide a novel approach for breast cancer chemoprevention. METHODS: In total, 13 women with core breast biopsies diagnostic of atypical hyperplasia (AH) were treated for 10 days with pasireotide, a somatostatin analog which uniquely inhibits IGF-I action in the mammary gland. They then had excision biopsies. 12 patients also had proliferative lesions and one a ductal carcinoma in situ (DCIS). Primary outcomes were changes in cell proliferation and apoptosis after treatment. Expression of estrogen receptor (ER), progesterone receptor (PR), and phosphorylated Insulin-like growth factor I receptor (IGF-1R), protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2) were also assessed. Core and excision biopsies from 14 untreated patients served as non-blinded controls. Hyperglycemia and other side effects were carefully monitored. RESULTS: Pasireotide decreased proliferation and increased apoptosis in all AH (from 3.6 ± 2.6% to 1.3 ± 1.2% and from 0.3 ± 0.2% to 1.5 ± 1.6%, respectively) and proliferative lesions (from 3.8 ± 2.5% to 1.8 ± 1.8% and from 0.3 ± 0.2% to 1.3 ± 0.6%, respectively). The DCIS responded similarly. ER and PR were not affected by pasireotide, while IGF-1R, ERK1/2 and AKT phosphorylation decreased significantly. In contrast, tissue from untreated controls showed no change in cell proliferation or phosphorylation of IGF-1R, AKT or ERK 1/2. Mild to moderate hyperglycemia associated with reduced insulin levels was found. Glucose fell into the normal range after discontinuing treatment. Pasireotide was well tolerated and did not cause symptoms of estrogen deprivation. CONCLUSIONS: IGF-I inhibition by pasireotide, acting through the IGF-1R, was associated with decreased proliferation and increased apoptosis in pre-malignant breast lesions and one DCIS. Assuming hyperglycemia can be controlled, these data suggest that inhibiting the IGF-I pathway may prove an effective alternative for breast cancer chemoprevention. TRIAL REGISTRATION: NCT01372644 Trial date: July 1, 2007.