Extremely Low Testosterone due to Relative Energy Deficiency in Sport: A Case Report

Objective: Recognize extremely low testosterone due to hypothalamic dysfunction from overtraining syndrome in a male athlete with relative energy deficiency in sport (RED-S). Methods: Clinical and laboratory information are described. Results: A 20-year-old male division I collegiate swimmer was found to have strikingly low total, free, and bioavailable testosterone levels with normal sex hormone–binding globulin and inappropriately normal follicle-stimulating hormone and luteinizing hormone. Lab testing ruled out hyperprolactinemia and hypothyroidism as etiologies, and pituitary imaging was normal. A diagnosis of RED-S was made, and the patient worked with the sports medicine team to increase nutrition and modify physical activity. His repeat testosterone levels improved after minor weight gain and decreased training regimen and eventually returned to normal. Conclusion: Secondary hypogonadism with extremely low testosterone can be seen in male athletes with suspected RED-S. Abbreviation: RED-S = relative energy deficiency in spor

Role of Serum Amyloid A in Abdominal Aortic Aneurysm and Related Cardiovascular Diseases

Epidemiological data positively correlate plasma serum amyloid A (SAA) levels with cardiovascular disease severity and mortality. Studies by several investigators have indicated a causal role for SAA in the development of atherosclerosis in animal models. Suppression of SAA attenuates the development of angiotensin II (AngII)-induced abdominal aortic aneurysm (AAA) formation in mice. Thus, SAA is not just a marker for cardiovascular disease (CVD) development, but it is a key player. However, to consider SAA as a therapeutic target for these diseases, the pathway leading to its involvement needs to be understood. This review provides a brief description of the pathobiological significance of this enigmatic molecule. The purpose of this review is to summarize the data relevant to its role in the development of CVD, the pitfalls in SAA research, and unanswered questions in the field

Low Yield of Thyroid-Function Tests in Adult Hospitalized Patients -- A Retrospective Analysis

Background: In the US, serum thyroid-stimulating hormone (TSH) and thyroxine measurements are the fourth- and tenth-commonest laboratory tests ordered, respectively. Diagnosis of thyroid disorder requires clinical suspicion supported by laboratory values. However, in the setting of acute illness, both the clinical and laboratory pictures can be confounded. Objective: To study clinical outcomes and derangement patterns of inpatient thyroid-function tests. Design: This retrospective study was conducted at an academic center on admissions aged ≥18 years and TSH tests performed over a 1-year period. Admissions with active pregnancy and/or prior thyroid-related diagnosis were excluded. Main Outcomes: Clinical outcomes were divided based on new diagnosis of thyroid-related disorder, newly prescribed thyroxine replacement, or antithyroid drugs/ endocrinology referrals, or both. In order to analyze the derangement patterns of abnormal TSH, only the results of the first test ordered were considered (as some admissions had multiple TSH tests ordered). Results: A total of 7,204 admissions aged ≥18 years had TSH tests done. Of these, 1,912 were excluded. Of the 5,292 admissions with no prior thyroid disorder or active pregnancy, 183 (3.46%) were assigned a new diagnosis of thyroid-related disorder, 54 (1.02%) received treatment/referral, and 46 (0.87%) received both a new diagnosis and treatment/referral. Based on the TSH results (reference range 0.42-4.0 mIU/L) of the 5,292 admissions, 4,312 (81.5%) and 980 (18.5%) admissions were flagged normal and abnormal, respectively. Of the 980 admissions with one or more abnormal TSH results, 21 (2.14%) had first ordered TSH10 mIU/L. Conclusion: There is low value in testing inpatients for thyroid disorders, and testing comes at significant expense to the health-care system

Circadian Disruption with Constant Light Exposure Exacerbates Atherosclerosis in Male \u3cem\u3eApolipoproteinE\u3c/em\u3e-Deficient Mice

Disruption of the circadian system caused by disordered exposure to light is pervasive in modern society and increases the risk of cardiovascular disease. The mechanisms by which this happens are largely unknown. ApolipoproteinE-deficient (ApoE−/−) mice are studied commonly to elucidate mechanisms of atherosclerosis. In this study, we determined the effects of light-induced circadian disruption on atherosclerosis in ApoE−/− mice. We first characterized circadian rhythms of behavior, light responsiveness, and molecular timekeeping in tissues from ApoE−/− mice that were indistinguishable from rhythms in ApoE+/+ mice. These data showed that ApoE−/− mice had no inherent circadian disruption and therefore were an appropriate model for our study. We next induced severe disruption of circadian rhythms by exposing ApoE−/− mice to constant light for 12 weeks. Constant light exposure exacerbated atherosclerosis in male, but not female, ApoE−/− mice. Male ApoE−/− mice exposed to constant light had increased serum cholesterol concentrations due to increased VLDL/LDL fractions. Taken together, these data suggest that ApoE−/− mice are an appropriate model for studying light-induced circadian disruption and that exacerbated dyslipidemia may mediate atherosclerotic lesion formation caused by constant light exposure

Prevention of Renal ApoB Retention is Protective Against Diabetic Nephropathy: Role of TGF-β Inhibition

Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr−/− mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-β (TGF-β), in some experiments mice were injected with either the TGF-β-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect on renal apoB accumulation, but led to modest attenuation of DN with ∼30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF-β. Use of 1D11 led to sustained suppression of TGF-β for approximately 8 weeks at a time. The 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy, and improved survival, compared with the 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of DN. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-β inhibition is nephroprotective

Serum Amyloid A Is Not Incorporated into HDL during HDL Biogenesis

Liver-derived serum amyloid A (SAA) is present in plasma where it is mainly associated with HDL and from which it is cleared more rapidly than are the other major HDL-associated apolipoproteins. Although evidence suggests that lipid-free and HDL-associated forms of SAA have different activities, the pathways by which SAA associates and disassociates with HDL are poorly understood. In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral vector. Alternatively, we incubated primary hepatocytes from SAA-deficient mice with purified SAA. We analyzed conditioned media to determine the lipidation status of endogenously produced and exogenously added SAA. Examining the migration of lipidated species, we found that SAA is lipidated and forms nascent particles that are distinct from apoA-I-containing particles and that apoA-I lipidation is unaltered when SAA is overexpressed or added to the cells, indicating that SAA is not incorporated into apoA-I-containing HDL during HDL biogenesis. Like apoA-I formation, generation of SAA-containing particles was dependent on ABCA1, but not on scavenger receptor class B type I. Hepatocytes degraded significantly more SAA than apoA-I. Taken together, our results indicate that SAA\u27s lipidation and metabolism by the liver is independent of apoA-I and that SAA is not incorporated into HDL during HDL biogenesis

Serum Amyloid A3 is a High Density Lipoprotein-Associated Acute-Phase Protein

Serum amyloid A (SAA) is a family of acute-phase reactants. Plasma levels of human SAA1/SAA2 (mouse SAA1.1/2.1) can increase ≥ 1,000-fold during an acute-phase response. Mice, but not humans, express a third relatively understudied SAA isoform, SAA3. We investigated whether mouse SAA3 is an HDL-associated acute-phase SAA. Quantitative RT-PCR with isoform-specific primers indicated that SAA3 and SAA1.1/2.1 are induced similarly in livers (∼2,500-fold vs. ∼6,000-fold, respectively) and fat (∼400-fold vs. ∼100-fold, respectively) of lipopolysaccharide (LPS)-injected mice. In situ hybridization demonstrated that all three SAAs are produced by hepatocytes. All three SAA isoforms were detected in plasma of LPS-injected mice, although SAA3 levels were ∼20% of SAA1.1/2.1 levels. Fast protein LC analyses indicated that virtually all of SAA1.1/2.1 eluted with HDL, whereas ∼15% of SAA3 was lipid poor/free. After density gradient ultracentrifugation, isoelectric focusing demonstrated that ∼100% of plasma SAA1.1 was recovered in HDL compared with only ∼50% of SAA2.1 and ∼10% of SAA3. Thus, SAA3 appears to be more loosely associated with HDL, resulting in lipid-poor/free SAA3. We conclude that SAA3 is a major hepatic acute-phase SAA in mice that may produce systemic effects during inflammation

Assessment of Gender-Affirming Hormone Therapy Requirements

Purpose: There are currently no recommendations regarding the starting doses of hormone therapy for individuals with gender dysphoria. The purpose of this study was to assess the hormone dose needed to achieve target hormone levels in transgender men and transgender women, and whether body mass index (BMI) affects these doses. Methods: A retrospective chart review of subjects seeking gender-affirming hormone therapy was performed. Height, weight, hormone doses, and serum hormone levels were collected from charts. Data were analyzed for a correlation between BMI and effective hormone dosing (dose that achieved hormone levels in the target range). Results: Charts from 319 subjects were reviewed; however, only 84 transgender women and 71 transgender men had serum hormone levels available and only 40 transgender women and 54 transgender men had plasma hormone levels in the target range (normal range for affirmed gender). For transgender women, there was a significant negative correlation between BMI and effective estradiol dose (r = −0.337, p = 0.04). For transgender men, there was a positive correlation between BMI and effective testosterone dose (r = 0.409, p = 0.002). Conclusion: Increased BMI was associated with lower estrogen dose requirements in transgender women. In transgender men, an increase in BMI was associated with increased testosterone dose requirements. These results suggest that BMI may influence effective gender-affirming hormone dosing; however, further studies are needed to examine its utility in determining the initial hormone dose