bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of the Endocrinologist in the Gender Adequacy Process and the Barriers for Adequate Transgender Health Care
Authors: Saliba Alexandra
Published: May 2021

The transgender universe comprises a wide range of individuals who do not identify with the gender role related to their birth sex, presenting distinct gender identities that transcend the binary concept of female and male. The follow-up of this population requires specific knowledge and training for its demands and peculiarities. Hormone therapy is a key point in the process of gender adequacy, and despite the increase in demand for specialized health services, there are still many barriers to full and free of prejudice health care. This is a descriptive and exploratory study about the characteristics of the professional training of the doctors involved in transgender health care, in particular the endocrinologist, and to enable an overview of the doctor-patient relationship and medical follow-up in the context of transsexuality in the Federal District. For this purpose, questionnaires were used for physicians: endocrinologists, family and community physicians, urologists, and psychiatrists; and transgender people residents of the Federal District. This study shows that most of the professionals involved in the process of gender adequacy, in particular the endocrinologist, do not present confidence or knowledge to accomplish it, and prejudice is still presented in a striking way in health care. In Federal District, services are not adequately structured for the care of this population, both from the perspective of doctors and transgender people. Moreover, in this sample, it was observed that the higher degree of specific knowledge in the subject increases the sensation of confidence of the professional to treat transgender people but does not correlate with the prejudice.
Hepatic Abnormalities in Youth With Turner Syndrome
Authors: Singh Isani , Noel Gillian , Barker Jennifer M , Chatfield Kathryn C , Khanna Amber D , Nokoff Natalie , Davis Shanlee M
Published: May 2021

Background: While cardiac complications, short stature, and infertility are often discussed in the context of Turner Syndrome (TS), abnormalities of liver function are less well described. In order to address this gap in knowledge, we sought to better characterize hepatic abnormalities in youth with TS. Methods: PEDSnet is a collaboration across 7 major US pediatric institutions that unifies electronic medical data including diagnoses, prescriptions, and laboratory measurements for over 6 million children. 2,145 females with a diagnosis of TS were matched to 8,580 females without TS (1:4 ratio) on site, race (68% White), ethnicity (15% Hispanic), payer source, year of birth, age at most recent visit (median 14 years), and duration of care (mean 8 years). Outcomes of interest included highest recorded liver enzyme values (AST and ALT) categorized as normal or above the upper limit of normal (ULN) defined as >95th percentile for their age, and specific liver diagnoses. Proportions were compared between the cohorts using odds ratios (OR) and 95% confidence intervals (CI) from a generalized estimating equations approach. Multinomial logistic regression was conducted to investigate potential risk factors for liver abnormalities within the TS cohort. Results: Out of 1,159 girls with TS who had liver enzymes recorded in PEDSnet, 58% had at least one AST or ALT above the ULN. TS patients were more likely to have enzymes 1-2 times ULN (OR: 1.7, 95% CI: 1.4-1.9), more likely to be in the 2-3 times ULN category (OR: 2.7, 95% CI: 1.7-3.3), and more likely to be in the >3 times ULN category (OR: 1.7, 95% CI: 1.3-2.2) compared to girls without TS. TS patients were also more likely to have any liver diagnosis (OR: 2.4, 95% CI: 1.7-3.3), including significantly higher risk of fatty liver disease (OR: 1.9, 95% CI: 1.1-3.2), hepatitis (OR: 3.7, 95% CI: 1.9-7.1), cirrhosis/fibrosis (OR: 5.8, 95% CI: 1.3-25.0), and liver tumor/malignancy (OR: 4.8, 95% CI: 1.4-17.0). In the multinomial model, age, BMI, and the presence of a thyroid condition, cardiovascular diagnosis, or diabetes significantly (p < 0.05) increased the risk for elevated liver enzymes in girls with TS, while mosaicism, estrogen prescription, and celiac disease did not. Stratifying by age groups, over 40% of girls with TS had ALT elevations (24% > 2 times ULN, some with diagnosed liver conditions) under age 10, when liver screening is officially recommended per TS guidelines. Conclusions: Prevalence of elevated liver enzymes and diagnoses of liver disease are significantly higher in youth with TS vs. controls, emphasizing the need for clinical monitoring and additional research. Given the high percentage of girls <10 years of age with clinically significant liver enzyme elevation, there should be strong consideration for modifying the current guidelines to start screening earlier.
Cortisol Levels Is Associated With Left Ventricular Diastolic Dysfunction in Diabetic Patients
Authors: Sagara Rikako , Inoue Tomoaki , Sonoda Noriyuki , Yano Chieko , Motoya Misato , Umakoshi Hironobu , Sakamoto Ryuichi , Ogawa Yoshihiro
Published: May 2021

Introduction: Diabetes mellitus (DM) is a major cause of cardiovascular disease including heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular diastolic dysfunction (LVDD). It is reported that Cushing’s syndrome is also associated with LVDD. The relationship between plasma cortisol concentration and LVDD, however, has not been investigated in patients with DM. Methods: In this study, 109 patients with DM and 104 patients with non-DM without overt heart failure were enrolled. Left ventricular function were assessed using echocardiography. The ratio of early diastolic velocity (E) from transmitral inflow to early diastolic velocity (e’) of tissue Doppler at mitral annulus (E/e’) was used as an index of diastolic function. Parameters of plasma cortisol concentration, glycemic control, lipid profile, treatment with anti-diabetic drugs and other clinical characteristics were evaluated, and their association with E/e’ determined. Patients taking steroids, undergoing dialysis treatment and with overt heart failure were excluded. Results: Univariate analysis showed that E/e’ was significantly correlated with age (p<0.001), duration of diabetes (p=0.039), systolic blood pressure (SBP) (p<0.001), eGFR (p=0.002), sodium glucose cotransporter 2 (SGLT2) inhibitor use (p<0.001) and cortisol (p=0.009) in patients with DM. Multivariate linear regression analysis showed that log E/e’ was positively correlated with age (p=0.018), log SBP (p= 0.005), eGFR (p=0.015), cortisol (p=0.028) and that log E/e’ was inversely with inhibitor use (p=0.018). There was no association between E/e’ and cortisol in patients with non-DM. Conclusions: Cortisol may be important in the development of LVDD in patients with DM.
Understanding, Communication, Concerns and Repercussions of Sexual Development Differences by Mothers’ Perspectives
Authors: Lousada Lia Mesquita , Domenice Sorahia , Elaine Maria Frade Costa L , Bachega Tania A , Batista Rafael Loch , Fontenele Eveline Gadelha Pereira , Coutinho Debora Cabral , Carina Marques Barroso Barroso L , Geroldo Sandra Regina , Mendonca Berenice Bilharinho
Published: May 2021

Introduction: Differences of sexual development (DSD) define congenital diseases in which an atypical development of chromosomal, gonadal or anatomical sex occurs. The approach involves complex themes: gender designation, genitoplasty, hormonal treatment and fertility. Mothers’ understanding optimizes their children’s assistance. Objective/methods: To analyze the mothers’ understanding about the DSD condition, doubts, concerns, barriers to communication and repercussion in gender, sexual orientation and relationships in a cohort followed in reference centers in São Paulo (SP) and Ceará (CE), through an interview. Results: 112 mothers (72 from SP and 50 from CE) were interviewed. Mothers’ mean age was 35 y. The satisfaction related to the understanding about their children’s condition (on a scale from 1 to 5) was higher in the SP: medians of 4 (SP) and 3 (CE). Significant differences were evidenced between the numbers of mothers who knew the condition’s name, 56.3% (SP) and 38.6% (CE); who knew why the children had been affected by it, 38.5% (SP) and 16.7% (CE); and who knew the drugs’ function, 89.3% (SP) and 70.4% (CE). 70% to 83% of the mothers referred doubts, mainly related to the diagnosis and their feeling of guilt. Considering only children with atypical genitalia at birth (n:115), the difference was not diagnosed at hospital in 15% (4 from SP and 14 from CE). Pediatricians and obstetricians first communicated to mothers about the atypical genitalia in 73% of the reports. 70% (SP) and 41% (CE) of the mothers considered the first approach inappropriate. 89% of all mothers feel uncomfortable in talking to other people about the DSD condition and 68% experienced negative comments. Around 70% of mothers reported discomfort in exposing their children’s genitalia and 64% considered genitoplasty as an urgency. 47% referred that the DSD may influence the gender identity, 65.4% referred it may prejudice relationships and 33.3% believed it may influence on sexual orientation. The concern related to stigma was higher than related to fertility, genitalia appearance, relationships, treatments, gender identity and sexuality. Conclusion: Most of the mothers of DSD children, even in reference centers, showed unsatisfaction and lack of knowledge. The health team should be trained and the approach should consider the mothers’ perspectives and be appropriate to the cultural context. Educational actions may improve understanding and reduce the DSD stigma.
A Steroid Receptor Coactivator Stimulator MCB-613 Attenuates Adverse Remodeling After Myocardial Infarction
Authors: Mullany Lisa K , Rohira Aarti , Kim Jong H , Leach John P , Ortiz Andrea , Stork Brittany , York Brian L , Song Yongcheng , Dacso Clifford C , Lonard David M , Martin James F , O’Malley Bert W
Published: May 2021

Previous work from ours and other laboratories have shown that steroid receptor coactivators (SRCs) are involved in heart development and in mitigating cardiac dysfunction in cardiac injury models. Members of the p160 SRC family, SRC-1 (NCOA1), SRC-2 (NCOA2/TIF2/GRIP1) and SRC-3 (NCOA3/AIB1/ACTR/pCIP), interact with nuclear receptors and other transcription factors to drive target gene expression by assembling transcriptional coactivator complexes to increase transcription. This indicates a potential for SRC targeting drugs pertinent to cell migration, proliferation and survival-promoting paracrine interactions in cardiac tissue injury responses. We have identified a small molecule activator of SRCs (MCB-613) that selectively and reversibly binds to SRCs as shown by surface plasmon resonance and is a potent SRC stimulator that acts to greatly enhance SRC transcriptional activity with no apparent toxicity in mice. We postulated that MCB-613 could enable wound repair and preservation of cardiac function after an acute MI by reducing the extent of injury-related fibrosis and the subsequent chronic loss of cardiac function associated with non-contracting scar tissue. We thus tested the effect of MCB-613 on the cardiac injury response by administering MCB-613 two hours after ischemic injury in a mouse model of MI. Along with measurements of functional cardiac output and damage, we sought to identify the cell-type specific responses responsible for MCB-613’s cardio-protective effects by utilizing single cell transcriptomics of cardiac interstitial cells to characterize the effects of SRC stimulation on cardiac function post-MI. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post-MI, induces lasting protection from adverse remodeling concomitant with: (i) inhibition of macrophage inflammatory signaling and IL-1 signaling which attenuates the acute inflammatory response, (ii) attenuation of fibroblast differentiation, and (iii) promotion of Tsc22d3 expressing macrophages - all of which may limit inflammatory damage. Our results indicate MCB-613 controls the cellular interstitial cardiac repair response to ischemia. Distinct molecular and cellular mechanisms related to stimulation of SRC-3 have been identified that pave the way for the further exploration of SRCs as drug targets that can be engaged to improve the management of myocardial injury response outcomes. SRC stimulation with MCB-613 (and derivatives) is a potential novel therapeutic approach for inhibiting cardiac dysfunction after MI.
Improving the Diagnosis, Treatment, and Prevention of Endocrine Diseases Through Accurate and Reliable Laboratory Measurements With CDC Clinical Standardization Programs
Authors: Sugahara Otoe , Danilenko Uliana , Poynter Krista , Collins Lynn , Khoshnam Nasim , Buchannan Tatiana , Coffman Clark , Ribera Ashley , Laughlin Brandon , Dahya Komal , Smith Bianca , Dabbs-Brown Amonae , Pokuah Fidelia , Wirtz Douglas , Ulmer Candice Zena , Zhou Hui , Lyle Alicia , Zhang Li , Vesper Hubert W
Published: May 2021

Laboratory measurements are critical for correct diagnosis and treatment of patients with chronic diseases such as hypogonadism, PCOS, and thyroid diseases. Inaccurate measurements of disease biomarkers can lead to misclassification of patients/incorrect treatment and prevent the effective use of research findings in patient care. The CDC Clinical Standardization Programs (CDC CSP) improve the accuracy and reliability of clinical biomarker measurements by assessing and improving the analytical performance of assays. The CDC CSP assist with assay calibration, the certification of analytical performance, and the monitoring of routine patient and research testing. The CDC CSP work with clinical/research laboratories and assay manufacturers to improve laboratory measurements. Its current programs include the following analytes: total testosterone (TT), estradiol (E2), vitamin D (VD), free thyroxine (FT4), total cholesterol (TC), total glycerides (TG), HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C). The work is being conducted through certification/monitoring programs and technical assistance. Most assays participating in the certification programs have seen performance improvements and maintain performance over time by continuous participation. Most major commercial laboratories and assays manufactures are enrolled in the certification programs. Currently certified and non-certified assays are available. Assays certified by CDC CSP are listed on the website at https://www.cdc.gov/labstandards/hs.html. The CDC Lipid Standardization Programs and CDC Accuracy-based Monitoring Programs allow for weekly monitoring of analytical performance of routine tests for analytes including TT, VD, TC, TG, HDL-C, apolipoprotein A1 and B. These monitoring programs assist researchers with assessing measurement accuracy of research studies over time and across laboratories. The CDC CSP also support accuracy-based external quality assurance surveys such as those offered by the College of American Pathologists (CAP). The CDC CSP assist researchers and stakeholders with developing and establishing reference intervals and conducting studies to better assess and diagnose patients. Based on the needs and requests from clinical community, programs for new biomarkers such as Lp(a), PTH and glucose are being developed. The CDC CSP work with stakeholders, such as the Endocrine Society and the Partnership for the Accurate Testing of Hormones, to educate the clinical and laboratory communities about the importance of using standardized assays in patient care, research, and public health.
Mechanism of Action of Irilone as a Potentiator of Progesterone Receptor Signaling
Authors: Austin Julia R , Lee Jeongho , Murphy Brian T , Burdette Joanna Elizabeth
Published: May 2021

Progesterone signaling and its proper regulation is important for reproductive function. When progesterone signaling is dysregulated, gynecological diseases can occur, for example endometriosis, uterine fibroids, and endometrial cancer. While these diseases are treated with progestin therapy, progestins can bind to multiple steroid receptors, exerting side effects of weight gain, immunosuppression, cardiovascular disease, and stroke. Discovering an alternative progestin that is selective for the progesterone receptor (PR) is ideal. One potential source of such an alternative is botanical dietary supplements, which have become increasingly popular among consumers with sales reaching $9.6 billion in 2019. Although botanical supplements are popular, the chemical structures and biological action of botanical supplements would benefit from deeper scientific investigation. Studies of Trifolium pratense L. (red clover), primarily used for the treatment of menopausal symptoms, identified phytoestrogen compounds as the chemicals that mitigate those symptoms. Interestingly, irilone, identified from red clover, potentiated progesterone signaling via a progesterone response element luciferase (PRE/Luc) assay. Potentiation is when a compound has no activity by itself but when combined with another molecule, i.e. progesterone, that compound enhances PR activity. Prior to irilone, a natural compound with the ability to potentiate progesterone signaling had not been previously reported. The purpose of this study was to determine the mechanism of action of irilone. We hypothesized that irilone was potentiating PR by blocking PR degradation and by altering PR post-translational modifications. Irilone was found to potentiate 5 nM P4 using a PRE-luciferase assay in both T47D and Ishikawa PR expressing cells. Since PR is a downstream target gene of ER, we investigated if irilone also had ER activity. Irilone increased expression of an ERE-luciferase reporter gene. Next, we investigated if irilone could stabilize PR degradation and if irilone altered PR phosphorylation via western blot. Irilone was found to increase PR protein levels, but when ER was blocked, this was mitigated. In the presence of P4, irilone did not increase phosphorylation of serine 294 on PR. Future studies will determine if irilone is altering sumoylation of PR, and if irilone can potentiate PR signaling in vivo. Determining how irilone is potentiating progesterone will help us understand PR biology and could be an effective treatment for gynecological diseases by enhancing endogenous progesterone action.
Optimized Immunohistochemical Detection of Rat ESR2 Proteins Using the Specific Anti-ESR2 Monoclonal Antibody PPZ0506
Authors: Hattori Yujiro , Ishii Hirotaka , Higo Shimpei , Otsuka Mai , Kanaya Moeko , Matsumoto Keisuke , Ozawa Mina , Ozawa Hitoshi
Published: May 2021

Background: Research on ESR2, also known as estrogen receptor β (ERβ), is a notorious example of data distortion due to the use of inadequately validated antibodies. Although the absence of reliable specific antibodies against ESR2 has severely hindered the promotion of ESR2 research, a specific anti-human ESR2 monoclonal antibody (PPZ0506) was identified in 2017 [1]. Our previous study confirmed its cross-reactivity and specificity against rodent ESR2 proteins, enabling the elucidation of the true ESR2 distribution in rodents [2].

Objective: We aimed to determine the optimized conditions for immunohistochemical detection of rat ESR2 proteins using PPZ0506.  Several staining conditions using paraffin-embedded and frozen ovary sections were evaluated, and the distribution of rat ESR2 proteins was analyzed under optimal conditions.

Result: Immunohistochemical staining with PPZ0506 required appropriate antigen retrieval and antibody dilution. Subsequent immunohistochemical analysis in multiple tissues under optimized conditions revealed that rat ESR2 proteins are expressed in a more localized manner than previously assumed. Our optimized immunohistochemical detection of rat ESR2 proteins, using a well-validated antibody, revealed their distribution in limited tissues and cell types.

Conclusion: Our results suggest that previous immunohistochemical studies using inadequately validated antibodies against ESR2 proteins overestimated their distribution profiles. We expect that our optimized immunohistochemistry using the PPZ0506 antibody may solve conflicting problems in ESR2 research.

References: 1. Andersson S, et al. Nat Commun 15;8:15840 (2017) 2. Ishii H, et al. Int J Mol Sci 20(24):6312 (2019)
Paxillin Is Required for Androgen Receptor Expression in Granulosa Cells
Authors: Astapova Olga , Hammes Stephen R
Published: May 2021

Androgens are important in female reproduction, as evident from studies of mouse ovary-specific androgen receptor knockout models characterized by sub-fertility and diminished ovarian reserve. Androgen activity specifically promotes granulosa cell proliferation and follicle progression. However, the molecular mechanisms mediating androgen activity in granulosa cells are unknown. Our lab previously showed that the cytoplasmic adaptor protein paxillin is required for full transcriptional activity by the androgen receptor (AR) in prostate cancer cells, therefore we examined how paxillin affects the androgen receptor in granulosa cells. We found that paxillin knockdown results in significantly reduced AR protein levels, independently of AR gene transcription in human granulosa-derived KGN cells. Similar to previous data from other cell types, we found that paxillin directly interacts with poly-A binding protein (PABP) in KGN cells using proximity ligation assay. Ligand binding further increases AR protein expression by reducing its degradation. Using immunofluorescence, we confirm that in both KGN and primary mouse granulosa cells, similarly to the prostate, ligand-bound AR is primarily localized in the nucleus. Based on this and previous studies, we propose that paxillin enhances AR mRNA translation through interaction with PABP, and ligand binding further increases AR protein level by nuclear retention, protecting from degradation in the cytoplasm. Our findings highlight a previously unrecognized role of paxillin in granulosa cells, where it may be an important target for modulating androgen activity in androgen-related disorders of female reproduction.
Antiepileptic Drugs and Thyroid Hormone Homeostasis: Literature Review and Practical Guideline
Authors: Rochtus Anne Maria , Herijgers Dorien , Jansen Katrien , Decallonne Brigitte
Published: May 2021

Thyroid hormones play an essential role in central nervous system development, normal physiological brain function and repairing mechanisms. On one hand, thyroid hormone alterations influence cortical excitability and on the other hand anti-epileptic drugs (AEDs) are associated with alterations in thyroid hormone metabolism. Although this interaction has long been described, and epilepsy is a common and chronic neurological disease, studies describing the interplay are often small and retrospective.

We performed a systematic review of the current literature on epilepsy, AED therapy and thyroid hormone metabolism. Forty-seven studies were included.

Most studies were retrospective cross-sectional studies (n=25) and investigated thyroid function alterations in patients on older AEDs such as phenobarbital, phenytoin, carbamazepine and valproic acid. Overall, almost one third of patients with epilepsy had subclinical hypothyroidism, especially patients on valproate and carbamazepine. Studies with patients receiving polytherapy are scarce, but reported a higher risk for hypothyroidism in patients with older age, female sex, longer duration of epilepsy, intractable epilepsy and polytherapy. Studies on newer AEDs are also scarce and further studies essential to improve the care for epilepsy patients.

AEDs are associated with alterations in thyroid hormone metabolism. Thyroid function monitoring is indicated in patients on AEDs, especially those with refractory chronic epilepsy and those on polytherapy. We provide a practical guideline for thyroid function monitoring for the clinician taking care of patients on AEDs.
BMI Helps to Calculate the Initial Levothyroxine Dose After Total Thyroidectomy
Authors: Correia Sara , Almeida Lucia Santos , Silva José Diogo , Tavares Patrícia , Rocha Gustavo , Oliveira Maria
Published: May 2021

After total thyroidectomy, an initial dose of levothyroxine is often prescribed based on the patient’s body weight (1.6 mcg / kg / day), regardless of body mass index (BMI). The current literature required that hormone maintenance therapy (THR) in obese patients differs from non-obese patients. Review of the clinical processes of patients with papillary carcinoma followed in the multidisciplinary consultation of Endocrine Pathology at CHVNG / E followed a total thyroidectomy from 2015 to 2017. Patients who achieved euthyroidism with THR were included in the analysis and divided according with BMI. Statistical analysis was performed using SPSS version 25.0. A value of p <0.05 was considered statistically significant. The sample included 82 patients, 90.2% (n = 74) female and 9.8% (n = 8) male, with an average age of 53.02 ± 14.27 years. Of the female gender, 52.4% (n = 43) were in menopause. In the postoperative period, 14 patients (17.1%) had a normal BMI, 46 (50%) were overweight and 22 (32.9%) were obese. The average follow-up time was 75.3 months (32-128). A dose of LT4 required to achieve euthyroidism based on the BMI categories mentioned above was 1.70; 1.54 and 1.49 mcg / kg. Patients with a higher BMI needed a higher dose of LT4 to achieve euthyroidism (p <0.05), but the dose was lower in relation to weight (mcg / kg) (p <0.05). There were no differences related to age and need for L-T4 suplementation (p> 0.05). Our study shows that de calculation of the initial levothyroxine dose should also take into account BMI. Overweight and obese individuals should receive a lower dose than that used in normal weight patients, which goes against what has been described in the literature. The weight-based formula, unlike BMI, does not account for the volume of distribution of L-T4 well. Other methods, which include, for example, ideal body weight instead of actual weight, are being developed to help choose the starting levothyroxine dose.
Desiccated Thyroid Extract Versus Synthetic LT4/T3 Combination Versus LT4 Monotherapy in the Treatment of Primary Hypothyroidism With Special Attention to the Thr92AlaD2 Polymorphism. With Special Attention to the Gene Polymorphism
Authors: Hoang Thanh Duc , Brooks Daniel I , Bianco Antonio , Mcaninch Elizabeth A , Fonseca Tatiana L , Mai Vinh Q , Shakir Mohamed K M
Published: May 2021

Introduction: Before the availability of levothyroxine (LT4), patients were treated with desiccated thyroid extract (DTE). When switching from DTE to LT4, despite adequate dosing based on serum TSH levels, some patients still feel unwell with fatigue, mental fogginess, weight gain etc. A recent randomized, crossed over study between DTE vs. LT4 conducted in our department showed that once-daily DTE caused modest weight loss and possible improvement in mental health scores without appreciable adverse effects; also, nearly half of the study patients preferred DTE over LT4. A few studies have shown that LT4/T3 combination had beneficial effects in improving quality of life relative to LT4 alone. Furthermore, it has been reported that patients with CC genotype in the deiodinase type 2 polymorphism responded more favorably with LT4/T3 combination than T4 monotherapy. Hypothesis: This study investigated the efficacy and effectiveness of DTE vs. LT4/T3 combination vs. LT4 monotherapy in hypothyroid patients based on genotypic differences of deiodinase type 2.

Methodology: This was a prospective, randomized, double-blind, crossover study. 75 subjects completed the study. There were 3 arms: DTE, LT4+T3 combination, and LT4 alone. Each subject was randomly allocated to one of these 3 arms for 12 weeks randomly. The study was powered to detect the primary outcome. The primary endpoint was post-treatment score on the 36-point thyroid symptom questionnaire. Secondary endpoints were weight, general health questionnaire, the Beck depression inventory, Wechsler Memory testing, lipid panels and thyroid function tests. Analysis was performed with a linear mixed model using subject as a random factor and group as a fixed effect.

Results: There was no significant difference between the 3 arms on the thyroid symptom questionnaire (p=.32), and the secondary outcomes showed no between group differences. Auditory memory index (p=.008), and visual working memory index (p=.02) were higher in the Hashimoto’s than non-Hashimoto’s group. There was no significant primary or secondary outcome difference among various genotypes of deiodinase 2. There was no relationship between Hashimoto’s vs. non-Hashimoto’s based on genotypes or likelihood of carrying Thr92AlaD2 polymorphism. Though there was no statistically significant preference for any treatment, numerically more patients with Hashimoto’s preferred DTE and LT4/T3 combination than LT4-monotherapy.

Conclusions: There was no significant difference between hypothyroid patients taking DTE vs. LT4/T3 combination vs. LT4 monotherapy. Numerically, Hashimoto’s patients tended to prefer DTE and LT4/T3 combination. Also, there was no observed relationship between Hashimoto’s and polymorphism. Further studies with more patients may be needed.
Hydrocortisone Suspension Provides Similar Growth Outcomes as Hydrocortisone Tablets in Young Children With Congenital Adrenal Hyperplasia: A Cross Sectional Study
Authors: Al-Rayess Heba , Addo O Yaw , Palzer Elise , Jaber Mu’taz , Fleissner Kristin , Hodges James , Brundage Richard , Miller Bradley Scott , Sarafoglou Kyriakie
Published: May 2021

Young children with CAH require small doses (0.1–1.25mg) and incremental adjustments of hydrocortisone (HC) to control excess androgen production and avoid the negative effects of overtreatment. A recent 6 hour pharmacokinetic/pharmacodynamic study reported that alcohol-free HC suspension provides similar cortisol exposure to tablets (1), but more data is needed to assess its clinical efficacy. We performed a chart review to determine the effect of the alcohol-free HC suspension compared to tablets on height, weight, BMI, bone age z-scores and corrected height z-scores to target height z-scores in children aged 2 yrs and 4 yrs in a cohort with classic CAH. Independent 2-sample t-tests examined cumulative and average HC dose at 2 and 4 yrs. Triple logistic modeling of longitudinal heights were used to calculate predicted near-adult height. Adjusted linear regression models assessed the effect of HC suspension compared to tablets on final adult height. Charts of 130 children (70 females, 100 salt wasting and 30 simple virilizing) were reviewed. At 2 yrs, 97 were treated with tablets and 33 with suspension (17 previously switched from tablets). At 4 yrs, 89 were treated with tablets and 41 with suspension (25 switched). No significant differences in height or BMI z-scores at both 2 and 4 yrs, before or after adjusting for age at diagnosis and sex were found. Bone age z-scores averaged 7.2 SDs lower for patients treated with HC suspension only compared to patients on HC tablets at age 4 (p<0.001), and 5.93 SDs lower for patients switched from tablets to suspension compared to tablets (p<0.001). The suspension group received 16% lower (p=0.055) and 25% lower (p=0.002) cumulative HC doses by the ages of 2 yrs and 4 yrs respectively. Average daily HC dose was lower by 3.44 and by 4.46 mg/m2/d over the first 2 and 4 yrs of life respectively. No significant differences were found between patients treated with tablets and suspension in the predicted final adult height, its z-score or its corrected z-score to target height after adjusting for age at diagnosis, sex and diagnosis. Our data indicates that treatment with alcohol-free HC suspension decreased androgen exposure as shown by lower bone age z-scores, generated no significant differences in SDS in observed height, BMI or predicted near-adult height, and allowed for lower average and cumulative daily HC dose compared to HC tablets in children with CAH. Reference: (1) Sarafoglou et al., J Clin Pharmacol.2015;55(4):452–7.
Presentation and Outcome of Severe Graves’ Disease
Authors: Babu Priya Mohan , Bahl Suhani , Capatana Florin , Hamdan Khaliq , Khan Ishrat , Adlan Mohamed , Premawardhana Lakdasa D K E
Published: May 2021

Introduction: Subjects with “severe” Graves’ disease (GD) are known to have adverse outcomes. They have multisystem involvement (orbitopathy, dermopathy), more severe clinical features, large goitres and a higher relapse rate. Also, their response to thionamides is slower. There is a developing consensus that early definitive treatment improves prognosis in them. Methods: We retrospectively analysed the electronic case records and biochemistry databases of all subjects seen in our University Health Board between January 2017 and October 2019 with GD. Severe GD was defined by (1) a thyrotropin receptor antibody (TRAb) value greater than 10U/l (normal range: less than 0.9), (2) with any one of the following - (a) free thyroxine (T4) above 50pmol/l (reference range 9-19.1), (b) a combination of T4 more than 40 pmol/l with triiodothyronine (T3) above the detection range of the assay (46.1 pmol/l), (c) the presence of a large goitre, (d) active Graves’ orbitopathy (GO) or (e) dermopathy. We compared subjects with severe GD to those who did not fulfil the above criteria i.e. non-severe GD. Results: 176 GD subjects were seen during this period - 52 (29.5%) with severe and 124 (70.5%) with non-severe GD. However, 19 severe and 26 non-severe GD subjects were on active thionamide treatment at the time of analysis, and complete details were unavailable in 41 subjects. There was a significant difference in the following features between the severe and non-severe GD groups respectively (1) their median age (39 vs.52 years), (2) median TRAb levels (25.5 vs.18.5 U/l) (3) higher prevalence of GO (38.5 vs.13.3%) and active GO (15.4 vs.0%), (4) the presence of moderate/large goitre (51.3 vs.3.3%), (5) higher number failing to normalize biochemically within the first 6 months after treatment initiation (53.9 vs.39%), (6) the presence of a family history, and (8) a higher number requiring definitive treatment within 12 months of starting treatment (9.6vs.0.81%)(p=0.001-0.026 for the above). There was no difference between the two groups in gender, treatment regime i.e. dose titration regime or block and replacement regime, number biochemically normalizing within 12 months, and those who had more than 18 months of treatment and their relapse rates (55 vs. 59.1%, p=0.84). Conclusions: We have shown that those with severe GD were younger, have higher TRAb concentrations with multisystem involvement, and delayed initial normalization of thyroid hormones. A greater number of them require definitive treatment within 12 months of treatment initiation. However, the majority in both groups normalize thyroid hormones within 12 months irrespective of the treatment regime used. Early definitive treatment is required in a significantly higher percentage of subjects with severe GD and needs to be considered in them.
Survey of Practice: The Current Extent of Adjunctive Use of Lithium in the UK During Radioactive Iodine Therapy for Hyperthyroidism
Authors: Younes Younes R , Field Benjamin C T
Published: May 2021

Background: The latest United Kingdom National Institute for Health and Care Excellence (NICE) guideline recommends 131I as first-line definitive treatment for Graves’ disease in patients who are unlikely to achieve remission with antithyroid medication. A small but significant proportion of patients have recurrence of hyperthyroidism after 131I therapy. Lithium enhances thyroidal iodine retention and thus increases radiation dose delivered to the thyroid gland during 131I therapy. While clinical trial findings with adjuvant Lithium have not been universally positive, several studies have demonstrated a favorable effect on cure rate, speed of cure and stabilization of thyroid hormone status during131I therapy. Aim: To determine the extent to which Lithium is used as an adjunct to 131I therapy for hyperthyroidism in the UK. Methods: We conducted a survey of 82 nuclear medicine departments and 236 consultant endocrinologists in National Health Service (NHS) hospitals across the UK. Results: Responses were received from 43 departments and 64 endocrinologists. Ten nuclear medicine departments reported that they do not perform therapeutic procedures. Amongst the remainder, only one department stated that Lithium is considered routinely as an adjunct to 131I for selected patients. Amongst consultant endocrinologists, only two indicated that they use Lithium as an adjunct to 131I therapy. Conclusions: Owing to mixed trial evidence and a lack of guideline support for adjunctive Lithium with 131I, its use is not widespread the UK at present. However, some researchers report that it might offer faster control of hyperthyroidism and reduce the amplitude of post-therapy thyroid function fluctuations. As these could be important determinants not only of quality of life but also of safety of treatment, our findings may be valuable to those planning randomized controlled trials of adjunctive Lithium with 131I therapy for Graves’ disease.
Thyroid Immune-Related Adverse Events Are Associated With Improved Survival in Cancer Patients
Authors: Abdallah Duaa , Johnson Jake , Goldner Whitney Sears , Ganti Apar , Kotwal Anupam
Published: May 2021

Introduction: Thyroid immune-related adverse events (irAEs) occur frequently after immune checkpoint inhibitor (ICI) cancer therapy, but their risk factors and potential influence on survival need further investigation. Methods: We performed a retrospective single-center cohort study of adult cancer patients who received ICIs including CTLA-4, PD-1, PD-L1 inhibitors from 12/1/2012- 12/31/2019. Patients who developed thyroid irAEs after excluding surgical or ablative hypothyroidism were included. Survival analysis was performed by Kaplan-Meier curves and Cox-proportional hazards model. Results: Thyroid irAEs occurred in 145 (17.4%) of 834 ICI-treated patients (median age 64.9 y, 43.4% females) during a median follow-up of 11.6 mo. New-onset thyroid dysfunction occurred in 118 (14.2%), of which 55 presented with thyrotoxicosis (32 progressed to hypothyroidism, 22 returned to euthyroid state, 1 had Graves’ disease). Worsening of pre-existing autoimmune hypothyroidism (≥50% increase in levothyroxine dose) occurred in 27 (3.2%). Of those with new-onset thyroid dysfunction, 79 (67%) required levothyroxine eventually. Patients with thyroid irAE had similar age, sex and cancer type as compared to those without but had higher median pre-treatment TSH [2.4 vs. 1.7 mIU/L (p<0.0001); multivariable OR for TSH ≥2.4 mIU/L of 2 (95% CI 1.3, 3.2; p=0.004)] and higher frequency of autoimmune disease history [26.9% vs. 14.8% (p=0.0009); multivariable OR of 2 (95% CI 1.2, 3.5; p=0.013)]. Thyroid irAEs occurred after a median of 2.4 mo from ICI, most frequently with PD-1/PD-L1 inhibitor. Thyroid irAEs were associated with better median overall survival [38.8 mo (95% CI 26.6, not reached) vs. 18.9 (95% CI 14.2, 24.8); p<0.0001] which persisted on restricting to patients with new-onset thyroid dysfunction [40.1 mo (95% CI 26.6, not reached) vs. 18.8 (95% CI 13.6, 24.8); p<0.0001]. On multivariable analysis, thyroid irAEs had HR for mortality of 0.51 (95% CI 0.37, 0.71; p<0.0001), which persisted on restricting to new-onset thyroid dysfunction [HR 0.48 (95% CI 0.34, 0.69; p<0.0001)]. Conclusions: Thyroid irAEs frequently occur after PD-1/PD-L1 inhibitor therapy, presenting as hypothyroidism or thyrotoxicosis usually progressing to hypothyroidism. Higher TSH even within normal range and autoimmune disease history may be risk factors for thyroid irAE. Improved survival with thyroid irAEs suggests these could be a marker for anti-tumor activity.
Analysis of Hypothalamic TRH Neurons in Regulating Thyroid Hormone Levels
Authors: Costa e Sousa Ricardo H , Rorato Rodrigo , Hollenberg Anthony Neil , Vella Kristen R
Published: May 2021

Thyroid hormone (TH) is a major regulator of development and metabolism. An important mechanism controlling TH production is the negative feedback at the hypothalamic and pituitary level and it has been suggested that thyroid hormone receptor β (TRβ) is the main mediator of TH actions in the hypothalamic paraventricular nucleus (PVN). Nevertheless, the direct actions of TH and TRβ in the negative regulation of TRH have yet to be demonstrated in vivo. Here we used two approaches to investigate the TRH neuron. First, we used a chemogenetic tool to directly investigate the role of TRH neurons on the regulation of thyroid hormone levels. Mice expressing Cre-recombinase in TRH neurons received bilateral injections of the activating designer receptors exclusively activated by designer drugs (DREADD) directly into the PVN. Activation of TRH neurons produced a rapid and sustained increase in circulating TSH levels in both males and females. TSH levels increased approximately 10-fold from baseline within 15 minutes of injection of CNO, returning to baseline within 2.5 hours. TH levels were increased approximately 2-fold in males and females. Therefore, using a chemogenetic approach, we were able to directly evaluated the role of PVN TRH neurons on the control of thyroid activity, for the first time. Next, we generated mice deficient in TRβ specifically in neurons expressing melanocortin 4 receptor (MC4R), which overlaps with TRH expression in the PVN. Knockout mice (KO) developed normally and showed no change in TH and TSH levels. TRH mRNA levels in the PVN of KO mice were similar to control mice. To investigate if the deletion of TRβ in the PVN changes the sensitivity of the HPT axis to T3, mice were rendered hypothyroid and given increasing doses of T3 for 2 weeks. Results show no difference in TRH mRNA or serum TSH between controls and KO. Surprisingly, despite the presence of detectable genomic recombination on the TRβ gene in the PVN, there was no difference in TRβ mRNA expression between control and KO mice, suggesting that either MC4R-positive neurons do not express TRβ or they represent a very small population of TRβ-positive cells in the PVN. Present data show that TRH neuron activation rapidly stimulates TSH release and increases TH levels, demonstrating a major role of these neurons in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Nevertheless, deletion of TRβ from MC4R neurons had no major effect on either TRH or TH levels in in mice. Additionally, TRβ in MC4R-positive TRH neurons in the PVN is not necessary for TH-induced suppression of TRH mRNA. Although further studies are necessary, these data suggest that there are distinct populations of hypophysiotropic TRH neurons in the PVN, some of which are not regulated by thyroid hormone and TRβ.
Assessment of the Thyroid Function During the Three Trimesters of Pregnancy Among the Egyptian Population
Authors: Amara Mohamed Fahmy
Published: May 2021

Background: Pregnancy is associated with significant but reversible changes in the thyroid function that might cause maternal and fetal complications. Undetected and untreated thyroid disorders are associated with adverse maternal and fetal outcomes, thus screening is important. There are limited data on the prevalence of newly diagnosed thyroid disease during pregnancy from Egypt. Therefore, this study was designed to evaluate the prevalence of thyroid dysfunction during the three trimesters of pregnancy. Subjects and Methods: This was a cross-sectional study conducted at the antenatal clinic of El-Shatby Maternity Hospital at Alexandria University. The total sample population comprised of 90 pregnant women divided into 30 women for each trimester compared with 30 non- pregnant healthy women regarding thyroid function parameters and thyroid peroxidase antibody (anti - TPO) by using COBAS analyzer measured by the electrochemiluminescence immunoassay “WCLIA” employs monoclonal antibodies specifically directed against human thyroid-stimulating hormone (TSH), free thyroxine (FT4), FT3 and anti TPO. Results: 120 ladies were enrolled for this study aged between 20-45 years excluding subjects with previously diagnosed endocrinal anomalies. There were significant differences between pregnant and non-pregnant females regarding TSH and FT4, but no significant difference regarding FT3 and anti TPO in all trimesters. Conclusion: There is a discrepancy between FT4 & TSH in pregnancy due to the presence of other stimulatory and inhibitory factors in pregnancy, thyroid anomalies increased with the advance in pregnancy, thus screening of TSH and anti TPO is important. Considering the immense impact that maternal thyroid dysfunction has on maternal and fetal outcomes, prompt identification of thyroid dysfunction and its timely treatment is essential.
Maternal Hypothyroidism Delayed Retinal Opsin-Development in the Neonatal Period: Analysis of TRH-Deficient Mice
Authors: Saito Kazuma , Horiguchi Kazuhiko , Buyandalai Battsetseg , Nishikido Ayaka , Okamura Takashi , Toki Akiko , Ishida Emi , Matsumoto Shunichi , Yoshino Satoshi , Nakajima Yasuyo , Yamada Eijiro , Saito Tsugumichi , Ozawa Atsushi , Akiyama Hideo , Yamada Masanobu
Published: May 2021

Introduction: Retinal cone photoreceptor cells contain short (S) and medium (M) wavelength opsins, which are light-sensitive substances involved in color vision and visual acuity by sensing lights of different wavelengths. Thyroid hormones promote M-opsin expression and suppress S-opsin expression during the differentiation of cone photoreceptors. It was previously reported that M-opsin expression was delayed and S-opsin expression increased in TSH receptor-deficient mice and methimazole-induced hypothyroid mice. In addition, no M-opsin expression and increased S-opsin expression were observed in thyroid hormone receptor (TR) β2-deficient mice (Ng L et al, Nature Genetics. 2001; 27(1): 94-98.). This suggested that impaired thyroid function affects opsin development. We therefore examined retinal development in TRH-deficient mice, which are a model of central hypothyroidism established in our laboratory. Methods: We performed HE staining of the retina at postnatal 30 days and electroretinography at postnatal 10 weeks using TRH-/- and wild-type (WT) mice. We also examined expression levels of S/M opsin mRNA in WT, TRH-/- and TRH-/- pups born from TRH-/- dams at postnatal 12,17 and 30 days, and TRβΔ337T knock-in mice (TRβmut/mut) at postnatal 30 days. Furthermore, we performed immunohistochemistry to examine S/M opsin protein expression in these mice. Results: The retinal structures by HE staining and retinal functions by electroretinography in TRH-/- mice were unchanged compared with those in WT mice. Although M-opsin expression was not detected and S-opsin expression was higher in TRβmut/mut mice than in WT mice, the mRNA and protein expression levels of S/M-opsin did not significantly differ between TRH-/- pups born from TRH+/- dams and WT pups at all postnatal days. TRH-/- pups born from TRH-/- dams exposed to maternal hypothyroidism had similar serum total T4 levels to TRH-/- pups born from TRH+/- with normal maternal thyroid function. In contrast, the mRNA expression level of M-opsin was significantly lower (1.00±0.06 vs 0.64±0.05: mean ± SE, p<0.01) and the protein expression level was lower in TRH-/- pups born from TRH-/- dams than in WT pups at postnatal 12 days. However, these differences disappeared after postnatal 17 days, and there was no difference in M-opsin expression in TRH-/- pups born from TRH-/- dams compared with WT pups. Conclusions: Although no delay in opsin development was observed in TRH-/- pups born from TRH+/- dams, TRH-/- pups born from central hypothyroid dams exhibited delayed opsin development, suggesting that maternal hypothyroidism affects the development of retinal opsin in the neonatal period.