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Open access

Marcus Heldmann, Krishna Chatterjee, Carla Moran, Berenike Rogge, Julia Steinhardt, Tobias Wagner-Altendorf, Martin Göttlich, Hannes Schacht, Peter Schramm, Georg Brabant, Thomas F. Münte, and Anna Cirkel

Background: Thyroid hormone action is mediated by two forms of thyroid hormone receptors (α,β) with differential tissue distribution. Thyroid hormone receptor β (TRβ) mutations lead to resistance to thyroid hormone action in tissues predominantly expressing the β form of the receptor (pituitary, liver). This study seeks to identify effects of mutant TRβ on pituitary size.

Methods: High-resolution 3D T1-weighted magnetic resonance images were acquired in 19 patients with RTHβ in comparison to 19 healthy matched controls. Volumetric measurements of the pituitary gland were performed independently and blinded by four different raters (two neuroradiologists, one neurologist, one neuroscientist).

Results: Patients with mutant TRβ (Resistance to Thyroid Hormone β,RΤΗβ) showed elevated fT3/4 levels with normal TSH levels, whereas healthy controls showed normal thyroid hormone levels. Imaging revealed smaller pituitary size in RTHβ patients in comparison to healthy controls (F(1,35)=7.05, p=0.012, partial η2 =0.17).

Conclusion: RTHβ subjects have impaired sensitivity to thyroid hormones, along with decreased size of the pituitary gland.

Open access

Ningning Gong, Cuixia Gao, Xuedi Chen, Yu Wang, and Limin Tian

The purpose of our study was to observe adipokine expression and endothelial function in subclinical hypothyroidism (sHT) rats and to determine whether levothyroxine (LT4) treatment affects these changes. Sixty-five male Wistar rats were randomly divided into five groups: the control group; sHT A, B and C groups and the sHT + T4 group. The sHT rats were induced by methimazole (MMI) and the sHT + T4 rats were administered LT4 treatment after 8 weeks of MMI administration. Thyroid function and lipid levels were measured using radioimmunoassays and enzymatic colorimetric methods, respectively. Serum adiponectin (APN), chemerin, TNF-α, endothelin (ET-1) and nitric oxide (NO) levels were measured using ELISA kits and a nitric-reductive assay. The expression of APN, chemerin and TNF-α in visceral adipose tissue (VAT) was measured in experimental rats using RT-PCR and Western blotting. Hematoxylin–eosin (HE) staining was used to observe changes in adipose tissue. The sHT rats had significantly higher levels of thyroid-stimulating hormone (TSH), TNF-α, chemerin, ET-1, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and lower levels of APN and NO than those in control and sHT + T4 rats. Based on Pearson correlation analysis, the levels of chemerin, TNF-α, ET-1, LDL-C, TC and triglyceride (TG) were positively correlated with TSH, but APN and NO levels were negatively correlated with TSH. These findings demonstrated that high TSH levels contribute to the changes of adipokines and endothelial dysfunction in sHT, but LT4 treatment ameliorates those changes.

Open access

Aditya Dutta, Ganesh Jevalikar, Rutuja Sharma, Khalid J Farooqui, Shama Mahendru, Arun Dewan, Sandeep Bhudiraja, and Ambrish Mithal

Aim

To study the prevalence of thyroid dysfunction and its association with disease severity in hospitalized patients of coronavirus disease-19 (COVID-19).

Methods

In this retrospective cohort study, thyroid function tests (TFT) of 236 hospitalized patients of COVID-19 along with demographic, comorbid, clinical, biochemical and disease severity records were analysed. Patients were divided into previous euthyroid or hypothyroid status to observe the effect of prior hypothyroidism on the severity of COVID-19.

Results

TFT abnormalities were common. Low free T3 (FT3), high thyroid-stimulating hormone (TSH) and low TSH were seen in 56 (23.7%), 15 (6.4%) and 9 (3.8%) patients, respectively. The median levels of TSH (2.06 vs 1.26 mIU/mL, P = 0.001) and FT3 (2.94 vs 2.47 pg/mL, P < 0.001) were significantly lower in severe disease. Previous hypothyroid status (n = 43) was associated with older age, higher frequency of comorbidities, higher FT4 and lower FT3. TFT did not correlate with markers of inflammation (except lactate dehydrogenase); however, FT3 and TSH negatively correlated with outcome severity score and duration of hospital stay. Cox regression analysis showed that low FT3 was associated with severe COVID-19 (P = 0.032, HR 0.302; CI 0.101–0.904), irrespective of prior hypothyroidism.

Conclusions

Functional thyroid abnormalities (low FT3 and low TSH) are frequently seen in hospitalized patients of COVID-19. Although these abnormalities did not correlate with markers of inflammation, this study shows that low FT3 at admission independently predicts the severity of COVID-19.

Open access

Stine Linding Andersen, Louise Knøsgaard, Aase Handberg, Peter Vestergaard, and Stig Andersen

Objective

A high activity of the deiodinase type 2 has been proposed in overweight, obese, and smoking pregnant women as reflected by a high triiodothyronine (T3)/thyroxine (T4) ratio. We speculated how maternal adiposity and smoking would associate with different thyroid function tests in the early pregnancy.

Design

Cross-sectional study within the North Denmark Region Pregnancy Cohort.

Methods

Maternal thyroid-stimulating hormone (TSH), total T4 (TT4), total T3 (TT3), free T4 (fT4), and free T3 (fT3) were measured in stored blood samples (median gestational week 10) by an automatic immunoassay. Results were linked to nationwide registers, and live-birth pregnancies were included. The associations between maternal adiposity (overweight or obese), smoking, and log-transformed TSH, fT3/fT4 ratio, and TT3/TT4 ratio were assessed using multivariate linear regression and reported as adjusted exponentiated β coefficient (aβ) with 95% CI. The adjusted model included maternal age, parity, origin, week of blood sampling, and diabetes.

Results

Altogether 5529 pregnant women were included, and 40% were classified with adiposity, whereas 10% were smoking. Maternal adiposity was associated with higher TSH (aβ 1.13 (95% CI 1.08–1.20)), whereas maternal smoking was associated with lower TSH in the early pregnancy (0.875 (0.806–0.950)). Considering the T3/T4 ratio, both maternal adiposity (fT3/fT4 ratio: 1.06 (1.05–1.07); TT3/TT4 ratio: 1.07 (1.06–1.08)) and smoking (fT3/fT4 ratio: 1.07 (1.06–1.09); TT3/TT4 ratio: 1.10 (1.09–1.12)) were associated with a higher ratio.

Conclusions

In a large cohort of Danish pregnant women, adiposity and smoking showed opposite associations with maternal TSH. On the other hand, both conditions were associated with a higher T3/T4 ratio in early pregnancy, which may reflect altered deiodinase activity.

Open access

Chunyun Fu, Shiyu Luo, Yingfeng Li, Qifei Li, Xuehua Hu, Mengting Li, Yue Zhang, Jiasun Su, Xuyun Hu, Yun Chen, Jin Wang, Bobo Xie, Jingsi Luo, Xin Fan, Shaoke Chen, and Yiping Shen

Background

The incidence of congenital hypothyroidism (CH) differs significantly among different ethnicities and regions, and early differentiation of transient CH is important to avoid unnecessary prolonged treatment with L-T4.

Objective

To investigate the incidence of CH based on the newborn screening program in Guangxi Zhuang Autonomous Region, China, and to analyze the predictors that might allow for an early differentiation between permanent (P) and transient (T) CH.

Design and methods

Data from newborn screening program over a seven-year period (January 2009 to January 2016) at Guangxi Maternal and Child Health Hospital are analyzed. Blood samples were collected on filter paper between 3 and 7 days after birth, and TSH level was measured by time-resolved fluorescence assay. Individuals with increased TSH (TSH ≥ 8 IU/L) levels detected by newborn screening were recalled for further evaluation. Serum TSH, FT3 and FT4 were determined by electrochemiluminescence assay using venous blood samples. Diagnosis of CH is based on elevated TSH levels (>10 IU/L) and decreased FT4 levels (<12 pmol/L). Patients with elevated TSH levels and normal FT4 levels were diagnosed as hyperthyrotropinemia. Permanent or transient CH was determined by using the results of thyroid function tests after temporary withdrawal of L-T4 therapy at approximately 2–3 years of age.

Results

Among 1,238,340 infants in the newborn screening program, 14,443 individuals were recalled for reevaluation (re-call rate 1.18%), 911 and 731 individuals were subsequently determined to have hyperthyrotropinemia and CH respectively; thus, a prevalence of 1:1359 and 1:1694 for hyperthyrotropinemia and CH. Of the 731 patients with CH, 161 patients were diagnosed with permanent CH (PCH), and 159 patients were diagnosed with transient CH (TCH), the other 411 patients are too young to determine their subtypes. Patients with PCH required an increasing dose of L-T4 during the first few years, whereas patients with TCH required a decreased dose of L-T4. The TSH levels at diagnosis and the dose of L-T4 used were significantly higher in PCH cases than in transient cases. The FT4 levels at diagnosis were significantly lower in PCH cases than in TCH cases. The TSH levels at diagnosis, FT4 levels at diagnosis and L-T4 doses at 90 days were evaluated as predictors for differentiating PCH and TCH, and their accuracy at their respective optimal cutoffs were determined to be 60.6%, 66.7% and 93.9%, respectively.

Conclusions

The CH incidence in Guangxi Zhuang Autonomous Region is slightly higher (1:1694) compared to the worldwide levels (1/2000–1/4000). The PCH and TCH ratio is close to 1; thus, the estimated PCH incidence is 1/3388, which is similar to reported worldwide average incidence (1/3000). The L-T4 dose required at 90 days (>30 μg/day) has the highest predictive value for PCH. Earlier differentiation of PCH and TCH helps to determine appropriate treatment course.

Open access

John E M Midgley, Rolf Larisch, Johannes W Dietrich, and Rudolf Hoermann

Several influences modulate biochemical responses to a weight-adjusted levothyroxine (l-T4) replacement dose. We conducted a secondary analysis of the relationship of l-T4 dose to TSH and free T3 (FT3), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state l-T4 replacement for autoimmune thyroiditis or after surgery for malignant or benign thyroid disease. Peripheral deiodinase activity was calculated as a measure of T4–T3 conversion efficiency. In euthyroid subjects, the median l-T4 dose was 1.3 μg/kg per day (interquartile range (IQR) 0.94,1.60). The dose was independently associated with gender, age, aetiology and deiodinase activity (all P<0.001). Comparable FT3 levels required higher l-T4 doses in the carcinoma group (n=143), even after adjusting for different TSH levels. Euthyroid athyreotic thyroid carcinoma patients (n=50) received 1.57 μg/kg per day l-T4 (IQR 1.40, 1.69), compared to 1.19 μg/kg per day (0.85,1.47) in autoimmune thyroiditis (P<0.01, n=76) and 1.08 μg/kg per day (0.82, 1.44) in patients operated on for benign disease (P< 0.01, n=80). Stratifying patients by deiodinase activity categories of <23, 23–29 and >29 nmol/s revealed an increasing FT3–FT4 dissociation; the poorest converters showed the lowest FT3 levels in spite of the highest dose and circulating FT4 (P<0.001). An l-T4-related FT3–TSH disjoint was also apparent; some patients with fully suppressed TSH failed to raise FT3 above the median level. These findings imply that thyroid hormone conversion efficiency is an important modulator of the biochemical response to l-T4; FT3 measurement may be an additional treatment target; and l-T4 dose escalation may have limited success to raise FT3 appropriately in some cases.

Open access

Dorte Glintborg, Katrine Hass Rubin, Mads Nybo, Bo Abrahamsen, and Marianne Andersen

Aim

To investigate risk of thyroid disease in Danish women with PCOS.

Design

National register-based study on women with PCOS in Denmark. 18,476 women had a diagnosis of PCOS in the Danish National Patient Register. PCOS Odense University Hospital (PCOS OUH, n = 1146) was an embedded cohort of women with PCOS and clinical and biochemical examination. Three age-matched controls were included for each woman with PCOS (n = 54,757). The main outcome measures were thyroid disease (hypothyroidism, Graves’ disease, goiter, thyroiditis) according to hospital diagnosis codes and/or inferred from filled medicine prescriptions. Associations between baseline TSH and development of cardio-metabolic disease was examined in PCOS OUH.

Results

The median (quartiles) age at inclusion was 29 (23–35) years and follow-up duration was 11.1 (6.9–16.0) years. The hazard ratio (95% CI) for thyroid disease development was 2.5 (2.3–2.7) (P < 0.001). The event rate of thyroid disease was 6.0 per 1000 patient-years in PCOS Denmark versus 2.4 per 1000 patient-years in controls (P < 0.001). Women in PCOS OUH with TSH ≥2.5 mIU/L (n = 133) had higher BMI (median 29 vs 27 kg/m2), wider waist, higher triglycerides and free testosterone by the time of PCOS diagnosis compared to women in PCOS OUH with TSH <2.5 mIU/L (n = 588). Baseline TSH did not predict later development of cardio-metabolic diseases in PCOS OUH.

Conclusions

The event rate of thyroid disease was significantly and substantially higher in women with PCOS compared to controls.

Open access

Anastasia P Athanasoulia-Kaspar, Kathrin H Popp, and Gunter Karl Stalla

The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated – apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension – with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson’s disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson’s disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the regard and metabolic system, findings that merit further investigation in long-term studies.

Open access

Anastasia K Armeni, Konstantinos Assimakopoulos, Dimitra Marioli, Vassiliki Koika, Euthychia Michaelidou, Niki Mourtzi, Gregoris Iconomou, and Neoklis A Georgopoulos

Over the past decades, research attention has increasingly been paid to the neurobiological component of sexual behavior. The aim of the present study was to investigate the correlation of estrogen receptor α (ERA) gene polymorphism (rs2234693-PvuII) (T→C substitution) and oxytocin receptor gene polymorphism (rs53576) (G→A substitution) with sexuality parameters of young, healthy women. One hundred thirty-three Greek heterosexual women, students in higher education institutions, 20–25 years of age, sexually active, with normal menstrual cycles (28–35 days), were recruited in the study. Exclusion criteria were chronic and/or major psychiatric diseases, use of oral contraceptive pills (OCs), polycystic ovary syndrome (PCOS), thyroid diseases as well as drugs that are implicated in hypothalamus–pituitary–gonadal axis. T allele (wildtype) of rs2234693 (PvuII) polymorphism of ERA gene was correlated with increased levels of arousal and lubrication, whereas A allele (polymorphic) of rs53576 (OXTR) polymorphism was correlated with increased arousal levels. The simultaneous presence of both T allele of rs2234693 (PvuII) and A allele of rs53576 (OXTR) polymorphisms (T + A group) was correlated with increased arousal, orgasm levels as well as female sexual function index full score. To our knowledge, this is the first study to investigate the interaction between ERA and OXTR with regard to sexual function in women. Female sexuality is a complex behavioral trait that encompasses both biological and psychological components. It seems that variability in female sexual response stems from genetic variability that characterizes endocrine, neurotransmitter and central nervous system influences.

Open access

Salman Razvi, Sanaa Mrabeti, and Markus Luster

The current standard of care for hypothyroidism is levothyroxine (LT4) monotherapy to reduce levels of thyrotropin (thyroid-stimulating hormone, TSH) within its reference range and amelioration of any symptoms. A substantial minority continues to report hypothyroid-like symptoms despite optimized TSH, however. These symptoms are not specific to thyroid dysfunction and are frequent among the euthyroid population, creating a therapeutic dilemma for the treating clinician as well as the patient. We present a concise, narrative review of the clinical research and evidence-based guidance on the management of this challenging population. The clinician may endeavor to ensure that the serum TSH is within the target range. However, the symptomatic patient may turn to alternative non-evidence-based therapies in the hope of obtaining relief. Accordingly, it is important for the clinician to check for conditions unrelated to the thyroid that could account for the ongoing symptoms such as other autoimmune conditions, anemia or mental health disorders. Systematic and thorough investigation of the potential causes of persistent symptoms while receiving LT4 therapy will resolve the problem for most patients. There may be some patients that may benefit from additional treatment with liothyronine (LT3), although it is unclear as yet as to which patient group may benefit the most from combined LT4 + LT3 therapy. In the future, personalized treatment with LT4 + LT3 may be of benefit for some patients with persistent symptoms of hypothyroidism such as those with polymorphisms in the deiodinase enzyme 2 (DIO2). For now, this remains a subject for research.