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Open access

Charlotte Höybye, Andreas F H Pfeiffer, Diego Ferone, Jens Sandahl Christiansen, David Gilfoyle, Eva Dam Christoffersen, Eva Mortensen, Jonathan A Leff, and Michael Beckert

TransCon growth hormone is a sustained-release human growth hormone prodrug under development in which unmodified growth hormone is transiently linked to a carrier molecule. It is intended as an alternative to daily growth hormone in the treatment of growth hormone deficiency. This was a multi-center, randomized, open-label, active-controlled trial designed to compare the safety (including tolerability and immunogenicity), pharmacokinetics and pharmacodynamics of three doses of weekly TransCon GH to daily growth hormone (Omnitrope). Thirty-seven adult males and females diagnosed with adult growth hormone deficiency and stable on growth hormone replacement therapy for at least 3 months were, following a wash-out period, randomized (regardless of their pre-study dose) to one of three TransCon GH doses (0.02, 0.04 and 0.08 mg GH/kg/week) or Omnitrope 0.04 mg GH/kg/week (divided into 7 equal daily doses) for 4 weeks. Main outcomes evaluated were adverse events, immunogenicity and growth hormone and insulin-like growth factor 1 levels. TransCon GH was well tolerated; fatigue and headache were the most frequent drug-related adverse events and reported in all groups. No lipoatrophy or nodule formation was reported. No anti-growth hormone-binding antibodies were detected. TransCon GH demonstrated a linear, dose-dependent increase in growth hormone exposure without accumulation. Growth hormone maximum serum concentration and insulin-like growth factor 1 exposure were similar after TransCon GH or Omnitrope administered at comparable doses. The results suggest that long-acting TransCon GH has a profile similar to daily growth hormone but with a more convenient dosing regimen. These findings support further TransCon GH development.

Open access

Jia Liu, Min Liu, Zhe Chen, Yumei Jia, and Guang Wang

Objective

Autoimmune thyroiditis (AIT) is the most common autoimmune thyroid disease. Longitudinal relaxation time mapping (T1-mapping) measured by MRI is a new technique for assessing interstitial fibrosis of some organs, such as heart and liver. This study aimed to evaluate the relationship between T1-mapping value and thyroid function and determine the usefulness of T1-mapping in identifying thyroid destruction in AIT patients.

Methods

This case–control study recruited 57 drug-naïve AIT patients and 17 healthy controls. All participants were given thyroid MRI, and T1-mapping values were measured using a modified look-locker inversion-recovery sequence.

Results

AIT patients had significantly higher thyroid T1-mapping values than the healthy controls (1.077 ± 177 vs 778 ± 82.9 ms; P < 0.01). A significant increase in thyroid T1-mapping values was presented along with the increased severity of thyroid dysfunction (P < 0.01). Correlation analyses showed that increased thyroid T1-mapping values were associated with higher TSH and lower FT3 and FT4 levels (TSH: r = 0.75; FT3: r = −0.47; FT4: r = −0.72; all P < 0.01). Receiver-operating characteristic curve analysis revealed a high diagnostic value of T1-mapping values for the degree of thyroid destruction (area under the curve was 0.95, 95% CI: 0.90–0.99, P < 0.01).

Conclusions

AIT patients have higher thyroid T1-mapping values than the healthy controls, and the T1-mapping values increased with the progression of thyroid dysfunction. Thyroid T1-mapping value might be a new index to quantitatively evaluate the degree of thyroid destruction in AIT patients.

Open access

Guido Zavatta and Bart L Clarke

The first adjunctive hormone therapy for chronic hypoparathyroidism, recombinant human parathyroid hormone (1–84) (rhPTH(1–84)) was approved by the FDA in January 2015. Since the approval of rhPTH(1–84), growing interest has developed in other agents to treat this disorder in both the scientific community and among pharmaceutical companies. For several reasons, conventional therapy with calcium and activated vitamin D supplementation, magnesium supplementation as needed, and occasionally thiazide-type diuretic therapy remains the mainstay of treatment, while endocrinologists and patients are constantly challenged by limitations of conventional treatment. Serum calcium fluctuations, increased urinary calcium, hyperphosphatemia, and a constellation of symptoms that limit mental and physical functioning are frequently associated with conventional therapy. Understanding how conventional treatment and hormone therapy work in terms of pharmacokinetics and pharmacodynamics is key to effectively managing chronic hypoparathyroidism. Multiple questions remain regarding the effectiveness of PTH adjunctive therapy in preventing or slowing the onset and progression of the classical complications of hypoparathyroidism, such as chronic kidney disease, calcium-containing kidney stones, cataracts, or basal ganglia calcification. Several studies point toward an improvement in the quality of life during replacement therapy. This review will discuss current clinical and research challenges posed by treatment of chronic hypoparathyroidism.

Key points:

  • Conventional therapy with calcium and activated forms of vitamin D are currently the mainstays of treatment for most patients with chronic hypoparathyroidism.

  • Hormone therapy can be administered through FDA-approved once-daily rhPTH(1–84), or off-label multiple-daily injections of teriparatide. The former is the only FDA-approved drug, with safety and efficacy supported by a randomized placebo-controlled trial and open-label long-term extension trial data.

  • Twice-daily teriparatide has been used in children safely for up to 10 years.

  • New pharmacological options that replace the deficient hormone wi ll likely be available within the next few years.

Open access

Marek Niedziela

The term 'hyperthyroidism' refers to a form of thyrotoxicosis due to inappropriate high synthesis and secretion of thyroid hormone(s) by the thyroid. The leading cause of hyperthyroidism in adolescents is Graves’ disease (GD); however, one should also consider other potential causes, such as toxic nodular goitre (single or multinodular), and other rare disorders leading to excessive production and release of thyroid hormones. The term 'thyrotoxicosis' refers to a clinical state resulting from inappropriate high thyroid hormone action in tissues, generally due to inappropriate high tissue thyroid hormone levels. Thyrotoxicosis is a condition with multiple aetiologies, manifestations, and potential modes of therapy. By definition, the extrathyroidal sources of excessive amounts of thyroid hormones, such as iatrogenic thyrotoxicosis, factitious ingestion of thyroid hormone, or struma ovarii, do not include hyperthyroidism. The aetiology of hyperthyroidism/and thyrotoxicosis should be determined. Although the diagnosis is apparent based on the clinical presentation and initial biochemical evaluation, additional diagnostic testing is indicated. This testing should include: (1) measurement of thyroid-stimulating hormone receptor (TSHR) antibodies (TRAb); (2) analysis of thyroidal echogenicity and blood flow on ultrasonography; or (3) determination of radioactive iodine uptake (RAIU). A 123I or 99mTc pertechnetate scan is recommended when the clinical presentation suggests toxic nodular goitre. A question arises regarding whether diagnostic workup and treatment (antithyroid drugs, radioiodine, surgery, and others) should be the same in children and adolescents as in adults, as well as whether there are the same goals of treatment in adolescents as in adults, in female patients vs in male patients, and in reproductive or in postreproductive age. In this aspect, different treatment modalities might be preferred to achieve euthyroidism and to avoid potential risks from the treatment. The vast majority of patients with thyroid disorders require life-long treatment; therefore, the collaboration of different specialists is warranted to achieve these goals and improve patients’ quality of life.

Open access

Melinda Kertész, Szilárd Kun, Eszter Sélley, Zsuzsanna Nagy, Tamás Kőszegi, and István Wittmann

Background

Type 2 diabetes is characterized, beyond the insulin resistance, by polyhormonal resistance. Thyroid hormonal resistance has not yet been described in this population of patients. Metformin is used to decrease insulin resistance, and at present, it is assumed to influence the effect of triiodothyronine, as well.

Methods

In this open-label, pilot, hypothesis-generating, follow-up study, 21 patients were included; all of them were euthyroid with drug naïve, newly diagnosed type 2 diabetes. Before and after 4 weeks of metformin therapy, fructosamine, homeostasis model assessment for insulin resistance (HOMA-IR), thyroid hormones, T3/T4 ratio, and TSH, as well as blood pressure and heart rate using ambulatory blood pressure monitor were measured. We also conducted an in vitro study to investigate the possible mechanisms of T3 resistance, assessing T3-induced Akt phosphorylation among normal (5 mM) and high (25 mM) glucose levels with or without metformin treatment in a human embryonal kidney cell line.

Results

Metformin decreased the level of T3 (P < 0.001), the ratio of T3/T4 (P = 0.038), fructosamine (P = 0.008) and HOMA-IR (P = 0.022). All these changes were accompanied by an unchanged TSH, T4, triglyceride, plasma glucose, bodyweight, blood pressure, and heart rate. In our in vitro study, T3-induced Akt phosphorylation decreased in cells grown in 25 mM glucose medium compared to those in 5 mM. Metformin could not reverse this effect.

Conclusion

Metformin seems to improve T3 sensitivity in the cardiovascular system in euthyroid, type 2 diabetic patients, the mechanism of which may be supracellular.

Open access

Anastasia P Athanasoulia-Kaspar, Matthias K Auer, Günter K Stalla, and Mira Jakovcevski

Objective

Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing’s disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with aging and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing’s disease).

Design/methods

Here, we examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case–control (n = 106, age-, gender-matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length.

Results

We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (β = 0.377; P = 0.018) independent of potential confounders (gender, age, BMI, arterial hypertension, systolic blood pressure, number of antihypertensive drugs, total leukocyte count, waist-to-hip ratio, waist circumference, diabetes mellitus type 2, HbA1c, current statin use). Median split analysis revealed that higher hydrocortisone intake (>20 mg) was associated with significantly shorter telomeres.

Conclusion

These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.

Open access

Riying Liang, Meijun Wang, Chang Fu, Hua Liang, Hongrong Deng, Ying Tan, Fen Xu, and Mengyin Cai

Background:

Obesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated.

Methods:

Male C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated.

Results:

Liraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked.

Conclusions:

Liraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.

Open access

Lili Liu, Zhuo Shao, Ying Xia, Jiabi Qin, Yang Xiao, Zhiguang Zhou, and Zubing Mei

Objective

Combined treatment with an incretin-based drug, such as a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or a dipeptidyl peptidase-4 (DPP-4) inhibitor, and basal insulin is a new strategy for improving glucose control in type 1 diabetes mellitus (T1DM). We performed a meta-analysis to assess the effect of this combined treatment on glycaemic control, insulin dose, severe hypoglycaemia, weight gain and gastrointestinal side effects in T1DM patients.

Methods

We searched PubMed, EMBASE and the Cochrane Library for relevant studies published before July 16, 2018. The primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes included total daily insulin dose, body weight, severe hypoglycaemia and gastrointestinal side effects.

Results

Nine randomized controlled trials (RCTs) involving 2389 patients were ultimately included in the meta-analysis. The pooled data suggested that incretin-based therapy was associated with a reduction in HbA1c levels (weighted mean difference (WMD) −0.17%, 95% confidence interval (CI) −0.24 to −0.11, P < 0.001), total daily insulin dose (WMD −5.53 IU/day, 95% CI −8.89 to −2.17, P = 0.001) and body weight (WMD −3.24 kg, 95% CI −4.43 to −2.04, P < 0.001). Incretins did not increase the risk of severe hypoglycaemia (odds ratio (OR) 0.83, 95% CI 0.60–1.16, P = 0.287) but increased the occurrence of gastrointestinal side effects (OR 3.46, 95% CI 2.20–5.45, P < 0.001).

Conclusions

In T1DM patients, GLP-1 RAs, but not DPP-4 inhibitors, combined with insulin appear to be an effective therapy but may increase the occurrence of gastrointestinal side effects.

Open access

Yuerong Yan, Lili You, Xiaoyi Wang, Zhuo Zhang, Feng Li, Hongshi Wu, Muchao Wu, Jin Zhang, Jiayun Wu, Caixia Chen, Xiaohui Li, Biwen Xia, Mingtong Xu, and Li Yan

Objectives

A variety of factors differed between rural and urban areas may further influence iodine status and thyroid structure. Hence, this study compared iodine nutrition, the prevalence of thyroid goiter, and nodules between rural and urban residents in Guangzhou, a southern coastal city of China.

Methods

A total of 1211 rural residents and 1305 urban residents were enrolled in this cross-sectional study. A questionnaire regarding personal characteristics was administered. Urinary iodine concentration (UIC) was examined. Ultrasonography of the thyroid was performed to evaluate thyroid goiter and nodules. Multiple logistic analysis was used to identify the potential associated factors.

Results

The median UIC was significantly lower in rural residents than in urban residents (120.80 μg/L vs 136.00 μg/L, P < 0.001). Although the coverage rate of iodized salt was much higher in rural residents than in urban residents (99.59% vs 97.29%, P < 0.001), the percentages of seafood intake (8.60% vs 29.29%, P < 0.001), iodine-containing drug consumption (0.33% vs 1.24%, P = 0.011), and iodine contrast medium injection (0.58% vs 1.87%, P = 0.004) were lower in rural residents than in urban residents. Both the prevalence of thyroid goiters and nodules was significantly higher in rural residents than in urban residents (goiter: 8.06% vs 1.20%, P < 0.001; nodules: 61.89% vs 55.04%, P = 0.023). Living in rural areas was associated with thyroid goiter (OR 5.114, 95% CI 2.893–9.040, P < 0.001).

Conclusions

There were differences in iodine nutrition and the prevalence of thyroid goiter and nodules in rural and urban residents in Guangzhou. Differentiated and specialized monitoring is recommended in our area.

Open access

Sarah J Delforce, Eugenie R Lumbers, Celine Corbisier de Meaultsart, Yu Wang, Anthony Proietto, Geoffrey Otton, Jim Scurry, Nicole M Verrills, Rodney J Scott, and Kirsty G Pringle

A dysfunctional endometrial renin–angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium; mRNA levels of (pro)renin receptor (ATP6AP2), angiotensin II type 1 receptor (AGTR1), angiotensin-converting enzyme (ACE1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium (P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 (TGFB1), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue (P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2, AGTR1 and ACE1, key elements of the pro-angiogenic/proliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer.