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- Abstract: anti-androgenic x
- Abstract: Birth defect x
- Abstract: Drugs x
Search for other papers by Kennett Sprogøe in
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The fundamental challenge of developing a long-acting growth hormone (LAGH) is to create a more convenient growth hormone (GH) dosing profile while retaining the excellent safety, efficacy and tolerability of daily GH. With GH receptors on virtually all cells, replacement therapy should achieve the same tissue distribution and effects of daily (and endogenous) GH while maintaining levels of GH and resulting IGF-1 within the physiologic range. To date, only two LAGHs have gained the approval of either the Food and Drug Administration (FDA) or the European Medicines Agency (EMA); both released unmodified GH, thus presumably replicating distribution and pharmacological actions of daily GH. Other technologies have been applied to create LAGHs, including modifying GH (for example, protein enlargement or albumin binding) such that the resulting analogues possess a longer half-life. Based on these approaches, nearly 20 LAGHs have reached various stages of clinical development. Although most have failed, lessons learned have guided the development of a novel LAGH. TransCon GH is a LAGH prodrug in which GH is transiently bound to an inert methoxy polyethylene glycol (mPEG) carrier. It was designed to achieve the same safety, efficacy and tolerability as daily GH but with more convenient weekly dosing. In phase 2 trials of children and adults with growth hormone deficiency (GHD), similar safety, efficacy and tolerability to daily GH was shown as well as GH and IGF-1 levels within the physiologic range. These promising results support further development of TransCon GH.
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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.
Search for other papers by Adriano N Cury in
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Search for other papers by Verônica T Meira in
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Pediatric Endocrinology Unit, Endocrinology and Metabolism, Nuclear Medicine Laboratory, Pediatrics Department, Irmandade da Santa Casa de Misericórdia de São Paulo, 01221-020 São Paulo, Brazil
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Background/aims
Treatments for Graves' disease (GD) in children and adolescents include oral antithyroid drugs (ATDs), near total thyroidectomy, and radioactive iodine (RAI). ATDs remain the preferred choice in this age group, but because persistent remission occurs in 30% of cases, RAI is becoming a common option for definitive therapy.
Methods
We performed a review of 65 medical records of GD patients under age 19 years who were followed between 1985 and 2005.
Results
The prevalence of GD was higher in females (3:1) and during puberty (for both genders). If no remission was detected during ATD treatment, RAI was indicated when the following criteria were present: non-compliance, relapse, or side effects that were related to ATDs, large goiter, and long-term use of ATDs. The majority of patients developed hypothyroidism within 6 months after RAI. A progressive higher dose regimen was implemented in the last 10 years of the study period. A second RAI dose was necessary in eight cases. During the follow-up period, three pregnancies occurred. One patient with a thyroid nodule and benign cytology was detected.
Conclusions
RAI therapy is effective and safe in the treatment of GD in children and adolescents.
Search for other papers by Aldo Bonaventura in
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Department of Internal Medicine, Division of Cardiology, Division of Laboratory Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Department of Internal Medicine, Division of Cardiology, Division of Laboratory Medicine, First Clinic of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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The prevalence of type 2 diabetes mellitus (T2DM) is increasing all over the world. Targeting good glycemic control is fundamental to avoid the complications of diabetes linked to hyperglycemia. This narrative review is based on material searched for and obtained via PubMed up to April 2015. The search terms we used were: ‘hypoglycemia, diabetes, complications’ in combination with ‘iatrogenic, treatment, symptoms.’ Serious complications might occur from an inappropriate treatment of hyperglycemia. The most frequent complication is iatrogenic hypoglycemia that is often associated with autonomic and neuroglycopenic symptoms. Furthermore, hypoglycemia causes acute cardiovascular effects, which may explain some of the typical symptoms: ischemia, QT prolongation, and arrhythmia. With regards to the latter, the night represents a dangerous period because of the major increase in arrhythmias and the prolonged period of hypoglycemia; indeed, sleep has been shown to blunt the sympatho-adrenal response to hypoglycemia. Two main strategies have been implemented to reduce these effects: monitoring blood glucose values and individualized HbA1c goals. Several drugs for the treatment of T2DM are currently available and different combinations have been recommended to achieve individualized glycemic targets, considering age, comorbidities, disease duration, and life expectancy. In conclusion, according to international guidelines, hypoglycemia-avoiding therapy must reach an individualized glycemic goal, which is the lowest HbA1c not causing severe hypoglycemia and preserving awareness of hypoglycemia.
Search for other papers by Ashley N Reeb in
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Follicular thyroid cancer (FTC) is the second most common type of thyroid cancers. In order to develop more effective personalized therapies, it is necessary to thoroughly evaluate patient-derived cell lines in in vivo preclinical models before using them to test new, targeted therapies. This study evaluates the tumorigenic and metastatic potential of a panel of three human FTC cell lines (WRO, FTC-238, and TT1609-CO2) with defined genetic mutations in two in vivo murine models: an orthotopic thyroid cancer model to study tumor progression and a tail vein injection model to study metastasis. All cell lines developed tumors in the orthotopic model, with take rates of 100%. Notably, WRO-derived tumors grew two to four times faster than tumors arising from the FTC-238 and TT2609-CO2 cell lines. These results mirrored those of a tail vein injection model for lung metastasis: one hundred percent of mice injected with WRO cells in the tail vein exhibited aggressive growth of bilateral lung metastases within 35 days. In contrast, tail vein injection of FTC-238 or TT2609-CO2 cells did not result in lung metastasis. Together, our work demonstrates that these human FTC cell lines display highly varied tumorigenic and metastatic potential in vivo with WRO being the most aggressive cell line in both orthotopic and lung metastasis models. This information will be valuable when selecting cell lines for preclinical drug testing.
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Alendronate (ALN) is a commonly used drug for the treatment of osteoporosis. Atypical femur fractures (AFFs) have been associated with long-term use of ALN and have recently become the subject of considerable attention as ALN use increases. This meta-analysis aimed to determine the relationship between ALN and AFF. The Embase, PubMed, and Cochrane library databases were searched for relevant studies published before November 6, 2014. Studies clearly reporting the relationship between ALN and AFF were selected for our analysis. From these results, the relationship between ALN and AFF was analyzed. Weighted mean differences were calculated using a random-effects model. Five studies were included in this meta-analysis. The results revealed that the use of ALN will not increase the risk of AFF in short term (P>0.05), but there will be a risk of AFF (P<0.05) with long-term (>5 years) use of ALN. These findings indicate that long-term use of ALN is a risk factor for AFF and that more attention should be paid to the clinical applications of ALN.
Search for other papers by Xichang Wang in
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Search for other papers by Xiaochun Teng in
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Search for other papers by Chenyan Li in
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Search for other papers by Yushu Li in
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Search for other papers by Jing Li in
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Objective
To conduct a questionnaire survey of the current clinical practice for overt hyperthyroidism in China.
Methods
An online questionnaire survey was conducted in July 2020. The two questionnaires covered 35 and 8 questions about non-pregnancy and pregnancy clinical practice for overt hyperthyroidism, respectively.
Results
One thousand, two hundred fifty-six physicians participated. Chief physicians and associate chief physicians accounted for 58.6% of the participants. Approximately 95.2% of the respondents chose the thyrotropin receptor antibody (TRAb) test to clarify the etiology of thyrotoxicosis, while only 27.0% of them chose radioactive iodine uptake (RAIU). In terms of treatment for non-pregnant patients, anti-thyroid drugs (ATDs) were the first choice, and most of the clinicians chose methimazole. Compared with clinicians in recent studies, Chinese physicians used serum TRAb to diagnose Graves’ disease more commonly, and there were obviously more physicians preferring ATDs. For maternal hyperthyroidism, most physicians preferred propylthiouracil administration before or during the first trimester, which is consistent with the 2016 American Thyroid Association (ATA) guidelines. In terms of the initial ATD dose, monitoring the treatment process, indications for ATD withdrawal and treatment of special cases, the preferences of Chinese physicians were generally consistent with the guidelines.
Conclusion
Chinese physicians can generally follow the ATA guidelines for the diagnosis and treatment of hyperthyroidism. Moreover, there are small differences from foreign studies or the guidelines with respect to particular problems. These findings provide evidence for future clinical research in China.
Berlin Institute of Health (BIH), Berlin, Germany
Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
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Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany
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Core Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany
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Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Berlin Institute of Health (BIH), Berlin, Germany
Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
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Mitotane is the only drug approved for the therapy of adrenocortical carcinoma (ACC). Its clinical use is limited by the occurrence of relapse during therapy. To investigate the underlying mechanisms in vitro, we here generated mitotane-resistant cell lines. After long-term pulsed treatment of HAC-15 human adrenocortical carcinoma cells with 70 µM mitotane, we isolated monoclonal cell populations of treated cells and controls and assessed their respective mitotane sensitivities by MTT assay. We performed exome sequencing and electron microscopy, conducted gene expression microarray analysis and determined intracellular lipid concentrations in the presence and absence of mitotane. Clonal cell lines established after pulsed treatment were resistant to mitotane (IC50 of 102.2 ± 7.3 µM (n = 12) vs 39.4 ± 6.2 µM (n = 6) in controls (biological replicates, mean ± s.d., P = 0.0001)). Unlike nonresistant clones, resistant clones maintained normal mitochondrial and nucleolar morphology during mitotane treatment. Resistant clones largely shared structural and single nucleotide variants, suggesting a common cell of origin. Resistance depended, in part, on extracellular lipoproteins and was associated with alterations in intracellular lipid homeostasis, including levels of free cholesterol, as well as decreased steroid production. By gene expression analysis, resistant cells showed profound alterations in pathways including steroid metabolism and transport, apoptosis, cell growth and Wnt signaling. These studies establish an in vitro model of mitotane resistance in ACC and point to underlying molecular mechanisms. They may enable future studies to overcome resistance in vitro and improve ACC treatment in vivo.
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Our knowledge of vitamin D has come a long way since the 100 years it took for doctors to accept, between 1860 and 1890, that both sunlight and cod liver oil (a well-known folk remedy) cured and prevented rickets. Vitamins D2/D3 were discovered exactly a hundred years ago, and over the last 50 years vitamin D has been found to have many effects on virtually all human tissues and not just on bone health, while mechanisms affecting the actions of vitamin D at the cellular level are increasingly understood, but deficiency persists globally. Observational studies in humans have shown that better provision of vitamin D is strongly associated, dose-wise, with reductions in current and future health risks in line with the known actions of vitamin D. Randomised controlled trials, commonly accepted as providing a ‘gold standard’ for assessing the efficacy of new forms of treatment, have frequently failed to provide supportive evidence for the expected health benefits of supplementation. Such RCTs, however, have used designs evolved for testing drugs while vitamin D is a nutrient; the appreciation of this difference is critical to identifying health benefits from existing RCT data and for improving future RCT design. This report aims, therefore, to provide a brief overview of the evidence for a range of non-bony health benefits of vitamin D repletion; to discuss specific aspects of vitamin D biology that can confound RCT design and how to allow for them.
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Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.
