- Obesity in Type 1 Diabetes: Pathophysiology, Clinical Impact and Mechanisms. [Journal Article]
- EREndocr Rev 2018 Jul 27
- There has been an alarming increase in the prevalence of obesity in people with type 1 diabetes in recent years. Although obesity has long been recognized as a major risk factor for the development o...
There has been an alarming increase in the prevalence of obesity in people with type 1 diabetes in recent years. Although obesity has long been recognized as a major risk factor for the development of type 2 diabetes and a catalyst for complications, much less is known about the role of obesity in the initiation and pathogenesis of type 1 diabetes. Emerging evidence suggests that obesity contributes to insulin resistance, dyslipidemia and cardiometabolic complications in type 1 diabetes. Unique therapeutic strategies may be required to address these comorbidities within the context of intensive insulin therapy, which promotes weight gain. There is an urgent need for clinical guidelines for the prevention and management of obesity in type 1 diabetes. The development of these recommendations will require a transdisciplinary research strategy addressing metabolism, molecular mechanisms, lifestyle, neuropsychology and novel therapeutics. In this review, the prevalence, clinical impact, energy balance physiology, and potential mechanisms of obesity in type 1 diabetes are described, with a special focus on the significant gaps in knowledge in this field. Our goal is to provide a framework for the evidence-base needed to develop type 1 diabetes-specific weight management recommendations that account for the competing outcomes of glycemic control and weight management.
- Molecular actions of PPARα in lipid metabolism and inflammation. [Journal Article]
- EREndocr Rev 2018 Jul 17
- Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capac...
Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.
- Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance. [Journal Article]
- EREndocr Rev 2018 Jul 13
- Elite athletic competitions have separate male and female events due to men's physical advantages in strength, speed and endurance so that a protected female category with objective entry criteria is...
Elite athletic competitions have separate male and female events due to men's physical advantages in strength, speed and endurance so that a protected female category with objective entry criteria is required. Prior to puberty, there is no sex difference in circulating testosterone concentrations or athletic performance but from puberty onwards sex difference in athletic performance emerges as circulating testosterone concentrations rise in men because testes produce 30 times more testosterone than before puberty with circulating testosterone exceeding 15-fold those of women at any age. There is a wide sex difference in circulating testosterone concentrations and reproducible dose-response relationship between circulating testosterone and muscle mass and strength as well as circulating hemoglobin in both men and women. These dichotomies largely accounts for the sex differences in muscle mass and strength and circulating hemoglobin levels resulting in at least an 8-12% ergogenic advantage in men. Suppression of elevated circulating testosterone of hyperandrogenic athletes results in negative effects on performance, which are reversed when suppression ceases. Based on the non-overlapping, bimodal distribution of circulating testosterone concentration (measured by liquid chromatography-mass spectrometry) and making allowance for women with mild hyperandrogenism including that of polycystic ovarian syndrome, who are over-represented in elite athletics, the appropriate eligibility criterion for female athletic events should be a circulating testosterone of less than 5.0 nmol/L. This would include all women other than those with untreated hyperandrogenic disorders of sexual development (DSD), testosterone-treated female-to-male (F2M) transgender, noncompliant male-to-female (M2F) transgender or androgen doping.
- The Biology of Normal Zona Glomerulosa And Aldosterone-Producing Adenoma: Pathological Implications. [Journal Article]
- EREndocr Rev 2018 Jul 10
- The identification of several germline and somatic ion channel mutations in aldosterone-producing adenomas (APA) and detection of cell clusters that can be responsible for excess aldosterone producti...
The identification of several germline and somatic ion channel mutations in aldosterone-producing adenomas (APA) and detection of cell clusters that can be responsible for excess aldosterone production, as well as the isolation of autoantibodies activating the angiotensin II type 1 receptor, have rapidly advanced the understanding of the biology of primary aldosteronism (PA), in particular that of APA. Hence, the main purpose of this review is to discuss how discoveries of the last decade could impact on histopathology analysis and clinical practice. The structural remodeling through development and aging of the human adrenal cortex, in particular of the zona glomerulosa, and the complex regulation of aldosterone, with emphasis to the concepts of zonation and channelopathies, will be addressed. Finally, the diagnostic work-up for PA and its subtyping to optimize treatment is recapitulated.
- Children born small for gestational age: differential diagnosis, molecular-genetic evaluation and implications. [Journal Article]
- EREndocr Rev 2018 Jul 04
- Children born small-for-gestational age (SGA), defined as a birth weight and/or length <-2 SDS, comprise a heterogeneous group. The causes of SGA are multifactorial and include maternal life-style an...
Children born small-for-gestational age (SGA), defined as a birth weight and/or length <-2 SDS, comprise a heterogeneous group. The causes of SGA are multifactorial and include maternal life-style and obstetric factors, placental dysfunction, and numerous fetal (epi)genetic abnormalities. Short-term consequences of SGA include increased risks of hypothermia, polycythemia, and hypoglycemia. Although the majority of SGA infants show catch-up growth by 2 years of age, approximately 10% remain short. Short children born SGA are amenable to growth hormone (GH) treatment, which increases their adult height by on average 1.25 SD. Add-on treatment with a gonadotropin-releasing hormone agonist may be considered in early-pubertal children with an expected adult height <-2.5 SDS. A small birth size increases the risk of later neurodevelopmental problems and cardiometabolic diseases. GH treatment does not pose an additional risk.
- Novel concepts for inducing final oocyte maturation in IVF (In Vitro Fertilization) Treatment. [Journal Article]
- EREndocr Rev 2018 Jul 02
- Infertility affects 1 in 6 of the population and increasingly couples require treatment with assisted reproductive techniques (ART). In vitro fertilization (IVF) treatment is most commonly conducted ...
Infertility affects 1 in 6 of the population and increasingly couples require treatment with assisted reproductive techniques (ART). In vitro fertilization (IVF) treatment is most commonly conducted using exogenous FSH to induce follicular growth and human chorionic gonadotrophin (hCG) to induce final oocyte maturation. However, hCG may cause the potentially life-threatening iatrogenic complication 'ovarian hyperstimulation syndrome' (OHSS), which can cause significant morbidity and rarely even mortality in otherwise healthy women. The use of GnRH agonists (GnRHa) has been pioneered over the last two decades to provide a safer option to induce final oocyte maturation. More recently, the neuropeptide kisspeptin, a hypothalamic regulator of GnRH release, has been investigated as a novel inductor of oocyte maturation.The hormonal stimulus used to induce oocyte maturation has a major impact on the success (retrieval of oocytes and chance of implantation) and safety (risk of OHSS) of IVF treatment. This review aims to appraise experimental and clinical data of hormonal approaches used to induce final oocyte maturation by either hCG, GnRHa, both GnRHa and hCG administered in combination, recombinant LH, or kisspeptin. We also examine evidence for the timing of administration of the inductor of final oocyte maturation in relation to parameters of follicular growth and the subsequent interval to oocyte retrieval.In summary, we review data on the efficacy and safety of the major hormonal approaches used to induce final oocyte maturation in clinical practice, as well as some novel approaches that may offer fresh alternatives in future.
- Gonadotropins and their analogues: current and potential clinical applications. [Journal Article]
- EREndocr Rev 2018 Jul 02
- The gonadotropin receptors, luteinising hormone receptor, and follicle-stimulating hormone receptor, play a central role in governing reproductive competency/fertility. Gonadotropin hormone analogues...
The gonadotropin receptors, luteinising hormone receptor, and follicle-stimulating hormone receptor, play a central role in governing reproductive competency/fertility. Gonadotropin hormone analogues have been utilised clinically for decades, in assisted reproductive therapies, and in the treatment of various infertility disorders. While these treatments are effective, the clinical protocols demand multiple injections, and the hormone preparations can lack uniformity and stability. The past two decades have seen a drive to develop chimeric and modified peptide analogues with more desirable pharmacokinetic profiles with some displaying clinical efficacy, such as corifollitropin alfa which is now in clinical use. More recently, low molecular weight orally-active molecules with activity at gonadotropin receptors have been developed. Some have excellent characteristics in animals and in human studies but have not reached the market: largely due to acquisitions by large pharma. Nonetheless such molecules have the potential to mitigate risks currently associated with gonadotropin-based fertility treatments such as ovarian hyperstimulation syndrome and the demands of injection-based therapies. There is also scope for novel utilisation beyond the current remit of gonadotropin analogues in fertility treatments, including application as novel contraceptives, and in the treatment of polycystic ovary syndrome, the restoration of function to inactivating mutations of gonadotropin receptors, ovarian and prostate cancers, and in bone loss and weight gain in postmenopausal women. Here, we review the properties and clinical application of current gonadotropin preparations and their analogues, as well as the development of novel orally-active small-molecule non-peptide analogues.
- Interferences with thyroid function immunoassays: clinical implications and detection algorithm. [Journal Article]
- EREndocr Rev 2018 Jul 04
- Current automated immunoassays used to evaluate thyroid function are vulnerable to different types of interference that can impact clinical decision. This review provides a detailed overview of the s...
Current automated immunoassays used to evaluate thyroid function are vulnerable to different types of interference that can impact clinical decision. This review provides a detailed overview of the six main interferences affecting measurements of thyroid-stimulating hormone, free thyroxine and free triiodothyronine, namely macroTSH, biotin, anti-streptavidin antibodies, anti-ruthenium antibodies, thyroid hormone autoantibodies, and heterophilic antibodies. As the prevalence of some of these conditions has been reported to approach 1% and the frequency of testing for thyroid dysfunction is important, the scale of the problem might therefore be tremendous.Potential interferences in thyroid function testing should always be suspected whenever clinical or biochemical discrepancies arise. Their identification usually relies on additional laboratory tests that include assay method comparison, dilution procedures, blocking reagents studies, and polyethylene glycol precipitation. Based on the pattern of thyroid function test alterations, we propose a detection algorithm to screen for the six above-mentioned interferences.The review also aims at evaluating the clinical impact of thyroid interference on immunoassays, which has not been widely studied so far. Through the revision of reported data from more than 150 subjects, we found that at least 50% of documented thyroid interferences led to misdiagnosis and/or inappropriate management of the patients, including prescription of an unnecessary treatment (with side effects in some situations), inappropriate suppression or modification of an ongoing treatment, or utilization of unnecessary complementary tests such as I123 thyroid scan. We finally wish to emphasize the need for a strong interaction between the clinician and the laboratory to avoid such pitfalls.
- The Rasopathy family: Consequences of germline activation of the RAS/MAPK pathway. [Journal Article]
- EREndocr Rev 2018 Jun 18
- Noonan syndrome (NS; Mendelian Inheritance in Men (MIM) ♯163950) and related syndromes (Noonan syndrome with multiple lentigines (NS-ML, formerly called LEOPARD syndrome; MIM ♯151100), Noonan-like sy...
Noonan syndrome (NS; Mendelian Inheritance in Men (MIM) ♯163950) and related syndromes (Noonan syndrome with multiple lentigines (NS-ML, formerly called LEOPARD syndrome; MIM ♯151100), Noonan-like syndrome with loose anagen hair (NS-LAH; MIM ♯607721), Costello syndrome (CS; MIM ♯218040), Cardio-Facio-Cutaneous syndrome (CFCS; MIM ♯115150), type I Neurofibromatosis (NF1; MIM ♯162200), and Legius syndrome (LS; MIM ♯611431)) are a group of related genetic disorders, associating distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. Clinically described more than 50 years ago, disease genes have been identified throughout the three last decades, providing a molecular basis to better understand their physiopathology and to identify targets for therapeutic strategies. Most of those genes encode proteins belonging to or regulating the so-called RAS/Mitogen-Activated Protein Kinase (MAPK) signaling pathway, so that these syndromes have been gathered under the naming Rasopathies. In this review, we will provide a clinical overview of Rasopathies and an update of their genetics. We will then focus on the functional and pathophysiological impacts of Rasopathies-causing mutations, and discuss therapeutic perspectives and future directions.
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- Glucocorticoids and bone: consequences of endogenous and exogenous excess and replacement therapy. [Journal Article]
- EREndocr Rev 2018 Jun 13
- Osteoporosis associated with long-term glucocorticoid therapy remains a common and serious bone disease. In addition, in recent years it has become clear that more subtle states of endogenous glucoco...
Osteoporosis associated with long-term glucocorticoid therapy remains a common and serious bone disease. In addition, in recent years it has become clear that more subtle states of endogenous glucocorticoid excess may have a major impact on bone health. Adverse effects can be seen with mild systemic glucocorticoid excess but there is also evidence of tissue-specific regulation of glucocorticoid action within bone as a mechanism of disease. This review article will examine a) the role of endogenous glucocorticoids in normal bone physiology, b) the skeletal effects of endogenous glucocorticoid excess in the context of endocrine conditions such as Cushing's disease/syndrome and autonomous cortisol secretion (subclinical Cushing's syndrome), and c) the actions of therapeutic (exogenous) glucocorticoids on bone. We will review the extent to which the effect of glucocorticoids on bone is influenced by variations in tissue metabolising enzymes and glucocorticoid receptor expression and sensitivity. We will consider how the effects of therapeutic glucocorticoids on bone are complicated by the effects of the underlying inflammatory disease being treated. We will also examine the impact that glucocorticoid replacement regimens have on bone in the context of primary and secondary adrenal insufficiency. We conclude that even subtle excess of endogenous or moderate doses of therapeutic glucocorticoids are detrimental to bone. However in patients with inflammatory disorders there is a complex interplay between glucocorticoid treatment and underlying inflammation, with the underlying condition frequently representing the major component underpinning bone damage.