Zeeshan Javed

Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits

Subclinical hypothyroidism (SCH) is defined as elevated thyroid stimulating hormone (TSH) with normal levels of free triiodothyronine (FT3) and free thyroxine (FT4). SCH is further classified into a milder condition with TSH levels between 4.0 and 10.0 milli-international units (mIU)/l (mild-SCH) and a severe form with TSH >10.0 mIU/l (severe-SCH). SCH is a common problem (prevalence is greater in women than men), which increases further with increasing age and TSH levels. Even though the risk of progression to overt hypothyroidism is higher in patients with severe-SCH, the risk is also significant in patients having mild-SCH; it has been suggested that every twofold rise in serum TSH would increase the risk from 1 to 4%, which further increases to 38% if thyroid antibodies are positive. Current data have shown increased cardiovascular risk in patients with mild-SCH and have demonstrated some benefits of levothyroxine treatment in reducing these events. However, evidence on the association of mild-SCH and musculoskeletal system, cognitive dysfunction, mood disorders, dyslipidaemia, diabetes and goitre is conflicting. Similarly, the discussion regarding the exact upper limit of normal for serum TSH remains controversial. The data have also shown increased risk of adverse pregnancy outcomes in patient with mild-SCH, with some benefits of thyroxine treatment. The recent available guidelines related to management of patients with serum TSH <10 mIU/l have suggested decisions should be made taking into account the age of the patient, associated risk factors and comorbid conditions. This chronicle review assesses current evidence regarding the risks associated and the recommendations related to benefits of levothyroxine treatment in patients having mild-SCH.

Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus.

Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections.

Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with polycystic ovary syndrome

Animal studies suggest that cannabinoid receptor‐1 (CB‐1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk.

Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives.

There is an increasing deliberation regarding hypopituitarism following traumatic brain injury (TBI) and recent data have suggested that pituitary dysfunction is very common among survivors of patients having moderate-severe TBI which may evolve or resolve over time. Due to high prevalence of pituitary dysfunction after moderate-severe TBI and its association with increased morbidity and poor recovery and the fact that it can be easily treated with hormone replacement, it has been suggested that early detection and treatment is necessary to prevent long-term neurological consequences. The cause of pituitary dysfunction after TBI is still not well understood, but evidence suggests few possible primary and secondary causes. Results of recent studies focusing on the incidence of hypopituitarism in the acute and chronic phases after TBI are varied in terms of severity and time of occurrence. Although the literature available does not show consistent values and there is difference in study parameters and diagnostic tests used, it is clear that pituitary dysfunction is very common after moderate to severe TBI and patients should be carefully monitored. The exact timing of development cannot be predicted but has suggested regular assessment of pituitary function up to 1 year after TBI. In this narrative review, we aim to explore the current evidence available regarding the incidence of pituitary dysfunction in acute and chronic phase post-TBI and recommendations for screening and follow-up in these patients. We will also focus light over areas in this field worthy of further investigation.

The role of kisspeptin signalling in the hypothalamic-pituitary-gonadal axis--current perspective.

The discovery of kisspeptins in the recent past remoulded current understanding of the neuroendocrine axis relating to the regulation of human puberty and reproduction. Kisspeptins have been recognised to act upstream of GnRH and have been shown to play a vital role in the control of the hypothalamic-pituitary-gonadal axis via regulation of gonadotrophin secretion, onset of puberty, and control of fertility. KNDy (kisspeptin/neurokinin-B/dynorphin) neurons have been suggested to modulate GnRH pulsatile secretion, which is required to support reproductive function in both sexes. They have also been involved in mediating both positive and negative sex steroid feedback signals to GnRH neurons and serve as a vital connection between reproduction and metabolic status of the body. When kisspeptin is administered to healthy humans, and in patients with reproductive disorders, it strongly and directly stimulates GnRH and subsequent LH secretion and enhances LH pulse frequency. These observations suggest that kisspeptins are a potential novel therapeutic approach for treating disorders with either pathologically reduced or augmented gonadotrophins pulsatile secretion and is currently a focus of translational research. Kisspeptins have also been identified in several peripheral reproductive organs, indicating their role in modulation of ovarian function, embryo implantation, and placentation, but a great deal of work remains to be done to explore further in this regard, and the evidence is only available from studies done on animal models. In this review we will mainly focus on current available evidence related to the role of kisspeptins in controlling GnRH pulse frequency, specifically their role in puberty, fertility, and reproduction. We will also be appraising other factors that regulate the kiSS1/Kisspeptin/GPR-54 system.

Effects of Growth Hormone Replacement on Peripheral Muscle and Exercise Capacity in Severe Growth Hormone Deficiency

Objective The aim of this study is to evaluate the effect of growth hormone therapy (rGH) on mitochondrial function on peripheral muscle and to correlate with exercise capacity in subjects with severe adult growth hormone deficiency (GHD). Design Six months, double-blind, randomized, crossover, placebo-controlled trial of subcutaneous rGH in 17 patients with GHD. Measurements Quadriceps muscle biopsies were obtained at baseline, 3 months, and 6 months to measure succinate dehydrogenase (SDH) to assess mitochondrial activity. Exercise capacity was measured with cardiopulmonary exercise testing. Lipids, glycemic parameters, and body fat levels were also measured. Results Serum insulin-like growth factor 1 (IGF1) levels reduced fat mass by 3.2% (p < 0.05) and normalized with rGH in the active phase (p < 0.005). Patients showed an increase in SDH (p < 0.01) from base line that differed between placebo and rGH therapy treatment groups (p < 0.05): those treated by rGH followed by placebo showed a significant increase in SDH (p < 0.001) followed by a decrease, with a significant between group difference at the end of 6 months (p < 0.05). No significant improvements or correlation with exercise capacity was found. Conclusion Short-term rGH for 3 months normalized IGF1 levels, reduced fat mass, and had a significant effect on mitochondrial function, but exercise capacity was unchanged. Clinical Trial Registration Number ISRCTN94165486.

Environmental effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes mellitus

This study aimed to explore the effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes.

Soy Protein Improves Cardiovascular Risk in Subclinical Hypothyroidism: A Randomized Double-Blinded Crossover Study

Background: Soy protein with isoflavones appears to have an adverse effect on thyroid function, but it is not known whether it is the protein or isoflavone component that is deleterious. The effect of isoflavone-free soy on thyroid function was determined in patients with subclinical hypothyroidism, with a secondary aim of assessing its effect on cardiovascular risk indices. Methods: This was a randomized, double-blind, crossover study involving 80 patients with subclinical (compensated) hypothyroidism. Patients were randomly assigned to either isolated soy (isoflavone-free) protein (SP) or casein protein (CP) supplementation for 8 weeks, washed out for 8 weeks, and then crossed over for a further 8-week period. Results: Thyroid function was unaffected by either a SP or CP. There were significant decreases in fasting glucose (4.7 ± 0.6 vs 5.5 ± 1.4, P < 0.01), insulin resistance (3.3 ± 3.0 vs 3.8 ± 3.4, P = 0.05), total cholesterol (4.4 ± 0.9 vs 5.3 ± 1.2, P < 0.01), triglycerides (0.9 ± 0.5 vs 1.7 ± 0.9, P < 0.1), and highly sensitive C-reactive protein (hsCRP; 0.8 ± 0.7 vs 2.6 ± 2.8, P < 0.01) in the SP group compared with the CP group. Blood pressure, low-density lipoprotein, and high-density lipoprotein remained unchanged in both groups. Conclusion: SP alone had no effect on thyroid function in patients with subclinical hypothyroidism and resulted in a significant reduction in fasting glucose, insulin resistance, total cholesterol, triglycerides, and hsCRP compared with CP.

Effects of human recombinant growth hormone on exercise capacity, cardiac structure, and cardiac function in patients with adult-onset growth hormone deficiency

Objective Epidemiological studies suggest that adult-onset growth hormone deficiency (AGHD) might increase the risk of death from cardiovascular causes. Methods This was a 6-month double-blind, placebo-controlled, randomised, cross-over trial followed by a 6-month open-label phase. Seventeen patients with AGHD received either recombinant human growth hormone (rGH) (0.4 mg injection daily) or placebo for 12 weeks, underwent washout for 2 weeks, and were then crossed over to the alternative treatment for a further 12 weeks. Cardiac magnetic resonance imaging, echocardiography, and cardiopulmonary exercise testing were performed at baseline, 12 weeks, 26 weeks, and the end of the open phase (12 months). The results were compared with those of 16 age- and sex-matched control subjects. Results At baseline, patients with AGHD had a significantly higher systolic blood pressure, ejection fraction, and left ventricular mass than the control group, even when corrected for body surface area. Treatment with rGH normalised the insulin-like growth factor 1 concentration without an effect on exercise capacity, cardiac structure, or cardiac function. Conclusion Administration of rGH therapy for 6 to 9 months failed to normalise the functional and structural cardiac differences observed in patients with AGHD when compared with a control group.

Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with PCOS

Context: Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk. Objective: To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women. Design: Randomised, open-labelled parallel study. Setting: Endocrinology outpatient clinic in a referral centre. Subjects: Twenty patients with PCOS and biochemical hyperandrogenaemia with a body mass index of ≥ 30kg/m2 were recruited. Patients were randomised to 1.5g daily of metformin or 20mg daily of rimonabant. Main Outcome Measures: Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks treatment. Results: After 12 weeks of rimonabant there was a significant increase in VEGF (99.2±17.6 vs 116.2±15.8pg/ml, p<0.01) and IL-8 (7.4±11.0 vs 18.1±13.2pg/ml, p<0.05) but not after metformin (VEGF p=0.7; IL-8 p=0.9). There was no significant difference in the proinflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following