Higher Growth Hormone Levels are Associated with Erectile Dysfunction in Male Patients With Acromegaly

Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly.Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls.Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 μg/L [interquartile range of 9.5 to 34.5 μg/L] versus 5.9 μg/L [interquartile range of 3.4 to 13.9 μg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 μg/L for random GH and 5.3 μg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 μmol/L versus 19.19 ± 5.02 μmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 μmol/L versus 12.09 ± 3.44 μmol/L; P = .027).Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required.Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic     

Diagnosis by Serendipity: Cushing Syndrome Attributable to Cortisol-Producing Adrenal Adenoma as the Initial Manifestation of Multiple Endocrine Neoplasia Type 1 Due to a Rare Splicing Site Men1 Gene Mutation

ObjectiveTo report a case that highlights the potential for Cushing syndrome to be the first manifestation of multiple endocrine neoplasia type 1 (MEN 1) syndrome and to describe the rare underlying genetic mutation and the heterogeneous manifestations of the syndrome within the same family.MethodsWe present a case report including biochemical and radiologic findings, review family data, and discuss the results of genetic analyses.ResultsA 16-year-old girl who was not known to have any medical illness and had no known family history of MEN 1 syndrome presented with Cushing syndrome attributable to a cortisol-producing adrenal adenoma. During her evaluation, she was found to have primary hyperparathyroidism and a pituitary microprolactinoma. These findings raised the possibility of MEN 1 syndrome. She did not have clinical, biochemical, or radiologic evidence of islet cell pancreatic tumors. Family screening showed that her father had evidence of primary hyperparathyroidism, mild hyperprolactinemia, normal findings on magnetic resonance imaging of the pituitary, and a 1.2- cm nodule in the tail of the pancreas in conjunction with slight elevation of serum insulin and normal gastrin levels. The patient’s 5 siblings had evidence of primary hyperparathyroidism, and 2 of them also had mild hyperprolactinemia. Genetic screening confirmed the presence of a MEN1 gene missense G to A mutation in the patient, her father, and her siblings at the splicing site of intron 6 (IVS6 + 1G > A). This mutation leads to frameshift and truncation of the MEN1 gene.ConclusionIn MEN 1, Cushing syndrome is an extremely rare and usually late manifestation. Most cases are due to corticotropin-producing pituitary adenomas. Although Cushing syndrome generally develops years after the more typical manifestations of MEN 1 appear, it may be the primary manifestation of MEN 1 syndrome. There is considerable heterogeneity in the manifestations of MEN 1, even within a family having the same genetic mutation. (Endocr Pract. 2008;14:595-602)     

Levothyroxine Replacement In Obese Hypothyroid Females After Total Thyroidectomy

Objective: Levothyroxine (LT4) replacement in hypothyroid obese patients is poorly understood. We assessed whether the LT4 regimen required to achieve euthyroidism differs between nonobese and obese hypothyroid females.Methods: We retrospectively identified nonobese and obese females who received LT4 starting with a standard dose of 1.6 μg/kg after total thyroidectomy for preoperative diagnosis of benign goiter. We examined the association between LT4 dosage required to achieve euthyroid state (thyroid-stimulating hormone [TSH] 0.4–2.5 mIU/L) and patient characteristics using linear regression models with and without adjustment for age, ethnicity, medication use, and postoperative hypoparathyroidism.Results: We identified 32 females (15 nonobese/17 obese) who achieved euthyroid state. Obese patients weighed more (104.1 ± 22.5 vs. 64.9 ± 10.0 kg, P<.0001) and required a higher final LT4 than nonobese (146 ± 38 vs. 102 ± 12 μg, P = .0002) but LT4 requirements per kg total body weight (TBW) were similar (1.60 ± 0.29 vs. 1.42 ± 0.38 μg/kg, P = .15). LT4 dose per kg ideal body weight (IBW) was higher in obese than in nonobese females (2.62 ± 0.67 vs. 1.88 ± 0.28 μg/kg, P = .0004) and this difference persisted after adjustments (P<.05). During LT4 titration, 47% and 20% of obese and nonobese patients had subnormal TSH episodes, respectively (P = .11). After taking LT4 compliance, malabsorption, and competing medication use into consideration, we found marked LT4 dose variability in obese patients. Patients who needed a mean daily LT4 dose ≤150 mg (124 ± 16 μg/day) compared with >150 μg (198 ± 4 μg/day) demonstrated lower LT4 per TBW (1.25 ± 0.18 vs. 1.84 ± 0.43 μg/kg, P = .03) and IBW (2.28 ± 0.47 vs. 3.44 ± 0.18 μg/kg, P<.0001), respectively.Conclusion: The standard approach to LT4 replacement in obese and nonobese females after thyroidectomy is imprecise. Mean daily LT4 doses in obese and nonobese patients were similar if expressed per kg TBW, though there was variability in the final LT4 among obese patients. We suggest initiating LT4 at a dose lower than that routinely recommended in obese females.Abbreviations:AACE = American Association of Clinical EndocrinologistsATA = American Thyroid AssociationBMI = body mass indexIBW = ideal body weightLT4 = levothyroxineTBW = total body weightTSH = thyroid-stimulating hormone     

Deterioraron of Ovarian Function After Total Abdominal Hysterectomy with Preservaron of Ovaries

Objective: To evaluate ovarian function after total abdominal hysterectomy in premenopausal women.Methods: In the present cross-sectional study, we enrolled 52 healthy female subjects having normal menstrual cycle as controls and 37 female patients (age <45 years) who had undergone total abdominal hysterectomy (TAH) with preservation of at least one ovary for the evaluation of ovarian function. Serum antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) were measured by enzyme-linked immunosorbent assay in both groups. Transvaginal Doppler ultrasonography was done to measure ovarian stromal blood flow indices (resistive index [RI] and pulsatility index [PI]). The means obtained from different sample groups were compared using the nonparametric Mann-Whitney U test, and correlations between two variables were evaluated using the Spearman nonparametric correlation test. A value of P<.05 was considered statistically significant.Results: Mean postoperative duration of patients who had undergone hysterectomy was 2.5 years. Mean serum AMH level was 7.68 ± 6.70 ng/mL in the cases, significantly lower than the level in controls (10.98 ± 7.83 ng/mL) (P = .016). Serum FSH level in controls was 12.01 ± 6.27 μIU/mL, which was significantly higher in the cases (20.27 ± 12.91 μIU/mL) (P = .001). An inverse correlation between serum AMH and FSH was observed (P = .0006; r = -0.4583). However, the ovary RI and PI values in both groups were similar.Conclusion: TAH affects ovarian function, despite normal ovarian blood supply.Abbreviations:AMH = antimüllerian hormoneFSH = follicle-stimulating hormoneRI = resistive indexPI = pulsatility indexTAH = total abdominal hysterectomy     

Gender Determines Serum Free Cortisol: Higher Levels in Men

Objective: Because only the free fraction of serum cortisol can readily access glucocorticoid receptors, we investigated whether or not a gender-related difference in serum free cortisol (FC) exists in the basal and adrenocorticotropic hormone (ACTH)-stimulated state.Methods: Serum total cortisol (TC) and FC were measured in 323 subjects (175 men; 148 women). Additionally, the low-dose 1-μg ACTH test was performed in 56 subjects (30 women, 26 men). Subjects were healthy volunteers, recruited in a preventive medicine screening program and an outpatient clinic.Results: Overall, basal serum TC and FC level were ~18 and ~33%, respectively, higher in men than in women (TC, 14.5 ± 0.33 μg/dL vs. 12.3 ± 0.33 μg/dL; P<.0001; FC, 0.68 ± 0.02 μg/dL vs. 0.51 ± 0.02 μg/dL; P<.0001). The higher FC in men relative to women was apparent across a wide age range (17 to 86 years) and persisted after adjustment for age and body mass index. The FC fraction (%FC, out of TC) was concordantly higher in men (5.4 ± 0.09% vs. 4.8 ± 0.3%; P = .046). FC was not related to the estimated menopausal status (women age below and above 47, 50, or 53 years). ACTH-stimulated FC levels were significantly higher in men compared to women, as reflected by the area under the response curve (49.4 ± 3.4 μg × min vs. 39.6 ± 2.2 μg × min; P = .0014).Conclusion: Gender is an unrecognized determinant of serum FC in humans. The possibility of lifelong exposure to the higher bioactive fraction of cortisol under basal conditions or daily stress involving ACTH stimulation should be further investigated in the context of gender-related phenotypic features such as “android” (visceral) fat deposition and longevity.Abbreviations:ACTH = adrenocorticotropic hormoneBMI = body mass indexCBG = cortisol-binding globulinFC = free cortisolHPA = hypothalamic-pituitary-adrenalTC = total cortisol     

Activity of three cytotoxic isoflavonoids from Erythrina excelsa and Erythrina senegalensis (neobavaisoflavone,sigmoidin H and isoneorautenol) toward multi-factorial drug resistant cancer cells

IntroductionResistance of cancer cells to chemotherapy has become a worldwide concern. Naturally occuring isoflavonoids possess a variety of biological activities including anti-cancer effects. The present study was aimed at investigating the cytotoxicity and the modes of action of three naturally occuring isoflavonoids, neobavaisoflavone (1), sigmoidin H (2) and a pterocarpan that is a special type of isoflavonoid, isoneorautenol (3) against a panel of nine cancer cell lines, including various sensitive and drug-resistant phenotypes.MethodsThe cytotoxicity of the compounds was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with compounds 3. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS).ResultsCompounds 3 showed significant cytotoxicity toward sensitive and drug-resistant cancer cell lines. Compounds 1 and 2 were selectively active, and IC50 values below 115 μM were obtained on 6/9 and 4/9 cell lines respectively with values ranging from 42.93 μM (toward CCRF-CEM cells) to 114.64 μM [against HCT116 (p53^+/+) cells] for 1 and 25.59 μM (toward U87MG) to 110.51 μM [against HCT116 (p53^+/+) cells] for 2. IC50 values ranging from 2.67 μM (against MDA-MB 237BCRP cells) to 21.84 (toward U87MG) were measured for compound 3 and between 0.20 μM (toward CCRF-CEM cells) and 195.12 μM (toward CEM/ADR5000 cells) for doxorubicin as control drug. BCRP-transfected MDA-MB-231 cells, HCT116 (p53^+/+) and U87MG.ΔEGFR cells were hypersensitive (collateral sensitive) to compound 3 as compared to their counterpart cell lines. Compound 3 induced apoptosis in CCRF-CEM cells via activation of caspases 3/7, 8 and 9 as well as the loss of MMP and increased ROS production.ConclusionsThe cytotoxicity of the studied isoflavonoids and especially the pterocarpan 3 deserve more detailed exploration in the future to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.     

New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species

Three series of salicylanilides, esters of N-phenylsalicylamides and 2-hydroxy-N-[1-(2-hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides, in total thirty target compounds were synthesized and characterized. The compounds were evaluated against seven bacterial and three mycobacterial strains. The antimicrobial activities of some compounds were comparable or higher than the standards ampicillin, ciprofloxacin or isoniazid. Derivatives 3f demonstrated high biological activity against Staphylococcus aureus (?0.03 μmol/L), Mycobacterium marinum (?0.40 μmol/L) and Mycobacterium kansasii (1.58 μmol/L), 3g shows activity against Clostridium perfringens (?0.03 μmol/L) and Bacillus cereus (0.09 μmol/L), 3h against Pasteurella multocida (?0.03 μmol/L) and M. kansasii (?0.43 μmol/L), 3i against methicillin-resistant S. aureus and B. cereus (?0.03 μmol/L). The structure–activity relationships are discussed for all the compounds.     

Inpatient Hypoglycemic Events in a Comparative Effectiveness Trial for Glycemic Control in a High-Risk Population

Objective: Inpatient hypoglycemia (glucose ≤70 mg/dL) is a limitation of intensive control with insulin. Causes of hypoglycemia were evaluated in a randomized controlled trial examining intensive glycemic control (IG, target 140 mg/dL) versus moderate glycemic control (MG, target 180 mg/dL) on post–liver transplant outcomes.Methods: Hypoglycemic episodes were reviewed by a multidisciplinary team to calculate and identify contributing pathophysiologic and operational factors. A subsequent subgroup case control (1:1) analysis (with/without) hypoglycemia was completed to further delineate factors. A total of 164 participants were enrolled, and 155 patients were examined in depth.Results: Overall, insulin-related hypoglycemia was experienced in 24 of 82 patients in IG (episodes: 20 drip, 36 subcutaneous [SQ]) and 4 of 82 in MG (episodes: 2 drip, 2 SQ). Most episodes occurred at night (41 of 60), with high insulin amounts (44 of 60), and during a protocol deviation (51 of 60). Compared to those without hypoglycemia (n = 127 vs. n = 28), hypoglycemic patients had significantly longer hospital stays (13.6 ± 12.6 days vs. 7.4 ± 6.1 days; P = .002), higher peak insulin drip rates (17.4 ± 10.3 U/h vs. 13.1 ± 9.9 U/h; P = .044), and higher peak insulin glargine doses (36.8 ± 21.4 U vs. 26.2 ± 24.3 U; P = .035). In the case-matched analysis (24 cases, 24 controls), those with insulin-related hypoglycemia had higher median peak insulin drip rates (17 U/h vs. 11 U/h; P = .04) and protocol deviations (92% vs. 50%; P = .004).Conclusion: Peak insulin requirements and protocol deviations were correlated with hypoglycemia.Abbreviations:DM = diabetes mellitusICU = intensive care unitIG = intensive glycemic controlMELD = Model for End-stage Liver DiseaseMG = moderate glycemic controlSQ = subcutaneous     

Hypothyroidism as A Cause of Hyponatremia: Fact or Fiction?

ObjectiveTo illustrate that severe primary hypothyroidism alone may not be enough to cause hyponatremia in the otherwise healthy ambulatory patient.Methods:A retrospective chart review was conducted using an academic health center enterprise-wide electronic health record to identify 10 patients with primary hypo thyroidism and same-day serum thyroid-stimulating hormone (TSH), sodium, creatinine, and calculated glomerular filtration rate (GFR). Same-day free triiodothyronine or free thyroxine was also recorded if tested. Patients were included in our case series if they met the following inclusion criteria: TSH level > 100 μU/mL and same-day sodium and creatinine levels. All laboratory tests were collected on an outpatient basis.ResultsThe 10 subjects (2 men and 8 women) were ages 19 to 97 years (median, 51.5 years). Median TSH was 193 μU/mL (range, 104.2 to 515.6 μU/mL; normal, 0.40 to 5.50 μU/mL) with median sodium of 138 mmol/L (range, 136 to 142 mmol/L; normal, 135 to 146 mmol/L). The lowest sodium was 136 mmol/L with concurrent TSH of 469.7 μU/mL, free triiodothyronine of 1.0 pg/mL (normal, 1.8 to 4.6 pg/mL), and free thyroxine of 0.2 ng/ dL (normal, 0.7 to 1.8 ng/dL). Median GFR was 67.5 mL/ min/1.73 m² (range, 44 to 114 mL/min/1.73 m²; normal, 90 to 120 mL/min/1.73 m²).ConclusionIn our small series of patients with extreme TSH elevations, none had a serum sodium level below normal (< 135 mmol/L), even in the presence of a reduced GFR. Hyponatremia can be a common occurrence in hospitalized and/or chronically ill patients; however, in an otherwise relatively healthy ambulatory patient, hypothyroidism, even when severely undertreated, may be a less clinically relevant cause of hyponatremia. (Endocr Pract. 2012;18:894-897)     

A case of systemic pseudohypoaldosteronism with a novel mutation in the SCNN1A gene

We report a neonatal case of systemic pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene (homozygous c.1052 + 2dupT in intron 3) in which the patient presented with life-threatening hyperkalemia, hyponatremia and metabolic acidosis. It remains uncertain if there is genotype–phenotype correlation, due to the rarity of the disease. This mutation, which to our best knowledge has not been described before, was associated with a very severe phenotype requiring aggressive therapy.     

Serum Free Cortisol During Glucagon Stimulation Test In Healthy Short-Statured Children And Adolescents

Objective: The total cortisol (TC) response may be measured during the glucagon stimulation test (GST) for growth hormone (GH) reserve in order to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. Measurements of TC are unreliable in conditions of albumin and cortisol-binding globulin (CBG) alterations (e.g., hypoproteinemia or CBG deficiency). We aimed to measure the serum free cortisol (sFC) response to the GST in children and adolescents and determine whether it could predict the GH response to glucagon stimulation.Methods: Infants and children with either short stature or growth attenuation who were referred for evaluation of GH reserve underwent the GST.Results: The study population consisted of 103 subjects (62 females), median age 3.9 years (range, 0.5–14). The mean basal and peak TC levels were 13.3 ± 6.7 μg/dL and 29.6 ± 8.8 μg/dL, respectively. The mean basal and peak sFC levels were 0.7 ± 0.8 μg/dL and 1.7 ± 1.1 μg/dL, respectively. There was a negative correlation between peak TC and age (r = -0.3, P = .007) but not between peak sFC and age (r = -0.09, P = .36). Ninety-five percent of the patients had peak TC levels >15.8 μg/dL and peak sFC levels >0.6 μg/dL.Conclusion: Our results on a cohort of healthy short-statured children can serve as reference values for the sFC response during GST. Based on these results, we propose peak TC levels >15.8 μg/dL and peak sFC levels >0.6 μg/dL for defining normalcy of the HPA axis during the GST in children and adolescents.Abbreviations:ACTH = adrenocorticotrophic hormoneBMI = body mass indexCBG = cortisol-binding globulinGH = growth hormoneGST = glucagon stimulation testHPA = hypothalamic-pituitary-adrenalSDS = standard deviation scoresFC = serum free cortisolTC = total cortisol     

Advanced Bone Age and Hyperinsulinemia in Overweight and Obese Children

ObjectiveIn obese children, bone age (BA) tends to significantly exceed chronological age (CA). In vitro studies in mice suggest that insulin may directly modulate skeletal growth. We investigated whether there is an association between fasting insulinand BAmaturationinobesechildren.MethodsThe study cohort comprised 74 overweight and obese children ages 4 to 13 years. BA divided by CA was used as an index for bone advancement. Participants were classified into tertiles based on their BA:CA ratio. Advanced BA maturation was defined as the third tertile, with BA:CA > 1.21. Components of the metabolic syndrome, including fasting insulin, fasting glucose, triglycerides, and high-density lipoprotein (HDL) levels, were measured.ResultsChildren with advanced BA were significantly younger, had a higher body mass index (BMI)-Z score (BMI-Z), and were taller than children with bone advancement in the lower tertiles. Females had a 4.7-fold increased risk for advanced BA compared with males (95% confidence interval [CI], 1.29-17.1; P = .02). Children with a BMI-Z ≥ 1.96 and fasting insulin ≤ 30 μU/L had a 3.6-fold increased risk of advanced BA (95% CI, 1.00-12.8; P = 0.05). Moreover, hyperinsulinemia (fasting insulin > 30 μU/L) was associated with a 6.8-fold increased risk for advanced BA, independent of the degree of obesity (95% CI, 1.45-32.1; P = .01).ConclusionMarked hyperinsulinemia is associated with advanced BA in obese children. Insulin appears to modulate skeletal growth in humans. (Endocr Pract. 2014;20:62-67)     

Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy

Hereditary ataxias are genetic disorders characterized by uncoordinated gait and often poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. Many ataxias are autosomal dominant, but autosomal recessive (AR) disease occurs as well. Homozygosity mapping in a consanguineous family with three affected children with progressive cerebellar ataxia and atrophy revealed a candidate locus on chromosome 1, containing the CABC1/ADCK3 (the chaperone, ABC1 activity of bc1 complex homologue) gene. CABC1/ADCK3 is the homologue of the yeast Coq8 gene, which is involved in the ubiquinone biosynthesis pathway. Mutation analysis of this gene showed a homozygous nonsense mutation (c.1042C > T, p.R348X). Eight additional patients with AR cerebellar ataxia and atrophy were screened for mutations in the CABC1/ADCK3 gene. One patient was compound heterozygous for the same c.1042C > T mutation and a second nonsense mutation (c.1136T > A, p.L379X). Both mutations created a premature stop codon, triggering nonsense mediated mRNA decay as the pathogenic mechanism. We found no evidence of a Dutch founder for the c.1042C > T mutation in AR ataxia. We report here the first nonsense mutations in CABC1 that most likely lead to complete absence of a functional CABC1 protein. Our results indicate that CABC1 is an important candidate for mutation analysis in progressive cerebellar ataxia and atrophy on MRI to identify those patients, who may benefit from CoQ10 treatment.     

Aspernolides F and G,new butyrolactones from the endophytic fungus Aspergillus terreus

Two new butyrolactones: aspernolides F (6) and G (7), together with three stigmasterol derivatives: (22E,24R)-stigmasta-5,7,22-trien-3-β-ol (1), stigmast-4-ene-3-one (2), and stigmasta-4,6,8(14), 22-tetraen-3-one (3), two meroterpenoids: terretonin A (4) and terretonin (5), and a butyrolactone derivative: butyrolactone VI (8) have been isolated from the endophytic fungus Aspergillus terreus isolated from the roots of Carthamus lanatus (Asteraceae). Their structures were determined by spectroscopic means (1D, 2D NMR, and HRESIMS), as well as optical rotation measurement and comparison with literature data. The isolated compounds were evaluated for their anti-microbial, anti-malarial, anti-leishmanial, and cytotoxic activities. Compound 1 displayed a potent activity against MRSA and C. neoformans with IC₅₀ values of 0.96 μg/mL and 4.38 μg/mL, respectively compared to ciprofloxacin (IC₅₀ 0.07 μg/mL) and amphotericin B (IC₅₀ 0.34 μg/mL), respectively. While, 6 showed good activity against C. neoformans (IC₅₀ 5.19 μg/mL) and mild activity against MRSA (IC₅₀ 6.39 μg/mL). Moreover, 1 and 2 exhibited very good anti-leishmanial activity towards L. donovani with IC₅₀ values of 4.61 and 6.31 μg/mL, respectively and IC₉₀ values of 6.02 and 16.71 μg/mL, respectively.     

Increased Atherogenic Low-Density Lipoprotein Cholesterol in Untreated Subclinical Hypothyroidism

ObjectiveTo evaluate the effects of physiologic doses of levothyroxine replacement on the lipoprotein profile in patients with subclinical hypothyroidism (SCH).MethodsIn a prospective, double-blind, placebo- controlled study, we enrolled 120 patients—mostly, but not exclusively, premenopausal women—with SCH. Patients were randomly assigned to either a levothyroxine- treated group (n = 60) or a placebo (control) group (n = 60). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured before and 52 weeks after assignment to either group.ResultsIn the levothyroxine-treated group, the lipoprotein mean values before and after the 52-week study were as follows: TC, 5.05 ± 0.98 mmol/L versus 4.74 ± 0.87 mmol/L (P < .0001); LDL-C, 3.30 ± 0.90 mmol/L versus 2.89 ± 0.59 mmol/L (P < .01); TG, 1.18 ± 0.71 mmol/L versus 0.95 ± 0.53 mmol/L (P < .002); and HDL-C, 1.20 ± 0.33 mmol/L versus 1.19 ± 0.32 mmol/L (P = .29). In the control group, TC, HDL-C, and TG values remained unchanged after 52 weeks in comparison with baseline, but LDL-C mean values increased from 2.79 ± 0.60 mmol/L to 3.11 ± 0.77 mmol/L, a change that was statistically significant (P < .001). At the end of the study, the lipid profile changes between levothyroxine- treated and control groups were compared. Total cholesterol and LDL-C were significantly lower in the levothyroxine-receiving group (P < .029 and P < .0001, respectively) in comparison with the control group. The difference did not reach statistical significance for TG and HDL-C values.ConclusionIn premenopausal women, SCH has a negative effect on the lipoprotein profile and may translate into a sizable cardiovascular risk if left untreated. (Endocr Pract. 2008;14:570-575)     

ACTN3 Gene R577X Polymorphism Associated with High-Density Lipoprotein Cholesterol and Adiponectin in Rugby Players

Objective: To determine the relationship between the R577X polymorphism of the α-actinin-3 (ACTN3), which may play a role in the individual differences observed in the effects of exercise on health benefits and antiatherogenic markers (i.e., high-density lipoprotein cholesterol [HDL-C] and adiponectin) in athletes.Methods: Seventy-six male rugby players (mean age 19.8 years) were enrolled in this study. Genomic DNA was extracted from peripheral blood samples, and restriction fragment length polymorphism-polymerase chain reactions were conducted to assess ACTN3 genotypes. Body mass index (BMI), waist circumference, serum lipids including HDL-C, and adiponectin levels were measured. Current smoking and alcohol intake habits were evaluated with a questionnaire. All of the parameters were compared between 2 groups displaying frequently observed genotypes: one group consisting of patients having either the R/R or R/X genotype and a second group with the X/X genotype.Results: The frequency of the X allele was 0.55 and the distribution of the genotypes was 35.5% (n = 27) for X/X, 39.5% (n = 30) for R/X, and 25.0% (n = 19) for R/R. Serum HDL-C and adiponectin levels were significantly higher in X/X genotype compared to the R/R or R/X genotype (HDL-C 1.6 ± 0.3 [SD] vs. 1.4 ± 0.2 mmol/L; P<.01, adiponectin 8.8 ± 2.6 vs. 6.9 ± 2.3 μg/mL; P<.01), even after adjustments for confounders (P<.01).Conclusion: There may be a relationship between the ACTN3 genotype and HDL-C and adiponectin levels in rugby players. This may be useful information when determining the individual responses of antiatherogenic markers to exercise.Abbreviations:ACTN3 = α-actinin-3BMI = body mass indexCVD = cardiovascular diseaseHDL-C = high-density lipoprotein cholesterolLDL-C = low-density lipoprotein cholesterolR = arginine (R) at amino acid position 577 of the ACTN3 proteinTC = total cholesterolTG = triglycerideX = truncation at amino acid position 577 of the ACTN3 protein     

Impact of Ramadan Fasting on Thyroid Status and Quality of Life in Patients with Primary Hypothyroidism: a Prospective Cohort Study from karachi,pakistan

Objective: Ramadan is the ninth month in the lunar calendar, during which Muslims fast from predawn to sunset and major changes occur in their dietary, sleep, and physical activity patterns. Most patients with hypothyroidism are unable to comply with the proper timings of levothyroxine (LT4) administration. The objective of the study was to determine the change in thyroid-stimulating hormone (TSH) level and quality of life (QOL) before and after Ramadan in patients with primary hypothyroidism.Methods: This prospective cohort study included adult patients on stable doses of LT4 who fasted for at least 20 days during the month of Ramadan in the Islamic year 1437 Hijri (June/July 2016). Baseline characteristics and TSH levels were recorded on all consenting patients within 6 weeks prior to Ramadan. Post-Ramadan TSH was tested within 1 to 2 weeks after Eid-ul-Fitr.Results: During the study period, 64 patients with hypothyroidism were enrolled, of which 58 were female. The mean age of participants was 44.2 ± 13.2 years. Average daily dose of LT4 was 95.3 ± 35.4 μg. On average, patients fasted for 26.5 days and missed a dose of LT4 on 1.27 days. Mean TSH pre-Ramadan was 2.37 ± 1.35 mIU/L, and post-Ramadan, it was 4.69 ± 3.87 mIU/L. Mean difference between TSH pre- and post-Ramadan was 2.32 ± 3.80 mIU/L (P<.001). However, the difference in TSH was not significantly different between those who were compliant with meals and LT4 interval versus those who were not (compliant, 2.04 mIU/L; noncompliant, 3.15 mIU/L; P = .30). Overall, an increase in QOL scores in the domains of physical health, psychological health, and social relationships was observed after Ramadan.Conclusion: We observed statistically significant changes in TSH concentrations after the month of Ramadan in hypothyroid patients who fasted. The change in TSH was not affected by timing of LT4 intake and interval from meal.Abbreviations: AKUH = Aga Khan University Hospital; LT4 = levothyroxine; QOL = quality of life; TSH = thyroid-stimulating hormone     

Menstrual Disorders and Androgen-Related Traits in Young Women with Type 1 Diabetes Mellitus: a Clinical Study

Objective: To investigate possible causes of menstrual disorders and androgen-related traits in young women with type 1 diabetes mellitus (T1DM).Methods: Fifty-three women with T1DM (duration 8.0 ± 5.6 years), 41 women with (polycystic ovary syndrome) PCOS, and 51 controls matched for age (19.4 ± 4.3 years vs. 21.2 ± 2.7 years vs. 20.8 ± 3.1 years; P>.05) and body mass index (BMI) (22.2 ± 2.7 kg/m² vs. 21.9 ± 2.0 kg/m² vs. 21.4 ± 1.9 kg/m²; P>.05) were prospectively recruited.Results: Two women (3.8%) in the T1DM group had not experienced menarche (at 15.5 and 16.6 years); of the rest, 23.5% had oligomenorrhea, 32.1% hirsutism, and 45.3% had acne. The age at menarche was delayed in the T1DM group compared to controls (12.7 ± 1.3 vs. 12.0 ± 1.0 years; P = .004), while no difference was observed with the polycystic ovary syndrome (PCOS) group (12.4 ± 1.2 years). There were no differences in total testosterone (0.43 ± 0.14 ng/mL vs. 0.39 ± 0.14 ng/mL; P>.05), dehydroepiandrosterone sulfate (DHEA-S) (269 ± 112 μg/dL vs. 238 ± 106 μg/dL; P>.05) or Δ4-androstenedione (2.4 ± 1.3 ng/mL vs. 1.9 ± 0.5 ng/mL; P>.05) concentrations between T1DM and controls. However, patients with T1DM had lower sex hormone binding globulin (SHBG) concentrations than controls (61 ± 17 nmol/L vs. 83 ± 18.1 nmol/L; P = .001), which were even lower in the PCOS group (39.5 ± 12.9 nmol/L; P = .001 compared with T1DM). The free androgen index (FAI) was higher in the PCOS group compared with both other groups (T1DM vs. PCOS vs. controls: 2.53 ± 0.54 vs. 7.88 ± 1.21 vs. 1.6 ± 0.68; P<.001). FAI was higher in patients with T1DM compared to controls as well (P = .038). There was no difference in DHEA-S concentrations between T1DM and PCOS patients (269 ± 112 μg/dL vs. 297 ± 100 μg/dL; P>.05).Conclusion: Menstrual disorders and androgen-related traits in young women with T1DM may be attributed to an increase in androgen bioavailability due to decreased SHBG concentrations.     

Pinostrobin and Cajanus lactone isolated from Cajanus cajan (L.) leaves inhibits TNF-α and IL-1β production: In vitro and in vivo experimentation

The tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) inhibitory activities of Cajanus cajan (leaves) crude methanolic extract, its fractions and its phytochemical constituents were evaluated in lipopolysaccharide (LPS) stimulated RAW 264.7 and J774A.1 cells. Phytochemical investigation of the active ethyl acetate (CCE) and n-butanol (CCB) fractions of C. cajan L. leaves yielded 14 compounds. It was observed that both pinostrobin (9) and cajanus lactone (4) were found to be most active in inhibiting TNF-α (IC₅₀ < 22 μM) and IL-1β (IC₅₀ < 40 μM) whereas compounds 2, 3, 5–8, 10 and 14 showed moderate and mild effects (IC₅₀ = 35.50–81.22 μM for TNF-α and 38.23–89.10 μM for IL-1β) in both the cell lines. Furthermore, at dose of 20 mg/kg, both pinostrobin (9) and cajanus lactone (4) were found to reduce LPS-induced TNF-α levels by 48.6% and 55.0% respectively and IL-1β levels by 53.1% and 41.8% respectively in Sprague Dawley (SD) rats. These findings suggest that C. cajan L. leaves can be developed as an effective herbal remedy for the treatment and prevention of inflammation or associated ailments.     

Different roles of zinc plus arachidonic acid on insulin sensitivity between high fructose- and high fat-fed rats

AimsThis study was to determine the effects of zinc plus arachidonic acid (ZA) treatment on the insulin action in the specific ZA target organs using hyperinsulinemic euglycemic clamp method.Main methods18 Sprague–Dawley rats weighing ~ 130 g were divided into 3 groups of 6 rats and treated them with 1) normal rat chow, 2) high fructose (60.0%) diet only, or 3) the same fructose diet plus drinking water containing 10 mg zinc plus 50 mg arachidonic acid (AA)/L. In a separate study, male Wistar rats weighing ~ 250 g were fed normal rat chow (n = 4) or high fat (66.5%) diet with drinking water containing zero (n = 9) or 10 mg AA plus 20 mg zinc /L (n = 9). After 4 week treatment, insulin action was assessed using the hyperinsulinemic eguglycemic clamp technique.Key findingsHigh fructose feeding impaired suppression of hepatic glucose output by insulin compared to controls during the clamp procedure (4.39 vs. 2.35 mg/kg/min; p < 0.05). However, ZA treatment in high fructose-fed rats showed a significant improvement of hepatic insulin sensitivity compared to non-treatment controls (4.39 vs. 2.18 mg/kg/min; p < 0.05). Glucose infusion rates in Wistar rats maintained on a high fat diet (HFD) were significantly lower compared to control rats (22.8 ± 1.3 vs. 31.9 ± 1.4 mg/kg/min; p < 0.05). ZA treatment significantly improved (~ 43%) peripheral tissue insulin sensitivity in HFD fed animals (26.7 ± 1.3 [n = 9] vs. 22.8 ± 1.3 mg/kg/min; p < 0.05).SignificanceThese data demonstrate that ZA treatment is effective in improving glucose utilization in hyperglycemic rats receiving either a high-fructose or a high-fat diet.