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     

Nonobese Young Females with Polycystic Ovary Syndrome Have Nutritive Microvascular Dysfunction: A Pilot Study

ObjectiveTo investigate nutritive microvascular function in young nonobese females with polycystic ovary syndrome (PCOS) and to correlate microvascular reactivity with sex steroids, inflammatory markers, and metabolic variables.MethodsFourteen nonobese females with PCOS (24.6 ± 2.7 years, body mass index [BMI] 23.7 ± 3.1 kg/ m²) and 13 age- and BMI-matched controls (22.8 ± 2.3 years, 22.5 ± 3.4kg/m2) underwent anthropometric, hormonal, and microvascular evaluations. The main outcome measures were capillary density, red blood cell velocity (RBCV) at resting and peak during postocclusive reactive hyperemia (RBCV_max), and time taken to reach RBCV_max (TRBCV_max).ResultsSubjects with PCOS had lower RBCV and higher TRBCV_max compared to controls, respectively (0.237 [0.220-0.324] vs. 0.362 [0.297-0.382] mm/s, F < .01) and (5 [5-6] vs. 4 [3-5] s, P < .05]. The free androgen index (FAI) and sex hormone-binding globulin (SHBG) level were different between groups. FAI correlated to RBCV_max (ρ = -0.49, P < .05) and to TRBCV_max (ρ = 0.41, P < .05). SHBG correlated with RBCV_max (ρ = 0.52, P < .01) while estradiol (E₂) levels correlated with RBCV (ρ = 0.80, P < .001) and RBCV_max (ρ = 0.46, P < .05).ConclusionMicrovascular dysfunction characterized by reduced RBCV_maxand prolonged TRBCV_maxwas present in young, nonobese PCOS subjects. FAI was associated with observed impairments, suggesting a possible common mechanism linking sex hormones and microvascular dysfunction. (Endocr Pract. 2014;20:1281-1289)     

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.     

Cardiac Structural and Functional Abnormalities in Females with Untreated Hypopituitarism due to Sheehan Syndrome: Response to Hormone Replacement Therapy

Objective: Data on cardiac abnormalities in females with untreated hypopituitarism are limited. We investigated echocardiographic abnormalities in females with untreated hypopituitarism and their response to treatment.Methods: Twenty-three females with treatment-naïve hypopituitarism and 30 matched healthy controls were evaluated for cardiac structure and function. Echocardiographic evaluation was done at presentation and after achieving a euthyroid and eucortisol state.Results: Fourteen (61%) patients had mitral regurgitation, and 11 (48%) had pericardial effusion as against none among controls. Indices of left ventricular (LV) size like LV end diastolic dimension (LVEDD; 44.5 ± 3.5 mm in cases vs. 47.6 ± 3.8 mm in controls, P = .004), and LV diastolic volume (LVEDV; 91.8 ± 18.0 mL versus 106.5 ± 20.4 mL, P = .009) were significantly lower in the SS group compared with controls. LV mass (LVM) was 70.8 ± 19.2 g in cases and 108.0 ± 33.2 g in controls (P = .02). Similarly, indices of LV systolic function like stroke volume (SV; 59.1 ± 12.0 mL in cases and 74.4 ± 15.8 mL in controls; P = .000), ejection fraction (EF; 64.3 ± 6.2 % in cases against 69.9 ± 9.2 % in controls; P = .03), and fractional shortening (FS; 34.9 ± 4.7% versus 40.1 ± 4.4%, P = .000) were significantly decreased in patients compared with controls. Cardiac abnormalities normalized with restoration of a euthyroid and eucortisol state.Conclusion: Pericardial effusion, mitral regurgitation, and diminished LVM are common in females with untreated hypopituitarism.Abbreviations:ACTH = adrenocorticotrophic hormoneBMI = body mass indexDT = deceleration timeEDV = end-diastolic volumeEF = ejection fractionFS = fractional shorteningGH = growth hormoneIGF-1 = insulin growth factor-1ITT = insulin tolerance testIVSd = interventricular septal diameterLH = luteinizing hormoneLV = left ventricularLVEDD = LV end diastolic dimensionLVEDV = LV end diastolic volumeLVM = LV massMRI = magnetic resonance imagingMVP = mitral value prolapsePPH = postpartum hemorrhagePWd = posterior wall diameterSS = Sheehan syndromeSV = stroke volumeT3 = triiodothyronineT4 = thyroxineTSH = thyroid-stimulating hormone     

Dpp4 Inhibitor Sitagliptin As A Potential Treatment Option In Metformin-Intolerant Obese Women With Polycystic Ovary Syndrome: A Pilot Randomized Study

Objective: Metformin has an established role in the management of polycystic ovary syndrome (PCOS). Some patients cannot tolerate it due to associated gastrointestinal adverse events. The present study evaluated the dipeptidyl peptidase 4 inhibitor sitagliptin as a potential treatment option in metformin-intolerant PCOS.Methods: We conducted a 12-week, prospective, randomized, open-label study with 30 obese metformin-intolerant women with PCOS (age 35.0 ± 7.2 years; body mass index, 36.9 ± 5.5 kg/m²). After metformin withdrawal, they were randomized to lifestyle intervention and sitagliptin 100 mg daily (SITA) or lifestyle intervention alone as controls (CON). All participants underwent anthropometric and endocrine measurements and oral glucose tolerance testing. Model-derived indexes of insulin resistance and beta-cell function were calculated.Results: SITA improved beta-cell function as assessed by the homeostasis model assessment for beta-cell function index (HOMA-B) of 45.9 ± 35.8 (P = .001), modified beta-cell function index (MBCI) of 7.9 ± 7 (P = .002), and quantitative insulin-sensitivity check index (QUICKI) of -0.03 ± 0.03 (P = .002). By contrast, beta-cell function decreased in CON. The between-group differences were significant for HOMA-B (P = 0.001), MBCI (P = .010), and QUICKI (P = .025). The conversion rate to impaired glucose homeostasis was prevented in SITA: 3 of 15 subjects had impaired glucose tolerance (IGT) before and after the study. In CON, none had type 2 diabetes (T2D), and 4 had IGT at the beginning. After 12 weeks, IGT was observed in 2 and T2D in 3 subjects.Conclusion: SITA improved beta-cell function and prevented a conversion to IGT and T2D in metformin-intolerant obese PCOS patients.Abbreviations: BMI = body mass index; DPP-4 = dipeptidyl peptidase-4; DXA = dual energy X-ray absorptiometry; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1; HOMA-B = homeostasis model assessment for beta-cell function; HOMA-IR = homeostasis model assessment of insulin resistance; IAI = insulin action index; IGT = impaired glucose tolerance; IR = insulin resistance; MBCI = modified beta-cell function index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index; PCOS = polycystic ovary syndrome; SHBG = sex hormone–binding globulin; T2D = type 2 diabetes     

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     

Health-Related Quality of Life After Percutaneous Radiofrequency Ablation of Cold,Solid, Benign Thyroid Nodules: A 2-Year Follow-Up Study in 40 Patients

Objective: We studied the impact of radiofrequency ablation (RFA) on health-related quality of life (HRQL) in patients with benign thyroid nodules (TN) in a 2-year follow-up.Methods: Forty patients (35 women and 5 men; age, 54.9 ± 14.3 years) with cold thyroid solitary nodules or a dominant nodule within a normofunctioning multi-nodular goiter (volume range, 6.5 to 90.0 mL) underwent RFA of thyroid nodular tissue under ultrasound real-time assistance.Results: Data are mean and standard deviation. Energy delivered was 37,154 ± 18,092 joules, with an output power of 37.4 ± 8.8 watts. Two years after RFA, nodule volume decreased from 30.0 ± 18.2 mL to 7.9 ± 9.8 mL (-80.1 ± 16.1% of initial volume; P<.0001). Thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels remained stable. Symptom score measured on a 0- to 10-cm visual analogue scale (VAS) declined from 5.6 ± 3.1 cm to 1.9 ± 1.3 cm (P<.0001). Cosmetic score (VAS 0–10 cm) declined from 5.7 ± 3.2 cm to 1.9 ± 1.5 cm (P<.0001). Two patients became anti-thyroglobulin antibody–positive. Physical Component Summary (PCS)-12 improved from 50.4 ± 8.9 to 54.5 ± 5.3, and the Mental Component Summary (MCS)-12 improved from 36.0 ± 13.3 to 50.3 ± 6.3 (P<.0001 for both score changes).Conclusion: Our 2-year follow-up study confirms that RFA of benign TNs is effective in reducing nodular volume and compressive and cosmetic symptoms, without causing thyroid dysfunction or life-threatening complications. Our data indicate that the achievement of these secondary endpoints is associated with HRQL improvement, measured both as PCS and MCS.Abbreviations: fT₃ = free triiodothyronine fT₄ = free thyroxine HRQL = health-related quality of life MCS-12 = Mental Component Summary-12 PLA = percutaneous laser ablation PCS-12 = Physical Component Summary-12 RF = radiofrequency RFA = radiofrequency ablation SF-12 = Short-Form 12 Health Survey TgAb = anti-thyroglobulin antibody TN = thyroid nodule TRAb = anti-TSH-receptor antibody TSH = thyroid-stimulating hormone US = ultrasound VAS = visual analogue scale     

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 &lsqb;interquartile range of 9.5 to 34.5 μg/L] versus 5.9 μg/L &lsqb;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     

Vitamin D-Binding Protein in Healthy Pre- and Postmenopausal Women: Relationship with Estradiol Concentrations

Objective: To examine the relationship between endogenous serum estradiol and vitamin D–binding protein (DBP) and total, free, and bioavailable 25-hydroxyvitamin D (25OHD) concentrations in pre- and postmenopausal women.Methods: In 165 healthy women (ages, 26 to 75 years) not taking any form of exogenous estrogen, the serum concentrations of estradiol, 25OHD, DBP, parathyroid hormone, and albumin were measured. Free and bioavailable 25OHD (free + albumin-bound) levels were calculated from total 25OHD, DBP, and serum albumin levels.Results: Premenopausal women had higher serum 25OHD (31.5 ± 7.9 ng/mL), DBP (45.3 ± 6.2 mg/dL), and estradiol (52.8 ± 35.0 pg/mL) levels than postmenopausal women (26.5 ± 4.9 ng/mL, 41.7 ± 5.7 mg/dL, and 12.9 ± 4.9 pg/mL), respectively. In addition, the calculated free and bioavailable 25OHD levels were higher in prethan postmenopausal women (P<.05). Serum estradiol correlated with DBP (r = 0.22; P<.01) and total 25OHD (r = 0.27; P<.01). In multivariate regression models (with or without serum 25OHD), estradiol was independently associated with DBP (P<.05).Conclusion: Lower estradiol level is one of the factors that contribute to lower DBP levels in older women. Our data indicate that besides well-known factors such as age, gender, and race, serum estradiol concentrations are also a physiologic predictor of DBP concentration.Abbreviations: 25OHD = 25-hydroxyvitamin D BMI = body mass index CV = coefficient of variation DBP = vitamin D–binding protein PTH = parathyroid hormone SHBG = sex hormone–binding globulin     

High-Dose Glucocorticoid Treatment Does Not Induce Severe Hyperglycemia in Young Patients with Autoimmune Diseases by Cgms

Objective: High-dose glucocorticoids (HDG) are used in the treatment of autoimmune diseases. Glucocorticoids-induced hyperglycemia (GIH) is often described in elderly patients. In young patients with autoimmune diseases, however, the risk for GIH has not been well characterized.Methods: We recruited 24 inpatients (median age, 32 years; interquartile range, 25–42) with exacerbations of autoimmune diseases, receiving 1 to 2 mg/kg/day prednisone or equivalent methylprednisone. Fourteen subjects were naïve to glucocorticoids (group 1) and 10 subjects were on glucocorticoid maintenance (≤15 mg/day prednisone at least 3 months) (group 2) prior to HDG. All subjects were monitored by continuous glucose monitoring system (CGMS) for 3 days.Results: GIH developed in 21 (91%) subjects, 11/13 in group 1 and 10/10 in group 2. The main peak of glucose excursion (128.7 ± 6.4 mg/dL, group 1; 143.9 ± 10.0 mg/dL, group 2) occurred at 2 to 3 pm. Another peak occurred before sleep. Two-hour mean postprandial glucose levels were normal in both groups: breakfast, 105.0 ± 28.4 versus 125.6 ± 24.4 mg/dL, P = .065; lunch, 115.7 ± 21.1 versus 135.9 ± 29.0 mg/dL, P = .082; dinner, 122.8 ± 18.5 versus 137.8 ± 26.4 mg/dL, P = .144 in groups 1 and 2, respectively. There was a positive association between pretreatment hemoglobin A1C and peak glucose levels (P<.0001). Notably, 35% of our subjects experienced early morning hypoglycemia (65.2 ± 2.8 mg/dL).Conclusion: In hospitalized young patients with auto-immune diseases, CGMS data revealed that short-term consistent HDG treatment induced mild hyperglycemia, peaking in the early afternoon and before sleep. Early morning hypoglycemia was found in 35%.Abbreviations: A1C = hemoglobin A1C; AUC = the area under the curve; BG = blood glucose; BMI = body mass index; CGMS = continuous glucose monitoring system; DM = diabetes mellitus; FBG = fasting blood glucose; GA = glycated albumin; GCs = glucocorticoids; GIH = glucocorticoids-induced hyperglycemia; HDG = high-dose glucocorticoids; HOMA-IR = Homeostasis Model Assessment-Insulin Resistance; IG = interstitial glucose; IQR = interquartile range; PUMCH = Peking Union Medical College Hospital; SLE = systemic lupus erythematosus     

Eating and Glycemic Control Among Critically Ill Patients Receiving Continuous Intravenous Insulin

Objective: Consensus guidelines recommend that intensive care unit (ICU) patients with blood glucose (BG) levels >180 mg/dL receive continuous intravenous insulin (CII). The effectiveness of CII at controlling BG levels among patients who are eating relative to those who are eating nothing by mouth (nil per os; NPO) has not been described.Methods: We conducted a retrospective cohort study of 260 adult patients (156 eating, 104 NPO) admitted to an ICU between January 1, 2014, and December 31, 2014, who received CII. Patients were excluded for a diagnosis of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic syndrome, admission to an obstetrics service, or receiving continuous enteral or parenteral nutrition.Results: Among 22 baseline characteristics, the proportion of patients receiving glucocorticoid treatment (GCTx) (17.3% eating, 37.5% NPO; P<.001) and APACHE II score (15.0 ± 7.5 eating, 17.9 ± 7.9 NPO; P = .004) were significantly different between eating and NPO patients. There was no significant difference in the primary outcome of patient-day weighted mean BG overall (153 ± 8 mg/dL eating, 156 ± 7 mg/dL NPO; P = .73), or day-by-day BG (P = .37) adjusted for GCTx and APACHE score. Surprisingly, there was a significant difference in the distribution of BG values, with eating patients having a higher percentage of BG readings in the recommended range of 140 to 180 mg/dL. However, eating patients showed greater glucose variability (coefficient of variation 23.1 ± 1.0 eating, 21.2 ± 1.0 NPO; P = .034).Conclusion: Eating may not adversely affect BG levels of ICU patients receiving CII. Whether or not prandial insulin improves glycemic control in this setting should be studied.Abbreviations: BG = blood glucose; CII = continuous insulin infusion; CV = coefficient of variation; HbA1c = hemoglobin A1c; ICU = intensive care unit; NPO = nil per os; PDWMBG = patient day weighted mean blood glucose     

Timing of GH Peak in Both Glucagon and Clonidine Tests is of Major Clinical Importance

Objective: To detect a possible correlation between timing of the peak value of growth hormone (GH) during stimulatory tests (STs) and the effectiveness of treatment with recombinant human growth hormone (rhGH) in children with idiopathic GH deficiency (iGHD).Methods: We retrospectively studied 92 patients with iGHD (57 boys; mean age at diagnosis: 9.93 years). Diagnosis was confirmed by 2 different STs, glucagon stimulation test (GST), and clonidine stimulation test (CST). Auxologic parameters were recorded, while observed and predicted (according to KIGS Prediction Model) height velocity during the first year of treatment and the index of responsiveness (IoR) were calculated for the prepubertal children (n = 65).Results: Atypical GST was defined as that with peak GH value at time 0 minutes, 30 minutes, 60 minutes, or 180 minutes, whereas atypical CST was defined as that with peak timing at 0 minutes, 30 minutes, or 120 minutes. Atypical GST was detected in 18 patients (19.57%). IoR was lower in the prepubertal children with atypical GST (-1.81 ± 0.67 versus -1.34 ± 0.85; P = .051). In the CST, the 18 children who had atypical timing, had significantly lower IoR (-1.86 ± 0.66 versus -1.35 ± 0.84; P = .047). When the patients were categorized according to the number of atypical tests, significant differences in the IoR were detected (-2.09 ± 0.68 with 2 atypical STs &lsqb;n = 6], -1.64 ± 0.61 with 1 atypical ST &lsqb;n = 16], and -1.29 ± 0.87 with no atypical ST &lsqb;n = 43], P = .045).Conclusion: The presence of atypical peak GH timing during ST may be a factor that predicts lower growth hormone velocity during the first year of rhGH treatment in prepubertal children with iGHD.Abbreviations: CST = clonidine stimulation test; GH = growth hormone; GHD = growth hormone deficiency; GST = glucagon stimulation test; iGHD = idiopathic growth hormone deficiency; IoR = index of responsiveness; rhGH = recombinant human growth hormone; SDS = standard deviation scores; ST = stimulatory test     

Nonfunctioning Adrenal Incidentalomas are not Clinically Silent: A Longitudinal Cohort Study

Objective: The association between nonfunctioning adrenal incidentalomas (NFAIs) and cardiometabolic diseases remains controversial. This retrospective cohort study investigated whether NFAIs are related with prevalent and incident cardiometabolic diseases.Methods: This study included 154 patients with biochemically confirmed NFAIs and 1:3 age and sex-matched controls without adrenal incidentalomas (n = 462) among subjects who underwent abdominal computed tomography at a single healthcare center in 2003–2012. Electronic medical records were reviewed for comorbidities at baseline and during a mean follow-up of 7.5 years. The logistic regression analysis for prevalent cardiometabolic diseases and the survival analysis for incident cardiometabolic diseases were performed.Results: The subjects were 55.7 ± 8.8 years of age and predominantly male (73.1%). The NFAI group had a higher body mass index compared to the age and sex-matched control group (25.1 ± 2.8 vs. 24.0 ± 2.8 kg/m²; P<.001). In a cross-sectional design, covariate-adjusted logistic regression showed significantly higher odds ratios (ORs) for diabetes mellitus and hypertension in the NFAI group (adjusted OR [95% confidence interval [CI]], 1.89 [1.17 to 3.06] and 2.26 [1.47 to 3.50], respectively). The NFAI group had a 2-fold higher risk of insulin resistance (adjusted ORs [95% CI], 2.03 [1.06 to 3.90]). Moreover, NFAI subjects with diabetes mellitus had a greater increase in size of adrenal lesions than those without diabetes mellitus (3.4 ± 5.5 vs. 1.4 ± 5.5 mm; P =.048). However, in the survival analysis, the incidence of any cardiometabolic diseases did not differ between the NFAI and control groups.Conclusion: NFAIs are related to prevalent diabetes mellitus or hypertension in our cross-sectional study. However, the presence of NFAIs did not affect the development of cardiometabolic diseases.Abbreviations: ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; BMI = body mass index; CI = confidence interval; CT = computed tomography; HbA1c = hemoglobin A1c; HOMA-IR = homeostasis model assessment of insulin resistance; HU = Hounsfield units; MACE = mild autonomous cortisol excess; NFAI = nonfunctioning adrenal incidentaloma; OR = odds ratio     

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     

Hospital Insulin Protocol Aims For Glucose Control In Glucocorticoid-Induced Hyperglycemia

Objective: To compare the effectiveness of 2 insulin protocols to treat glucocorticoid-induced hyperglycemia in the nonintensive care hospital setting.Methods: A randomized, open-label, parallel-arm study was conducted comparing standard recommended care of complete insulin orders (CIO) (i.e., 3-part insulin regimen of long-acting basal [background], rapid-acting bolus [mealtime], and rapid-acting correction factor) to an experimental group following a regimen of Neutral Protamine Hagedorn (NPH) plus CIO (NPH-CIO). The primary outcome was mean blood glucose (BG), and the secondary outcome was percent of BG in target range of 70 to 180 mg/dL. Hypoglycemia was also evaluated.Results: Sixty-one patients completed 2 to 5 consecutive inpatient days (31 CIO; 30 NPH-CIO). Baseline mean BG results were 237.2 ± 50.2 and 221.9 ± 35.8 mg/dL (P = .30) in the CIO and NPH-CIO groups, respectively. No significant difference in overall mean BG between the 2 groups was detected; however, a significant difference arose on day 3: mean BG 181.8 ± 32.6 mg/dL (CIO) versus 157.2 ± 6.1 mg/dL (NPH-CIO) (P = .03). Moreover, the total daily doses (TDDs) of insulin did not differ: 34.8 ± 43.0 units (CIO) versus 35.8 ± 25.0 units (NPH-CIO) (P = .13). Percent of BG in target was 54.6% (CIO) and 62% (NPH-CIO) (P = .24). Incidence of severe hypoglycemia (<50 mg/dL) was the same in both groups (0.1%).Conclusion: NPH added to 3-part insulin regimen (CIO) may be an effective way to a combat glucocorticoid-induced hyperglycemia, though further research is needed in a larger population.Abbreviations:A1C = hemoglobin A1CBG = blood glucoseCIO = complete insulin ordersDM = diabetes mellitusNPH = neutral protamine HagedornNPH-CIO = neutral protamine Hagedorn plus CIOTDD = total daily dose     

Visceral and Subcutaneous Fat Increased after Treatment of Graves Disease

Objective: Patients with Graves disease (GD) tend to gain weight after treatment, but it remains unknown if weight gain is associated with an increase in the visceral and/or subcutaneous fat areas (VFA, SFA).Methods: We enrolled 25 newly diagnosed GD patients (22 females, median age 33.0 years) and studied their clinical parameters, and VFA and SFA measured by a dual bioelectric impedance analysis. We divided them into 2 groups based on the rates of change in the VFA and SFA, and we compared clinical parameters at the baseline between the groups to evaluate factors that influence increases in the VFA and/or SFA with treatment.Results: The patients' body weight (BW), VFA, and SFA were significantly increased after a 6-month treatment (BW: from 54.3 ± 10.3 kg to 58.0 ± 11.2 kg; P<.001; VFA: from 47.1 ± 21.3 cm² to 54.7 ± 23.4 cm²; P = .004; SFA: from 159.8 ± 85.9 cm² to 182.2 ± 82.9 cm²; P = .008). The percent changes of BW correlated with the SFA (ρ = .591, P = .002), but not with the VFA. The patients with larger VFA increases had significantly less VFA at the baseline compared to those with smaller increases, expressed as median and interquartile range (33.9 cm² [22.7 to 47.5 cm²] versus 54.5 cm² [45.2 to 64.0], respectively; P = .011). A larger increase in the SFA was negatively associated with serum alkaline phosphatase. An increase in the SFA was associated with free triiodothyronine (T3) in a multivariate logistic analysis (odds ratio: 0.80 [0.59 to 0.97]; P = .013).Conclusion: The patients' BW, VFA, and SFA were increased after GD treatment. The increase in SFA seemed to contribute to weight gain and was associated with a low baseline level of free T3.Abbreviations: ALP = alkaline phosphatase; BMI = body mass index; BW = body weight; GD = Graves disease; SFA = subcutaneous fat area; T3 = triiodothyronine; T4 = thyroxine; TG = triglycerides; VFA = visceral fat areas     

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     

Dysregulation Of The Hypothalamic-Pituitary-Adrenal Axis Increases Central Body Fat Accumulation In Males Affected By Diabetes Mellitus And Late-Onset Hypogonadism

Objective: Functional hypercortisolism (FH) is a condition which occurs in some clinical states, such as major depression, eating disorders, numerous psychiatric conditions, and diabetes mellitus (DM) and which exerts several negative systemic effects. No data exist on the potentially harmful role of FH on body composition. In this retrospective study, we evaluated the influence of hypothalamic-pituitary-adrenal (HPA) axis dysregulation on body composition in men affected by DM-associated late-onset hypogonadism (LOH).Methods: Fourteen subjects affected by FH (FH-LOH) and 18 subjects not affected (N-LOH) were studied. Clinical, hormonal, and body composition measures were considered.Results: The 2 groups had comparable age and weight. FH-LOH patients had lower levels of total (2 ± 0.27 ng/mL versus 2.31 ± 0.26 ng/mL; P = .003) and free (39.5 ± 6.44 pg/mL versus 46.8 ± 7.23 pg/mL; P = .005) (median, 38.7 &lsqb;interquartile range, 36.1 to 41.3] pg/mL versus median, 46.1 &lsqb;interquartile range, 40.4 to 52.7] pg/mL) testosterone compared to N-LOH patients. Abdominal fat amount was greater in FH-LOH than in N-LOH patients, even after adjustment for total testosterone. None of the bivariate correlations between body composition measures and hormonal variables were significant in N-LOH. Conversely, in FH-LOH, cortisol area under the curve (AUC) was found to be positively and significantly correlated with trunk (r = 0.933; P<.001) and abdominal fat (r = 0.852; P<.001) and negatively with lean leg (r = -0.607; P = .021). All of these associations were further confirmed upon linear regression analysis in FH-LOH (respectively, unstandardized β = 10.988 &lsqb;P<.001]; β = 1.156 &lsqb;P<.001]; β = -7.675 &lsqb;P = .021]). Multivariate regression analysis confirmed AUC cortisol as a predictor of trunk and abdominal fat in FH-LOH.Conclusion: Dysregulation of the HPA axis in LOH-associated DM seems to be involved in abdominal fat accumulation.Abbreviations:ACTH = adrenocorticotropic hormoneAUC = area under the curveCRH = corticotropin-releasing hormoneCT = computed tomographyDEXA = dual-energy X-ray absorptiometryDM = diabetes mellitusFH = functional hypercortisolismFH-LOH = subjects affected by functional hypercortisolismFSH = follicle-stimulating hormoneHPA = hypothalamic-pituitary-adrenalLH = luteinizing hormoneLOH = late-onset hypogonadismN-LOH = subjects not affected by functional hypercortisolismOST = overnight low-dose dexamethasone suppression testSHBG = sex hormone–binding globulinUFC = urinary free cortisol     

Markedly Delayed Insulin Secretion and a High Rate of Undetected Overt Diabetes Characterize Glucose Metabolism in Adult Patients with Cystic Fibrosis After Lung Transplantation

Objective: Cystic fibrosis–related diabetes (CFRD) is associated with adverse clinical outcomes and should be screened for by an annual oral glucose tolerance test (OGTT). Since pathophysiologic studies have mainly been performed in a pediatric/adolescent, nontransplanted collective, we aimed to assess parameters of insulin secretion and sensitivity in adult cystic fibrosis (CF) patients after lung transplantation (LT).Methods: Twelve adult CF patients after LT without known diabetes (33.3 ± 11.5 years; body mass index &lsqb;BMI] 21.5 ± 3.3 kg/m²) and 8 control subjects matched by age (36.0 ± 6.6 years; P>.05), BMI (22.3 ± 1.5 kg/m²; P>.05), and gender (CON group) underwent a 3-hour OGTT with glucose, insulin, and C-peptide measurements. Parameters of insulin secretion and sensitivity as well as lipid profiles were assessed.Results: In the CF group, 4 patients were diagnosed with overt diabetes (CFRD) compared to CF patients without diabetes (CF-noDM), of whom 6 had indeterminate glycemia with 1-h glucose values >200 mg/dL. The insulin peak after glucose load occurred after 30 minutes in CON, after 90 minutes in CF-noDM, and was missing in CFRD. Insulin sensitivity was comparable between the groups. Beta-cell glucose sensitivity was markedly reduced in CFRD (10.7 ± 5.8 pmol/min*m²*mM), higher in CF-noDM (39.9 ± 23.4 pmol/min*m²*mM), but still significantly lower compared to CON (108.3 ± 53.9 pmol/min*m²*mM; P = .0008). CFRD patients exhibited increased triglyceride levels and decreased high-density lipoprotein levels.Conclusion: Adult CF patients after LT have profound disturbances in glucose metabolism, with a high rate of undetected diabetes and markedly delayed insulin secretion. Curbed beta-cell glucose sensitivity rather than insulin resistance explains postprandial hyperglycemia and is accompanied by abnormalities in lipid metabolism.Abbreviations: AUC = area under the curve; BMI = body mass index; CF = cystic fibrosis; CFRD = cystic fibrosis–related diabetes; CFTR = cystic fibrosis transmembrane-conductance regulator; CF-TX = cystic fibrosis patients who underwent lung transplantation; CGM = continuous glucose monitoring; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; INDET = indeterminate glycemia; LDL = low-density lipoprotein; LT = lung transplantation; OGIS = oral glucose sensitivity index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index     

Metformin-Sustained Weight Loss and Reduced Android Fat Tissue At 12 Months In Empowir (Enhance The Metabolic Profile Of Women With Insulin Resistance): A Double Blind,Placebo-Controlled,Randomized Trial of Normoglycemic Women with Midlife Weight Gain

Objective: To assess 12-month body weight (BW) and body composition changes in normoglycemic women with midlife weight gain, after dietary and pharmacologic interventions targeting hyperinsulinemia.Methods: EMPOWIR (Enhance the Metabolic Profile of Women With Insulin Resistance; NCT00618072) was a double-blind, placebo-controlled, 12-month trial of women with >20-pound weight gain, normal glucose tolerance test, and increased area-under-the-curve insulin. Subjects (mean ± SD, 46.7 ± 6.5 years of age; body mass index, 30.8 ± 2.8 kg/m²; 50% white) attended 4 nutrition workshops to introduce a novel carbohydrate-modified diet (CMD) and were then randomized to one of three arms for 6 months (phase 1): CMD alone (D), or in combination with metformin (M), or metformin + rosiglitazone (MR), with rerandomization of the D group to one of the active treatment arms (phase 2, months 7 through 12). Repeated measure analysis of variance was used to assess BW at baseline, 6 months, and 12 months in 32 subjects with 12-month data; paired t tests compared baseline and 12-month dual-energy X-ray absorptiometry–derived body composition.Results: Mean (±SD) BW decreased significantly at 12 months in the M arm: 85.1 ± 8.5 kg to 79.8 ± 9.0 kg (P = .0003), with 54% of variance in weight over time explained by M treatment. Mean (±SD) percent android fat decreased significantly in the M and D arms: 53.5 ± 4.8% to 49.3 ± 7.6% (P = .010) and 52.9 ± 6.2% to 48.1 ± 8.7% (P = .021).Conclusion: In combination with a novel carbohydrate modified diet, metformin enhanced 12-month weight loss and improved body composition in ethnically diverse normoglycemic, hyperinsulinemic women with midlife weight gain. These findings suggest that EMPOWIR's easily implemented dietary interventions, alone and in combination with pharmacotherapies that target hyperinsulinemia, merit additional investigation in larger, long-term studies.Abbreviations:ANOVA = analysis of varianceBC = body compositionBW = body weightCMD = carbohydrate-modified dietD = diet alone groupDXA = dual-energy X-ray absorptiometryEMPOWIR = Enhance the Metabolic Profile of Women With Insulin ResistanceM = metformin groupMR = metformin + rosiglitazone group