Mary H. Samuels

Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss.

Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (S(I)) by frequently sampled intravenous glucose tolerance test; and adipocyte 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased S(I). Increased 11beta-HSD-1 gene expression correlated with both IAF and SQF and with decreased S(I). With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11beta-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11beta-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.

Hot flashes and estrogen therapy do not influence cognition in early menopausal women

Objective: To examine how menopausal symptoms and estrogen therapy (ET)-induced symptom relief affect cognition in early menopause. Design:: There were two components. Part 1 was a cross-sectional study of 37 healthy, recently postmenopausal women with diverse menopausal symptoms. Women were categorized as having low (n = 20) or high symptoms (n = 17) based on a validated symptom questionnaire. Women completed mood and sleep questionnaires and underwent cognitive testing, which included verbal memory, visual memory, emotional memory, and verbal fluency. Thirty-two of these women went on to part 2 of the study. Fourteen were randomly assigned to receive ET and 18 to receive placebo for 8 weeks. Before treatment and at 4 and 8 weeks, women completed the same measures as in part 1 of the study. Results: High symptom women had more negative mood (P = 0.01) and lower quality sleep (P < 0.001) than low symptom women. Despite suffering from more menopausal symptoms, worse mood, and poorer sleep, women in the high symptom group performed the same on cognitive testing as women in the low symptom group. Women receiving ET had greater improvements in menopausal symptoms and sleep compared with those receiving the placebo (P ≤ 0.05). ET did not improve mood compared with placebo. Women receiving ET did not have any improvement in cognitive performance compared with those receiving the placebo. Conclusions: Menopausal symptoms do not impair cognition. ET does not improve cognition despite alleviating symptoms and improving sleep in recently naturally menopausal women with diverse menopausal symptoms.

Efficacy of Nodal Dissection for Treatment of Persistent/Recurrent Papillary Thyroid Cancer†

Context: Although commonly performed, data are lacking regarding efficacy and safety of lymph node dissection (LND) for recurrent/persistent papillary thyroid cancer (PTC).

Cognitive function in untreated hypothyroidism and hyperthyroidism.

Purpose of reviewThe brain is an important target organ for thyroid hormone, and alterations in mood and cognition may occur with thyroid dysfunction. Recent advances in the field of cognitive neurosciences have allowed more sensitive and focused testing of cognitive domains in patients with altered thyroid function. Recent findingsBased on recent population-based studies, there do not appear to be major deficits in cognitive functioning in overt or subclinical thyroid disease. However, interventional and functional imaging studies suggest that subtle deficits in specific cognitive domains probably do exist. The most commonly affected domains are working memory and executive function. Also present are alterations in mood, manifested by increased rates of depressive and anxiety symptoms. SummaryPatients with overt or subclinical thyroid dysfunction commonly complain of decrements in cognitive function, but studies suggest that such decrements are most likely to be minor or not related to the thyroid dysfunction. More common are mood alterations, which often improve with treatment.

Perioperative parathyroid hormone levels in thyroid surgery

Objective: Perioperative hypocalcemia from temporary parathyroid gland dysfunction is common after thyroid surgery. No reliable cutoff values for parathyroid hormone (PTH) and the subsequent possibility of developing hypocalcemia exist. The purpose of this study is to determine a criterion for predicting hypocalcemia based on different PTH levels as cutoff values.

Thyroid Function and Mortality in Older Men: A Prospective Study

CONTEXT Mild abnormalities of thyroid function have been associated with both beneficial and detrimental effects on mortality. OBJECTIVE Our objective was to determine the association between continuous TSH as well as categories of thyroid function with total and cause-specific mortality in a cohort of older men. DESIGN, SETTING, AND PARTICIPANTS Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community-dwelling U.S. men aged 65 yr and older. A total of 1587 participants randomly selected for thyroid function testing were included in this analysis. TSH and free T4 were measured at baseline, and four categories of thyroid function were defined. (subclinical hyperthyroid; euthyroid; subclinical hypothyroid TSH<10 mIU/liter; and subclinical hypothyroid, TSH≥10 mIU/liter.) MAIN OUTCOME MEASURE Total mortality, cardiovascular (CV) and cancer deaths were confirmed by review of death certificates. RESULTS There were 432 deaths over a mean follow-up of 8.3 yr. In fully adjusted models, there was no association between baseline TSH and any death [relative hazard (RH)=1.01 per mIU/liter, 95% confidence interval (CI)=0.95-1.06], CV death (RH=1.05 per mIU/liter, 95% CI 0.96-1.15), or cancer death (RH=0.96 per mIU/liter, 95% CI=0.85-1.07). There was also no statistically significant association between thyroid function category and total or cause-specific mortality, but few men (n=8) had subclinical hypothyroidism with TSH levels of 10 mIU/liter or higher. CONCLUSIONS A single measurement of thyroid function did not predict total or cause-specific mortality in this cohort. These data support neither a beneficial nor a detrimental effect of subclinical thyroid dysfunction in older men. SUMMARY Subclinical thyroid dysfunction is not associated with an increased risk of all-cause or CV mortality in older men.

Cognition Is Not Modified by Large but Temporary Changes in Sex Hormones in Men

CONTEXT Little is known about the role of testosterone and estradiol on cognition in healthy older men. OBJECTIVE The cognitive effects of increasing or lowering testosterone or estradiol were examined. DESIGN Cognition was assessed before and after 6 wk of double-blind placebo-controlled hormone modification. SETTING The study was conducted at an academic medical center. PARTICIPANTS Healthy older (ages 60-80 yr) and younger men (ages 25-35 yr) were recruited from the community. INTERVENTION Men were randomized to one of four treatments: 1) maintain testosterone and estradiol at eugonadal levels for young men (GnRH agonist + testosterone gel); 2) block testosterones conversion to estradiol (GnRH agonist + testosterone gel + aromatase inhibitor); 3) induce hypogonadism (GnRH agonist alone); and 4) all placebo. MAIN OUTCOME MEASURES Measures of executive function, memory, and spatial cognition were obtained before and after treatment. Hormone levels were obtained 10 times over the course of the study. RESULTS Counter to expectations, hormone treatment did not affect cognition (P > 0.10). Free testosterone was positively related to spatial cognition in older men after treatment and controlling for age and estradiol level or exclusion of the hypogonadal men (P = 0.02). Estradiol was negatively associated with working memory controlling for the same variables (P = 0.01). Blinding to treatment assignment was maintained, with the exception of the hypogonadal group. CONCLUSIONS A significant change in sex hormone status, including complete hypogonadism, does not modify cognition in men. These findings, along with studies that show a risk for neurodegenerative disease in those with low testosterone, suggest that sex hormone status may be important for neuroprotection in aging but not modulation of normal day-to-day cognitive function.

Cortisol production rate measurement by stable isotope dilution using gas chromatography-negative ion chemical ionization mass spectrometry.

Presented here is a stable isotope dilution technique for determining cortisol production rate (CPR). The method involves extraction and derivatization of cortisol isoforms from serum (0.5 ml), separation of derivatives by gas chromatography, and detection by using negative ion chemical ionization mass spectrometry. This method provides 50-100-fold greater sensitivity than positive ion mass spectrometry and allows for estimations of cortisol production rate with the use of small amounts of pooled serum, even in the presence of high concentrations of lipophilic contaminants. The area under the curve for the total selected ion chromatogram of fluoroacyl derivatives of cortisol (d0, m/z 782) and deuterated cortisol (d3, m/z 785) were used to determine the isotopic dilution ratio in three types of samples: 1) standards: d0/d3 ratios ranging from 1 to 8%; 2) controls: d3-cortisol added to serum with known cortisol concentration; 3) subjects: 24-h pooled serum samples (q 30 min over 24 h) from healthy children (male 10-13 years; female 7-11 years) receiving continuous infusions of d3-cortisol at 2-4% of their estimated CPR. Recovery after the solid phase extraction and derivatization process was >90%, as determined by thin-layer chromatography. Expected versus measured ratios for d3/d0 in standards and serum controls were highly correlated (r2(standard) = 0.99; r2(control) = 0.99) over a wide range of d3-cortisol enrichment (1.0-10.0%). Mean 24-h CPRs were 4.8 +/- 0.6 mg/m2/24 h (mean +/- SEM, n = 7) in male children and 4.4 +/- 0.5 mg/m2/24 h in female children (n = 4). These CPR values are lower than those derived by radio tracer methods, but are in agreement with previous isotopic dilution studies. This technique is an important tool for assessing CPRs in a wide range of disease states affecting cortisol production.

Extensions, Validation, and Clinical Applications of a Feedback Control System Simulator of the Hypothalamo-Pituitary-Thyroid Axis

BACKGROUND We upgraded our recent feedback control system (FBCS) simulation model of human thyroid hormone (TH) regulation to include explicit representation of hypothalamic and pituitary dynamics, and updated TH distribution and elimination (D&E) parameters. This new model greatly expands the range of clinical and basic science scenarios explorable by computer simulation. METHODS We quantified the model from pharmacokinetic (PK) and physiological human data and validated it comparatively against several independent clinical data sets. We then explored three contemporary clinical issues with the new model: combined triiodothyronine (T(3))/thyroxine (T(4)) versus T(4)-only treatment, parenteral levothyroxine (L-T(4)) administration, and central hypothyroidism. RESULTS Combined T(3)/T(4) therapy--In thyroidectomized patients, the L-T(4)-only replacement doses needed to normalize plasma T(3) or average tissue T(3) were 145 microg L-T(4)/day or 165 microg L-T(4)/day, respectively. The combined T(4) + T(3) dosing needed to normalize both plasma and tissue T(3) levels was 105 microg L-T(4) + 9 microg T(3) per day. For all three regimens, simulated mean steady-state plasma thyroid-stimulating hormone (TSH), T(3), and T(4) was within normal ranges (TSH: 0.5-5 mU/L; T(4): 5-12 microg/dL; T(3): 0.8-1.9 ng/mL). Parenteral T(4) administration--800 microg weekly or 400 microg twice weekly normalized average tissue T(3) levels both for subcutaneous (SC) and intramuscular (IM) routes of administration. TSH, T(3), and T(4) levels were maintained within normal ranges for all four of these dosing schemes (1x vs. 2x weekly, SC vs. IM). Central hypothyroidism--We simulated steady-state plasma T(3), T(4), and TSH concentrations in response to varying degrees of central hypothyroidism, reducing TSH secretion from 50% down to 0.1% of normal. Surprisingly, TSH, T(3), and T(4) plasma concentrations remained within normal ranges for TSH secretion as low as 25% of normal. CONCLUSIONS Combined T(3)/T(4) treatment--Simulated standard L-T(4)-only therapy was sufficient to renormalize average tissue T(3) levels and maintain normal TSH, T(3), and T(4) plasma levels, supporting adequacy of standard L-T(4)-only treatment. Parenteral T(4) administration-TSH, T(3), and T(4) levels were maintained within normal ranges for all four of these dosing schemes (1x vs. 2x weekly, SC vs. IM), supporting these therapeutic alternatives for patients with compromised L-T(4) gut absorption. Central hypothyroidism--These results highlight how highly nonlinear feedback in the hypothalamic-pituitary-thyroid axis acts to maintain normal hormone levels, even with severely reduced TSH secretion.

A prospective study of thyroid function, bone loss, and fractures in older men: The MrOS study

Excess thyroid hormone is associated with increased bone loss and fracture risk in older women, but few data exist for men. We sought to determine if thyroid function is independently associated with bone loss and fracture risk in older men. Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community‐dwelling U.S. men aged 65 years and older. Using a case‐cohort design, fasting baseline serum archived at −80°C was assayed for thyroid‐stimulating hormone (thyrotropin) (TSH) and free thyroxine (FT4) in 397 men with confirmed nonspine fracture, including 157 hip fractures, and 1420 randomly selected men without fracture. TSH and FT4 were analyzed as continuous variables and as thyroid function categories (subclinical hyperthyroid, euthyroid, and subclinical hypothyroid). Hip dual‐energy X‐ray absorptiometry (DXA) (Hologic QDR4500) was measured at baseline and after a mean follow‐up of 4.6 years. Incident nonspine fractures were centrally adjudicated. Bone loss was evaluated with multivariate regression methods and fractures risk was evaluated using hazard models that accounted for the case‐cohort sampling, adjusted for age, clinic‐site, body mass index (BMI), race, physical activity, corticosteroid use, smoking, alcohol intake, and thyroid medication use. In fully adjusted analyses, TSH was not associated with risk of nonspine fracture (relative hazard [RH] 0.92 per SD decrease in TSH; 95% confidence interval [CI], 0.74–1.14), but was significantly associated with risk of hip fracture (RH 1.31; 95% CI, 1.01–1.71), which persisted among normal range TSH values (RH 1.21; 95% CI, 1.00–1.47). There was no association between TSH or FT4 and bone loss, and fracture risk did not differ significantly by thyroid function category. We conclude that although neither TSH nor FT4 are associated with bone loss, lower serum TSH may be associated with an increased risk of hip fractures in older men.