Showing papers in "The Journal of Clinical Endocrinology and Metabolism in 2005"
TL;DR: The findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures, and the need for increased awareness and monitoring.
Abstract: Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces. Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.
1,344 citations
TL;DR: HR-pQCT appears promising to assess bone density and microarchitecture at peripheral sites in terms of reproducibility and ability to detect age- and disease-related changes.
Abstract: Context: Assessment of trabecular microarchitecture may enhance the prediction of fracture risk and improve monitoring of treatment response. A new high-resolution peripheral quantitative computed tomography (HR-pQCT) system permits in vivo assessment of trabecular architecture and volumetric bone mineral density (BMD) at the distal radius and tibia with a voxel size of 82 μm3. Objective and Patients: We determined the short-term reproducibility of this device by measuring 15 healthy volunteers three times each. We compared HR-pQCT measurements in 108 healthy premenopausal, 113 postmenopausal osteopenic, and 35 postmenopausal osteoporotic women. Furthermore, we compared values in postmenopausal osteopenic women with (n = 35) and without previous fracture history (n = 78). Design and Setting: We conducted a cross-sectional study in a private clinical research center. Intervention and Main Outcome Measure: We took HR-pQCT measurements of the radius and tibia. Femoral neck and spine BMD were measured in post...
1,124 citations
TL;DR: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated.
Abstract: Background: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also. Methods: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteoporosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment. Findings: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P = 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P = 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture ( age >= 74 yr and femoral neck bone mineral density T score <=-3, corresponding to -2.4 according to NHANES reference) (n = 1977), the RR reduction for hip fracture was 36% (P = 0.046). RR of vertebral fractures was reduced by 39% (P < 0.001) in the 3640 patients with spinal x-rays and by 45% in the subgroup without prevalent vertebral fracture. Strontium ranelate increased bone mineral density throughout the study, reaching at 3 yr (P < 0.001): +8.2% (femoral neck) and +9.8% (total hip). Incidence of adverse events (AEs) was similar in both groups. Conclusion: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated. It confirms that strontium ranelate reduces vertebral fractures. Strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.
1,072 citations
TL;DR: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence, and may be a useful molecular marker to assist in risk stratification for patients withPTC.
Abstract: Context: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. Objective: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. Design, Setting, and Subjects: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. Main Outcome Measure: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. Results: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjus...
919 citations
TL;DR: It is reported that serum androgen levels decline steeply in the early reproductive years and do not vary because of natural menopause and that the postmenopausal ovary appears to be an ongoing site of testosterone production.
Abstract: Context: Changes in androgen levels across the adult female life spanandtheeffectsofnaturalmenopauseandoophorectomyhavenot been clearly established. Objective: The objective of this study was to document the effects of age on androgen levels in healthy women and to explore the effects of natural and surgical menopause. Design, Setting, and Participants: A cross-sectional study was conducted of 1423 non-healthcare-seeking women, aged 18–75 yr, randomly recruited from the community over 15 months. Main Outcome Measures: Serum levels by age of total testosterone (T), calculated free T, dehydroepiandrosterone sulfate, and androstenedione in a reference group of women free of confounding factors. Women in the reference group had no usage of exogenous steroid therapy; no history of tubal ligation, hysterectomy, or bilateral oophorectomy; and no hyperprolactinemia or polycystic ovarian syndrome. The effects of natural and surgical menopause on sex steroid levels were also examined. Results:Inthereferencepopulation(n595),totalT,calculatedfree T, dehydroepiandrosterone sulfate, and androstenedione declined steeply with age (P 0.001), with the decline of each being greater in the earlier than the later decades. Examination of serum androgen levels by year in women aged 45–54 yr showed no independent effect of menopausal status on androgen levels. In women aged 55 yr or older, those who reported bilateral oophorectomy and were not on exogenous steroids had significantly lower total T and free T levels than women 55 yr or older in the reference group. Conclusions: We report that serum androgen levels decline steeply intheearlyreproductiveyearsanddonotvarybecauseaconsequence of natural menopause and that the postmenopausal ovary appears to be an ongoing site of testosterone production. These significant variationsinandrogenswithagemustbetakenintoaccountwhennormal ranges are reported and in studies of the role of androgens in women. (J Clin Endocrinol Metab 90: 3847–3853, 2005)
855 citations
TL;DR: It is concluded that the MBS and its components are common in women with PCOS, placing them at increased risk for cardiovascular disease and different features that may reflect more severe insulin resistance.
Abstract: The polycystic ovary syndrome (PCOS) is characterized by insulin resistance with compensatory hyperinsulinemia. Insulin resistance also plays a role in the metabolic syndrome (MBS). We hypothesized that the MBS is prevalent in PCOS and that women with both conditions would present with more hyperandrogenism and menstrual cycle irregularity than women with PCOS only. We conducted a retrospective chart review of all women with PCOS seen over a 3-yr period at an endocrinology clinic. Of the 161 PCOS cases reviewed, 106 met the inclusion criteria. The women were divided into two groups: 1) women with PCOS and the MBS (n = 46); and 2) women with PCOS lacking the MBS (n = 60). Prevalence of the MBS was 43%, nearly 2-fold higher than that reported for age-matched women in the general population. Women with PCOS had persistently higher prevalence rates of the MBS than women in the general population, regardless of matched age and body mass index ranges. Acanthosis nigricans was more frequent in women with PCOS and the MBS. Women with PCOS and the MBS had significantly higher levels of serum free testosterone (P = 0.002) and lower levels of serum SHBG (P = 0.001) than women with PCOS without the MBS. No differences in total testosterone were observed between the groups. We conclude that the MBS and its components are common in women with PCOS, placing them at increased risk for cardiovascular disease. Women with PCOS and the MBS differ from their counterparts lacking the MBS in terms of increased hyperandrogenemia, lower serum SHBG, and higher prevalence of acanthosis nigricans, all features that may reflect more severe insulin resistance.
845 citations
TL;DR: The findings-that the sensitivity of the human alerting response to light and its thermoregulatory sequelae are blue-shifted relative to the three-cone visual photopic system-indicate an additional role for these novel photoreceptors in modifying human alertness, thermophysiology, and heart rate.
Abstract: Light can elicit acute physiological and alerting responses in humans, the magnitude of which depends on the timing, intensity, and duration of light exposure. Here, we report that the alerting response of light as well as its effects on thermoregulation and heart rate are also wavelength dependent. Exposure to 2 h of monochromatic light at 460 nm in the late evening induced a significantly greater melatonin suppression than occurred with 550-nm monochromatic light, concomitant with a significantly greater alerting response and increased core body temperature and heart rate ( approximately 2.8 x 10(13) photons/cm(2)/sec for each light treatment). Light diminished the distal-proximal skin temperature gradient, a measure of the degree of vasoconstriction, independent of wavelength. Nonclassical ocular photoreceptors with peak sensitivity around 460 nm have been found to regulate circadian rhythm function as measured by melatonin suppression and phase shifting. Our findings-that the sensitivity of the human alerting response to light and its thermoregulatory sequelae are blue-shifted relative to the three-cone visual photopic system-indicate an additional role for these novel photoreceptors in modifying human alertness, thermophysiology, and heart rate.
787 citations
TL;DR: Prevalence of suboptimal 25(OH)D was significantly higher in subjects who took less than 400 vs. 400 IU/d or more vitamin D, and there was a significant negative correlation between serum PTH concentrations and 25( OH)D.
Abstract: Purpose: To evaluate serum 25-hydroxyvitamin D [25(OH)D] concentrations and factors related to vitamin D inadequacy in postmenopausal North American women receiving therapy to treat or prevent osteoporosis. Methods: Serum 25(OH)D and PTH were obtained in 1536 community-dwelling women between November 2003 and March 2004. Multivariate logistic regression was used to assess risk factors for suboptimal (<30 ng/ml) 25(OH)D. Results: Ninety-two percent of study subjects were Caucasian, with a mean age of 71 yr. Thirty-five percent resided at or above latitude 42° north, and 24% resided less than 35° north. Mean (sd) serum 25(OH)D was 30.4 (13.2) ng/ml: serum 25(OH)D was less than 20 ng/ml in 18%; less than 25 ng/ml in 36%; and less than 30 ng/ml in 52%. Prevalence of suboptimal 25(OH)D was significantly higher in subjects who took less than 400 vs. 400 IU/d or more vitamin D. There was a significant negative correlation between serum PTH concentrations and 25(OH)D. Risk factors related to vitamin D inadequacy ...
765 citations
TL;DR: The potential role of CRH in circadian-dependent alerting, aside from its role in the stress response, is discussed, as is the role the HPA axis plays in secondary effects of primary sleep disorders.
Abstract: The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid receptor, or mineralocorticoid receptor) can disrupt sleep. Herein, we review normal sleep, normal HPA axis physiology and circadian rhythm, the effects of the HPA axis on sleep, as well as the effects of sleep on the HPA axis. We also discuss the potential role of CRH in circadian-dependent alerting, aside from its role in the stress response. Two clinically relevant sleep disorders with likely HPA axis dysfunction, insomnia and obstructive sleep apnea, are discussed. In insomnia, we discuss how HPA axis hyperactivity may be partially causal to the clinical syndrome. In obstructive sleep apnea, we discuss how HPA axis hyperactivity may be a consequence of the disorder and contribute to secondary pathology such as insulin resistance, hypertension, depression, and insomnia. Mechanisms by which cortisol can affect slow wave sleep are discussed, as is the role the HPA axis plays in secondary effects of primary sleep disorders.
742 citations
TL;DR: The results suggest that thyroid function could be one of several factors acting in concert to determine body weight in a population and even slightly elevated serum TSH levels are associated with an increase in the occurrence of obesity.
Abstract: Context: Increasing prevalence of overweight in the population is a major concern globally; and in the United States, nearly one third of adults were classified as obese at the end of the 20th century. Few data have been presented regarding an association between variations in thyroid function seen in the general population and body weight. Objective: The aim of this study was to investigate the association between thyroid function and body mass index (BMI) or obesity in a normal population. Design: A cross-sectional population study (The DanThyr Study) was conducted. Participants: In all, 4649 participants were investigated, and 4082 were eligible for these analyses after exclusion of subjects with previous or present overt thyroid dysfunction. Main Outcome Measures: The study examined the association between category of serum TSH or serum thyroid hormones and BMI or obesity in multivariate models, adjusting for possible confounding. Results: We found a positive association between BMI and category of se...
676 citations
TL;DR: In this paper, the association of adiposity with serum 25-hydroxyvitamin D (25-OH-D) and serum PTH levels in a large population-based study including older men and women was assessed.
Abstract: Objective: In small case-control studies, obesity was associated with worse vitamin D status. Our aim was to assess the association of adiposity (anthropometric measures as well as dual energy x-ray absorptiometry) with serum 25-hydroxyvitamin D (25-OH-D) and serum PTH levels in a large population-based study including older men and women. Methods: Subjects were participants of the Longitudinal Aging Study Amsterdam and were aged 65 yr and older. In 453 participants, serum 25-OH-D and PTH were determined, and body mass index, waist circumference, waist to hip ratio, sum of skin folds, and total body fat percentage by dual energy x-ray absorptiometry were measured. Results: After adjustment for potential confounders, higher body mass index, waist circumference, and sum of skin folds were statistically significantly associated with lower 25-OH-D (standardized β values were −0.136, −0.137, and −0.140, respectively; all P < 0.05) and with higher PTH (0.166, 0.113, and 0.114, respectively; all P < 0.05). Total...
TL;DR: It appears that the presence of EDS is more strongly associated with depression and metabolic factors than with sleep-disordered breathing or sleep disruption per se, and patients with a complaint of E DS should be thoroughly assessed for depression and obesity/diabetes independent of whether sleep- disordered breathing is present.
Abstract: Design and Setting: We examined this question in the Penn State cohort (a random sample of 16,583 men and women from central Pennsylvania, ranging in age from 20 to 100 yr) A random subset of thiscohort(n1,741)wasfurtherevaluatedforonenightinthesleep laboratory Main Outcome Measure: The main measure was a complaint of EDS Results: The final logistic regression model indicated depression was the most significant risk factor for EDS followed by body mass index, age, typical sleep duration, diabetes, smoking, and finally sleep apnea The strength of the association with EDS decreased with increasing age, whereas the association of depression with EDS was stronger in the young EDS is more prevalent in the young (30 yr), suggesting the presence of unmet sleep needs and depression, and in theveryold(75yr),suggestingincreasingmedicalillnessandhealth problems EDS was associated with a reduced report of typical sleep duration without any association with objective polysomnographic measures Conclusions: It appears that the presence of EDS is more strongly associated with depression and metabolic factors than with sleepdisordered breathing or sleep disruption per se Our findings suggest that patients with a complaint of EDS should be thoroughly assessed for depression and obesity/diabetes independent of whether sleepdisordered breathing is present (J Clin Endocrinol Metab 90: 4510–4515, 2005)
TL;DR: The data suggest that effects of maternal PTSD related to cortisol can be observed very early in the life of the offspring and underscore the relevance of in utero contributors to putative biological risk for PTSD.
Abstract: Context: Reduced cortisol levels have been linked with vulnerability to posttraumatic stress disorder (PTSD) and the risk factor of parental PTSD in adult offspring of Holocaust survivors. Objective: The purpose of this study was to report on the relationship between maternal PTSD symptoms and salivary cortisol levels in infants of mothers directly exposed to the World Trade Center collapse on September 11, 2001 during pregnancy. Design: Mothers (n = 38) collected salivary cortisol samples from themselves and their 1-yr-old babies at awakening and at bedtime. Results: Lower cortisol levels were observed in both mothers (F = 5.15, df = 1, 34; P = 0.030) and babies of mothers (F = 8.0, df = 1, 29; P = 0.008) who developed PTSD in response to September 11 compared with mothers who did not develop PTSD and their babies. Lower cortisol levels were most apparent in babies born to mothers with PTSD exposed in their third trimesters. Conclusions: The data suggest that effects of maternal PTSD related to cortisol ...
TL;DR: IPSS best identifies EAS and although only 47% achieved cure, survival is good except in patients with small-cell lung cancer, medullary thyroid cancer, and gastrinoma.
Abstract: Context: Ectopic ACTH secretion (EAS) is difficult to diagnose and treat. We present our experience with EAS from 1983 to 2004. Setting: The study was performed at a tertiary care clinical research center. Patients: Ninety patients, aged 8–72 yr, including 48 females were included in the study. Interventions and Outcome Measures: Tests included 8 mg dexamethasone suppression, CRH stimulation, inferior petrosal sinus sampling (IPSS), computed tomography, octreotide scan, magnetic resonance imaging, and/or venous sampling. Therapies, pathological examinations, and survival were noted. Results: Eighty-six to 94% of patients did not respond to CRH or dexamethasone suppression, whereas 66 of 67 had negative IPSS. To control hypercortisolism, 62 patients received medical treatment, and 33 had bilateral adrenalectomy. Imaging localized tumors in 67 of 90 patients. Surgery confirmed an ACTH-secreting tumor in 59 of 66 patients and cured 65%. Nonthymic carcinoids took longest to localize. Deaths included three of ...
TL;DR: Kisspeptin-54 infusion significantly increased plasma LH, FSH, and testosterone concentrations compared with saline infusion and was designed to determine the effects of elevating circulating kisspeptin levels on LH,FSH,and testosterone in male volunteers.
Abstract: Context: Mutation of the G protein-coupled receptor 54 is associated with a failure of reproductive function. The endogenous neuropeptide agonist for G protein-coupled receptor 54, kisspeptin, potently stimulates the hypothalamic-pituitary-gonadal axis in rodents and primates. Objective: The present study was designed to determine the effects of elevating circulating kisspeptin levels on LH, FSH, and testosterone in male volunteers. Design: This was a double-blind, placebo-controlled, crossover study. Setting: This was a hospital-based study. Participants: Male volunteers (n = 6) were recruited. Interventions: Each volunteer received a 90-min iv infusion of kisspeptin-54 (4 pmol/kg·min) and a control infusion of saline (0.9%) in random order. Main Outcome Measure: Plasma LH, FSH, and testosterone concentrations were measured. Results: Kisspeptin-54 infusion significantly increased plasma LH, FSH, and testosterone concentrations compared with saline infusion (mean 90-min LH: kisspeptin, 10.8 ± 1.5 vs. sali...
TL;DR: The findings call attention to the many older women who suffer hip fracture but do not have particularly low antecedent BMD measures and help begin to identify risk factors associated with higher bone density levels.
Abstract: The proportion of fractures that occur in women without osteoporosis has not been fully described, and the characteristics of nonosteoporotic women who fracture are not well understood. We measured total hip bone mineral density (BMD) and baseline characteristics including physical activity, falls, and strength for 8065 women aged 65 yr or older participating in the Study of Osteoporotic Fractures and then followed these women for hip fracture for up to 5 yr after BMD measurement. Among all participants, 17% had osteoporosis (total hip BMD T-score < or = -2.5). Of the 243 women with incident hip fracture, 54% were not osteoporotic at start of follow-up. Nonosteoporotic women who fractured were less likely than osteoporotic women with fracture to have baseline characteristics associated with frailty. Nevertheless, among nonosteoporotic participants, several characteristics increased fracture risk, including advancing age, lack of exercise in the last year, reduced visual contrast sensitivity, falls in the last year, prevalent vertebral fracture, and lower total hip BMD. These findings call attention to the many older women who suffer hip fracture but do not have particularly low antecedent BMD measures and help begin to identify risk factors associated with higher bone density levels.
TL;DR: It is indicated that postmenopausal women displaying the MHO phenotype also have a favorable inflammation profile as shown by lower CRP and alpha-1 antitrypsin levels compared with insulin-resistant women, which suggests that a lower inflammation state, as attested by low CRP levels, could play a role in the protective profile of theMHO individual.
Abstract: 4.8 vs. 45.5 4.4%; not significant), MHO individuals had significantly lower levels of visceral fat, fasting insulin, plasma triglycerides, high-sensitivity C-reactive protein (CRP), and -1 antitrypsin levels and higher levels of high-density lipoprotein cholesterol than at risk individuals (P 0.05). Stepwise regression analysis showed that CRP, fasting triglycerides, and the lean body mass index explained 19.5, 8.5, and 4.0%, respectively, of the variance observed in glucose disposal (total r 2 0.320; P 0.001) Conclusion: Results of the present study indicate that postmenopausal women displaying the MHO phenotype also have a favorable inflammation profile as shown by lower CRP and -1 antitrypsin levels compared with insulin-resistant women. This suggests that a lower inflammation state, as attested by low CRP levels, could play a role in the protective profile of the MHO individual, and this may be associated metabolically to a lower risk for cardiovascular disease. (J Clin Endocrinol Metab 90: 4145–4150, 2005)
TL;DR: MCP-1 is correlated with specific macrophage markers, adiposity, and AT localization, but the relationship seems to be related to the number of AT-resident macrophages, which suggests that these antidiabetic compounds have antiinflammatory properties improving the low-grade inflammatory state observed in obesity.
Abstract: Human adipose tissue (AT) produces several adipokines including monocyte chemoattractant protein (MCP)-1, involved in the pathogenesis of atherosclerosis. Objective: Human AT cultures, isolated adipocytes, and stromal-vascular cells were used to investigate the relationship among AT-resident macrophages, MCP-1, and adiposity and the regulation of MCP-1. Results: mRNA levels of specific macrophage markers (CD68 and CD14) are correlated with adiposity in sc AT and visceral AT (P < 0.05). MCP-1 production is higher in stromal-vascular cells vs. adipocytes (P < 0.01) and correlates with macrophage markers in both AT compartments (P < 0.05). MCP-1 release is higher in obese subjects (P < 0.05) and in VAT (P < 0.01), but after adjusting for AT-resident macrophages, the differences disappear. MCP-1 is stimulated by IL-1β, TNF-α, IL-8, IL-4, and IL-6 + IL-6-soluble receptor and is decreased by dexamethasone, IL-10, metformin, and thiazolidinediones. Discussion: MCP-1 is correlated with specific macrophage markers...
TL;DR: It is demonstrated that T therapy in older men with low serum T improves physical performance and strength over 36 months, when administered alone or when combined with F, and suggested that high serum levels of dihydrotestosterone are not essential for these beneficial effects of T in men.
Abstract: Testosterone (T) therapy in older men with low serum T levels increases lean body mass and decreases fat mass. These changes might improve physical performance and strength; however, it has not been established whether T therapy improves functional outcome in older men. Moreover, concerns exist about the impact of T therapy on the prostate in older men. The administration of finasteride (F), which partially blocks the conversion of T to the more potent androgen, dihydrotestosterone, attenuates the impact of T replacement on prostate size and prostate-specific antigen. We hypothesized that T replacement in older, hypogonadal men would improve physical function and that the addition of F to this regimen would continue to provide the T-induced improvements in physical performance, strength, and body composition. Seventy men with low serum T (<350 ng/dl), age 65 yr and older, were randomly assigned to receive one of three regimens for 36 months: 1) T enanthate, 200 mg im every 2 wk, with placebo pills daily (...
TL;DR: An excellent survival rate is highlighted and risk classifications of persistent and recurrent disease based on the numbers of LN metastases and ECE-LN, LN Metastases location, tumor size, and thyroglobulin level are suggested.
Abstract: Context: Reliable prognostic factors are needed in papillary thyroid cancer patients to adapt initial therapy and follow-up schemes to the risks of persistent and recurrent disease. Objective and Settings: To evaluate the respective prognostic impact of the extent of lymph node (LN) involvement and tumor extension beyond the thyroid capsule, we studied a group of 148 consecutive papillary thyroid cancer patients with LN metastases and/or extrathyroidal tumor extension. Initial treatment, performed at the Institut Gustave Roussy between 1987 and 1997, included in all patients a total thyroidectomy with central and ipsilateral en bloc neck dissection followed by radioactive iodine ablation. Results: Uptake outside the thyroid bed, demonstrating persistent disease, was found on the postablation total body scan (TBS) in 22% of the patients. With a mean follow-up of 8 yr, eight patients (7%) with a normal postablation TBS experienced a recurrence. Ten-year disease-specific survival rate was 99% (confidence int...
TL;DR: F GF-23 was inversely related to renal Pi transport and serum calcitriol levels in healthy young men, suggesting that FGF-23 may be implicated in the physiological regulation of Pi homeostasis in response to dietary phosphate changes, independent of PTH.
Abstract: The renal handling of inorganic phosphate (Pi) is controlled not only by PTH, but also by hitherto undetermined mechanisms dependent on phosphate intake. Recently, fibroblast growth factor (FGF)-23 was identified as a novel phosphaturic factor in tumor-induced osteomalacia and autosomal-dominant hypophosphatemic rickets. We hypothesized that phosphate intake could influence FGF-23 concomitantly to the changes in renal Pi handling. Twenty-nine healthy males were subjected to a 5-d low-phosphate diet and a phosphate binder, followed by a high-phosphate diet including supplements. Concomitant modifications in calcium intake allowed minimizing PTH changes in response to dietary phosphate. Serum FGF-23 levels significantly decreased on the low-phosphate diet, then increased with the oral phosphate load. Changes in FGF-23 were positively correlated with changes in 24-h urinary Pi excretion and negatively correlated with changes in the maximal tubular reabsorption of Pi and 1,25(OH)(2)D(3) (calcitriol), whereas PTH was not. In multivariate analysis, changes in FGF-23 remained the most significantly correlated to changes in 1,25(OH)(2)D(3) and maximal tubular reabsorption of Pi. Moreover, FGF-23 was positively correlated to serum osteocalcin, a marker of osteoblastic activity. In summary, FGF-23 was inversely related to renal Pi transport and serum calcitriol levels in healthy young men. These data suggest that FGF-23 may be implicated in the physiological regulation of Pi homeostasis in response to dietary phosphate changes, independent of PTH.
TL;DR: Throughout the glucose tolerance range, dynamic parameters of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) and insulin sensitivity are independent determinants of 2-h plasma glucose levels.
Abstract: The nature of the progressive beta-cell failure occurring as normal glucose tolerant (NGT) individuals progress to type 2 diabetes (T2DM) is incompletely understood. We measured insulin sensitivity (by a euglycemic insulin clamp) and insulin secretion rate (by deconvolution of plasma C-peptide levels during an oral glucose tolerance test) in 188 subjects [19 lean NGT (body mass index [BMI]
Journal Article•
TL;DR: In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.
Abstract: In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.
TL;DR: It is concluded that insulin resistance is associated with a decrease in Leydig cell T secretion in men with a spectrum of insulin sensitivity.
Abstract: Insulin resistance is associated with low testosterone (T) levels in men, the mechanism of which is unclear. Thus, the aim of this study was to evaluate the hypothalamic-pituitary-gonadal axis in men with a spectrum of insulin sensitivity. Twenty-one men (aged 25-65 yr) had a glucose tolerance test and assessment of insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Insulin sensitivity, expressed as the M value (milligrams per kilograms(-1) per minute(-1)), was calculated from the glucose disposal rate during the final 30 min of the clamp. Eighteen subjects had blood sampling every 10 min for 12 h to assess LH pulsatility. Hypogonadism was then induced with a GnRH antagonist, followed by sequential stimulation testing with GnRH (750 ng/kg, iv) and human chorionic gonadotropin (hCG; 1000 IU, im) to assess pituitary and testicular responsiveness, respectively. Nine subjects had normal glucose tolerance, nine had impaired glucose tolerance, and three had diabetes mellitus. There was a positive relationship between M and T levels (r = 0.46; P < 0.05). No relationship was seen between M and parameters of LH secretion, including mean LH levels, LH pulse amplitude, LH pulse frequency, and LH response to exogenous GnRH administration. In contrast, a strong correlation was observed between M and the T response to hCG (r = 0.73; P < 0.005). Baseline T levels correlated with the increase in T after hCG administration (r = 0.47; P < 0.05). During the clamp, T levels increased from a baseline level of 367 +/- 30 to 419 +/- 38 ng/dl during the last 30 min (P < 0.05). From these data we conclude that insulin resistance is associated with a decrease in Leydig cell T secretion in men. Additional studies are required to determine the mechanism of this effect.
TL;DR: Older men are as responsive as young men to testosterone's anabolic effects; however, older men have lower testosterone clearance rates, higher increments in hemoglobin, and a higher frequency of adverse effects.
Abstract: Although testosterone levels and muscle mass decline with age, many older men have serum testosterone level in the normal range, leading to speculation about whether older men are less sensitive to testosterone. We determined the responsiveness of androgen-dependent outcomes to graded testosterone doses in older men and compared it to that in young men. The participants in this randomized, double-blind trial were 60 ambulatory, healthy, older men, 60–75 yr of age, who had normal serum testosterone levels. Their responses to graded doses of testosterone were compared with previous data in 61 men, 19–35 yr old. The participants received a long-acting GnRH agonist to suppress endogenous testosterone production and 25, 50, 125, 300, or 600 mg testosterone enanthate weekly for 20 wk. Fat-free mass, fat mass, muscle strength, sexual function, mood, visuospatial cognition, hormone levels, and safety measures were evaluated before, during, and after treatment. Of 60 older men who were randomized, 52 completed the...
TL;DR: Higher testosterone and SHBG levels in aging males are independently associated with a higher insulin sensitivity and a reduced risk of the metabolic syndrome, independent of insulin levels and body composition measurements, suggesting that these hormones may protect against the development of metabolic syndrome.
Abstract: Background: Sex hormone levels in men change during aging. These changes may be associated with insulin sensitivity and the metabolic syndrome. Methods:Westudiedtheassociationbetweenendogenoussex hormones and characteristics of the metabolic syndrome in 400 independently living men between 40 and 80 yr of age in a crosssectionalstudy.Serumconcentrationsoflipids,glucose,insulin, total testosterone (TT), SHBG, estradiol (E2), and dehydroepiandrosterone sulfate (DHEA-S) were measured. Bioavailable testosterone (BT) was calculated using TT and SHBG. Body height, weight, waist-hip circumference, blood pressure, and physical activity were assessed. Smoking and alcohol consumption was estimated from self-report. The metabolic syndrome was defined according to the National Cholesterol Education Program definition, and insulin sensitivity was calculated by use of the quantitative insulin sensitivity check index. Results: Multiple logistic regression analyses showed an inverse relationship according to 1 SD increase for circulating TT [odds ratio (OR) 0.43; 95% confidence interval (CI), 0.32– 0.59], BT (OR 0.62; 95% CI, 0.46–0.83), SHBG (OR 0.46; 95% CI, 0.33–0.64), and DHEA-S (OR 0.76; 95% CI, 0.56–1.02) with the metabolic syndrome. Each SD increase in E2 levels was not significantly associated with the metabolic syndrome (OR 1.16; 95% CI, 0.92–1.45). Linear regression analyses showed that higher TT, BT, and SHBG levels were related to higher insulin sensitivity; -coefficients (95% CI) were 0.011 (0.008– 0.015), 0.005 (0.001–0.009), and 0.013 (0.010–0.017), respectively, whereas no effects were found for DHEA-S and E2. Estimates were adjusted for age, smoking, alcohol consumption, and physical activity score. Further adjustment for insulin levels and body composition measurements attenuated the estimates, and the associations were similar in the group free of cardiovascular disease and diabetes. Conclusions: Higher testosterone and SHBG levels in aging males are independently associated with a higher insulin sensitivity and a reduced risk of the metabolic syndrome, independent of insulin levels and body composition measurements, suggesting that these hormones may protect against the development of metabolic syndrome. (J Clin Endocrinol Metab 90: 2618–2623, 2005)
TL;DR: More widespread and liberal screening for the disorder appears be a cost-effective strategy, leading to earlier diagnosis and intervention and possibly the amelioration and prevention of serious sequelae.
Abstract: Context: The polycystic ovary syndrome (PCOS) is the most common endocrine abnormality of reproductive-aged women today, affecting approximately 6.6% of unselected reproductive-aged women (∼4 million women in the United States) (1990 National Institutes of Health criteria), and potentially represents a significant financial burden to our health care. Objective: The objective of the study was to define, using current definitions and prevalence or incidence data, the minimal economic burden that PCOS in reproductive-aged women represents for the United States. Design: The study design was a literature review. Setting: The study was conducted at a tertiary care center. Patients or Other Participants: There were no patients or other participants. Intervention(s): We performed a systematic review of the published medical literature to identify studies evaluating epidemiology of reproductive-age PCOS and its clinical consequences and costs. We tied general societal cost data for the different health consequence...
TL;DR: The absence of a compensatory increase in ghrelin concentrations that usually occurs with diet-induced weight loss, and the exaggerated postprandial PYY response after RYGBP, may contribute to weight loss and to the ability of an individual to maintain weight loss after this surgical procedure.
Abstract: To help understand the mechanisms by which weight loss is maintained after Roux-en-Y gastric bypass (RYGBP), we measured circulating concentrations of total and bioactive octanoylated ghrelin, peptide YY (PYY), glucose, and insulin in the fasted state and in response to a liquid test meal in three groups of adult women: lean (n = 8); weight-stable 35 +/- 5 months after RYGBP (n = 12; mean body mass index, 33 kg/m(2)); and matched to the surgical group for body mass index and age (n = 12). Fasting plasma total ghrelin levels were nearly identical between RYGBP (425 +/- 54 pg/ml) and the matched controls (424 +/- 28 pg/ml) and highest in lean controls (564 +/- 103 pg/ml). The response to the test meal was comparable between lean and RYGBP groups, with 27% and 20% maximal suppression, respectively, whereas the magnitude of suppression was significantly diminished in the matched controls (17%) compared with the lean group. Fasting levels of octanoylated ghrelin were highest in the lean controls, 220 +/- 36 pg/ml vs. 143 +/- 27 in the RYGBP group (P = 0.05) and 127 +/- 12 pg/ml in the matched controls (P < 0.05). The magnitude of maximal postmeal suppression of octanoylated ghrelin was more marked than with total ghrelin, but similar among groups, ranging from 44-47%. In response to the test meal, there was an early exaggerated rise in PYY in the RYGBP group, such that the peak PYY concentration was 163 +/- 24 pg/ml compared with 58 +/- 17 (P < 0.01) and 77 +/- 23 (P < 0.05) in the matched and lean controls, respectively; area under the curve at 90 min was significantly greater compared with both control groups. Leptin and fasting insulin concentrations and homeostasis model of assessment insulin resistance indices were nearly identical between lean and RYGBP subjects and significantly higher in the body mass index-matched controls. In summary, the absence of a compensatory increase in ghrelin concentrations that usually occurs with diet-induced weight loss, and the exaggerated postprandial PYY response after RYGBP, may contribute to weight loss and to the ability of an individual to maintain weight loss after this surgical procedure.
TL;DR: The leadership of AACE, ATA, and TES determined that it would not be appropriate for practicing clinicians and the regulatory elements of the health care industry to be left with the impression that the membership of these three organizations unanimously agreed with all of the consensus conference recommendations, despite their sponsorship of the conference itself.
Abstract: UBCLINICAL THYROID DYSFUNCTION is a common clinical problem for which there are many controversial issues regarding screening, evaluation, and management. Subclinical hypothyroidism is defined as an elevated serum thyroidstimulating hormone (TSH) level associated with normal total or free thyroxine (FT4) and free triiodothyronine (FT3) levels. The overall prevalence is 4% to 10% in the general population, and up to 20% in women older than 50 years (1‐3). Several alternative names have been proposed to describe this condition and include “compensated hypothyroidism,” “preclinical hypothyroidism,” “mild thyroid failure,” and “mild hypothyroidism.” While each term has subtle implications that may be more or less appropriate in various circumstances, we will use the term “subclinical hypothyroidism” in the interest of consistency with a recent publication that is the topic of this discussion. Subclinical hyperthyroidism is defined as low serum TSH levels associated with normal FT4 and FT3 levels. The prevalence is approximately 2%, being more common in women, in blacks, and in the elderly (4,5). In order to develop an evidence-based approach to the various unresolved clinical issues regarding subclinical thyroid disease, the American Association of Clinical Endocrinologists (AACE), the American Thyroid Association (ATA), and The Endocrine Society (TES) jointly sponsored a Consensus Development Conference, which was held in September 2002. A number of questions were presented to a panel of 13 experts, including 8 experts in thyroid disease; the remaining 5 had expertise in cardiology, epidemiology, biostatistics, evidence-based medicine, health-services research, general internal medicine, and clinical nutrition. The consensus panel report is the result of an extensive review of the published literature on these topics available at the time. The conference participants meticulously followed the principles of evidence-based medicine (EBM) to summarize all existing pertinent data (a summary of the data reviewed is available at www.endo-society.org/education/evidencereport.cfm) and to make EBM recommendations on the controversial issues of screening, evaluation, and management of patients with subclinical thyroid disease. The recently published consensus panel’s conclusions and recommendations (6) were developed independently and therefore did not require official review or approval by the three sponsoring societies. Recognizing the EBM methodology cannot adequately address gray areas where existing evidence is inadequate and that EBM-based guidelines cannot specifically address the multitude of variations encountered by clinicians in their management of individual patients, the consensus authors also published an accompanying case-based discussion illustrating how the guidelines could be applied in several patient scenarios (7). The authors of these two outstanding articles are to be congratulated for these excellent publications and thanked for their service to the community of providers who care for patients with thyroid disorders. Subsequently, having carefully studied the consensus conference data, summaries, and recommendations, the leadership of AACE, ATA, and TES determined that it would not be appropriate for practicing clinicians and the regulatory elements of the health care industry to be left with the impression that the membership of these three organizations unanimously agreed with all of the consensus conference recommendations, despite their sponsorship of the conference itself. They felt that the data in several areas were inconclusive and that further alternative interpretations and recommendations was not only reasonable but also warranted in the interest of academic fairness. Two members from each of these respective organizations were therefore invited to form a panel to review the consensus conference recommendations to determine if there were areas of legitimate and significant disagreement. All members of this panel
TL;DR: The Intimate SM 1 study as mentioned in this paper evaluated the efficacy and safety of a testosterone patch in surgically menopausal women with Hypoactive Sexual Desire Disorder (HSDD) after bilateral salpingo-oophorectomy.
Abstract: Context: Hypoactive sexual desire disorder (HSDD) is one of the most common sexual problems reported by women, but few studies have been conducted to evaluate treatments for this condition. Objective: The objective of this study was to evaluate the efficacy and safety of a testosterone patch in surgically menopausal women with HSDD. Design: The design was a randomized, double-blind, parallel-group, placebo-controlled, 24-wk study (the Intimate SM 1 study). Setting: The study was performed at private or institutional practices. Patients: The subjects studied were women, aged 26–70 yr, with HSDD after bilateral salpingo-oophorectomy who were receiving concomitant estrogen therapy. Placebo (n = 279) or testosterone 300 μg/d (n = 283) was administered. There were 19 patients who withdrew due to adverse events in the placebo group and 24 in the 300 μg/d testosterone group. Intervention: Testosterone (300 μg/d) or placebo patches were applied twice weekly. Main Outcome Measure(s): The primary end point was the ...