Leptin regulates CD16 expression on human monocytes in a sex-specific manner.

Fat mass is linked mechanistically to the cardiovascular system through leptin, a 16 kDa protein produced primarily by adipocytes. In addition to increasing blood pressure via hypothalamic-sympathetic pathways, leptin stimulates monocyte migration, cytokine secretion, and other functions that contribute to atherosclerotic plaque development. These functions are also characteristics of CD16-positive monocytes that have been implicated in the clinical progression of atherosclerosis. This investigation sought to determine if leptin promoted the development of such CD16-positive monocytes. Cells from 45 healthy men and women with age ranging from 20 to 59 years were analyzed. Circulating numbers of CD14(++)16(++) monocytes, which are primary producers of TNFα, were positively related to plasma leptin concentrations (P < 0.0001), with a stronger correlation in men (P < 0.05 for leptin × sex interaction). In vitro, recombinant human leptin induced CD16 expression in a dose-related manner (P = 0.02), with a stronger influence on monocytes from men (P = 0.03 for leptin × sex interaction). There were no sex-related differences in total leptin receptor expression on any monocyte subtypes, relative expression of long versus short isoforms of the receptor, or soluble leptin receptor concentrations in the plasma. The number of circulating CD14(+)16(++) monocytes, which preferentially migrate into nascent plaques, was positively related to systolic blood pressure (R = 0.56, P = 0.0008) and intima-media thickness (R = 0.37, P = 0.03), and negatively related to carotid compliance (R = -0.39, P = 0.02). These observations indicate that leptin promotes the development of CD16-positive monocyte populations in a sex-specific manner and that these subpopulations are associated with diminished vascular function.

Follicle-stimulating hormone, interleukin-1, and bone density in adult women.

Recent studies have indicated that follicle-stimulating hormone (FSH) promotes bone loss. The present study tested the hypothesis that FSH enhances the activity of bone-resorbing cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6], either by inducing their secretion or by altering their receptor expression. Thirty-six women between the ages of 20 and 50 were assessed for bone mineral density (BMD), reproductive hormone, cytokine ligand and soluble receptor concentrations, and surface expression of cytokine receptors on monocytes. In addition, isolated mononuclear cells were incubated in vitro with exogenous FSH. Univariate regression analyses indicated that BMD was inversely related to serum FSH (r = -0.29 to -0.51, P = 0.03-0.001, depending upon the skeletal site). Physical activity and body composition were also identified as significant factors by multiple regressions. Exogenous FSH induced isolated cells to secrete IL-1beta, TNF-alpha, and IL-6 in proportion to the surface expression of FSH receptors on the monocytes. Endogenous (serum) FSH concentrations correlated with the circulating concentrations of these cytokines. None of these individual cytokines was related to BMD, but the IL-1beta to IL-1 receptor antagonist (IL-1Ra) ratio was inversely related to BMD (r = -0.53, P = 0.002) in all but the most physically active women, who had significantly lower expression of IL-1 type I receptors relative to type II (decoy receptors, P = 0.01). Physical activity also correlated positively with secretion of inhibitory soluble IL-1 receptors (r = 0.53, P = 0.003). Moreover, IL-1Ra correlated strongly with percent body fat (r = 0.66, P < 0.0001). These results indicate that BMD is related to FSH concentration, physical activity, and body composition. Although each of these factors likely has direct effects on bone, the present study suggests that each may also influence BMD by modulating the activity of the osteoresorptive cytokine IL-1beta.

Optimal use of intraoperative PTH levels in parathyroidectomy.

OBJECTIVES/HYPOTHESIS: Localization and the intraoperative parathyroid hormone assay (IOPTH) have facilitated minimally invasive parathyroidectomy. The precise algorithm governing use of IOPTH has been debated. Numerous authors advocate acquisition of a so-called pre-excision (P-E) baseline level (obtained after dissection of the adenoma, but prior to excision) in addition to a preincision baseline, to guard against spurious elevation in the baseline that might confuse interpretation of postexcision levels. We sought to clarify the optimal timing of PTH level determination. STUDY DESIGN: Consecutive single-surgeon case series with planned data collection from patients undergoing parathyroid surgery at a university hospital. METHODS: Demographic data and intraoperative laboratory and surgical findings from patients undergoing parathyroidectomy were prospectively gathered and analyzed. Attention was paid to the value of P-E and 5-minute postexcision levels and their impact on intraoperative decision-making. RESULTS: One hundred twelve patients underwent parathyroidectomy. Thirty were for secondary or tertiary hyperparathyroidism and were excluded. Seventy-nine (96.3%) of the 82 patients with primary hyperparathyroidism were rendered eucalcemic. In no case did the P-E value change what was otherwise destined to be a successful result. In 65.3% of cases, operative time was conserved as the procedure was correctly stopped after the 5-minute level, without the need to wait until the 10-minute postexcision level was reported. CONCLUSIONS: Pre-excision baseline IOPTH levels, although logical in their original proposal, appear to play little role in determining the completeness of an exploration. A 5-minute postexcision level adds value in nearly two thirds of cases by allowing earlier termination of the operation.

Value of sestamibi scans in tertiary hyperparathyroidism.

OBJECTIVES: To determine the value of preoperative Tc-sestamibi scans and the incidence of ectopic glands in tertiary hyperparathyroidism. DESIGN: Prospective, non-randomized analysis of a consecutive cohort of surgical patients from the Medical College of Georgia Thyroid/Parathyroid Center. MATERIALS AND METHODS: A consecutive series of patients with tertiary hyperparathyroidism undergoing parathyroidectomy was analyzed. Demographic data, preoperative Tc-sestamibi scintigraphy results, location of diseased glands, pre- and postoperative calcium, and parathyroid hormone levels were collected. RESULTS: Twenty-one patients underwent parathyroidectomy for tertiary hyperparathyroidism between March 2004 and September 2006. Of these 21 patients, 3 were re-operative cases for persistent hypercalcemia and each was found to have a single diseased gland. Of the 18 patients undergoing first time surgery, 15 had four-gland hyperplasia, 2 patients had single adenomas, and 1 patient had a double adenoma. Nine of the 21 patients (43%) had ectopic glands (2 of these patients had 2 ectopic glands each). The overall sensitivity of the preoperative Tc-sestamibi scintigraphy was 76% and was not significantly different when comparing patients with ectopic glands (78%) and those without (75%). CONCLUSIONS: Tc sestamibi scintigraphy has high positive predictive value and sensitivity in patients with tertiary hyperparathyroidism. Sestamibi scanning is particularly valuable in this patient population since the incidence of ectopic glands may be higher than previously recognized.

Hyperthyroidism: a secondary cause of isolated systolic hypertension.

Isolated systolic hypertension is the most common form of hypertension, especially among patients 50 years or older. What is not appreciated is that there are secondary causes of isolated systolic hypertension. Hyperthyroidism increases systolic blood pressure by decreasing systemic vascular resistance, increasing heart rate, and raising cardiac output. Potential cardiovascular consequences of hyperthyroidism include atrial arrhythmias (especially atrial fibrillation), pulmonary hypertension, left ventricular hypertrophy, and heart failure. The prevalence of hypertension is greater among hyperthyroid patients than euthyroid patients. Whether there is a blunted nocturnal decline in ambulatory blood pressure among hyperthyroid patients is more controversial. Treatment is associated with a reduction in systolic blood pressure, heart rate, and cardiac output.

Glucose-dependent insulinotropic polypeptide receptor knockout mice have altered bone turnover.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone, which is secreted from endocrine cells in the small intestine after meal ingestion. GIP has been shown to affect osteoblastic function in vitro; however, the in vivo effects of GIP on bone remodeling remain unclear. In the present study, we investigated the role of GIP in modulating bone turnover, by evaluating serum markers of bone turnover, bone density, bone morphology, and changes in biomechanical bone strength over time (one to five months) in GIP receptor knockout mice (GIPR-/- mice). The GIPR-/- mice showed a decreased bone size, lower bone mass, altered bone microarchitecture and biomechanical properties, and altered parameters for bone turnover, especially in bone formation. Moreover, the effects of GIP on bone mass were site-specific and compensatory mechanism developed over time and ameliorated the impact of the loss of GIP signaling on bone mass. Further, GIPR-/- mice had earlier age-related changes than wild-type mice in body composition, including bone mass, lean body mass, and fat percentage. In summary, our results indicate that GIP has an anabolic effect on bone mass and bone quality and suggests that GIP may be a hormonal link between nutrient ingestion and utilization.

Primary ovarian lymphoma manifesting with severe hypercalcemia.

OBJECTIVE: To describe a case of primary ovarian lymphoma manifesting with severe hypercalcemia. METHODS: We report the occurrence of a substantially increased serum calcium level in a 74-year-old female patient who presented with progressive weakness, volume depletion, confusion, slurred speech, cardiac abnormalities, and renal insufficiency. The patient's clinical course is reviewed, and the results of laboratory and imaging studies leading to the underlying diagnosis are presented. RESULTS: Initial evaluation revealed hemodynamic instability, disorientation, cardiac rhythm abnormalities, high levels of blood urea nitrogen and creatinine, and a serum calcium level of 18 mg/dL. A cranial computed tomographic scan showed no evidence of pronounced atrophy or stroke. Aggressive rehydration was initiated, and a permanent pacemaker was inserted. A suppressed level of parathyroid hormone and a high serum 1,25-dihy-droxyvitamin D concentration were found, but no evidence of granulomatous disease, infection, or overt malignant lesion was detected. The patient showed clinical improvement and was dismissed from the hospital, but the hypercalcemic state recurred soon thereafter. A computed tomographic scan of the abdomen and pelvis revealed a pelvic mass, which was diagnosed as ovarian lymphoma after surgical removal. The serum calcium and 1,25-dihy-droxyvitamin D levels normalized postoperatively. CONCLUSIONS: Primary ovarian lymphoma can be a cause of, and can manifest solely as, a severe and symptomatic increase in the serum calcium level, which is mediated by an increased serum concentration of 1,25-dihy-droxyvitamin D. It should be considered in the differential diagnosis of unexplained nonparathyroid hypercalcemia.

Glucose-dependent insulinotropic peptide stimulates proliferation and TGF-beta release from MG-63 cells.

Glucose-dependent insulinotropic peptide (GIP) is known to modulate alkaline phosphatase activity and collagen type I message in osteoblastic-like cells. GIP effects on cell proliferation are not known. We report that GIP dose dependently stimulated 3H-thymidine incorporation in the osteoblastic-like cell line MG-63. Furthermore, GIP increased message and secretion of transforming growth factor beta (TGF-beta), an agent known to regulate osteoblastic proliferation and differentiation. However, when GIP was added to MG-63 cells concurrently with a TGF-beta neutralizing antibody, there was no effect on 3H-thymidine incorporation in these cells. These data demonstrate that GIP stimulates osteoblastic-like cell proliferation but that this effect is not mediated by TGF-beta.

Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either agent alone. Changes in bone mineral density after discontinuation of therapy have not been compared directly. OBJECTIVE: To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued. DESIGN: Double-blind, placebo-controlled discontinuation trial. SETTING: 18 U.S. centers. PATIENTS: 244 postmenopausal, hysterectomized women 44 to 77 years of age. INTERVENTION: 2 years of therapy with alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); alendronate and conjugated estrogen (n = 140); or placebo (n = 50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo. MEASUREMENTS: Bone mineral density and biochemical markers of bone turnover. RESULTS: Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P < 0.001 for both treatment comparisons) and 3.5% (CI, 2.3% to 4.6%) and 3.0% (CI, 1.8% to 4.2%) higher, respectively, at the trochanter (P < 0.001 for both treatment comparisons) than that in women previously taking estrogen who were switched to placebo. In contrast, women who were taking estrogen and were switched to placebo during year 3 experienced a 4.5% decrease at the spine (95% CI, -5.0% to -4.0%) and a 2.4% decrease at the trochanter (CI, -2.7% to -2.1%) (P < 0.001 for both changes). Compared with women who took placebo for 3 years, women who took estrogen for 2 years and were then switched to placebo had a bone mineral density that was 2.9% higher (CI, 1.2% to 4.6%) at the spine (P < 0.05) and 2.9% higher (CI, 1.6% to 4.2%) at the trochanter (P < 0.001). Changes in biochemical markers during year 3 did not differ among the groups that discontinued active treatment. CONCLUSIONS: Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.