Hypothalamic dysfunction in "cured" acromegaly is treatment modality dependent

The current definition of cure after treatment for acromegaly stipulates a reduction in GH levels to less than 2 ng/mL (< 5 mU/L), as such GH concentrations are believed to be associated with normalization of long term survival. We sought to further define the nature of the cure in such patients, when cure has been achieved by alternative therapeutic modalities, in the expectation that hypothalamic neuroregulatory control of GH secretion might be affected differently by radiotherapy or surgery. In particular we wished to determine the effect of therapy modality on endogenous somatostatin (SMS) tone, using the GH response to i.v. arginine as a paradigm. We studied 20 patients with cured acromegaly (mean 24-h GH concentration, < 2 ng/mL). Eight patients had been cured by surgery only (S; 4 women and 4 men; mean +/- SEM age, 52 +/- 5 yr), and 12 patients had been cured by radiotherapy (R; 4 women and 8 men; age, 52 +/- 3 yr). Sixteen healthy subjects were studied as a control group (C; 6 women and 10 men; age 53 +/- 3]. The median (range) GH during 24-h profiles was similar in each group: S, 1.3 (0.7-1.8) ng/mL; R, 0.6 (0.4-1.8) ng/mL; and C, 0.7 (0.4-3.2) ng/mL (P = 0.57). The median incremental GH responses to arginine were significantly lower in the R group compared with those in the S and C groups: S, 6.4 (2.1-16.6) ng/mL; R, 0.1 (0-1.7) ng/mL; and C, 9.2 (0-16.1) ng/mL (P = 0.0002; S vs. R, P < 0.01; S vs. C, P > 0.05; R vs. C, P < 0.001). We conclude that in acromegalic patients deemed to be cured (GH, < 2 ng/mL), the mode of therapy has considerable influence on the remaining hypothalamic-somatotroph function. In view of the putative mechanism by which arginine releases GH, we suggest that radiotherapy leads to a reduction or complete loss of endogenous SMS tone. This may have implications for the treatment of those acromegalic patients who are not cured (GH, > 2 ng/mL) and who require SMS analog therapy.     

Risk factors for coronary atherosclerosis. Comparison between two Argentine regions

The prevalence of risk factors for coronary atherosclerosis were studied in two population samples, Northeast (Posadas, n = 498) and South (Viedma, C. Rivadavia and Cipolletti, n = 652) of 20 years and older, males and females. The diet in the Northeast (n = 102) contained more monounsaturated acids and polyunsaturated acids than the one in the South (n = 62), 9.5 +/- 4.1 vs. 8.1 +/- 3.5% TCV (Total Caloric Value) (P < 0.02) and 8.1 +/- 4.1 vs. 6.2 +/- 3.0% TCV (P < 0.001) respectively. The P/S relationship was greater in the Northeast, 1.02 +/- 0.44 vs. 0.85 +/- 0.50 (P < 0.001). Total cholesterol (TC) in the Northeast was less than in the South, in males 176 +/- 41 vs. 213 +/- 43 mg/dl (P < 0.001); CLDL (LDL cholesterol) 109 +/- 37 vs. 141 +/- 41 mg/dl (P < 0.001). The most frequent risk factors in the South vs. Northeast (males) were: TC > or = 240 mg/dl, 26.7% vs. 9.5% (P < 0.001); LDL-C > or = 160 mg/dl, 30.3% vs. 10.9% (P < 0.001); Cig > or = 10/d (equal or more than 10 cigarettes per day), 30.0% vs. 16.4% (P < 0.001). The hypertension prevalence (HTA, 160/95), in males, was higher in the Northeast than in the South, 23.7% vs. 11.5% (P < 0.001). BMI > 27 Kg/m2 was higher in the women of Northeast than in the South, 38.4% vs. 24.2% (P < 0.001). In the males of the Northeast, the combination Cig > or = 10/d and HTA, 4.1 vs 0.9% was more common; in the South Cig > or = 10/d and LDL-C > or = 160 mg/d, 8.2% vs. 1.8% (P < 0.001) was more common. The differences in the prevalence of the risk factors between the population samples indicate the need to plan the prevention of coronary atherosclerosis locally.     

Acromegaly. Clinical and biochemical features in 500 patients

This prospective study defines the clinical and biochemical features of acromegaly in a large cohort of patients. There was no difference in sex distribution, and for men and women the mean ages at diagnosis (40 +/- 12 and 40 +/- 14 yr, respectively) were similar. Nearly three-quarters of patients were overweight and some 12% severely overweight; the frequency and severity of obesity also was not different between the sexes. Half of patients were hypertensive or were taking anti-hypertensive drugs. Neither GH nor insulin levels were significantly different between normotensive and hypertensive patients. Acral growth and facial coarsening, soft tissue swelling, and excessive perspiration were present in the majority (98%) of patients. Mean serum GH, Sm-C, and PRL levels did not differ between the sexes. Sm-C levels correlated with mean GH concentration (r = 0.31, p < 0.001), both variables inversely related to age. With each decade of life, mean GH and Sm-C levels declined by 7.6 +/- 0.2 ng/mL and 0.5 +/- 0.2 U/mL, respectively. Impaired glucose tolerance was diagnosed in 36% and frank diabetes mellitus in 30% of patients. Hyperprolactinemia was noted in 18% of patients. Galactorrhea was noted in 43 (9%) patients, most of whom were female; the mean GH levels of patients with galactorrhea (60.1 +/- 13 ng/mL) were higher than those of patients without (35.4 +/- 2.6 ng/mL, p = 0.02). Acromegaly appears to afflict men and women equally with a preponderance of presentation in the fourth decade of life.(ABSTRACT TRUNCATED AT 250 WORDS)     

Do androgens regulate growth hormone-binding protein in adult man?

To determine whether adult serum GH-binding protein (GHBP) is regulated by androgen, serum GHBP concentrations were compared between 20 normal and 18 hypogonadal men matched for age and body mass index, and the effect of im testosterone treatment (250 mg testosterone enanthate) on GHBP levels in the 18 hypogonadal men was studied. Nine of the hypogonadal subjects had coexistent GH deficiency. Serum GHBP concentration was measured by a ligand immunofunctional assay. The mean serum GHBP level in untreated hypogonadal men was not significantly different from that of normal men (0.98 +/- 0.15 vs. 1.17 +/- 0.16 nmol/L). The mean serum insulin-like growth factor I (IGF-I) level was significantly lower in the hypogonadal men (132 +/- 22 vs. 206 +/- 17 ng/mL; P < 0.01). Basal testosterone (3.7 +/- 0.7 nmol/L) in hypogonadal men increased during treatment to a mean level of 29.1 +/- 2.8 nmol/L, which was not significantly higher than that in normal men (22.6 +/- 1.9 nmol/L). The mean serum GHBP level in hypogonadal men fell significantly during treatment to 0.60 +/- 0.11 nmol/L (P = 0.0003), whereas the serum IGF-I level rose significantly to 151 +/- 26 ng/mL (P < 0.04). The decrease in GHBP level was significant in both the GH-sufficient and GH-deficient subjects (P < 0.02 in both instances), whereas the increase in IGF-I level was significant in the GH-sufficient group (199 +/- 22 to 235 +/- 29 ng/mL; P < 0.04) but not in the GH-deficient group (53 +/- 7 to 55 +/- 5 ng/mL; P > 0.8). Thus, serum GHBP is normal in hypogonadal men but is reduced by testosterone treatment irrespective of endogenous GH-secretory status. It was concluded that the effect of testosterone on GHBP is pharmacological and occurs independent of GH mediation.     

Outcome from treatment for spinal arteriovenous malformation

BACKGROUND: prospective studies have demonstrated that a predominance of small, dense LDL particles (pattern B) precedes the clinical onset of coronary heart disease. Prevalence and characteristics of subjects with this LDL size abnormality were studied in young, nonobese, Japanese normolipidemic men. METHODS AND RESULTS: LDL peak particle diameter (PPD) was measured by continuous disc polyacrylamide gel electrophoresis in 223 nonobese normolipidemic men aged 18-20 years (mean+/-S.D. body mass index: 21.9+/-3.7 kg/m2, total cholesterol: 180+/-29 mg/dl, triglyceride: 62+/-34 mg/dl, HDL cholesterol: 58+/-12 mg/dl). Men with small LDL (PPD < 25.8 nm) were found in only 5.4% (n=12) whereas 197 men (88.3%) had a preponderance of large LDL (PPD 26.3 nm). As compared with men in a top tertile (PPD 27.5 nm) those in a low tertile (PPD < 26.9 nm) had higher serum levels of LDL cholesterol (120+/-31 vs 104+/-24 mg/dl), triglyceride (72+/-39 vs 49+/-16 mg/dl) and apolipoprotein (apo) B (84+/-21 vs 68+/-14 mg/dl), and lower HDL cholesterol (54+/-10 vs 60+/-12 mg/dl). They also had greater body mass index (23.2+/-4.6 vs 20.9+/-3.1 kg/m2) and percent body fat (21.5+/-7.7 vs 17.5+/-4.9%). LDL-PPD was positively correlated with HDL cholesterol (R=0.20, P=0.002) and was negatively correlated with apoB (R=0.34, P < 0.001), triglyceride (R=0.32, P < 0.001). percent body fat (R=0.26, P < 0.001), body mass index (R=0.24, P < 0.001), fat mass (R=0.23, P=0.001), total cholesterol (R=0.20, P=0.002). In multiple regression analysis, apoB, triglyceride, HDL cholesterol, apoAI and percent body fat explained 18% of LDLPPD variability. CONCLUSION: even in young, nonobese, normolipidemic men, LDL size appears to be associated with triglyceride-rich lipoprotein metabolism and body fat.     

Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the beta-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01) after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1 protein (from 64.9 +/- 9.1 to 44.8 +/- 6.1 ng/mL; P < 0.05). No change in the functional activity of tissue plasminogen activator (from 5.3 +/- 0.4 to 5.1 +/- 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 +/- 0.9 to 8.2 +/- 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to thrombosis in these subjects. We conclude that administration of troglitazone to women with PCOS and impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome. Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.     

Fracture after cardiac transplantation: a prospective longitudinal study

Cardiac transplantation is associated with increased prevalence of vertebral fractures, but the natural history of and risk factors for fracture after this life-saving procedure are unclear. We evaluated 47 patients (34 men and 13 postmenopausal women) before transplantation with spinal radiographs, determination of bone density by dual energy x-ray absorptiometry, and measurement of biochemical indexes of mineral metabolism. During the first year after transplantation, incident fractures were documented radiographically. Associations among demographic characteristics, bone density, biochemistries, and fracture risk were evaluated with logistic regression analysis. Despite supplementation with elemental calcium (1000 mg/day) and vitamin D (400 IU/day), 17 patients (7 women and 10 men) sustained a total of 34 fractures. Most fractures involved the spine, and 85% of the patients who experienced fracture did so within 6 months of transplantation. Fifty-four percent of the women and 29% of the men experienced fracture. Femoral neck bone mineral density was significantly lower in women who experienced fracture than in those who did not (0.604 +/- 0.11 vs. 0.760 +/- 0.12 g/cm2; P < 0.04), but did not differ in men according to fracture outcome. The amount of bone loss at the femoral neck by 6 months after transplantation was significantly greater in men with fracture than in men without fracture (12.0 +/- 6.4% vs. 6.8 +/- 5.3%; P < 0.04), but did not differ in women according to fracture outcome. Pretransplant 1,25-dihydroxyvitamin D levels were significantly lower (25 +/- 9 vs. 39 +/- 17 pg/mL; P < 0.007) and intact PTH levels tended to be higher in men who did not experience fracture (37 +/- 15 vs. 69 +/- 46 pg/mL; P < 0.06). Individual pretransplant bone density measurements demonstrated substantial overlap between patients who did and did not experience fracture, and normal bone density did not necessarily protect against fracture after transplantation. We conclude that fractures are a common and early complication of cardiac transplantation. No pretransplant measurement has yet been identified that reliably predicts fracture after transplantation in the individual patient.     

Effects of growth hormone (GH) replacement on bone metabolism and mineral density in adult onset of GH deficiency: results of a double-blind placebo-controlled study with open follow-up

It is known that GH stimulates bone turnover and that GH-deficient adults have a lower bone mass than healthy controls. In order to evaluate the influences of GH replacement therapy on markers of bone turnover and on bone mineral density (BMD) in patients with adult onset GH deficiency, a double-blind placebo-controlled study of treatment with recombinant human GH (rhGH; mean dose 2.4 IU daily) in 20 patients for 6 months and an extended open study of 6 to 12 months were conducted. Eighteen patients, fourteen men and four women, with a mean age of 44 years with adult onset GH deficiency were evaluated in the study. Compared with placebo, after 6 months serum calcium (2.39 +/- 0.02 vs 2.32 +/- 0.02 mmol/l, P = 0.037) and phosphate (0.97 +/- 0.06 vs 0.75 +/- 0.05 mmol/l, P = 0.011) increased and the index of phosphate excretion (0.03 +/- 0.03 vs 0.19 +/- 0.02, P < 0.001) decreased significantly, and there was a significant increase in the markers of bone formation (osteocalcin, 64.8 +/- 11.8 vs 17.4 +/- 1.8 ng/ml, P < 0.001; procollagen type I carboxyterminal propeptide (PICP), 195.3 +/- 26.4 vs 124.0 +/- 15.5 ng/ml, P = 0.026) as well as those of bone resorption (type I collagen carboxyterminal telopeptide (ICTP), 8.9 +/- 1.2 vs 3.3 +/- 0.5 ng/ml, P < 0.001; urinary hydroxyproline, 0.035 +/- 0.006 vs 0.018 +/- 0.002 mg/100 ml glomerular filtration rate, P = 0.009). BMD did not change during this period of time. IGF-I was significantly higher in treated patients (306 +/- 45.3 vs 88.7 +/- 22.5 ng/ml, P < 0.001). An analysis of the data compiled from 18 patients treated with rhGH for 12 months revealed similar significant increases in serum calcium and phosphate, and the markers of bone turnover (osteocalcin, PICP, ICTP, urinary hydroxyproline). Dual energy x-ray absorptiometry (DXA)-measured BMD in the lumbar spine (1.194 +/- 0.058 vs 1.133 +/- 0.046 g/cm2, P = 0.015), femoral neck (1.009 +/- 0.051 vs 0.936 +/- 0.034 g/cm2, P = 0.004), Ward's triangle (0.881 +/- 0.055 vs 0.816 +/- 0.04 g/cm2, P = 0.019) and the trochanteric region (0.869 +/- 0.046 vs 0.801 +/- 0.033 g/cm2, P = 0.005) increased significantly linearly (compared with the individual baseline values). At 12 months, BMD in patients with low bone mass (T-score < -1.0 S.D.) increased more than in those with normal bone mass (lumbar spine 11.5 vs 2.1%, P = 0.030, and femoral neck 9.7 vs 4.2%, P = 0.055). IGF-I increased significantly in all treated patients. In conclusion, treatment of GH-deficient adults with rhGH increases bone turnover for at least 12 months. BMD in the lumbar spine and the proximal femur increases continuously in this time (open study) and the benefit is greater in patients with low bone mass. Therefore, GH-deficient patients exhibiting osteopenia or osteoporosis should be considered candidates for GH supplementation. However, long-term studies are needed to establish that the positive effects on BMD are persistent and are associated with a reduction in fracture risk.     

Sex differences in lean and adipose tissue distribution by magnetic resonance imaging: anthropometric relationships

This study compared total and regional adipose tissue (AT) and lean tissue (LT) distribution measured by magnetic resonance imaging (MRI) in obese, android women (n = 40) and mean (n = 17). Women had significantly (P < 0.01) greater subcutaneous AT (39.6 +/- 11.6 vs 30.7 +/- 7.5 L) but significantly (P < 0.01) less visceral AT (2.5 +/- 1.1 vs 4.8 +/- 2.1 L) and LT (42.8 +/- 4.7 vs 58.2 +/- 6.2 L) compared with men. Segmentation of the visceral AT volume demonstrated that women had significantly (P < 0.01) less intraperitoneal (1.98 +/- 0.84 vs 3.74 +/- 1.61 L) and extraperitoneal AT (0.51 +/- 0.23 vs 1.04 +/- 0.47 L). When the legs, hip and pelvic region, and abdomen and torso regions were compared, women had significantly greater absolute quantities of subcutaneous AT and significantly less LT in all regions (P < 0.01); however, in all regions the relative distribution of both was similar. Anthropometric prediction of MRI-measured total AT gave SEs of 7.7% for women and 7.5% for men, for visceral AT 30% for women and 19% for men. Anthropometric prediction of LT gave SEs of 6.5% for women and 3.6% for men.     

Carnitine measurements in liver, muscle tissue, and blood in normal subjects

We determined carnitine concentrations in blood and in liver and abdominal muscle biopsy specimens in 13 men and 16 women undergoing elective surgery (mostly gallbladder removal). The data suggest that the carnitine pools of plasma and erythrocytes are different. The erythrocytes show a higher acylcarnitine concentration than does plasma (P < 0.001). Several reference bases for values in tissues have been used--dry weight, noncollagen protein (NCP), and DNA--because these may be differently influenced by disease. In liver specimens, the quotient NCP (g)/DNA (g) was significantly higher in men, 54.4 +/- 6.3 (mean +/- SD), than in women, 47.7 +/- 7.0 (P < 0.01). Liver total carnitine content in relation to DNA was significantly higher in men than in women: 0.29 +/- 0.06 vs 0.22 +/- 0.08 mmol/g DNA (P < 0.01). Free carnitine content was significantly higher in men than in women independently of the reference base, e.g., 3.7 +/- 1.0 mumol/g NCP for men vs 2.9 +/- 1.0 for women (P < 0.05). No difference was found between the sexes in the abdominal muscle carnitine content, 20.6 +/- 6.7 mumol/g NCP for men vs 17.9 +/- 5.0 for women. Our study establishes control ranges, thereby providing an important basis for studies of patients with abnormal carnitine metabolism.     

Incremental threading optimization (TITO) to help alignment and modelling of remote homologues

OBJECTIVE: To evaluate the role of thyroid hormones in maintaining early pregnancy and to examine the association between thyroid physiological functions and immunological parameters. METHODS: Forty-five pregnant women with a clinical diagnosis of threatened abortion and a live fetus and 30 normal pregnant women were included in the study. Blood samples were taken on admission to the hospital. The patients were divided retrospectively into two groups on the basis of outcome: 1) 31 women who did not miscarry (positive outcome) and 2) 14 women who miscarried (negative outcome). Plasma TSH, free triiodothyronine (fT3), free thyroxine (fT4), hCG, immunoglobulin (Ig) G and IgM concentrations and blood counts were determined in each patient. RESULTS: Human chorionic gonadotropin was significantly higher in women who did not abort (39.4 +/- 16.9 IU/mL) than in women who miscarried (17.6 +/- 14.8 IU/mL, P < .001). Free thyroxine but not fT3 was lower in patients with negative outcome (1.25 +/- 0.26 ng/mL compared with 1.98 +/- 0.22 ng/mL, P < .001) and IgG and IgM plasma levels were higher (780 +/- 500 ng/mL compared with 470 +/- 300 ng/mL and 930 +/- 400 ng/mL compared with 650 +/- 280 ng/mL, respectively, P < .05). Plasma TSH levels were higher in patients with negative outcomes (1.72 +/- 0.84 mIU/mL compared to 1.01 +/- 0.41 mIU/mL, P < .001). Plasma concentrations of hCG and thyroid hormones were significantly correlated with peripheral blood lymphocyte and neutrophil counts only in the group of women who aborted. CONCLUSION: Our results indicate that maternal immune response, trophoblast function, and maternal thyroid function are somehow correlated. The presence of low concentrations of hCG and fT4 and high levels of TSH and gamma globulins in women with threatened abortion suggests a negative outcome for the pregnancy.     

Insulin-like growth factor-I in men with idiopathic osteoporosis

The etiology of osteoporosis in most men without a history of alcohol abuse, hypogonadism, or glucocorticoid excess is unknown. Several histomorphometric reports have demonstrated a reduction in indices of bone formation. We tested the hypothesis that the putative reduction in bone formation in men with idiopathic osteoporosis may be related to deficiencies in skeletal mechanisms that are mediated by insulin-like growth factor I (IGF-I). Twenty-four middle-aged men (50.5 +/- 1.9 yr) with severe idiopathic osteoporosis (mean lumbar spine T-score -3.5 +/- 0.16) were studied. The following biochemical indices were all normal: serum calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, testosterone, osteocalcin, carboxyterminal propeptide of type I collagen, bone specific alkaline phosphatase, urinary calcium, and collagen crosslinks. Parathyroid hormone level was in the lower range of normal, 25 +/- 2 pg/mL (nl: 10-65). Mean serum IGF-I level was also in the lower range of normal, 157.9 +/- 7.6 ng/mL (normal age-matched range, 140-260 ng/mL). Eight men had IGF-I levels that were below 140 ng/mL. The mean IGF-IZ score was -0.75, significantly different from the expected mean of zero (P = 0.0002). IGF-I was correlated negatively with age (r = -0.49, P < 0.02). With age held constant, serum IGF-I accounted for 15% of the variance in lumbar bone mineral density (BMD; P < 0.001). The osteocalcin concentration correlated well with bone density at the distal 1/3 radius (r = +0.44; P < 0.002). Histomorphometric analysis of bone biopsy specimens showed significant reductions in cancellous bone volume (31%; P < 0.001), cortical width (28%; P < 0.05), osteoid surface (33%; P < 0.01), and bone formation rate (54%; P < 0.01) when results were compared with age-matched control subjects. Percent eroded surface was normal and was correlated inversely with serum IGF-I levels (r = -0.5; P < 0.04). These results suggest that serum IGF-I levels are reduced in men with idiopathic osteoporosis and that IGF-I correlates with and may contribute to the reduction in lumbar spine bone mass density (BMD). The low IGF-I levels may reflect the reduction in bone formation demonstrated by histomorphometry. Insights into the etiology of idiopathic osteoporosis in men may be revealed by further studies of the IGF-I axis.     

Serum beta-2 microglobulin is a marker of high bone remodelling in elderly women

Beta-2 microglobulin (beta2m), the water soluble extrinsic light chain of class I MHC, has been recently isolated from the adult bone culture medium. Serum beta2m plays a role as a bone-derived growth factor regulating both osteoblast and osteoclast cell activity. Serum beta2m has been proposed as a bone remodeling biological marker in high bone turnover conditions. The purpose of our study was to determine the relationship between beta2m and vitamin D status in post-menopausal women. We have studied 44 healthy women from 20 to 80 years with normal hepatic and renal function, without diabetes mellitus and/or inflammatory, tumoral or infectious diseases. We measured the serum levels of calcium, phosphorus, parathyroid hormone (PTH), vitamin D binding protein (DBP), 25-OHD3 (calcidiol), 1,25(OH)2D3 (calcitriol) and beta2m. Serum beta2m levels increased with age (r = 0.54, P < 0.001). Post-menopausal women had higher serum levels than pre-menopausal women of beta2m (1.76 +/- 0.22 mg/l vs. 1.35 +/- 0.2 mg/l, P < 0.01); PTH (61.5 +/- 7.5 ng/ml vs. 39 +/- 6 ng/ml, P < 0.001) and lower serum levels of 25-OHD3 (7.5 +/- 2.3 ng/ml vs. 18.2 +/- 2.5 ng/ml, P < 0.001). Moreover, serum levels of beta2m were negatively correlated with 25-OHD3 (r = -0.34, P < 0.05) and with ionized calcium (r = -0.45, P < 0.01) and positively with PTH (r = 0.48, P < 0.01). These results support the role of beta2m as a regulator of bone metabolism and its potential use as a marker of high bone turnover in post-menopausal women, specially in elderly women with vitamin D deficiency and secondary hyperparathyroidism.     

Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial

A decline in testicular function is recognized as a common occurrence in older men. However data are sparse regarding the effects of hypogonadism on age-associated physical and cognitive declines. This study was undertaken to examine the year-long effects of testosterone administration in this patient population. Fifteen hypogonadal men (mean age 68 +/- 6 yr) were randomly assigned to receive a placebo, and 17 hypogonadal men (mean age 65 +/- 7 yr) were randomly assigned to receive testosterone. Hypogonadism was defined as a bioavailable testosterone <60 ng/dL. The men received injections of placebo or 200 mg testosterone cypionate biweekly for 12 months. The main outcomes measured included grip strength, hemoglobin, prostate-specific antigen, leptin, and memory. Testosterone improved bilateral grip strength (P < 0.05 by ANOVA) and increased hemoglobin (P < 0.001 by ANOVA). The men assigned to testosterone had greater decreases in leptin than those assigned to the control group (mean +/- SEM: -2.0 +/- 0.9 ng/dL vs. 0.8 +/- 0.7 ng/dL; P < 0.02). There were no significant changes in prostate-specific antigen or memory. Three subjects receiving placebo and seven subjects receiving testosterone withdrew from the study. Three of those seven withdrew because of an abnormal elevation in hematocrit. Testosterone supplementation improved strength, increased hemoglobin, and lowered leptin levels in older hypogonadal men. Testosterone may have a role in the treatment of frailty in males with hypogonadism; however, older men receiving testosterone must be carefully monitored because of its potential risks.     

Single serum progesterone as a screen for ectopic pregnancy: exchanging specificity and sensitivity to obtain optimal test performance

OBJECTIVE: To investigate the diagnostic accuracy of screening serum P in diagnosis of ectopic pregnancy (EP) and to identify a cutoff value that provides the best compromise between test sensitivity and specificity. DESIGN: Retrospective analysis. SETTING: University hospital. INTERVENTIONS: Observation only. PATIENTS: First trimester pregnant women at risk for EP. MAIN OUTCOME MEASURE: Single P measurements were obtained from 3,674 pregnancies with outcomes defined as EP, viable intrauterine pregnancy (IUP), and spontaneous abortion (SAB). Diagnostic accuracy of the test was analyzed by generating receiver operating characteristic (ROC) curves, which quantify the ability of the test to distinguish EP and SAB from IUP. RESULTS: Diagnostic accuracy for EP versus IUP was 88.7% +/- 0.1% (mean +/- SEM); for SAB versus IUP, 93.8% +/- 0.4%; and for SAB + EP versus IUP, 92.8% +/- 0.4%. Diagnostic accuracy for SAB versus EP was only 39.4% +/- 0.2%. In the interval of 15.0 to 19.9 ng/mL (47.7 to 63.3 nmol/L), P missed 5.3% of the EPs and incorrectly included 84.3% of the viable IUPs; in the interval of 20.0 to 24.9 ng/mL (63.6 to 79.2 nmol/L), sensitivity improved in that only 3.5% of the EPs were missed but 88.8% of viable IUPs were included incorrectly. A cutoff value of > or = 17.5 ng/mL (55.7 nmol/L), the median point of the 15.0 to 19.9 ng/mL (47.7 to 63.3 nmol/L) interval, missed only 35 of 423 (8.3%) total EPs in the study. CONCLUSION: Analysis of ROC curves demonstrates that single serum P has high diagnostic accuracy for differentiating accidents of pregnancy (SAB and EP) from viable IUP, both individually (SAB versus IUP and EP versus IUP) and collectively (SAB + EP versus IUP); it cannot efficiently discriminate SAB versus EP. We conclude that for P > or = 17.5 ng/mL (55.7 nmol/L), patients thought to be at risk for EP may be followed reasonably without ultrasound or further invasive diagnostic studies.     

Results of transition zone biopsy in black and white men with suspected prostate cancer

OBJECTIVES: To determine whether biopsy-detectable transition zone tumors are more common in black than in white men with suspected Stage T1c and T2 prostate cancer. METHODS: We performed a prospective study of transition zone prostate biopsy (TZ biopsy) in 1 78 black and 261 white men who had not undergone previous prostate biopsy and in 61 black and 65 white men who had undergone one benign sextant peripheral zone prostate biopsy (PZ biopsy). RESULTS: The mean age of the 239 black and 326 white study patients was 68.6+/-7.4 and 67.2+/-7.2 years, respectively (P = 0.02), the mean prostate-specific antigen (PSA) was 8.4+/-7.4 and 6.4+/-5.4 ng/mL, respectively (P = 0.003), and the mean PSA density was 0.20+/-0.23 and 0.16+/-0.16 ng/mL/mL, respectively (P = 0.006). Overall, cancer was diagnosed by TZ biopsy only in 7 black men (3%) and in no white men (0%) (P = 0.003). However, cancer detection with a TZ biopsy only was not significantly different in the black and white men when controlled for age, PSA, or PSA density (P>0.90). A TZ biopsy only detected cancer in 1% of patients who had not undergone prior PZ biopsy and in 2% of patients who had undergone prior PZ biopsy. Of the seven cancers detected with TZ biopsy, six (86%) had a Gleason score of 2 to 6. CONCLUSIONS: Prostate cancer detection with a TZ biopsy only is not common and when controlled for confounding variables is the same in black and white men. The preferential use of TZ biopsies in black men is not warranted, and the low diagnostic yield argues against routine use of the biopsy technique in men of either race.     

Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year

The gene product from the ob gene, leptin, has recently been characterized in humans. The circulating level of leptin is related to body mass index (BMI) and more closely to estimates of total body fat, whereas visceral fat has been reported to be of minor importance. However, it is unknown if leptin is directly regulated by hormones that influence substrate metabolism and body composition. We studied leptin in adult growth hormone (GH)-deficient (GHD) patients substituted with GH treatment for 12 months in a parallel double-blind, placebo-controlled study. Twenty-seven GHD adults aged 44.9 +/- 1.9 years underwent anthropometric measurements for determination of regional and total body fat (BMI, waist to hip ratio [WHR], computed tomographic [CT] scan, dual-energy x-ray absorptiometry [DEXA] scan, and bioimpedance analysis [BIA]) before and after 12 months of placebo-controlled GH substitution (2 IU/m2) in a parallel design. The same measurements were performed in 42 healthy adults aged 39.1 +/- 1.7 years. The logarithm of serum leptin levels correlated positively with abdominal subcutaneous fat and total body fat (BIA and DEXA) in untreated GHD patients and healthy subjects. Fasting insulin did not correlate with leptin levels in either of the groups. After 12 months of GH administration, the body composition of GHD patients was significantly changed with respect to a marked decrease in body fat. The relations of leptin to the estimates of body fat were maintained, and leptin was furthermore related to BMI and fasting insulin. In multiple linear regression analyses, additional estimates of visceral adiposity (intraabdominal fat and maximal anterior-posterior diameter determined by CT scan) were significant determinants of leptin in the healthy subjects. The increase in fasting insulin levels during GH substitution correlated negatively with the reduction in leptin levels (r = -.823, P = .003). At baseline, leptin levels were increased in the patients compared with controls in both sexes (women, 21.8 +/- 3.3 v 11.3 +/- 1.4 ng/mL, P = .002; men, 8.1 +/- 1.2 v 4.7 +/- 0.7 ng/mL, P = .008). Leptin levels were similar in GHD patients treated for 12 months compared with healthy controls for both women and men (women, 15.9 +/- 2.3 and 11.3 +/- 1.4 ng/mL, P = .163; men, 7.1 +/- 2.8 and 4.7 +/- 0.7 ng/mL, P = .759). In healthy adults and in GHD patients, leptin levels were significantly higher in women than in men (11.3 +/- 1.4 v 4.7 +/- 0.7 ng/mL, P < .001; 21.8 +/- 3.3 v 8.1 +/- 1.2 ng/mL, P < .001). Gender remained a significant determinant of leptin levels in several models of multiple linear regression analysis also including age, estradiol levels, insulin, and estimates of body fat. We conclude that leptin is increased but not differently regulated in GHD patients compared with normal subjects, and that leptin levels are closely related to estimates of body fat. This relationship is maintained during a decrease in body fat due to GH substitution.     

Outcome of differentiated thyroid cancer diagnosed in pregnant women

The clinical features and outcome of thyroid cancer in 61 pregnant women (mean age, 26.0 +/- 5.9 SD yr) and in 528 female, age-matched controls who were not pregnant (mean age, 26.3 +/- 5.9 SD yr) were compared. Median follow-up was 22.4 and 19.5 yr [P = not significant (NS)] in the two groups, respectively. The thyroid nodule was asymptomatic and discovered on routine examination more often in the pregnant women (74%) than in controls (43%, P < 0.001); other clinical and tumor features were similar in the two groups. Most of the pregnant women underwent thyroidectomy after delivery (77%) or during the second trimester of pregnancy (20%). Near-total thyroidectomy was done in 43 (73%) of the pregnant women and 265 (59%) of the controls (P = NS), and nearly the same proportion of both groups (30% and 25%, respectively) were treated with 131I postoperatively. Outcome in the pregnant women and controls, respectively, was: cancer recurrence 9 (15%) and 107 (23%, P = NS); distant recurrences 1 (2%) and 12 (3%, P = NS), and cancer deaths 0 and 6 (1.2%, P = NS). Outcomes were similar when surgery was done during or after pregnancy, despite a longer delay in treatment of the latter (1.1 +/- 1.0 vs. 16.1 +/- 19.7 months, P < 0.001). This study suggests that the prognosis of differentiated thyroid cancer is the same in pregnant women and nonpregnant women of the same age, and that the diagnosis and treatment of thyroid cancer occurring during pregnancy can be delayed until after delivery in most patients.     

Vascular patterns of gestational trophoblastic tumors by color Doppler ultrasound

BACKGROUND: Destruction of uterine vasculature is a common phenomenon in gestational trophoblastic tumors. The authors categorized such uterine vasculature by color Doppler ultrasound and studied its clinical significance. METHODS: Color Doppler ultrasound was performed in 28 patients with gestational trophoblastic tumors. The vascular morphologic manifestations were recorded, and the peak systolic velocity and resistance index of uterine artery were calculated. Serum beta-human chorionic gonadotropin (hCG) levels were measured periodically to monitor chemotherapy response. Seventeen uneventful postmole uteri were used as controls. Two-tailed Student's t-test and Fisher's exact test were used for statistical analysis. RESULTS: The gestational trophoblastic tumors were categorized as diffuse type (N = 7), lacunar type (N = 16), and compact type (n = 5) according to their vascular patterns. The mean serum beta-hCG level at diagnosis in diffuse type lesions (6608 +/- 6320 mIU/mL) was significantly lower than in the lacunar type (40462 +/- 39735 mIU/mL; P = 0.04) and compact type (212114 +/- 205126 mIU/mL; P = 0.02), whereas the level in compact type lesions was significantly higher than in the lacunar type (P = 0.003). Lacunar type lesions exhibited a significantly lower uterine artery resistance index (0.51 +/- 0.13) than diffuse type (0.66 +/- 0.10; P = 0.03) or compact type lesions (0.70 +/- 0.06; P = 0.02). All lesions exhibited significantly higher peak systolic velocity than control subjects (P < 0.001); however, no significant difference was observed among them. Brief courses (< 5 cycles) of chemotherapy cured more diffuse type (6 of 7) than lacunar type (3 of 15, P = 0.006) or compact type lesions (0 of 5, P = 0.008). Histopathologic diagnosis was available for 11 lesions. They were invasive mole in seven lacunar type lesions and choriocarcinoma in four compact type lesions. CONCLUSION: Vascular morphologic patterns of gestational trophoblastic tumors by color Doppler ultrasound correlated well with beta-hCG levels, uterine hemodynamics, chemotherapy response, and possibly the histopathologic diagnosis.