Reduction in hematocrit level after pioglitazone treatment is correlated with decreased plasma free testosterone level, not hemodilution, in women with polycystic ovary syndrome

Thiazolidinediones have gained widespread use for the treatment of type 2 diabetes mellitus and other insulin resistance states, including polycystic ovary syndrome (PCOS). In thiazolidinedione-treated patients a small reduction in hemoglobin and hematocrit levels often is observed, and this generally has been attributed to fluid retention. Because testosterone is a hematopoietic hormone, we investigated whether a reduction in plasma free testosterone concentration was associated with the decrease in hemoglobin and hematocrit levels in 22 nondiabetic women (9 with normal glucose tolerance and 13 with impaired glucose tolerance; mean age, 29 +/- 5 years; mean body mass index, 35.6 +/- 5.8 kg/m2) with PCOS who were treated with pioglitazone, 45 mg/d. Before treatment and after 4 months, subjects underwent an oral glucose tolerance test and measurement of total body water content with bioimpedance. Plasma testosterone, androstenedione, dehydroepiandrosterone sulfate, hemoglobin, and hematocrit levels were evaluated at baseline and every month for 4 months. The fasting plasma glucose concentration (98 +/- 9 mg/dL) was unchanged after pioglitazone treatment, whereas the 2-hour plasma glucose concentration declined from 146 +/- 41 to 119 +/- 20 mg/dL (P = .002). Both the free androgen index and the free testosterone levels calculated according to Vermeulen et al decreased significantly (from 14.4 +/- 7.1 to 10.6 +/- 7.8 [P = .02] and from 59.4 +/- 23.4 to 46.6 +/- 23.3 [P = .03], respectively). The plasma androstenedione level declined from 259 +/- 134 to 190 +/- 109 ng/dL (P = .01), whereas the dehydroepiandrosterone sulfate level did not change significantly (from 139 +/- 90 to 127 +/- 84 mug/dL, P = .2 [not significant]). The levels of both hemoglobin (from 13.6 +/- 1.0 to 12.8 +/- 1.1 g/dL, P = .0002) and hematocrit (from 39.7% +/- 2.2% to 37.9% +/- 2.7%, P = .002) fell slightly after 4 months of pioglitazone administration. Collectively, before and after pioglitazone administration, the plasma free testosterone level according to Vermeulen et al correlated positively with the levels of hemoglobin (r = 0.49, P < .0001) and hematocrit (r = 0.40, P < .0001), as well as the free androgen index (r = 0.38 [P < .0003] with hemoglobin and r = 0.29 [P < .006] with hematocrit); the decrement in plasma free testosterone level and free androgen index also correlated with the decrements in the levels of both hemoglobin (r = 0.51 [P = .01] and r = 0.54 [P = .01], respectively) and hematocrit (r = 0.42 [P = .05] and r = 0.50 [P = .02], respectively). Body weight increased from 90.5 +/- 17.3 to 92.4 +/- 18.8 kg after pioglitazone administration (P = .05), as did body fat content (from 42.7 +/- 15.3 to 44.8 +/- 17.1 kg, P = .03), which could explain the increase in weight, because edema did not develop in any of the subjects. Total body water content did not change significantly after pioglitazone administration (from 37.7 +/- 5.0 to 37.8 +/- 4.9 L, P = .68 [not significant]). In summary, pioglitazone treatment is associated with a mild decline in hematocrit or hemoglobin level, which is correlated with the reduction in plasma testosterone level. These results suggest that increased body water content cannot explain the reduction in hematocrit or hemoglobin level in women with PCOS. Further studies are necessary to evaluate whether the same scenario is applicable to normoandrogenic women and individuals with type 2 diabetes mellitus.     

Anemia with erythropoietin deficiency occurs early in diabetic nephropathy

OBJECTIVE: The normochromic normocytic anemia of erythropoietin (EPO) deficiency is recognized in advanced renal failure but not in early renal disease. The aim of this study was to determine whether anemia with EPO deficiency is found in type 1 diabetic patients with diabetic nephropathy in the absence of advanced renal failure and to compare them with patients with nondiabetic renal disease of similar severity. RESEARCH DESIGN AND METHODS: A total of 27 type 1 diabetic patients with diabetic nephropathy (DN), defined as having persistent proteinuria (mean 1,086 mg/day [CI 120-5,1901), a serum creatinine < or = 180 micromol/l, and retinopathy, were compared with 26 nondiabetic patients with glomerulonephritis (GN) and persistent proteinuria (1,874 mg/day [349-5,005]). The Hb concentration, red cell indexes, and serum EPO levels were measured, and other causes for the anemia were excluded. The EPO values were compared with a normal reference range obtained from nondiabetic patients with a microcytic anemia. The DN patients were tested for signs of diabetic peripheral and autonomic neuropathy. RESULTS: We found that 13 of the 27 DN patients were anemic (Hb 10.6 +/- 0.9 g/dl) in marked contrast to none of the GN patients (Hb 13.7 +/- 1.4 g/dl, P < 0.005). In the DN group, serum EPO concentrations failed to increase in response to anemia compared with the response seen in patients with microcytic anemia. Thus, the anemia of the DN group was associated with EPO deficiency. The anemic DN patients showed evidence of more severe proteinuria and diabetic neuropathy than the nonanemic DN patients. CONCLUSIONS: Anemia associated with EPO deficiency can occur early in DN before the onset of advanced renal failure, but does not normally occur in nondiabetic renal disease of similar severity. The pathogenesis requires elucidation.     

Testosterone concentration in young patients with diabetes

OBJECTIVE—We have previously shown that hypogonadotrophic hypogonadism is common in middle-aged patients with type 2, but not with type 1, diabetes. We have now investigated the total and free testosterone concentrations in young (aged 18–35 years) type 1 and type 2 diabetic patients.RESEARCH DESIGN AND METHODS—In this study carried out in a tertiary referral center, serum concentrations of total and free testosterone were measured in 38 type 1 diabetic (mean age 26.45 ± 0.89 years) and 24 type 2 diabetic (mean age 27.87 ± 0.97 years) subjects. The mean BMI of type 1 and type 2 diabetic patients was 27.41 ± 1.18 and 38.55 ± 2.04 kg/m², respectively (P < 0.001).RESULTS—The mean total testosterone concentration of type 1 and type 2 diabetic patients was 22.89 ± 1.23 and 11.14 ± 0.99 nmol/l, respectively (P < 0.001). The mean free testosterone concentration of type 1 and type 2 diabetic patients was 0.489 ± 0.030 and 0.296 ± 0.022 nmol/l, respectively (P < 0.001). Eight of 24 (33%) type 2 diabetic patients had subnormal free testosterone concentrations (<0.225 nmol/l). Using an age-based reference range, 14 of 24 (58%) type 2 diabetic patients had low free testosterone concentrations (<0.278 nmol/l). Three of 38 (8%) type 1 diabetic patients had free testosterone concentrations below the lower limit of normal (P = 0.02 when compared with type 2 diabetes). Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations in type 2 diabetic patients with low free testosterone concentrations were in the normal range and were similar to those in type 1 diabetic patients.CONCLUSIONS—Young type 2 diabetic patients have significantly lower plasma concentrations of total and free testosterone and inappropriately low LH and FSH concentrations with a very high prevalence of hypogonadotrophic hypogonadism, when compared with type 1 diabetic patients of a comparable age. The potential implications for their sexual and reproductive function during prime reproductive years are profound.We have previously shown that patients with type 2 diabetes have a frequent occurrence of hypogonadotrophic hypogonadism, as reflected in low plasma concentrations of testosterone and inappropriately low luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (1). These studies were carried out in patients with a mean age of 55 years. Other studies (2,3), also carried out in middle-aged populations, have confirmed the frequent occurrence of this defect in type 2 diabetes. We have also shown that the prevalence of this defect is very low in type 1 diabetes (4). In view of the increasing incidence of obesity and type 2 diabetes in younger populations and in children, the occurrence of this defect in younger populations needs to be investigated, since such an abnormality would affect their sexual function, reproductive capacity, and the quality of life during their peak reproductive years. In addition, the lack of testosterone would also potentially promote further weight gain and loss of skeletal muscle and would thus promote insulin resistance (5–7). In view of the above observations, we have now hypothesized that younger patients with type 2 diabetes have significantly lower testosterone concentrations and a higher prevalence of low testosterone concentrations (hypogonadism) when compared with patients with type 1 diabetes.     

Sex hormone suppression by intrathecal opioids: a prospective study

OBJECTIVE: Sexual dysfunction and low testosterone levels have been observed previously in males with chronic noncancer pain treated with intrathecal opioids. To investigate the hypothesis that intrathecal opioids suppress the hypothalamic-pituitary-gonadal axis, a prospective nonrandomized investigation of the function of this axis was undertaken. DESIGN: Ten males with chronic noncancer pain were evaluated for clinical and biochemical evidence of hypogonadism at baseline and during the first twelve weeks of intrathecal opioid therapy. RESULTS: Intrathecal opioid administration resulted in a significant (p <0.0001) reduction in serum testosterone, from 7.7 +/- 1.1 (mean +/- SEM) nmol/L at baseline to 2.0 +/- 0.7, 2.8 +/- 0.5, and 4.0 +/- 0.9 nmol/L at 1, 4, and 12 weeks, respectively. This was associated with a reduction in libido and potency. Luteinizing hormone and follicle-stimulating hormone levels remained within reference ranges, indicating central rather than peripheral suppression. CONCLUSIONS: Administration of intrathecal opioids may result in hypogonadotrophic hypogonadism. As part of the consent for therapy process, patients should be informed about this effect and its management. With long-term intrathecal opioid administration, the hypothalamic-pituitary-gonadal axis should be monitored. Where indicated, testosterone replacement should be undertaken to improve sexual function and prevent the potential metabolic effects of hypogonadism, in particular, osteoporosis.     

Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain.

Hypogonadotrophic hypogonadism is characteristically induced in men by intrathecal, transdermal, or sustained-action opioids. Although women receiving intrathecal opioids have similar changes, often accompanied by amenorrhea, hypogonadotrophic hypogonadism has not been documented in women receiving sustained-action, transdermal, or oral opioids. Dehydroepiandrosterone sulfate deficiency, indicating adrenal inhibition, is present in most men and women chronically consuming sustained-action oral or transdermal opioids. We recorded menstrual histories and measured gonadotrophin, androgen, and estradiol levels in 47 women ages 30 to 75 years who were consuming sustained-action oral or transdermal opioids for control of nonmalignant pain and in 68 non-opioid-consuming control subjects. Testosterone, estradiol, and dehydroepiandrosterone sulfate values were 48% to 57% lower in opioid-consuming women with intact ovarian tissue than in control subjects (P < .01-.05). Luteinizing hormone and follicle-stimulating hormone values averaged 30% lower in premenopausal and 70% lower in postmenopausal opioid consumers (P < .001). Among oophorectomized women not consuming estrogen, free testosterone levels were 39% lower in opioid consumers (P < .05), indicating impaired adrenal androgen production. Additional lowering of free testosterone levels was associated independently with oral estrogen replacement and low body mass index. Menses had often ceased soon after beginning sustained-action opioid therapy. Our observations document hypogonadotrophic hypogonadism plus decreased adrenal androgen production in most women consuming sustained-action oral or transdermal opioids. PERSPECTIVE: These observations demonstrate profound inhibition of ovarian sex hormone and adrenal androgen production among women chronically consuming sustained-action opioids. Related consequences include altered menstrual flow, probable reduced fertility, and possible contributions to opioid-associated depression, osteoporosis, and hyperalgesia. Measurements of bone density, estradiol, and free testosterone may guide appropriate therapy.     

Pancytopenia caused by unsuspected pernicious anemia complicating sickle cell beta-thalassemia.

We have described a a 23-year-old black woman with sickle cell beta-thalassemia who had a urinary tract infection and who was incidentally found to be pancytopenic. Although her anemia was categorized as "normocytic, normochromic" by an electronic particle counter, evaluation of the pancytopenia confirmed unsuspected pernicious anemia. Greater vigilance and a higher index of suspicion are crucial for early diagnosis of pernicious anemia in patients with other known hemoglobinopathies.     

Anemia in acute phase of spinal cord injury

Anemia is a frequent complication during the acute phase of spinal cord injury (SCI), even in the absence of detectable blood loss. Since an improved understanding of the etiology of anemia in this population is a prerequisite to its ultimate prevention, a prospective study was conducted on 28 persons with SCI whose lesions were between C3 and C7. The injuries were either neurologically complete, incomplete with sensory sparing only, or incomplete with nonfunctional motor preservation. Laboratory profiles were obtained during the first few weeks postinjury. No persons had below-normal plasma volumes, while 9% had below-normal blood volumes. However, 82% had below-normal red cell masses, 25% had below-normal serum erythropoietin levels, and 11% had below-normal reticulocyte counts. Other below-normal values included erythrocyte count (75%), hemoglobin (79%), hematocrit (71%), mean corpuscular volume (11%), mean corpuscular hemoglobin (11%), serum iron (50%), total iron binding capacity (86%), iron saturation (50%), serum total protein (57%), serum albumin (89%), serum globulin (32%), and serum transferrin (79%). Most persons (71%) were found to have normochromic, normocytic anemia, although 14% had normochromic, microcytic anemia. Only 14% did not develop anemia. Although these cases of anemia were not severe enough to require transfusions, they might be an important factor in the development of other secondary complications and may combine with other nutritional and hematologic deficiencies to prolong the rehabilitation process.     

Hormone changes in men with spinal cord injuries.

The steady state profiles of 63 men with traumatic spinal cord injuries (24 quadriplegics and 39 paraplegics; average age of 31.2 +/- 6.8 yr; 18-44 yr) were studied. The average length of post-traumatic period was 6.2 +/- 5.0 yr, ranging from 8 months to 20 yr. It was found that all the subjects had normal serum thyroxine, thyrotropin, cortisol, growth hormone and plasma adrenocorticotropic hormone. Seven cases (11.1%) had low serum triiodothyronine and eight cases (12.7%) had low serum testosterone. On the other hand, 17 cases (27.0%) had hyperprolactinemia; 9 cases (14.3%) had elevated serum testosterone level; 6 cases (9.5%) had elevated serum follicle-stimulating hormone; and 4 cases (6.3%) had elevated serum luteinizing hormone. The level of spinal cord injury, injury period and patient age had no correlation with other serum hormone changes except that quadriplegic subjects had lower serum triiodothyronine than the paraplegic, with a mean of 1.42 +/- 0.30 v 1.70 +/- 0.36 nmol/liter (P < 0.005). Of the eight subjects who had low serum testosterone, none had elevated gonadotropin. There were also eight subjects with elevated follicle-stimulating hormone and/or luteinizing hormone, six of them had normal serum testosterone and two had elevated serum testosterone. This suggested their hypogonadism did not result primarily from classic primary gonadal failure. It could be speculated that other testicular paracrine factors and/or alteration of hypothalamus-pituitary-testicular axis are involved in the pathogenesis of hypogonadism. Further studies in this field will provide information regarding male reproductive physiology and may have impact on fertility enhancement options for men with spinal cord injuries.     

Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes

OBJECTIVE: There is evidence to suggest that low concentrations of testosterone are associated with an increased risk of cardiovascular disease in men. The aim of this study was to evaluate the relationship between serum testosterone concentration and carotid atherosclerosis as well as major cardiovascular risk factors in men with type 2 diabetes. RESEARCH DESIGN AND METHODS: Serum free and total testosterone concentrations were measured in 253 consecutive men with type 2 diabetes. The relationships between serum testosterone concentration and carotid atherosclerosis, determined by ultrasonographically evaluated intima-media thickness (IMT) and plaque score (PS) in a subgroup of 154 diabetic patients, as well as major cardiovascular risk factors, including age, blood pressure, and lipid concentrations, were evaluated. RESULTS: Inverse correlations were found between free testosterone (F-tes) concentration and IMT (r = -0.206, P = 0.0103) and between F-tes concentration and PS (r = -0.334, P < 0.001). The IMT and PS were significantly greater in patients with lower concentrations of F-tes (<10 pg/ml) than in patients with higher concentrations of F-tes (1.01 +/- 0.29 vs. 0.91 +/- 0.26 mm, P = 0.038; 4.5 +/- 3.8 vs. 2.4 +/- 3.2, P = 0.0003; respectively). An inverse correlation was found between serum F-tes concentration and age (r = -0.420, P < 0.0001). A positive correlation was found between serum F-tes and total cholesterol concentrations (r = 0.145, P = 0.0238). CONCLUSIONS: Serum F-tes concentration is inversely associated with carotid atherosclerosis determined by ultrasonographically evaluated IMT and PS in men with type 2 diabetes.     

The activity of nonspecific inflammation in hypertensive patients

AIM: To study the indices of nonspecific inflammation (C-reactive protein--CRP, interleukine 6--IL-6) in patients with essential hypertension (EH) as compared to a circadian profile of blood pressure (BP); changes of CRP in the course of therapy with indapamide-retard and ACE inhibitor perindopril. MATERIAL AND METHODS: The trial enrolled 81 patients with hypertension of stage I-II, moderate and high risk, aged 45.1 +/- 1.3 years, free of chronic inflammatory disease exacerbation, 2 months and more after acute respiratory diseases and 2-week absence of antihypertensive therapy. CRP was estimated by turbidimetry, IL-6--by ELISA, circadian BP monitoring was made using TM 2421 device. Seventeen patients were randomized to receive ariphon retard (Servier), twenty patients--prestarium. The data were processed with STATISTICA 6 programs. RESULTS: CRP level in the patients was 7.0 +/- 1.6 mg/l; an elevated CRP concentration (> 3 mg/l) was registered in 55% patients. These patients demonstrated a positive correlation of CRP concentration with the data of 24-h systolic BP (r = 0.37, p < 0.05) and 24-h diastolic BP (r = 0.43, p = 0.003) monitoring, abnormal circadian rhythm of BP (nondippers). IL-6 in the examinees was 6.7 +/- 1.3 pg/ml. An elevated IL-6 concentration was detected in 30%. In such patients a positive correlation was found between IL-6 and 24-h systolic and diastolic BP (r = 0.88; p < 0.05 and r = 0.97; p < 0.01, respectively). CONCLUSION: A positive correlation between CRP, IL-6 and BP may evidence for involvement of nonspecific inflammation in the course of EH. Patients with elevated CRP responded to ariphon retard with positive CRP dynamics. This can be explained by a relief of chronic hemodynamic stress. A positive CRP dynamics in response to prestarium can be mediated by block of angiotensin II.     

Associations Among Hypogonadism,C-Reactive Protein,Symptom Burden,and Survival in Male Cancer Patients with Cachexia: A Preliminary Report

ContextCachexia is characterized by muscle wasting, anorexia, and elevated inflammatory markers. In patients without cancer, hypogonadism is associated with lower lean body mass, increased symptom burden, and decreased survival. Hypogonadism in cancer cachexia could exacerbate symptoms, facilitate a proinflammatory state, and decrease survival.ObjectivesTo explore the relationships among these factors, a retrospective study of male cancer patients was conducted.MethodsThe charts of 98 consecutive male patients referred to a cachexia clinic at a comprehensive cancer center were reviewed. All patients reported weight loss of >5% within the preceding six months; the median age was 60 years. Fifty-seven (58%) had serum C-reactive protein (CRP), and 68 (69%) had total testosterone evaluated. Symptoms were evaluated by the Edmonton Symptom Assessment Scale.ResultsMedian CRP was 20 mg/L, and median testosterone level was 185 ng/dL (6.42 nmol/L) (normal ≥240 ng/dL or 8.36 nmol/L). There was an inverse correlation between testosterone and CRP levels (P < 0.01). Lower testosterone was associated with increased dyspnea and insomnia (P < 0.05). Poor appetite and insomnia (P < 0.05) correlated with elevated CRP. Survival of patients with testosterone levels ≤185 ng/dL (6.42 nmol/L) was decreased compared with that of those with levels >185 ng/dL (13 vs. 62 weeks, P = 0.004). Patients with CRP levels >10 mg/L had decreased survival compared with those with levels ≤10 mg/L (15 vs. 46 weeks, P = 0.01). The combination of hypogonadism and elevated CRP was associated with poorer prognosis. Elevated CRP levels were associated with increased symptom burden and decreased survival. Low testosterone was associated with decreased survival and correlated inversely with CRP levels, dyspnea, and insomnia.ConclusionOur preliminary results suggest that testosterone and CRP may be additive or synergistic as markers for survival in male patients and could be useful in future prognostic models.     

Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men

OBJECTIVE: The goal of this study was to examine the relationship between serum testosterone levels and insulin sensitivity and mitochondrial function in men. RESEARCH DESIGN AND METHODS: A total of 60 men (mean age 60.5 +/- 1.2 years) had a detailed hormonal and metabolic evaluation. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Mitochondrial function was assessed by measuring maximal aerobic capacity (V(O2max)) and expression of oxidative phosphorylation genes in skeletal muscle. RESULTS: A total of 45% of subjects had normal glucose tolerance, 20% had impaired glucose tolerance, and 35% had type 2 diabetes. Testosterone levels were positively correlated with insulin sensitivity (r = 0.4, P < 0.005). Subjects with hypogonadal testosterone levels (n = 10) had a BMI >25 kg/m(2) and a threefold higher prevalence of the metabolic syndrome than their eugonadal counterparts (n = 50); this relationship held true after adjusting for age and sex hormone-binding globulin but not BMI. Testosterone levels also correlated with V(O2max) (r = 0.43, P < 0.05) and oxidative phosphorylation gene expression (r = 0.57, P < 0.0001). CONCLUSIONS: These data indicate that low serum testosterone levels are associated with an adverse metabolic profile and suggest a novel unifying mechanism for the previously independent observations that low testosterone levels and impaired mitochondrial function promote insulin resistance in men.     

C-reactive protein in patients on chronic hemodialysis with different techniques and different membranes.

In hemodialysis patients, C-reactive protein (CRP), an acute-phase reactant, is a sensitive and independent marker of malnutrition, anemia, and cardiovascular mortality. The aim of the present study was to evaluate CRP levels in plasma samples from long-term hemodialysis patients on different extracorporeal modalities and dialyzed with different membranes, at baseline and after 6 months. Two hundred and forty-seven patients were recruited in eight hospital-based centers. All patients had been on their dialytic modality for at least 3 months and were prospectively followed in their initial dialytic modality for 6 months. Patients were treated with conventional bicarbonate dialysis (N = 127) or hemodiafiltration (N = 120). Patients treated with conventional bicarbonate dialysis were dialyzed with different membranes: Cuprophane (N = 51), low-flux cellulose modified membrane (N = 37) and synthetic membranes (N = 39). Hemodiafiltration was performed in post-dilution mode with polysulfone (N = 66) and polyacrylonitrile (N = 54) membranes. Analysis of baseline CRP values in the clinically stable patients showed that an unexpectedly high proportion (47%) of the patients had CRP values higher than 5 mg/l (upper limit in normal subjects). The mean +/- S.D. CRP values were significantly higher (P < 0.05) in hemodiafiltration with infusion volumes < 10 l per session (14.6+/-3.1 mg/l) than in standard hemodialysis (5.1 +/- 2.1 mg/l) and hemodiafiltration with infusion volumes > 20 l per session (4.9 +/- 2.1 mg/l). These values did not significantly change after 6 months of follow-up. Concerning the membranes, the highest levels of CRP were observed in patients dialyzed with Cuprophane with a significant increase from 15.1 +/- 3.6 to 21.2 +/- 3.1 mg/l after 6 months (P < 0.05); a significant reduction of CRP levels was observed in patients dialyzed with polysulfone in the same follow-up period (from 13.5 +/- 2.9 to 8.1 +/- 2.4 mg/l; P < 0.05). The CRP increase following low volume HDF can be related to back-filtration of bacterial derived contaminants.; moreover, an important effect on CRP of the hemodialysis membrane is observed and new synthetic membranes can be used to decrease these levels.     

Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes

OBJECTIVE

One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH.

RESEARCH DESIGN AND METHODS

A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks.

RESULTS

Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (−3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all).

CONCLUSIONS

Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.     

Erythropoietin requirement in patients with type 2 diabetes mellitus on maintenance hemodialysis therapy

Diabetes is known to be a risk factor for the severity of anemia in non-dialyzed patients with renal failure. The aim of this study was to evaluate differences in hemoglobin (Hb) response to erythropoietin (EPO) in diabetic and nondiabetic patients on chronic hemodialysis (CHD). Sixty-four patients on CHD were included in the study: 24 type 2 diabetics (mean age, 59+/-11 years; 10 men, 14 women) and 40 nondiabetics (age, 53+/-14 years; 21 men, 19 women). All patients received a fixed dose of 50 mg ferric saccharate and EPO per week, dosed individually to achieve a target Hb level of 12 g/dl. Hb levels, ferritin, transferrin saturation (TSAT), EPO requirement (IU/kg/week), folic acid, vitamin B12 and C-reactive protein (CRP) were measured every two months. Additionally, the incidence of infectious diseases during the observation period of six months was evaluated, and a univariate correlation analysis of CRP and EPO requirements was performed in both groups. Patients with and without diabetes were divided into two groups each: those with normal CRP and those with elevated CRP. The EPO requirements of these groups were compared. Under identical iron substitution the mean Hb level increased more, but not significantly, in non-diabetic patients than in diabetic patients. After 6 months the mean Hb levels were 12.1+/-1.2 versus 11.5+/-1.2 g/dl (NS), although the actual EPO requirement was higher in diabetic than in non-diabetic subjects (244+/-122 versus 183+/-118 IU/kg/week; p<0.05). CRP after 6 months was significantly higher in diabetic than in non-diabetic patients (2.6+/-2.2 versus 1.5+/-1.3 mg/dl; p<0.05), as was the incidence of infectious disease (n/patient/month) (0.24 versus 0.08; p<0.05). The correlation coefficient between CRP and EPO requirements was statistically significant in both diabetic (r=0.547 p<0.01) and non-diabetic subjects (r=0.577; p<0.001). All other laboratory indices were similar in both groups. In the diabetic patients with normal CRP (n=6) the Hb levels achieved after six months were similar to those of non-diabetic patients (n=10) with normal CRP (11.9+/-1.1 versus 12.1+/-1.2%), and the required EPO was comparable. We conclude that the Hb response to EPO is reduced in diabetic patients on CHD. This elevated EPO requirement may be explained by a greater prevalence of infectious diseases, characterized by a significantly higher CRP level, in these patients. Other causes for the elevated EPO requirement could be excluded.     

Clinical associations of C-reactive protein in systemic sclerosis

AIM: To evaluate incidence of C-reactive protein (CRP) rise and CRP associations with clinical manifestations in systemic sclerosis (SS). MATERIAL AND METHODS: CRP concentrations in blood serum were estimated with solid phase enzyme immunoassay in 21 SS patients (8 patients with diffuse SS--dSS and 13 patients with limited SS--lSS). Two patients with ISS had documented rheumatoid arthritis (RA)--SS/RA. Forty two healthy donors with normal levels of CRP served control. RESULTS: CRP was elevated in 10 (48%) of 21 SS patients. Mean CRP content was 9.87 +/- 7.73 mg/l (about 3 times higher than in the control group, p < 0.0001) in 20 eligible patients. A mean CRP level did not differ between ISS and dSS patients. RA patients had higher levels of CRP (p = 0.001). CRP was elevated in 4 of 5 (80%) patients with digital ulcers and only in 5 (27%) of 15 patients without ulcers, but the difference was insignificant as well as those in mean CRP in these subgroups. Content of von Willebrand factor antigen (Ag:vW) was high in 7 (33%) patients (mean 1.70 +/- 0.84 IU/ml) this being significantly higher than in the control group (p < 0.0001). CPR concentration closely correlated with that of Ag:vW (r = 0.52; p = 0.017). Close association was found between CRP level and ESR (r = 0.75; p < 0.001) and titer of antinuclear factor (r = 0.52; p = 0.035). CONCLUSION: A moderate rise of CRP level in about 50% cases of SS is associated with arthritis and cutaneous ulcers. A positive correlation between CRP content and Ag:vW in blood suggests that CPB concentrations may reflect severity of vascular damage in SS.     

Hematological parameters in characterization of anemia in leptospirosis

Blood samples from 46 patients with leptospirosis were analyzed on a Cobas Vega (ABX, France) device over the course of disease. Hemoglobin content, erythrocyte count, mean volume of erythrocytes, mean content and mean concentration of hemoglobin in an erythrocyte, anisocytosis index, reticulocyte count, and content of free hemoglobin (FH) were analyzed. Anemia (normocytic normochromic hyperregeneratory) is a typical manifestation of leptospirosis during the second week of disease. The leading pathogenetic mechanism of anemia associated with leptospirosis is erythrocyte hemolysis, whose intensity during the acute period depends on the severity of intoxication and extracorporeal methods of detoxication. Persistence of anemia during convalescent period is due to involvement of the kidneys (nephrotic nephritis).     

Association between acute-phase reactants and advanced glycation end products in type 2 diabetes

OBJECTIVE: Type 2 diabetes is associated with chronic low-grade inflammation, but the underlying mechanism(s) is not well understood. Because in vitro studies have shown that advanced glycation end products (AGEs) can trigger inflammatory responses, the present study has investigated whether serum concentration of AGEs is an important determinant of circulating levels of inflammatory markers, like C-reactive protein (CRP), in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Diabetic patients (n = 210) and healthy control subjects (n = 110) of similar BMI were recruited. Serum AGEs were assayed by competitive enzyme-linked immunosorbent assay using a polyclonal rabbit anti-sera raised against AGE-RNase. Plasma high-sensitivity CRP was measured by an immunoturbidimetric assay and interleukin (IL)-6 by enzyme-linked immunosorbent assay. RESULTS: Serum AGEs were increased in diabetic patients compared with control subjects (4.24 +/- 0.88 vs. 3.15 +/- 0.81 unit/ml, respectively, P < 0.01). Both plasma CRP (1.55 [0.81-2.95] vs. 0.88 mg/dl [0.51-1.89], respectively, P < 0.01; median [interquartile range]) and IL-6 (0.80 [0.68-0.97] vs. 0.69 pg/ml [0.48-0.84], respectively, P < 0.01) were also higher in diabetic patients than in control subjects. In the diabetic patients, log(CRP) correlated with AGEs (r = 0.22, P = 0.002) and with log(IL-6) (r = 0.29, P < 0.001). Forward stepwise linear regression analysis showed that BMI, log(IL-6), and AGEs were significant independent determinants of log(CRP) in the diabetic patients, accounting for 17, 12, and 10% of the variation in log(CRP), respectively. CONCLUSIONS: Serum concentration of AGEs is increased in patients with diabetes and is an independent determinant of plasma CRP levels. Subclinical inflammation in these patients may therefore be partly due to activation of the inflammatory response by AGEs.     

A practical guide to male hypogonadism in the primary care setting

There is a high prevalence of hypogonadism in the older adult male population and the proportion of older men in the population is projected to rise in the future. As hypogonadism increases with age and is significantly associated with various comorbidities such as obesity, type 2 diabetes, hypertension, osteoporosis and metabolic syndrome, the physician is increasingly likely to have to treat hypogonadism in the clinic. The main symptoms of hypogonadism are reduced libido/erectile dysfunction, reduced muscle mass and strength, increased adiposity, osteoporosis/low bone mass, depressed mood and fatigue. Diagnosis of the condition requires the presence of low serum testosterone levels and the presence of hypogonadal symptoms. There are a number of formulations available for testosterone therapy including intramuscular injections, transdermal patches, transdermal gels, buccal patches and subcutaneous pellets. These are efficacious in establishing eugonadal testosterone levels in the blood and relieving symptoms. Restoration of testosterone levels to the normal range improves libido, sexual function, and mood; reduces fat body mass; increases lean body mass; and improves bone mineral density. Testosterone treatment is contraindicated in subjects with prostate cancer or benign prostate hyperplasia and risks of treatment are perceived to be high by many physicians. These risks, however, are often exaggerated and should not outweigh the benefits of testosterone treatment.     

Hyperfibrinogenemia. An important risk factor for vascular complications in diabetes.

OBJECTIVE--To evaluate the determinants of elevated fibrinogen levels and the impact of hyperfibrinogenemia on vascular complications in diabetes. RESEARCH DESIGN AND METHODS--Plasma fibrinogen, glucose, HbA1, and lipids were measured in 116 ambulatory type I and type II diabetic patients with (n = 59) or without (n = 57) clinical evidence of micro- or macrovascular complications. In 56 of these patients, factor VII activity and CRP also were measured. Univariate and multivariate data analyses were conducted. RESULTS--Overall mean +/- SE fibrinogen levels in patients (339 +/- 7.3 mg/dl) were elevated markedly compared with control subjects (248 +/- 9.1 mg/dl). Fibrinogen levels were elevated disproportionately in patients with type II diabetes (P less than 0.0001), hypertension (P = 0.0001), obesity (P less than 0.0001), and vascular complications (P less than 0.0001). Fibrinogen was correlated significantly with age (P less than 0.001), cholesterol (P = 0.002), CRP (P less than 0.001), and factor VII activity (P = 0.032), but not with plasma glucose, triglycerides, HDL cholesterol, or disease duration. Stepwise multiple regression analyses revealed that type II diabetes and presence of vascular complications were major determinants of fibrinogen. For vascular complications, fibrinogen emerged as one of only three independent predictors, the other two being diabetes duration and hypertension.