Relationship between testosterone deficiency and cardiovascular risk and mortality in adult men.

Classic male hypogonadism is associated with known adverse effects including decreased libido, erectile dysfunction, osteoporosis, and changes in body composition. Recently, we have come to appreciate that reduction in serum testosterone (T) levels resulting from aging or chronic disease or androgen deprivation therapy (ADT) have consequences similar to those seen in classic male hypogonadism which include increased fat mass, decreased lean body mass, decreased muscle strength, and sexual dysfunction. These data suggest that low T levels may represent a newly recognized cardiometabolic risk factor. Therefore, we carried out a careful review of the literature, focusing on major turning points of research and studies which gave more important and controversial contribution to the cardiovascular role of T. Observational studies and clinical trials investigating the relationship between T levels and cardiovascular disease and mortality were identified byMedline search. The results were synthesized, tabulated, and interpreted. The aim of this review is to discuss the association between low T levels and adverse metabolic profile such as insulin resistance, metabolic syndrome, and diabetes. We will also investigate the potential mechanisms by which male hypogonadism, especially age related or induced by ADT, may increase cardio-metabolic risk. Finally we will detail the emerging relationship between low T and mortality in men addressing also the reverse hypothesis that low T has a protective role by turning off T-dependent functions.

Effect of physiological exercise on osteocalcin levels in subjects with adrenal incidentaloma.

AIM: In the present study, we have evaluated whether physical exercise affect low osteocalcin concentrations observed in patients with subclinical hypercortisolism. SUBJECTS AND METHODS: Sixteen patients (10 men and 6 women, age 38-55 yr) with adrenal incidentaloma were studied. Fifteen healthy volunteers matched for age (range 35-47 yr) were used as controls. Subjects were submitted to a 8-week exercise-training program with cycle-ergometer for 1 h/day 3-4 days/week at 60% of their individual VO2 max. Before and after this period, resting venous serum osteocalcin and GH concentrations were measured in the same batch. The blood sampling after 8 weeks of the training program were performed after resting for one day. All patients and controls underwent also the following endocrine evaluation: serum cortisol, plasma ACTH. RESULTS: Our results demonstrate a significant increase of osteocalcin after physical exercise and a positive correlation between osteocalcin and GH. This later might suggest a role of GH in the increased osteocalcin secretion. CONCLUSIONS: The data of the present study suggest a positive effect of physical exercise on bone metabolism in patients with adrenal incidentaloma.

Systemic oxytocin administration modulates NPY response to insulin-induced hypoglycemia in man.

The present study was undertaken to establish whether oxytocin (OT) is able to modify the NPY response to insulin-induced hypoglycemia in man. At 8:00 AM of 2 different days at least 1 week apart, 10 normal men were tested with insulin (0.15 IU/kg) and with the administration of OT (infused from time -15-60 min, at a constant rate of 2 mIU/ml) or placebo. Plasma NPY concentrations rose significantly during insulin tolerance test (ITT). Oxytocin treatment significantly reduced the NPY response to hypoglycemia. The finding demonstrates for the first time in humans that the systemic administration of OT exerts an inhibitory effect on the NPY rise caused by insulin-induced hypoglycemia.

Somatostatin reduces neuropeptide Y rise induced by physical exercise.

The effect of an i. v. infusion of somatostatin (SRIH) 4.1 µg/min×90 min on the basal secretion of NPY and on the NPY response to physical exercise was studied in normal men. Basal NPY secretion was not modified by SRIH infusion, whereas the NPY response to physical exercise was significantly lower in the presence of SRIH. These data suggest the involvement of a somatostatinergic mechanism in the regulation of NPY response to physical exercise.

Update on low molecular weight heparins at the beginning of third millennium. Focus on reviparin.

BACKGROUND: This review provides an outline of the main pharmacological and clinical features of low molecular weight heparins (LMWHs) and a wider description of reviparin. The basic pharmacological properties of LMWHs are compared with those of unfractionated heparin, showing clear advantages of the former, mainly as for pharmacokinetic profile. DESIGN: Consequently LMWHs are characterized by a more predictable behaviour. A key issue is the lack of "bioequivalence": LMWHs are in fact distinct chemical entities, with typical pharmacological and clinical profile for each agent. Therefore, they are not reciprocally interchangeable. The efficacy and safety of reviparin, a second generation LMWH, has been evaluated in many clinical trials as both thrombosis prevention and treatment. Reviparin use is documented in general and orthopaedic surgery. In patients undergoing abdominal surgery reviparin resulted more effective and better tolerated than unfractionated heparin (UFH). In total hip replacement patients, reviparin compared favourably with enoxaparin, showing the same efficacy but better safety. In patients who undergone total hip replacement, also the long-term, out of hospital prevention of deep vein thrombosis (DVT) has been proven. CONCLUSIONS: The comparison with acenocoumarol demonstrated that reviparin was more effective in preventing DVT recurrences and far better tolerated than oral anticoagulant treatment. Reviparin was also effective and well tolerated in immobilised patients following leg injury with plaster casts or braces applications. Positive results were also obtained in the treatment of venous thromboembolism in well-designed studies on large patient populations. In this indication reviparin compared favourably with iv UFH. As for the use in cardiology patient, reviparin is at present the only approved LMWH for the prevention of acute thrombotic events in patients undergoing percutaneous transluminal coronary angioplasty.

Behavioral and hormonal effects of prolonged Sildenafil treatment in a mouse model of chronic social stress.

Chronic social defeat can inhibit the reproductive system of subordinate males and causes behavioral deficits. Sildenafil treatment increases mice testosterone levels through its effects on Leydig cells of mice and it has been found to work as an antidepressant drug both in humans and in animal models. Since previous findings showed that sildenafil can counteract the inhibitory effects of chronic social defeat on agonistic, reproductive and anxiety-like behaviors of subordinate male mice, we investigated whether these behavioral outcomes can be explained by Sildenafil stimulation of testosterone. CD1 mice underwent an intruder-resident paradigm. After the fifth day of test, subordinate mice were injected with either a 10 mg/kg Sildenafil or a saline solution for 4 weeks. The results of the present study showed that Sildenafil treatment increased counterattacking behaviors and sexual motivation of subordinate males in addition to limiting the increase in body weight often observed in subordinate mice following chronic psychosocial stress. Moreover, sildenafil treated mice showed a pattern of behaviors reflecting lower anxiety. In agreement with previous studies, Sildenafil also increased testosterone levels. These data demonstrate that sildenafil can counteract the effects of chronic stress, possibly through its stimulatory effects on Leydig cells. These data demonstrate that sildenafil might counteract the effects of chronic psychosocial stress through centrally and peripherally mediated mechanisms.

Naloxone decreases the inhibitory effect of ethanol on the release of arginine-vasopressin induced by physical exercise in man.

To establish whether ethanol and/or endogenous opioids play a role in the control of arginine-vasopressin (AVP) response to physical exercise, six healthy men underwent six bicycle-ergometer tests until exhaustion [exercise control test; exercise plus ethanol (50 of 110 ml proof whiskey orally), exercise plus naloxone (2 mg injected plus 5 mg infused or 4 mg injected plus 10 mg infused intravenously] or exercise plus ethanol plus naloxone). Plasma AVP levels, physiological and biochemical variables were measured during tests. Physiological and biochemical variables were similar in all tests. During the control test, exercise significantly increased plasma AVP levels, with a peak value five times higher than baseline. The AVP response to exercise was similar in the presence of naloxone, whereas it was abolished by ethanol. When ethanol tests were repeated in the presence of naloxone, at both lower and higher dose, ethanol inhibition on AVP secretion was only partial, with mean peak responses 2.5 times higher than basal values. Results indicate an ethanol involvement in regulation of the AVP response to physical exercise. Furthermore, naloxone-sensitive endogenous opioids appear to play a role in the mechanism underlying ethanol inhibitory action, but not in mediation of the AVP response to physical exercise.

Radiographic measurement of tibial joint angles in sheep.

The aim of this study was to establish normal reference values of anatomic and mechanical joint angles of the tibia in sheep at different age groups. Eighteen clinically healthy Santa Ines sheep were used. The animals were divided into three equal groups according to age: Group I - from six- to eight-months-old, Group II - 2-years-old, Group III - from three- to five-years-old. Anatomic medial proximal and lateral distal tibial angles, mechanical proximal and distal tibial angles, and anatomic caudal proximal and anatomic cranial distal tibial angles were measured from tibiae radiographs (n = 36). In the craniocaudal view, the mean values of the anatomic medial proximal, anatomic lateral distal, mechanical medial proximal, and mechanical lateral distal tibial joint angles were 89.6 masculine, 86.6 masculine, 91.4 masculine, and 85.19 masculine respectively. In mediolateral view, the mean values of the anatomic caudal proximal and anatomic cranial distal tibial angles were 64.55 masculine and 105.69 masculine, respectively. The joint orientation angles of the tibia in sheep showed similar values regardless of animal age for both anatomic and mechanical axes.

Evaluation of primary DNA damage, cytogenetic biomarkers and genetic polymorphisms for CYP1A1 and GSTM1 in road tunnel construction workers.

In tunnel construction workers, occupational exposure to dust (alpha-quartz and other particles from blasting), gases (nitrogen dioxide, NO(2)), diesel exhausts, and oil mist has been associated with lung function decline, induction of inflammatory reactions in the lungs with release of mediators that may influence blood coagulation, and increased risk of chronic obstructive pulmonary disease. The present molecular epidemiology study was designed to evaluate whether occupational exposure to indoor pollutants during road tunnel construction might result in genotoxic effects. A study group of 39 underground workers and a reference group of 34 unexposed subjects were examined. Primary and oxidative DNA damage, sister-chromatid exchanges (SCE), and micronuclei (MN) were measured in peripheral blood cells. The possible influences of polymorphisms in gene encoding for CYP1A1 and GSTM1 xenobiotic-metabolizing enzymes were also investigated. Exposure assessment was performed with detailed interviews and questionnaires. There were no significant differences in the level of primary and oxidative DNA damage and frequency of SCE between the tunnel workers and controls, whereas the frequency of MN showed a significant increase in exposed subjects compared to controls. No effects of CYP1A1 or GSTM1 variants were observed for the analyzed biomarkers. Since MN in peripheral blood lymphocytes are recognized as a predictive biomarker of cancer risk within a population of healthy subjects, the genotoxic risk of occupational exposure to various indoor environmental pollutants during road tunnel construction cannot be excluded by this biomonitoring study.

[Long-term outcome of large bone and osteochondral allografts]. / Devenir à long terme des allogreffes osseuses et ostéo-cartilagineuses massives cryopréservées.

Since 1978 the Marseille Bone Tissue Bank has stored 7466 specimens. Of these, 578 were large allografts, of which 529 have so far been used. The grafts are stored in liquid nitrogen with a cryopreserver, and are not sterilized by irradiation. They have been used to replace lost tissue after tumor excision, trauma, and repeated reconstructive surgery. Three hundred and thirteen patients were operated on between 1983 and 1998, and good integration was achieved in 82 % of cases. Immunological complications occurred in 14 % of cases. They were often confused with non microbial sepsis and responded well to immunosuppressive treatment, even though the fluid surrounding the graft sometimes fistulised to the skin. In 4.2 % of cases the graft had to be replaced, and in 6.4 % of cases a joint prosthesis had to be used.

Pharmacologic modulation of clodronate in local therapy of periodontal and implant inflammation.

Bisphosphonates are drugs used in the treatment of a variety of osteometabolic diseases. Recently they have been the object of research and studies on their potential application in dentistry and orthopedics. In particular, clodronate (non-aminobisphosphonates) has been studied, due to its reversible activity in comparison to apoptotic osteoclasts, the intrinsic action which stimulates the differentiation and activity of the osteoblasts, their antinflammatory activity, antipain and antioxidant action, represent the rational to estimate their clinical efficacy, for local use in dentistry, implatology, orthopaedic, rheumatology, oncology and dermatology.

Potential applications of biphosphonates in dental surgical implants.

Biphosphonates are largely used for their unquestionable properties of inhibiting bone resorption by osteoclasts in the treatment of various osteometabolic illnesses such as osteoporosis, multiple myeloma, tumors which metastasize to the bone and malignant hypercalcemia. In this literature review the physico-chemical properties, biologic activities and the mechanisms of action of biphosphonates are described. The use of these drugs is discussed, analyzing the quantity of results which have emerged through in vitro and in vivo experiments on animal models. In this study the efficiency of these drugs is demonstrated in contrasting the osteolitic processes of the alveolar bone, in promoting the neoformation and in bettering the quality of bone implants. However, it is important to draw attention to a worrying correlation which has emerged during the last 3-4 years, between osteonecrosis of the jaw (ONJ) and the systemic administration of aminobiphosphonates. This collateral effect did not emerge following the use of non-aminobiphosphonates. The aim of this review is to identify the guidelines for the use of biphosphonates in oral implant surgery.

Tibial segmental bone defect treated with bone plate and cage filled with either xenogeneic composite or autologous cortical bone graft. An experimental study in sheep.

Tibia segmental defect healing in sheep were clinically, radiographically and histologically evaluated. Twelve young sheep aged four to five months were divided into two groups, G1 and G2. A 3.5 cm long segmental defect was created in the right tibial diaphysis with maintenance of the periosteum. The bone defects in both groups were stabilized with a bone plate combined with a titanium cage. In G1 the cage was filled with pieces of autologous cortical bone graft. In G2 it was filled with a composite biomaterial which consisted of inorganic bovine bone, demineralized bovine bone, a pool of bovine bone morphogenetic proteins bound to absorbable ultra-thin powdered hydroxyapatiteand bone-derived denaturized collagen. Except for one G1 animal, all of them showed normal limb function 60 days after surgery. Radiographic examination showed initial formation of periosteal callus in both groups at osteo-tomy sites, over the plate or cage 15 days postoperatively. At 60 and 90 days callus remodeling occurred. Histological and morphometric analysis at 90 days after surgery showed that the quantity of implanted materials in G1 and G2 were similar, and the quantity of new bone formation was less (p = 0.0048) and more immature in G1 than G2, occupying 51 +/- 3.46% and 62 +/- 6.26% of the cage space, respectively. These results suggest that the composite biomaterial tested was a good alternative to autologous cortical bone graft in this experimental ovine tibial defect. However, additional evaluation is warranted prior to its clinical usage.

Seasonal variation of human semen parameters: A retrospective study in Italy.

INTRODUCTION: Human infertility is a common condition secondary to many primary or secondary causes. As for these latter, different seasonal and climatic patterns have been hypothesized to play a role. The aim of this study was to assess the presence of a possible seasonal pattern in the functional parameters of semen samples maintained in a large tertiary center database. MATERIALS AND METHODS: The reports of spermograms of 5188 consecutive subjects, collected at the Center for Reproductive Incapacity of the University Hospital of Parma during a 11-year period (2003-2014), were retrospectively analyzed. The reports included sperm motility, volume, and number, as well as pH, swelling and eosin tests. Data of different parameters were analyzed by season of sample collection. The ANOVA test was used for the evaluation of continuous variables, after Log transformation in case of a non-normal distribution, while χ(2) test was used for categorical variables. Moreover, logistic regression analysis was performed, to identify factors independently associated with normal sperm motility. RESULTS: Compared with the other seasons of the year, a higher sperm motility was found during the summer. Moreover, the prevalence of samples with a normal sperm pH (7.2-8) was higher during the spring, whilst the volume of sperm was higher in winter. Logistic regression analysis showed that normal sperm motility (>40%) was independently associated with spring (1.227; 95% CI 1.077-1.507, p = 0.005), summer (2.031; 95% CI 1.689-2.442, p < 0.001), swelling test (1.953; 95% CI 1.670-2.284, p < 0.001), eosin test (2.804; 95% CI 2.477-3.174, p < 0.001), pH (0.507; 95% CI 0.346-0.743, p < 0.001), LOG-number (2.949; 95% CI 2.470-3.522, p < 0.001) and LOG-volume (2.216; 95% CI 1.696-2.894, p < 0.001) of semen. CONCLUSION: This study suggests the existence of a positive relationship between some semen parameters and seasons.

Effect of systemic oxytocin administration on dexamethasone-induced leptin secretion in normal and obese men.

To establish whether the regulatory mechanism of leptin secretion is sensitive to oxytocin (OT), seven healthy nonobese men were tested with dexamethasone (dex; 4 mg, iv, at 0730 h) in feeding (2000 Cal given at 3 meals over 7 h) conditions either in the absence (iv normal saline infusion) or in the presence of a constant iv infusion of OT (1, 2, or 4 mIU/min from 0730 h for 10 h). In six additional subjects under similar experimental conditions, normal saline or OT (1, 2, or 4 mIU/min from 0730 h for 10 h) were infused iv without the previous treatment with dexamethasone. Serum leptin concentrations were measured in samples taken at 60-min intervals during infusion. Leptin levels remained constant during the infusion of normal saline or OT (1, 2, or 4 mIU/min) alone. In contrast, serum leptin concentrations rose significantly from the baseline after dex administration. The leptin response to dex was not modified by the concomitant infusion of 1 mIU/min OT, whereas it was completely abolished by the administration of 2 or 4 mIU/min OT. These findings led us to evaluate the secretory pattern of leptin in 12 obese patients in similar experimental conditions. In all patients basal leptin levels were significantly higher than those in normal weight subjects. In 6 obese subjects, the infusion of OT alone (1, 2, or 4 mIU/min) was unable to change serum leptin levels. In the remaining 6 obese subjects, dex administration significantly increased serum leptin levels; however, the leptin response to dex was not modified by the concomitant infusion of 1, 2, or 4 mIU/min OT. These data show inhibition by elevated circulating OT levels of glucocorticoid-induced, but not basal, leptin secretion in normal weight subjects, suggesting a possible role for OT in the regulatory control of leptin. Furthermore, the results obtained in obese subjects indicate that this regulation is disrupted in obesity.

The growth hormone response to thyrotropin-releasing hormone in insulin-dependent diabetics involves a cholinergic mechanism.

In order to establish whether cholinergic receptors mediate GH secretion induced by TRH in insulin-dependent diabetes, 10 patients were treated with pirenzepine, an anticholinergic agent, and tested with TRH. Basal concentrations of GH were elevated in these patients and 8 of 10 patients responded to TRH with a significant rise in GH levels. Pretreatment with pirenzepine (40 mg given iv 10 min before TRH) suppressed the TRH-induced GH rise. Pirenzepine had no effect on TRH-induced TSH release. This finding suggests that a cholinergic mechanism is involved in the paradoxical response of GH to TRH in diabetic patients.

Unreliability of TRH test but not dexamethasone suppression test as a marker of depression in chronic vasculopathic patients.

Thirteen vasculopathic nondepressed men, admitted to the hospital 2 weeks earlier because of stroke, 10 age- and weight-matched patients with major depression, and 10 age- and weight-matched normal controls were tested with TRH and on different occasion with the dexamethasone (DEX) suppression test (DST). Patients with stroke were tested again with TRH and DST after 1 year. All subjects were euthyroid. A blunted TSH response to TRH was observed in 77% of vasculopathic patients, 64% of depressed patients, and 27% of controls. Some depressed patients showed serum GH or cortisol increments in response to TRH. Nonsuppression to DEX was observed in 45% of depressed patients and 15% of vasculopathics but not in normal controls. These data indicate that, in contrast to cortisol nonsuppression to DEX, blunted TSH response to TRH has poor diagnostic value as a marker for depression after stroke and may merely represent the expression of neuroendocrine dysfunction associated with cerebral vasculopathy.

Lack of seasonal variation in abnormal TSH secretion in patients with seasonal affective disorder.

The circadian variations in thyroid-stimulating hormone (TSH) secretion, with particular attention to the nocturnal serum TSH surge and the TSH response to thyrotropin releasing hormone (TRH), were measured in seven patients with seasonal affective disorder (SAD) and in eight normal controls. Both patients with SAD and normal controls were tested in fall/winter, when patients were suffering depressive symptoms, and in spring/summer, when patients were euthymic. The TRH tests were performed in the morning. In all tests, the mean peak TSH response to TRH was significantly lower in the patients with SAD than in the normal controls. No significant differences were observed in either group between spring/summer and fall/winter tests. At both periods, patients with SAD showed normal TSH levels in the morning, but did not experience a nocturnal TSH surge. In this group, morning and night TSH levels were similar. In contrast, normal controls showed significantly higher TSH levels at night than in the morning. Serum-free thyroid hormone levels were in the normal range in all subjects. Morning and night serum cortisol levels and 24-hour urinary cortisol concentrations were similar in all subjects. These data show that the secretion of TSH is impaired in SAD, regardless of the phase of the psychiatric disease. The low TSH response to TRH in the presence of normal serum thyroid hormone levels and the lack of the TSH nocturnal surge suggest that patients with SAD might be affected by mild central hypothyroidism.

Opioid modulation of the gamma-aminobutyric acid-controlled inhibition of exercise-stimulated growth hormone and prolactin secretion in normal men.

The possible involvement of endogenous opioids in the gamma-aminobutyric acid-controlled (GABAergic) inhibition of growth hormone (GH) and prolactin (PRL) during physical exercise was evaluated in normal men. After fasting overnight, seven subjects were tested on four mornings at least 1 week apart. Exercise was performed on a bicycle ergometer. The workload was gradually increased at 3-min intervals until exhaustion and lasted about 15 min in all subjects. Tests were carried out under administration of placebo, the opioid antagonist naloxone (10 mg as an iv bolus injection), the GABAergic agonist sodium valproate (600 mg in three divided doses orally) or naloxone plus sodium valproate. During exercise, plasma GH and PRL levels rose 5.5- and 1.9-fold, respectively. The administration of naloxone did not modify, whereas sodium valproate significantly reduced the plasma GH and PRL rise during exercise. In the presence of sodium valproate, GH and PRL levels rose 3- and 1.5-fold, respectively, in response to exercise. When naloxone was given together with sodium valproate, both GH and PRL responses to exercise were abolished completely. These data suggest the involvement of a GABAergic mechanism in the regulation of GH and PRL responses to physical exercise in men. Furthermore, the data argue against a role of naloxone-sensitive endogenous opioids in the control of these hormonal responses to exercise, whereas they suggest a modulation by opioids of the GABAergic inhibitory action.