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L'Episcopo F.,OASI Institute for Research | Tirolo C.,OASI Institute for Research | Testa N.,OASI Institute for Research | Caniglia S.,OASI Institute for Research | And 5 more authors.
Rejuvenation Research | Year: 2011

Aging represents a major risk factor for the development and progression of Parkinson disease (PD), a chronic degenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc). Emerging evidence highlights the glia as a pivotal factor in PD etiology, and epidemiological studies indicate that certain nonsteroidal antiinflammatory drugs (NSAIDs) may prevent or delay the progression of PD. Given that the exaggerated inflammatory response observed in old age may play a critical role in exacerbating DAergic vulnerability, we hypothesize here that switching the harmful glial response to inflammation and oxidative stress might increase the ability of the SN to resist inflammatory attacks. To this end, we developed a treatment in which we combined the effects of nitric oxide (NO) with nonsteroidal antiinflammatory activity by using HCT1026, a NO-donating derivative of flurbiprofen that has a safe profile and additional immunomodulatory properties. Young and aged mice fed with control or HCT1026 (30mg kg -1 day -1) diet were exposed to a single systemic injection of a subtoxic dose (0.2mg kg -1) of lipopolysaccharide (LPS), one of the most extensively used glial activators. HCT1026 efficiently reversed the age-dependent increase of microglial activation in response to LPS to levels measured in younger mice. In aged mice, LPS induced a progressive loss of DAergic neurons with no recovery for their entire life span, whereas younger mice or aged mice fed with HCT1026 were resistant to systemic LPS-induced DAergic neurodegeneration, underscoring glia as a key pharmacological target for DAergic neuroprotection. © 2011 Mary Ann Liebert, Inc.


Fulghesu A.M.,University of Cagliari | Romualdi D.,Catholic University of the Sacred Heart | Di Florio C.,Catholic University of the Sacred Heart | Sanna S.,University of Cagliari | And 7 more authors.
Human Reproduction | Year: 2012

STUDY QUESTIONDo different dosages of metformin account for different clinical and biochemical outcomes in women with polycystic ovary syndrome (PCOS) and do basal anthropometric and metabolic characteristics of the patients provide any indications regarding the dose required to reach the target effect? Summary answerDifferent doses of metformin exerted the same effects on clinical, biochemical and metabolic parameters in patients affected by PCOS. WHAT IS KNOWN AND WHAT THIS PAPER ADDSSince the insulin-sensitizing agents came into use in the management of PCOS, metformin has shown a positive benefitsrisks ratio. Nonetheless, therapeutic schedules are not well standardized. This is the first study which systematically analyses the effect of different doses of metformin on clinical, hormonal and metabolic features of PCOS. On the basis of our results, higher doses are no more effective than lower doses. DESIGNA multicentric cohort prospective study. A total of 250 PCOS women were enrolled, 49 lost to follow-up. Menstrual cyclicity, hormonal assays, oral glucose tolerance test, lipid profile and ultrasonographic pelvic examination were evaluated at the baseline and after 6 months of metformin treatment at different doses (1000, 1500 and 1700 mg). PARTICIPANTS AND SETTINGA total of 201 PCOS patients completed the study without protocol violations in three university hospitals: seventy-three patients from Centre A (treated with metformin 500 mg twice a day), 60 patients from Centre B (treated with metformin 500 mg three times a day) and 68 patients from Centre C (treated with metformin 850 mg twice a day). MAIN RESULTS AND THE ROLE OF CHANCEMetformin exerted an overall positive effect on the clinical and endocrine-metabolic features of PCOS. The degree of these effects was independent of the administered dosage in every range of basal body mass index (BMI). When patients were stratified according to their insulinaemic status, scattered inter-doses differences were found in some of the outcome measures. Patients who exhibited an increase of >2 menstrual cycles/year were considered as responders to treatment. Responders had a higher basal BMI than non-responders and showed a greater reduction in plasma testosterone levels after metformin treatment, but other outcome measures did not differ significantly. Total insulin secretion in the 180 min following the glucose tolerance test before metformin treatment (basal AUC-I) was significantly correlated with the decrease in insulin secretion induced by metformin in both the whole group and in responders, but only correlated with the variation in the number of cycles in responders. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTIONThe different doses were administered in different centres, and between-centre variation is a potential confounding factor. GENERALIZABILITY TO OTHER POPULATIONSThe paradigm of using the minimum effective dose of metformin could be pursued in other pathological conditions characterized by insulin resistance. STUDY FUNDING/COMPETING INTEREST(S)No funding or competing interests to declare. © 2012 The Author.


Sagnella F.,Catholic University of the Sacred Heart | Moro F.,Catholic University of the Sacred Heart | Lanzone A.,OASI Institute for Research | Tropea A.,Catholic University of the Sacred Heart | And 6 more authors.
Fertility and Sterility | Year: 2011

Objective: To demonstrate the noninferiority of highly purified menotropin (HP-hMG) compared with recombinant FSH (rFSH) regarding clinical pregnancy rate (PR) in intrauterine insemination (IUI) cycles. Design: Prospective randomized noninferiority trial. Setting: Unit of physiopathology of human reproduction, university hospital. Patient(s): Five hundred twenty-three patients with unexplained infertility or mild male infertility undergoing controlled ovarian hyperstimulation for IUI. Intervention(s): Patients were randomized for treatment with rFSH (262 patients) or HP-hMG (261 patients). Insemination was performed 34-36 hours after hCG injection. Main Outcome Measure(s): The primary outcome was clinical pregnancy rate (PR). The secondary outcome was the number of interrupted cycles for high risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. Result(s): The clinical PR was 19.7% (95% confidence interval [CI] 15.3%-25.1%) in the HP-hMG group and 21.4% (95% CI 16.9%-26.8%) in the rFSH group [absolute difference -1.7% (95% CI -8.6%-5.2%)]; therefore, the noninferiority was demonstrated. The number of interrupted cycles for OHSS risk and multiple pregnancy was significanty higher in the rFSH group, 8.4% (95% CI 5.6%-12.4%) than in the HP-hMG group 1.2% (95% CI 0.4%-3.3%) [absolute difference -7.27% (95% CI -11.3 to -3.7)]. Conclusion(s): HP-hMG is not inferior compared with rFSH regarding clinical PR. © 2011 American Society for Reproductive Medicine, Published by Elsevier Inc.


Romualdi D.,Catholic University of the Sacred Heart | Giuliani M.,Catholic University of the Sacred Heart | Cristello F.,Catholic University of the Sacred Heart | Fulghesu A.M.,University of Cagliari | And 4 more authors.
Fertility and Sterility | Year: 2010

Objective: To investigate metformin effects on the endocrine-metabolic parameters and ovarian morphology in normoinsulinemic women with polycystic ovary syndrome (PCOS). Design: Randomized double-blind study. Setting: Operative Division of Endocrinological Gynecology, Università Cattolica del Sacro Cuore. Patient(s): Twenty-eight normal-weight normoinsulinemic PCOS women. Intervention(s): Patients were randomized to receive metformin 500 mg twice a day (group A, 15 subjects) or placebo (group B, 13 subjects) for 6 months. Ultrasonographic pelvic exams, hormonal and lipid features, and oral glucose tolerance test were performed at baseline and after 3 and 6 months of treatment. Main Outcome Measure(s): Hormonal and glycoinsulinemic assessment, ovarian ultrasound appearance. Result(s): Glycoinsulinemic assessment remained unvaried in both groups. About 70% of patients in group A experienced a restoration of menstrual cyclicity. Metformin significantly decreased testosterone levels at 3 and 6 months) and 17-hydroxyprogesterone levels at 6 months, and improved hirsutism score at 6 months. No clinical or hormonal modifications occurred in group B. Metformin, but not placebo, reduced ovarian volume and stromal/total area ratio at 3 and 6 months. Conclusion(s): Metformin seems to improve the menstrual pattern and ultrasonographic ovarian features in normoinsulinemic PCOS women. These effects seem to be, at least in part, independent of the insulin-lowering properties of the drug. © 2010 by American Society for Reproductive Medicine.


Romualdi D.,Catholic University of the Sacred Heart | De Cicco S.,Catholic University of the Sacred Heart | Busacca M.,Catholic University of the Sacred Heart | Gagliano D.,Catholic University of the Sacred Heart | And 3 more authors.
Journal of Endocrinological Investigation | Year: 2013

Background: The estrogenic component of estro- progestin (EP) is responsible for a negative impact on the metabolic and lipid assessment in women with polycystic ovary syndrome (PCOS). Aim: To evaluate the risk/benefit ratio of two EP combinations, containing the same progestin (3 mg drospirenone) and a different dose of ethinyl-estradiol (EE) (20 vs 30 μg) and to compare their effects on the clinical and endocrine-metabolic parameters in normal-weight PCOS women. Material/subjects and methods: In this randomized pilot study, we enrolled 30 young normal-weight PCOS women. Fifteen subjects were allocated to group A (20 μg EE) and 15 PCOS subjects to group B (30 μg EE). Hirsutism score, hormonal assays, oral glucose tolerance test, euglycemic hyperinsulinemic clamp and lipid profile were performed at baseline, and after 6 and 12 months of therapy. Main outcome measures were signs of hyperandrogenism, glucose and insulin metabolism, lipid profile. Results: Both treatment regimens induced a significant improvement in hirsutism score, testosterone, DHEAS, and SHBG levels. Androstenedione significantly dropped only in patients of Group A, while 17(OH)P only in those from Group B. Both the formulations did not significantly modify gluco-insulinemic metabolism. Total cholesterol, LDL cholesterol, and HDL cholesterol levels significantly increased in both groups. Triglycerides levels, which increased as well, resulted more markedly influenced by the formulation with 30 μg EE. Conclusions: In association with drospirenone, 20 μg EE results as effective as 30 μg in improving clinical and hormonal features of normal-weight PCOS women, while exhibiting a milder influence on lipidic parameters. © 2013, Editrice Kurtis.


Romualdi D.,Catholic University of the Sacred Heart | De Cicco S.,Catholic University of the Sacred Heart | Tagliaferri V.,Catholic University of the Sacred Heart | Proto C.,OASI Institute for Research | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: In the adult ovary, antimullerian hormone (AMH) is produced by the granulosa cells of preantral and small antral follicles and negatively regulates folliculogenesis. AMH is overproduced in the polycystic ovary and was recently proposed to play a role in the ovulatory dysfunction of polycystic ovary syndrome (PCOS). Objective: The aim of the study was to investigate the effects of metformin administration on AMH levels in relation with the clinical and endocrine-metabolic parameters in obese women with PCOS. Design and Setting: We conducted a pilot prospective study in an academic research environment. Patients: We studied 28 obese PCOS women. Interventions: We performed ultrasonographic pelvic exams, hirsutism score evaluation, hormonal profile assays, oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and lipid profile at baseline and after 6 months of metformin treatment (850 mg twice a day orally). Main Outcome Measures: We measured AMH, hormonal assays, ultrasound aspect of the ovaries, and indexes of glucose and insulin metabolism. Results: Insulin secretion and body mass index significantly decreased after treatment. Almost 70% of subjects experienced an amelioration of menstrual irregularities. Mean androstenedione, testosterone, and 17-hydroxyprogesterone levels and hirsutism score were significantly improved by metformin. However, no significant changes in AMH levels occurred. Data were further analyzed after dividing patients on the basis of pretreatment insulinemic response to the oral glucose tolerance test; metformin was effective in reducing insulin secretion, AMH levels, and, interestingly, ovarian volume exclusively in PCOS patients with hyperinsulinism; none of these changes occurred in the normoinsulinemic group. Conclusions: Metformin differentially affects the interplay between insulin and the ovarian function in obese PCOS women; the presence of hyperinsulinemia seems to be predictive of the efficacy of the treatment. Copyright © 2011 by The Endocrine Society.


Romualdi D.,Catholic University of the Sacred Heart | De Cicco S.,Catholic University of the Sacred Heart | Gagliano D.,Catholic University of the Sacred Heart | Busacca M.,Catholic University of the Sacred Heart | And 4 more authors.
Diabetes Care | Year: 2013

OBJECTIVE - Metformin has been reported to reduce the risk of gestational diabetes (GD) in women with polycystic ovarian syndrome (PCOS). However, little is known about the mechanisms of action of this drug during pregnancy. In the attempt to fill this gap, we performed a prospective longitudinal study providing a detailed examination of glucose and insulin metabolism in pregnant women with PCOS undergoing metformin therapy. RESEARCH DESIGN AND METHODS - We enrolled 60 women with PCOS who conceived while undergoing metformin treatment. An oral glucose tolerance test and a uglycemic-hyperinsulinemic clamp were performed at each trimester of gestation in 47 ongoing pregnancies. RESULTS - Twenty- two of the study subjects had development of GD despite the treatment. At baseline, insulin sensitivity was comparable between women who had development of GD and women who did not. A progressive decline in this parameter occurred in all subjects, independently of the trimester of GD diagnosis. Insulin secretion was significantly higher during the first trimester in patients with an early failure of metformin treatment. Women with third trimester GD and women with no GD exhibited a significant increase in insulin output as gestation proceeded. All newborns were healthy and only one case of macrosomia was observed. CONCLUSIONS - Women with PCOS who enter pregnancy in a condition of severe hyperinsulinemia have development of GD earlier, independently of metformin treatment. The physiologic deterioration of insulin sensitivity is not affected by the drug and does not predict the timing and severity of the glycemic imbalance. Despite the high incidence of GD observed, the drug itself or the intensive monitoring probably accounted for the good neonatal outcome. © 2013 by the American Diabetes Association.


Villa P.,Catholic University of the Sacred Heart | Suriano R.,Catholic University of the Sacred Heart | Ricciardi L.,Catholic University of the Sacred Heart | Tagliaferri V.,Catholic University of the Sacred Heart | And 5 more authors.
Fertility and Sterility | Year: 2011

Objective: To evaluate the effects of a daily E2 (1 mg) plus drospirenone oral formulation (2 mg) on glycoinsulinemic metabolism, lipid profile, and endothelial function in symptomatic healthy menopausal women. Design: Randomized, double-blind study. Setting: Operative Division of Endocrinological Gynecology, Catholic University of the Sacred Heart, Rome, Italy. Patient(s): Forty postmenopausal women. Intervention(s): Patients were randomly submitted to receive treatment with an oral dose of E2 (1 mg) plus drospirenone (2 mg) (group A) or placebo (group B). Main Outcome Measure(s): Hormonal and lipid assessment; evaluation of glucose and insulin metabolism by the clamp test and the oral glucose tolerance test; evaluation of endothelial function by the vascular reactivity test. Result(s): Total cholesterol levels, low-density lipoprotein cholesterol levels, and nonesterified fatty acids levels significantly decreased both after 3 and 6 months. No changes in high-density lipoprotein, triglycerides, apolipoprotein A1, apolipoprotein B, and lipoprotein (a) were found. Treatment resulted in few changes in glycoinsulinemic metabolism. We observed a significant reduction of the area under curve of insulin after 6 months of therapy. Endothelial function was significantly influenced by treatment, and an improvement in both flow-mediated dilatation and nitrate-mediated dilatation values after 6 months was observed. Conclusion(s): Low-dose E2/drospirenone treatment did not reveal any negative effect on carbohydrate metabolism, acting in a neutral way on insulin sensitivity. The treatment induced favorable changes in lipid profile and showed a significant improvement of vascular reactivity. © 2011 American Society for Reproductive Medicine, Published by Elsevier Inc.


Villa P.,Catholic University of the Sacred Heart | Rossodivita A.,Catholic University of the Sacred Heart | Sagnella F.,Catholic University of the Sacred Heart | Moruzzi M.C.,Catholic University of the Sacred Heart | And 5 more authors.
Clinical Endocrinology | Year: 2013

Objective To evaluate the role of mean ovarian volume (MOV) in the diagnosis of polycystic ovary syndrome (PCOS) during adolescence, and its relationship with metabolic and endocrine parameters. Design Observational study. Patients A total of 134 young girls, including 86 adolescents with PCOS and 48 controls, were studied. Measurements During the early follicular phase, a pelvic ultrasound examination was performed to measure the ovarian volume of both ovaries and to calculate the MOV. All subjects underwent hormonal assessment and an ultrasound examination. PCOS subjects were submitted to an oral glucose tolerance test. The homeostasis model assessment for insulin resistance (HOMA-IR) and several insulin resistance indexes were also determined. Results Androgens, free androgen index (FAI), LH and insulin resistance indexes were higher in the PCOS group. MOV was significantly different between the two groups: control group 4·6 ± 1·9 cm3, adolescent PCOS group 9·6 ± 4·4 cm 3. The MOV threshold of 5·596 cm3 offered the best compromise between sensitivity and specificity based on the characteristics of the operating receiver curve analysis. Therefore, an ovarian volume higher than 5·6 increased the risk of PCOS by about 15 times (OR 16·25 IC 95% 6·3-41·3). In adolescent PCOS girls, the ovarian volume was significantly associated with circulating testosterone and insulin, and indices of insulin resistance. Conclusions During early adolescence MOV evaluation may offer an effective means to screen and follow up young girls with irregular cycles in order to prevent the long-term metabolic disturbances of the polycystic ovary syndrome. © 2012 Blackwell Publishing Ltd.


Romualdi D.,Catholic University of the Sacred Heart | Franco Zannoni G.,Catholic University of the Sacred Heart | Lanzone A.,Catholic University of the Sacred Heart | Lanzone A.,Oasi Institute for Research | And 5 more authors.
Fertility and Sterility | Year: 2011

Objective: To identify a possible marker of follicular depletion in relation to some histologic parameters of endometriotic cysts. Design: Prospective study. Setting: Università Cattolica del Sacro Cuore, Operative Division of Endocrinological Gynecology. Patient(s): Seventy-seven patients (aged 20-40 years) with endometrioma. Intervention(s): Patients underwent laparoscopic surgery for ovarian endometriosis. Main Outcome Measure(s): After excision of the cyst wall, involuntarily removed follicles were correlated with age at surgery and with intrinsic histologic parameters of the specimen (thickness and composition of capsule; size of cyst). Result(s): There was a statistically significant relationship between patient age and number of follicles in the histologic section, a statistically significant inverse relationship between size of cyst and number of follicles, and no significant correlation between thickness of the capsule and number of follicles. Fibroblastic-type capsule, most frequently found in younger patients, was associated with removal of a significantly higher number of follicles. Conclusion(s): Our study suggests that patient age and cyst dimension are related to the histologic composition of the capsule, which is a marker of the aggressiveness of the cyst itself. Copyright © 2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

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