Daniela Romualdi

Metformin improves endothelial function in normoinsulinemic PCOS patients: a new prospective

BACKGROUND Metformin was reported to improve the alterations of endothelial reactivity in normal-weight subjects with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the mechanisms of action of this drug on the vascular function of this population. METHODS Thirteen normal-weight, normoinsulinemic and normolipemic PCOS women were studied before and after 6 months of metformin treatment (1000 mg/day). The endothelial function was assessed by evaluating the flow-mediated dilatation (FMD) of the brachial artery. We correlated this parameter with the endocrine-metabolic features of the patients. RESULTS Metformin significantly reduced testosterone (1.56 +/- 0.52 after 6 months versus 2.98 +/- 1.00 at baseline) and 17-hydroxyprogesterone (0.03 +/- 0.01 versus 0.06 +/- 0.02 nmol/ml) levels, without affecting gluco-insulinemic parameters. Concomitantly, the basal vessel diameter and the FMD significantly increased (4.12 +/- 0.68 versus 3.2 +/- 0.41 and 5.2 +/- 0.6 versus 3.76 +/- 0.5 mm, respectively), thus documenting an improved endothelial function. CONCLUSIONS Our data confirm the positive effects of metformin on the altered vascular reactivity, a precocious marker of cardiovascular risk, in normoinsulinemic PCOS subjects. This improvement seems to be mediated through hormonal changes, thus highlighting the detrimental role of hyperandrogenemia on the endothelial function, even beyond the metabolic factors. However, a direct effect of metformin on the endothelium should not be excluded.

Metformin effects on ovarian ultrasound appearance and steroidogenic function in normal-weight normoinsulinemic women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial.

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.

Plasma levels of neuropeptides in Alzheimer's disease

Background. In the central nervous system, several neuropeptides are believed to be involved in the pathophysiology of Alzheimers disease (AD). Indeed, previous studies have documented that glucagon-like peptide 1 (GLP-1) possesses neurotropic properties and can reduce amyloid-β peptide levels in the brain in vivo. Moreover, the concentrations of neuropeptide Y (NPY) seem to be altered in the cerebrospinal fluid of patients with AD and in subjects with major depression. Finally, among the modifications induced by aging, a dysregulation of the ghrelin–growth hormone (GH) system has been reported. Methods. We investigated the plasma concentrations of these neuropeptides in 14 subjects with AD. Data obtained from these patients were compared with data from an age- and weight-matched healthy group. Results. No significant differences were found between the two groups in relation to plasma levels of GLP-1, NPY, ghrelin and GH. Peripheral NPY concentrations were positively correlated with ghrelin levels in both groups, and with plasma GLP-1 concentration only in controls. Conclusion. On the basis of our results, peripheral levels of these neuropeptides seem not to serve as biochemical markers of AD.

Is there a dose–response relationship of metformin treatment in patients with polycystic ovary syndrome? Results from a multicentric study

STUDY QUESTION Do 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 ANSWER Different 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 ADDS Since the insulin-sensitizing agents came into use in the management of PCOS, metformin has shown a positive benefits-risks 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. DESIGN A 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 SETTING A 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 CHANCE Metformin 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 CAUTION The different doses were administered in different centres, and between-centre variation is a potential confounding factor. GENERALIZABILITY TO OTHER POPULATIONS The 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.

Alteration of ghrelin-neuropeptide Y network in obese patients with polycystic ovary syndrome: Role of hyperinsulinism

Objective  Insulin, ghrelin, neuropeptide Y (NPY) and leptin interact in the regulation of energy homeostasis. Most of these signals are altered in polycystic ovary syndrome (PCOS), which is characterized by a high prevalence of obesity. The present study was conducted to evaluate ghrelin–NPY and ghrelin–leptin interplays in relation to insulin secretion in obese PCOS subjects.

Is there a role for soy isoflavones in the therapeutic approach to polycystic ovary syndrome? Results from a pilot study

OBJECTIVE To evaluate the effect of the soy isoflavone genistein on the metabolic and hormonal disturbances of polycystic ovary syndrome (PCOS), we studied a group of obese, hyperinsulinemic, and dyslipidemic women presenting this syndrome during 6 months of phytoestrogen administration. DESIGN Pilot prospective study. SETTING Operative division of endocrinological gynecology in a university hospital. PATIENT(S) Twelve Caucasian obese, hyperinsulinemic, and dyslipidemic women with PCOS. INTERVENTION(S) Patients received 36 mg/d of genistein for 6 months. Ultrasonographic pelvic exams, hormonal and lipid features, oral glucose tolerance test, and euglycemic hyperinsulinemic clamp were performed at baseline and after 3 and 6 months of treatment. MAIN OUTCOME MEASURE(S) Basal hormonal assays, lipid profile, and glycoinsulinemic assessment. RESULT(S) Phytoestrogens supplementation significantly improved total cholesterol levels, reducing low-density lipoprotein (LDL) cholesterol and resulting in a significant decrease in the LDL-high-density lipoprotein ratio (LDL-HDL). Triglycerides showed a trend toward decrease, whereas no changes were detected in very low-density lipoprotein cholesterol plasma levels. Genistein treatment did not significantly affect anthropometric features, the hormonal milieu, and menstrual cyclicity. No significant changes occurred in glycoinsulinemic metabolism. CONCLUSION(S) The possible advantages derived from the therapeutic use of phytoestrogens in PCOS are limited to improvement of the lipidic assessment.

The Metabolic Status Modulates the Effect of Metformin on the Antimullerian Hormone-Androgens-Insulin Interplay in Obese Women with Polycystic Ovary Syndrome

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.

Clinical efficacy and metabolic impact of two different dosages of ethinyl-estradiol in association with drospirenone in normal-weight women with polycystic ovary syndrome: A randomized study

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.

Follicular loss in endoscopic surgery for ovarian endometriosis: quantitative and qualitative observations

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.

The Role of Anti-Müllerian Hormone in the Characterization of the Different Polycystic Ovary Syndrome Phenotypes

Rotterdam criteria identified 4 polycystic ovary syndrome (PCOS) phenotypes based on the combination of anovulation (ANOV), hyperandrogenism (HA), and polycystic ovaries (PCOs): phenotype 1 (ANOV + HA + PCO), phenotype 2 (ANOV + HA), phenotype 3 (HA + PCO), and phenotype 4 (ANOV + PCO). Anti-Müllerian hormone (AMH) was suggested to play a pathophysiologic and diagnostic role in this syndrome. The aim of this study was to compare AMH levels among the different phenotypes in relation to clinical, endocrine, and metabolic features. We enrolled 117 women with PCOS (body mass index: 25.89 ± 6.20 kg/m2, age range: 18-37 years) and 24 controls. Anthropometric characteristics, hirsutism score, ultrasound ovarian features, and hormonal parameters, including AMH, were evaluated. Each participant also underwent an oral glucose tolerance test and an euglycemic–hyperinsulinemic clamp. The prevalence of phenotypes 1 to 4 was 62.4%, 8.6%, 11.1%, and 17.9%, respectively. Body mass index and insulin resistance indexes were similar among the groups. Phenotype 1 showed the highest luteinizing hormone, androgens levels, ovarian volume, and AMH concentrations (9.27 ± 8.17 ng/mL, P < .05) versus phenotype 2 and controls. Phenotype 2 women were hirsute, showed an intermediate free androgen index value, low ovarian volume, and low AMH levels (4.05 ± 4.12 ng/mL). Phenotype 3 showed an intermediate state of HA and slightly augmented AMH levels (5.87 ± 4.35 ng/mL). The clinical and endocrine characteristics of phenotype 4 resembled those of controls, except for higher ovarian volume and AMH levels (7.62 ± 3.85 ng/mL; P < .05). Our results highlight the heterogeneity of the association between increased AMH levels, menstrual dysfunction, and HA in the different PCOS phenotypes, thus offering a key to an understanding of the current controversy on the value of AMH measurement in PCOS.