Maurizio Guido

Differential androgen response to adrenocorticotropic hormone stimulation in polycystic ovarian syndrome: relationship with insulin secretion *

OBJECTIVE To investigate the relationship between insulin and adrenal androgens in patients with polycystic ovarian disease (PCOD). DESIGN Patients with PCOD and a group of volunteers who attended the department during a period of 6 months were studied. SETTING Department of Gynaecology and Obstetrics, Università Cattolica del Sacro Cuore, Roma, Italy. PARTICIPANTS Healthy women with ovulatory cycles (hospital personnel, n = 8) and women affected by PCOD (n = 32) were studied on day 5 to 6 of their follicular phase. INTERVENTIONS All women had an oral glucose tolerance test (OGTT) (75 g) on day 5 to 6 of the cycle. Then plasma samples were collected at 7.00 A.M.; at 11.00 P.M., 2 mg of dexamethasone (DEX) were orally administered with blood samples collected the day after at 7.00 A.M. (effect of DEX). Then adenocorticotropic hormone (ACTH, Synacten; Ciba-Geigy, Varese, Italy) 250 micrograms was injected intravenously (IV) and samples collected 60 minutes later (effect of ACTH). MAIN OUTCOME MEASURES Plasma glucose and insulin concentration were assayed on OGTT samples collected at time 0, 30, 60, 90, 120, 180, and 240 minutes after glucose ingestion. Data are expressed as area under the curve. Cortisol, 17 alpha-hydroxyprogesterone (17-OHP), testosterone (T), androstenedione (A), and dehydroepiandrosterone sulphate (DHEAS) plasma levels were evaluated on the samples collected before and after DEX or ACTH administration. Data are expressed as absolute concentrations and percent increase in respect to values before the treatment. RESULTS According to the OGTT response, 21 patients were classified as hyperinsulinemic and 11 as normoinsulinemic. The ideal body weight was greater in hyperinsulinemic patients. No differences in baseline hormone levels were found between the two groups. Only sex hormone binding globulin levels were significantly greater in normoinsulinemic patients (P less than 0.05). Also, the plasma concentration of all steroids after DEX were similar in both groups. Intravenous injection of ACTH significantly increased plasma androgens levels. Cortisol, DHEAS, and T enhancement did not differ in normoinsulinemic and hyperinsulinemic patients, whereas significantly greater A (P less than 0.01) and 17-OHP (P less than 0.05) plasma concentrations were observed after ACTH injection in hyperinsulinemic when compared with normoinsulinemic PCOD subjects. Control group after IV ACTH showed an increase of A and 17-OHP similar to those found in normoinsulinemic PCOD group. CONCLUSIONS These data suggest that insulin could be involved in the androgen production by adrenal gland and it could influence the responsiveness of adrenal to its trophic hormones.

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.

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.

Assessment of insulin resistance in lean women with polycystic ovary syndrome.

OBJECTIVE To develop and validate a specific simple measure of insulin sensitivity using oral glucose tolerance test (OGTT) values for lean polycystic ovary syndrome (PCOS) women. DESIGN Retrospective study. SETTING Gynecologic Outpatient Clinic of University Hospital, affiliated with Unit of Gynecologic Endocrinology. PATIENT(S) Totals of 201 lean and 198 overweight/obese (ov-ob) nondiabetic PCOS patients were retrospectively selected. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) All patients underwent OGTT, euglycemic-hyperinsulinemic clamp, and androgenic and biochemical assays. The predictive performance of each insulin resistance (IR) index was analyzed with the use of receiver operating characteristic (ROC) curves. RESULT(S) Higher correlation coefficients with clamp studies were obtained with the Belfiore Area (RS=0.579) and the homeostasis-model assessment (HOMA)-M120 (RS=-0.576) in lean PCOS patients and with the Sib (RS=0.697) in ov-ob PCOS patients. The best predictive index of IR in lean PCOS was a HOMA-M120 value of ≥12.8 or more (area under the ROC curve [AUC] 92.4%). In the ov-ob PCOS population, the best predictive performance was obtained by a Sib of ≤10.2 or less (AUC 85.7%). CONCLUSION(S) IR should be assessed in all PCOS women, both lean and ov-ob subjects. The HOMA-M120 resulted as a very simple tool, validated specifically for the lean PCOS woman whose cardiometabolic impairment is more frequently misunderstood.