Valeria Tagliaferri

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.

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.

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.

Low-dose estrogen and drospirenone combination: effects on glycoinsulinemic metabolism and other cardiovascular risk factors in healthy postmenopausal women.

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.

Using a 16-French resectoscope as an alternative device in the treatment of uterine lesions: a randomized controlled trial

OBJECTIVE: To compare a 16-French resectoscope with a 22-French resectoscope and a 15-French hysteroscope for the treatment of uterine cavity lesions. METHODS: This was a prospective, randomized study of women with endometrial polyps or submucous myomas treated with a 16-French resectoscope, a traditional 22-French resectoscope, or a 15-French hysteroscope. The operating time, volume of distension medium delivered, discharge time, and patient discomfort by visual analog scale were recorded. Data were compared by one-way and two-way analysis of variance as appropriate. RESULTS: Four hundred one women were included in the analysis. All four parameters showed lower values in the 16-French resectoscope group (142 women) compared with the 15-French hysteroscope group (132 women; P<.01). The mean operating time was 10.87±2.87 minutes in the 22-French group (127 women), 8.33±2.94 minutes in the 16-French group, and 17.11±6.86 minutes in the 15-French group. The mean volume of distension medium delivered was 1,043±230 mL in the 22-French group, 991±442 mL in the 16-French group, and 1,489±566 mL in the 15-French group. The mean discharge time was 1.99±0.72 hours in the 22-French group, 1.08±0.18 hours in the 16-French group, and 1.89±0.68 hours in the 15-French group. Finally, the mean visual analog scale scores were 2.10±0.97 in the 22-French group, 1.93±1.03 in the 16-French group, and 4.00±1.61 in the 15-French group. An analysis of patients subdivided according to the lesion size (less than 1.5 cm and more than 1.5 cm in diameter) showed similar results. CONCLUSION: The new 16-French resectoscope is effective for the “see and treat” approach for both small (less than 1.5 cm diameter) and large (more than 1.5 cm diameter) uterine lesions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01430208. LEVEL OF EVIDENCE: I

Metformin versus myoinositol: which is better in obese PCOS patients? A randomized controlled crossover study

Due to the central role of metabolic abnormalities in the pathophysiology of polycystic ovary syndrome (PCOS), insulin sensitizing agents have been proposed as a feasible treatment option.

The link between metabolic features and TSH levels in polycystic ovary syndrome is modulated by the body weight: an euglycaemic-hyperinsulinaemic clamp study.

OBJECTIVE To evaluate the link among thyroid function, glucose/insulin metabolism and steroid hormones in women with polycystic ovary syndrome (PCOS), and to verify if the body mass index (BMI) might influence the interplay between PCOS features and subclinical hypothyroidism (SCH). STUDY DESIGN Case-control study conducted from January to December 2014. METHODS One-hundred fifty-four young women with PCOS, according to Rotterdam criteria, and 88 controls were enrolled in an academic research environment. Anthropometric evaluation, hormonal and lipid assays, oral glucose tolerance test (OGTT) and euglycaemic-hyperinsulinaemic clamp were performed. Hirsutism was assessed with the Ferriman-Gallwey (FG) score. MAIN RESULTS SCH was found in 14% of PCOS subjects and in 1% of controls (P < 0.01). In PCOS women, TSH levels were directly correlated with fasting glycaemia, but not with other hormonal and metabolic parameters. When PCOS patients were classified on the basis of BMI, TSH levels significantly correlated with insulin secretion, insulin resistance, DHEAS and cortisol levels in obese PCOS women. Inverse correlations were found between TSH and both oestradiol and SHBG in the same group. In nonobese PCOS patients, only waist-to-hip ratio values were correlated with TSH. The prevalence of SCH was not different between nonobese and obese PCOS groups (14 and 15% respectively). However, SCH was associated with higher levels of insulin, DHEAS, cortisol and FG score only in the obese subgroup. CONCLUSIONS Our data confirm that the prevalence of SCH is increased in PCOS women. The presence of SCH is associated with endocrine and metabolic imbalances of PCOS, and the excessive body weight seems to promote this interplay.

Melatonin Treatment May Be Able to Restore Menstrual Cyclicity in Women With PCOS: A Pilot Study:

The objective of the study was to investigate the effects of 6 months of melatonin administration on clinical, endocrine, and metabolic features of women affected by polycystic ovary syndrome (PCOS). This is a prospective cohort study including 40 normal-weight women with PCOS between January and September 2016, enrolled in an academic research environment. Ultrasonographic pelvic examinations, hirsutism score evaluation, hormonal profile assays, oral glucose tolerance test, and lipid profile at baseline and after 6 months of melatonin administration were performed. Melatonin treatment significantly decreased androgens levels (free androgen index: P < .05; testosterone: P < .01; 17 hydroxyprogesterone: P < .01). Follicle-stimulating hormone levels significantly raised (P < .01), and anti-Mullerian hormone serum levels significantly dropped after 6 months of melatonin treatment (P < .01). No significant changes occurred in glucoinsulinemic and lipid parameters after treatment except a significant decrease of low-density lipoprotein cholesterol. Almost 95% of participants experienced an amelioration of menstrual cycles. Until now, only few data have been published about the role of melatonin in women with PCOS. This is the first study focused on the effects of exogenous oral melatonin administration on the clinical, endocrine, and metabolic characteristics of patients with PCOS. After 6 months of treatment, melatonin seems to improve menstrual irregularities and biochemical hyperandrogenism in women with PCOS through a direct, insulin-independent effect on the ovary. Based on our results, melatonin could be considered a potential future therapeutic agent for women affected by PCOS.

Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action

Abstract The aim of our study was to investigate the effects of a combined treatment with alpha-lipoic acid (ALA) and myoinositol (MYO) on clinical, endocrine and metabolic features of women affected by polycystic ovary syndrome (PCOS). In this pilot cohort study, forty women with PCOS were enrolled and clinical, hormonal and metabolic parameters were evaluated before and after a six-months combined treatment with ALA and MYO daily. Studied patients experienced a significant increase in the number of cycles in six months (p < 0.01). The free androgen index (FAI), the mean androstenedione and DHEAS levels significantly decreased after treatment (p < 0.05). Mean SHBG levels significantly raised (p < 0.01). A significant improvement in mean Ferriman–Gallwey (F–G) score (p < 0.01) and a significant reduction of BMI (p < 0.01) were also observed. A significant reduction of AMH levels, ovarian volume and total antral follicular count were observed in our studied women (p< 0.05). No significant changes occurred in gluco-insulinaemic and lipid parameters after treatment. The combined treatment of ALA and MYO is able to restore the menstrual pattern and to improve the hormonal milieu of PCOS women, even in the absence of apparent changes in insulin metabolism.