Anna Maria Fulghesu

LH surge induction by GnRH agonist at the time of ovulation

Eight women were treated for 1 cycle at the time of ovulation with GnRH agonist (3 injections of 0.2 mg buserelin s.c. at 12-hour intervals) to obtain follicular rupture. Clomiphene citrate was administered to 1 patient and pure FSH to 2 patients, whilst in the case of a woman with hypothalamic amenorrhea a pulsatile GnRH regimen was used. Four patients had an untreated follicular phase. When the maximal follicular diameter was 20-22 mm all treatments were withheld and GnRH-A was administered. Plasma LH, FSH, progesterone and estradiol were determined 24 hours before, at the time of and 12, 24 and 48 hours after the 1st injection of buserelin. Ovulation was detected in all cycles. LH levels increased dramatically from baseline levels of 14.4 +/- 4.1 to 155 +/- 48 IU/l 12 hours after the beginning of treatment, then returned to preovulatory values 48 hours later (13.0 +/- 3.9 IU/l). The duration of the luteal phase was 13.2 days and normal mid-luteal progesterone plasma levels were detected (39.8 +/- 9.3 nmol/l). These data suggest that the GnRH agonist can be successfully used at the time of ovulation to induce an endogenous ovulatory LH peak and that it can be used in conjunction with different medical treatments to induce follicular maturation.

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.

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 312N variant of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR) confers up to 2·7‐fold increased risk of polycystic ovary syndrome in a Sardinian population

Polycystic ovary syndrome (PCOS) is a frequent condition, affecting about 15% of women of reproductive age. Because of its familial occurrence, a multifactorial model of susceptibility, including both genetic and environmental factors, has been proposed. However, the identification of genetic factors has been elusive.

IL-6 serum levels and production is related to an altered immune response in polycystic ovary syndrome girls with insulin resistance.

Polycystic ovarian syndrome (PCOS) is frequently characterized by obesity and metabolic diseases including hypertension, insulin resistance, and diabetes in adulthood, all leading to an increased risk of atherosclerosis. The present study aimed to evaluate serum and production of inflammatory markers in adolescent Sardinian PCOS. On the basis of HOMA findings, patients were divided into noninsulin resistant (NIR) and insulin resistant (IR), and were weight- and age-matched with healthy girls. Inflammatory cytokines (TNF-α, IL-6, Il-10, TGF-β) and lipokines (leptin, adiponectin), the reactant hs-CRP, and in vitro inflammatory lympho-monocyte response to microbial stimulus were evaluated. In healthy and PCOS subjects, leptin and hs-CRP were correlated with BMI, whereas adiponectin was significantly reduced in all PCOS groups. Although cytokines were similar in all groups, Interleukin-6 (IL-6) was significantly higher in IR PCOS. Moreover, in the latter group lipopolysaccharide-activated monocytes secreted significantly higher levels of IL-6 compared to NIR and control subjects. To conclude, IR PCOS displayed increased IL-6 serum levels and higher secretion in LPS-activated monocytes, whilst revealing no differences for other inflammatory cytokines. These results suggest that in PCOS patients an altered immune response to inflammatory stimuli is present in IR, likely contributing towards determining onset of a low grade inflammation.

Multiple serum marker assay in the diagnosis of endometriosis

Serum levels of CA-125, CA-15-3 and TAG-72 were measured in 81 patients with endometriosis, diagnosed by laparoscopy, and staged according to the Revised American Fertility Society, and in 31 control subjects. The values of CA-125 and CA-15-3 were also determined in peritoneal fluid. The aim of the present study was to evaluate the clinical usefulness of these various markers in the diagnosis of endometriosis by using them either by themselves or combined. High serum levels of CA-125 were found in 43 of 81 patients with endometriosis (53%) and in five of 38 control subjects (13%). The values of serum CA-125 progressively increased in relation to the severity of the disease. High serum values of CA-15-3 and TAG-72 were also found in patients with endometriosis, but with a similar incidence also in control patients. High CA-125 and CA-15-3 values in peritoneal fluid were found in all patients investigated. These results suggest that measurement of serum CA-15-3 and TAG-72 in addition to CA-125, does not provide any advantage for the diagnosis of endometriosis.

The quantitative insulin sensitivity check index is not able to detect early metabolic alterations in young patients with polycystic ovarian syndrome

Objective. To verify whether QUICKY is a suitable method for the identification of metabolic deterioration in normal weight patients affected by polycystic ovarian syndrome (PCOS). Design. Prospective clinical study. Patient(s). Seventy-nine PCOS normal weight adolescent subjects, 50 eumenorrheic, normal weight, non-hirsute controls matched for age and BMI. Method(s). Quantitative insulin sensitivity check index (QUICKY) and integrated secretory area under the curve of insulin values (I-AUC) during oral glucose tolerance test were calculated. Result(s). Seventy-nine PCOS and 50 controls were studied. Normal insulin sensitivity was defined as upper control 95th percentile by QUICKY values <0.31, I-AUC at 180 min < 16,645. When applying the calculated I-AUC cut-off, 41 PCOS were classified as normoinsulinemic and 38 as hyperinsulinemic, whereas using the calculated QUICKY cut-off, only 19 PCOS could be classified as insulin resistant (IR). Fifteen out of the 60 non-IR PCOS presented hyperinsulinemia; fasting glucose and insulin levels and QUICKY were not sufficient to identify these subjects. Thus, QUICKY displayed a low sensitivity (44%) and specificity (91%) in the diagnosis of the metabolic disorder disclosed by I-AUC. Conclusions. In young normal weight patients with PCOS the prevalence of early alterations of insulin metabolism are not detectable by QUICKY studies.

Pituitary–ovarian response to the gonadotrophin-releasing hormone-agonist test in anovulatory patients with polycystic ovary syndrome: predictive role of ovarian stroma

Objective  To evaluate the influence of ovarian stroma on basal and poststimulus androgen secretion in patients affected by secondary amenorrhoea and polycystic ovaries (PCO) at ultrasound (US).

The effect of age on the ovarian response to gonadotropin and on pregnancy rate in polycystic ovary syndrome.

Recent studies have proposed that ,in women affected by the polycystic ovary syndrome (PCOS) ,aging is able to regularize the menstrual cyclicity. To evaluate the ovarian response in PCOS patients according to their age ,we studied 33 PCOS patients ,20 of whom with an age ranging from 28 to 34 years (younger PCOS) and 13 ranging from 35 to 45 years (older PCOS). All patients underwent an ovulation induction therapeutic protocol with low-dose recombinant follicle stimulating hormone ,for a total of 80 cycles (44 cycles for the younger PCOS group and 36 cycles for the older PCOS group). No significant difference was found between the days of therapy (12.3 ± 5.4 vs. 13.5 ± 5.6 days) ,total amount of drugs (980.7 ± 568.9 IU vs. 1063.9 ± 469.5 IU) or ovulation rate (93% vs. 89%) in the two groups. The two groups showed a significant difference in the maximum estradiol level (2053.5 ± 1497.2 vs. 1269.0 ± 911.5 pmol/l ,p < 0.01) ,the number of the recruited and preovulatory follicles (1.7 ± 2.5 vs. 0.64 ± 0.9 ,p < 0.05 and 1.7 ± 1.1 vs. 1.2 ± 0.5 ,p < 0.01 ,respectively) and the pregnancy rate (36% vs. 14% ,p < 0.05). In conclusion ,our data clearly showed that ,also in PCOS ,advanced age is a negative prognostic factor in the ovarian response to ovulation induction therapies.

Ovulation induction in young girls with menometrorragia: a safe and effective treatment

Abstract The prevalence of menometrorrhagia in fertile women is 11.4–13.2% and increases with aging. The presence of metrorrhagia is a relatively common cause of concern among adolescents and their parents, as well as a frequent cause of visits to emergency departments, gynaecologists, and pediatricians. Clomiphene is a selective estrogen receptor modulator (SERM) that increases the production of gonadotropins by inhibiting negative feedback on the hypothalamus. Clomiphene is primarily used in the treatment of female infertility for ovulation induction to reverse oligoovulation or anovulation, as occurs in polycystic ovary syndrome. Objective: The aim of our study was to evaluate the use of clomiphene citrate in ovulation induction, and therefore, in the cessation of bleeding in adolescents with menometrorrhagia in the absence of uterine, ovarian, or systemic pathologies. Design: Cohort study. Materials and methods: The study group was comprised of 50 subjects (age range, 13–16 years) with menometrorrhagia (bleeding >7 days in length with an average blood loss >80 ml). The treatment with clomiphene citrate at a dose of 50 mg/day for 5 days during the attack cycle, and from days 3 to 7 of three subsequent cycles, was offered to the patients. Results: After three cycles of therapy, all patients had resolution of the menometrorrhagia and resumption of ovulatory cycles. No patient reported unwanted side effects. Conclusion: We propose that low-dose clomiphene should be the first step in the treatment of adolescent dysfunctional bleeding (DUB).