Rationale and design of two prospective, multicenter, observational studies on reproductive outcome in women with recurrent failures after spontaneous or assisted conception: OTTILIA and FIRST registries.

BACKGROUND: Spontaneous pregnancy loss and implantation failure after assisted reproductive technologies (ART) are very common occurrences. Although 50-60% of all cases remains unexplained, various predisposing factors, including thrombophilias, have been identified. Thus, the potential benefit of a prophylaxis with low-molecular-weight heparins in improving outcomes has been often investigated over the years. However, the majority of studies are observational and results from randomized clinical trials (RCTs) are inconclusive, probably due to heterogeneity and limited sample size. To cover these unmet needs and to have further data mainly based on the real-life clinical management, we designed these multicenter registries. METHODS: OTTILIA (Observational sTudy on antiThrombotic prevention in thrombophILIA and pregnancy loss) and FIRST (recurrent Failures in assIsted Reproductive Techniques) registries are two prospective, multicenter, observational studies to evaluate pregnancy or ART outcomes in consecutive women with previous reproductive failures after spontaneous or assisted conception, respectively. All enrolled women are observed from their first visit after positive pregnancy test (OTTILIA) or before commencing a new ART cycle (FIRST) until the end of pregnancy or ART procedure (negative pregnancy test/end of pregnancy, if successful cycle), respectively. Data are collected by means of questionnaires and recorded in a central database. Follow-up investigations are performed during hospital stay, routine clinical follow-up visits or telephone interviews. Primary outcome is live birth rate in the OTTILIA register and clinical pregnancy rate in the FIRST. DISCUSSION: Although RCTs are the 'gold standard' for evaluating treatment outcomes, we believe that our registries represent a valid alternative in improving knowledge on mechanisms involved in reproductive failures and supporting future clinical decisions. TRIAL REGISTRATION: NCT02385461 , retrospectively registered 5 March 2015 (OTTILIA); NCT02685800 , registered 10 February 2016 (FIRST).

Predictive value of ovarian stroma measurement for cardiovascular risk in polycyctic ovary syndrome: a case control study.

BACKGROUND: To verify the feasibility of ovarian stromal evaluation and correlate ovarian parameteres (echogenicity and volume) with hyperandrogenism, and both cardiovascular and metabolic risk factors in PCOS. METHODS: Twenty four young PCOS patients and twelve age-matched control women were enrolled. Diagnosis of PCOS was based on the Rotterdam criteria. Ultrasound ovarian study included ovarian volume, stromal volume, stromal area and stromal area/total ovarian area ratio (S/A). Concerning hormones, insulin, LH, FSH, estradiol, androstenedione, testosterone, DHEAS, 17-hydroxy-progesterone, and SHBG were measured during the early follicular phase (days 2-5). Cardiovascular risk factors were represented by fasting plasma levels of glucose, lipids (total and HDL-cholesterol), plasminogen activator inhibitor 1 (PAI-1), von-Willebrand factor (vWF), and adiponectin. Carotid intima-media thickness (C-IMT) was measured as a parameter of cardiovascular risk. RESULTS: A positive correlation between the S/A ratio and plasma levels of testosterone (p < 0.05) and androstenedione (p < 0.05) was found. The stromal volume, stromal area and S/A ratio were also significantly and positively correlated with PAI-1, and vWF levels, and with IMT in PCOS women (P < 0.05). CONCLUSIONS: This study shows that the ultrasound measurement of ovarian stroma is a predicting factor of hyperandrogenism degree, prothrombotic factors and cardiovascular risk in patients with PCOS.

Effect of finasteride on ovulation induction in nonresponder (hyperandrogenic) polycystic ovary syndrome (PCOS) women.

OBJECTIVE: To evaluate whether the addition of finasteride (a 5-reductase inhibitor) to conventional protocol of ovarian stimulation with gonadotropin can improve ovarian follicular growth in polycystic ovary syndrome (PCOS) women who did not respond to previous stimulation with gonadotropin alone. DESIGN: Double-blind randomized study. SETTING: Outpatient in an academic research environment. PATIENT(S): Thirty-six PCOS patients in whom the previous multifollicular stimulation protocols with gonadotropin failed. INTERVENTION(S): The patients were randomly assigned to two treatment groups: group 1 underwent ovarian stimulation with recombinant FSH (rFSH) plus finasteride, and group 2 received rFSH alone. When the dominant follicle reached a mean diameter of 18 mm, hCG was administered and finasteride withdrawn. MAIN OUTCOME MEASURE(S): Ovulation rate in women with PCOS. RESULT(S): Follicular growth and ovulation occurred in eight patients in group 1, whereas no cases were detected in group 2. CONCLUSION(S): This study confirms that hyperandrogenism interferes with follicular growth and suggests that administration of finasteride during ovarian stimulation with rFSH improves ovulation rate in selected hyperandrogenic anovulatory women.

Anteroposterior diameter of the infrarenal abdominal aorta is higher in women with polycystic ovary syndrome.

BACKGROUND: Women affected by polycystic ovary syndrome (PCOS) are known to be at higher risk of cardiovascular disease. The aim of this study was to identify the artery that first is affected by early pre-atherosclerotic changes in PCOS. METHODS: Twenty-nine women with PCOS aged 17 to 27 years and 26 healthy nonhyperandrogenic volunteers with regular menses (control women) aged 16 to 28 years were enrolled. All PCOS patients were overweight or obese (body mass index [BMI] > or = 25). Diagnosis of PCOS was performed in line with the 2003 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Accordingly, PCOS was defined when at least two of the following three features were present after exclusion of other etiologies: 1) oligomenorrhea and or anovulation; 2) hyperandrogenism and/or hyperandrogenemia; and 3) polycystic ovaries visible at ultrasound. Androgen excess or related disorders were excluded. The intima-media thickness (IMT) of common carotid arteries and common femoral arteries and the anteroposterior diameter of the infrarenal abdominal aorta were measured by ultrasound. Lutenizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, total testosterone, androstenedione, and sex hormone-binding globulin (SHBG) serum levels were measured between the 3rd and the 6th day of spontaneous or progestin-induced menstrual cycle. Our study was performed in the absence of any medical treatment. RESULTS: Women with PCOS showed a higher LH to FSH ratio (p < 0.01), increased fasting insulin (p < 0.001), total testosterone (p < 0.001), and androstenedione (p < 0.001) levels, and lower SHBG concentrations (p < 0.001) compared to control women. BMI and waist-to-hip ratio were also higher in women with PCOS (p < 0.000 and p < 0.001, respectively). Women with PCOS also showed increased total cholesterol (p < 0.001), triglyceride (p < 0.001), and apolipoprotein B (p < 0.001) levels. Vascular data showed women with PCOS had a higher anteroposterior diameter than control women (p < 0.005). However, when analysis of covariance was performed and BMI was entered into the model as a covariate, anteroposterior diameter did not maintain a significant association with PCOS. CONCLUSION: This study shows that anteroposterior diameter of the infrarenal abdominal aorta, but not IMT of common carotid arteries or common femoral arteries, is higher in women with PCOS than in women without this disease. This represents the earliest atherosclerotic change in women with PCOS. However, this alteration seems to be due to body weight secondary to PCOS and not due to PCOS per se.

Effects of pretreatment with estrogens on ovarian stimulation with gonadotropins in women with premature ovarian failure: a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the hypothesis that pretreatment with estrogens in women affected by premature ovarian failure (POF) may improve the results of ovarian stimulation. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: Outpatient department in an academic research environment. PATIENT(S): Fifty women with POF seeking pregnancy. INTERVENTION(S): Before starting ovarian stimulation, group 1 received 0.05 mg ethinyl-E(2) (EE) three times a day for 2 weeks, while group 2 received placebo. Ovarian stimulation was carried out with recombinant FSH (r-betaFSH), 200 IU/day/SC. Both EE and placebo were administered during ovarian stimulation. Human chorionic gonadotropin (10,000 IU/IM) was added when the follicle exceeded a mean diameter of 18 mm. MAIN OUTCOME MEASURE: Rate of ovulation in women with POF. RESULT(S): Levels of FSH before stimulation were significantly lower in group 1 than in group 2. The rate of ovulation in group 1 (8/25; 32%) was significantly higher than in group 2 (0/25; 0%). Notably, induction of ovulation was successful only in patients whose FSH levels after EE treatment were < or =15 mIU/mL. CONCLUSION(S): Our data suggest that pretreatment with EE improves the success of rate of ovulation induction with exogenous gonadotropins in patients with POF. A threshold of FSH < or =15 mIU/mL should be achieved before starting ovarian stimulation.