Massimo Moscarini

Environment and women's reproductive health

BACKGROUND There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this systematic review, we evaluate the evidence for an association between EDC exposure and womens reproductive health. METHODS Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure and womens reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy outcomes, transgenerational exposure and effects. RESULTS Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phthalates and polybrominated flame retardants). CONCLUSIONS A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for prevention and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect womens reproductive health.

Bisphenol a and the female reproductive tract: an overview of recent laboratory evidence and epidemiological studies

Bisphenol A (BPA) is a high production volume monomer used for making a wide variety of polycarbonate plastics and resins. A large body of evidence links BPA to endocrine disruption in laboratory animals, and a growing number of epidemiological studies support a link with health disorders in humans. The aim of this review is to summarize the recent experimental studies describing the effects and mechanisms of BPA on the female genital tract and to compare them to the current knowledge regarding the impact of BPA impact on female reproductive health. In particular, BPA has been correlated with alterations in hypothalamic-pituitary hormonal production, reduced oocyte quality due to perinatal and adulthood exposure, defective uterine receptivity and the pathogenesis of polycystic ovary syndrome. Researchers have reported conflicting results regarding the effect of BPA on premature puberty and endometriosis development. Experimental studies suggest that BPA’s mechanism of action is related to life stage and that its effect on the female reproductive system may involve agonism with estrogen nuclear receptors as well as other mechanisms (steroid biosynthesis inhibition). Notwithstanding uncertainties and knowledge gaps, the available evidence should be seen as a sufficient grounds to take precautionary actions against excess exposure to BPA.

The influence of endocrine disruptors in a selected population of infertile women

Abstract Several studies report that endocrine disrupting chemicals (EDC) able to interfere with endocrine homeostasis may affect women’s reproductive health. We analyzed EDC serum levels and nuclear receptors (NRs) expression in order to have an indication of the internal dose of biologically active compounds and a measurement of indicators of their effects, as a result of the repeated uptake from environmental source. The percentage of patients with detectable bisphenol A (BPA) concentrations was significantly higher in the infertile patients compared with fertile subjects. No significant difference was found between the groups with regard to perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), mono-ethylhexyl phthalate (MEHP) and di-(2-ethylhexyl) phthalate (DEHP) concentrations. Among infertile women, the mean expression of estrogen receptor alpha (ERα) and beta (Erβ), androgen receptor (AR) and pregnane X receptor (PXR) was significantly higher than fertile patients. The mean expression of aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARγ) did not show significant differences between two groups. Patients with endometriosis had higher levels of PPARγ than all women with other causes of infertility. This study led further support to EDC exposure as a risk factor for women’s fertility.

Expression of oct-4 and c-kit antigens in endometriosis

The objective of this study was to test the expression of the oct-4 and c-kit, both markers of stem cells, in the ectopic endometrial tissue of endometriotic lesions of women with severe endometriosis. Our findings show that ectopic epithelial cells express oct-4 and c-kit and this suggests that the ectopic endometrium in endometriosis has a stem cell origin and could explain the possible progression to ovarian cancer.

The influence of cigarette smoking on a population of infertile men and women

PurposeThis study aimed at investigating the effect of cigarette smoking on semen parameters in infertile men and on antral follicle count (AFC) and reproductive hormone levels in infertile women.MethodsIn 648 men (200 smokers and 448 non-smokers) sperm concentration, motility and morphology were compared according to smoking status. In the female population, AFC and basal follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were measured in 296 women (102 smokers and 194 non-smokers). Statistical analysis of data was performed using t test, χ²-test and Spearman’s correlation.ResultsAmong the male population, smokers had significantly lower sperm concentration and motility than non-smokers. Sperm normal morphology was reduced in smokers, although this difference did not reach statistical significance. No significant correlation was found between sperm parameters and the intensity of smoking. In the female population, AFC was reduced in smokers compared with non-smokers. Women who smoked had significantly higher FSH levels. No significant difference was found in LH and estradiol levels according to smoking status. The number of pack-years was negatively correlated to AFC and positively correlated to FSH levels.ConclusionCigarette smoking is associated with damaging effects on sperm parameters in infertile men and with ovarian reserve alteration in infertile women, as reflected by reduced AFC and increased FSH levels. Every smoker should be encouraged to stop smoking to prevent the damage of the toxins contained in cigarette smoking and preserve their own reproductive potential.

Exposure and effective dose biomarkers for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in infertile subjects: Preliminary results of the PREVIENI project

Perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been used as surfactants in various industry and consumer products. PFOS/PFOA are very persistent in the environment and bioaccumulate in humans. They are potential reproductive and developmental toxicants and are considered to be emerging endocrine disrupters (EDs). The Italian project PREVIENI, funded by the Italian Environment Ministry, aims to link environment and human health through the investigation of selected endocrine disrupters (EDs) exposure and associated biomarkers related to human infertility conditions. In the early PREVIENI phase, PFOS and PFOA were determined in 53 couples affected by an infertility status, enrolled in a metropolitan area, according to established inclusion criteria and informed consensus. Nuclear receptors related to chemical compounds interactions were selected as biomarkers of effect and their gene expression modulations were analyzed in human peripheral blood mononuclear cell (PBMC). Among couples, subjects not presenting infertility factors (IF--) were separated from affected subjects (IF++). Most IF-- serum samples showed PFOS and PFOA concentrations overlapping the limit of detection (LOD) of 0.5 ng/g wet weight (ww). A substantial percentage of IF++ serum samples showed PFOS concentrations >20-fold the LOD, i.e. from 3 to 50 ng/g ww. In male (50%, n=26) and from 3 to 144 ng/g ww in female (37%, n=30) samples. PFOA values were below the LOD levels in 90% of the total samples. Peroxisome proliferator-activated receptor-gamma (PPARγ) and aryl hydrocarbon receptor (AhR) showed a low level of expression in PBMC of both IF++ and IF-- groups. Whereas alpha and beta estrogen receptors (ERα and ERβ), androgen receptor (AR), and pregnane X receptor (PXR) were all upregulated in IF++ of both sexes with respect to IF-- group. Our preliminary results related to the metropolitan area indicate that subjects affected by infertility factors tend to have both higher PFOS levels and higher gene expression of specific nuclear receptors.

Maternal and perinatal outcomes in spontaneous versus assisted conception twin pregnancies

OBJECTIVE To compare maternal and perinatal outcomes in twin pregnancies conceived via assisted reproductive techniques (ART) compared with spontaneous twin pregnancies. STUDY DESIGN This retrospective study examined 345 dichorionic, di-amniotic twin pregnancies (207 conceived spontaneously and 138 conceived via ART), delivered between January 2007 and June 2011 at the San Pietro Fatebenefratelli Hospital, Rome, a tertiary medical centre. Maternal and perinatal outcomes were compared. A multiple logistic regression analysis was performed to calculate risk estimates as odds ratios (OR) adjusted for maternal age, parity and systemic diseases. Patient data were obtained from a computerized database and analyzed using Statistical Package for the Social Sciences Version 17. RESULTS Gestational age and birth weight were lower in the ART group, and preterm delivery, gestational diabetes and placental abruption were higher in the ART group compared with the spontaneous conception group. The incidence rates of respiratory complications, patent ductus arteriosus and admission to the neonatal intensive care unit were higher among ART newborns. Length of hospital stay for mothers and newborns was longer in the ART group. No differences in mode of delivery, Apgar score at 5min, congenital anomalies, perinatal mortality, and other considered pregnancy and neonatal complications were found between the two groups. Multivariate analysis adjusted for maternal age, parity and systemic diseases revealed that only the rates of placental abruption [OR 7.45, 95% confidence interval (CI) 2.05-26.98] and patent ductus arteriosus (OR 3.39, 95% CI 1.01-11.46) were significantly higher for the ART group. CONCLUSIONS Twin pregnancies conceived via ART are at greater risk of poorer outcomes than spontaneous twin pregnancies. This may be related to the type of conception and specific negative features of subfertile patients undergoing infertility treatment.

Metabolic syndrome and polycystic ovary syndrome: an intriguing overlapping

Abstract Metabolic syndrome is an increasing pathology in adults and in children, due to a parallel rise of obesity. Sedentary lifestyle, food habits, cultural influences and also a genetic predisposition can cause dyslipidemia, hypertension, abdominal obesity and insulin resistance which are the two main features of metabolic syndrome. Polycystic ovary syndrome (PCOS) is a condition directly associated with obesity, insulin resistance (HOMA index) and metabolic syndrome, and it is very interesting for its relationship and overlap with the metabolic syndrome. The relationship between the two syndromes is mutual: PCOS women have a higher prevalence of metabolic syndrome and also women with metabolic syndrome commonly present the reproductive/endocrine trait of PCOS. Prevention and treatment of metabolic syndrome and PCOS are similar for various aspects. It is necessary to treat excess adiposity and insulin resistance, with the overall goals of preventing cardiovascular disease and type 2 diabetes and improving reproductive failure in young women with PCOS. First of all, lifestyle changes, then pharmacological therapy, bariatric surgery and laparoscopic ovarian surgery represent the pillars for PCOS treatment.

Pretreatment with myo-inositol in non polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: A pilot study

BackgroundAim of this pilot study is to examine the effects of myo-inositol administration on ovarian response and oocytes and embryos quality in non PolyCystic Ovary Syndrome (PCOS) patients undergoing multiple follicular stimulation and in vitro insemination by conventional in vitro fertilization or by intracytoplasmic sperm injection.MethodsOne hundred non-PCOS women aged <40 years and with basal FSH <10 mUI/ml were down-regulated with triptorelin acetate from the mid-luteal phase for 2 weeks, before starting the stimulation protocol for oocytes recovery. All patients received rFSH, at a starting dose of 150 IU for 6 days. The dose was subsequently adjusted according to individual response. Group B (n = 50) received myo-inositol and folic acid for 3 months before the stimulation period and then during the stimulation itself. Group A (n-50) received only folic acid as additional treatment in the 3 months before and through treatment.ResultsTotal length of the stimulation was similar between the two groups. Nevertheless, total amount of gonadotropins used to reach follicular maturation was found significantly lower in group B. In addition, the number of oocytes retrieved was significantly reduced in the group pretreated with myo-inositol. Clinical pregnancy and implantation rate were not significantly different in the two groups.ConclusionsOur findings suggest that the addition of myo-inositol to folic acid in non PCOS-patients undergoing multiple follicular stimulation for in-vitro fertilization may reduce the numbers of mature oocytes and the dosage of rFSH whilst maintaining clinical pregnancy rate. Further, a trend in favor of increased incidence of implantation in the group pretreated with myo-inositol was apparent in this study. Further investigations are warranted to clarify this pharmacological approach, and the benefit it may hold for patients.

Evaluation of serum anti-Mullerian hormone levels to assess the ovarian reserve in women with severe endometriosis

OBJECTIVE The aim of this study was to measure anti-Mullerian hormone (AMH) serum levels in women with severe endometriosis, in order to demonstrate the effect of the disease on ovarian reserve. STUDY DESIGN Prospective case-control study. One hundred and ninety-five patients were enrolled: 130 fertile patients (group A) and 65 patients with stage III and IV endometriosis, diagnosed by laparoscopy and histological examination (group B). AMH serum levels were measured in both groups and were compared using Students t-test. RESULTS The two groups were homogenous for main demographic data. Group B had statistically significantly lower mean AMH serum levels (0.97±0.59ng/ml) than group A (1.72±0.63ng/ml) (p=0.001). CONCLUSIONS This study is a demonstration of the damage of endometriosis on ovarian reserve, leading to a form of incipient ovarian failure, which is considered as an early sign of advanced ovarian depletion in young women. These findings suggest that AMH could be used in the follow-up of patients with endometriosis, in order to assess promptly the decrease of ovarian reserve.