Roberto Marci

Cellular and molecular aspects of ovarian follicle ageing

It is well established that age-related decline of the biological capacity of a woman to reproduce is primarily related to the poor developmental potential of her gametes. This renders female ageing the most significant determinant of success in IVF. Starting with a reference picture of the main molecular and cellular failures of aged oocytes, granulosa cells and follicular microenvironment, this review focuses on age-related biochemical mechanisms underlying these changes. According to the most relevant concept of ageing, age-associated malfuction results from physiological accumulation of irreparable damage to biomolecules as an unavoidable side effect of normal metabolism. More than a decade after the free radical theory of ovarian ageing, biological and clinical research supporting the involvement of oxidative injuries in follicle ageing is discussed. Looking for the aetiology of oxidative stress, we consider the effect of ageing on ovarian and follicular vascularization. Then, we propose a potential role of advanced glycation end-products known to be involved in the physiological ageing of most tissues and organs. We conclude that future investigation of age-related molecular damage in the different ovarian components will be imperative in order to evaluate the possibility to save or rescue the developmental potential of aged oocytes.

Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women

Objective To assess the efficacy and safety of intravaginal estriol administration on urinary incontinence, urogenital atrophy, and recurrent urinary tract infections in postmenopausal women. Design Eighty-eight postmenopausal women with urogenital aging symptoms were enrolled in this prospective, randomized, placebo-controlled study. Participants were randomly divided into two groups, with each group consisting of 44 women. Women in the treatment group received intravaginal estriol ovules: 1 ovule (1 mg) once daily for 2 weeks and then 2 ovules once weekly for a total of 6 months as maintenance therapy. Women in the control group received inert placebo vaginal suppositories in a similar regimen. We evaluated urogenital symptomatology, urine cultures, colposcopic findings, urethral cytologic findings, urethral pressure profiles, and urethrocystometry before as well as after 6 months of treatment. Results After therapy, the symptoms and signs of urogenital atrophy significantly improved in the treatment group in comparison with the control group. Thirty (68%) of the treated participants, and only seven (16%) of the control participants registered a subjective improvement of their incontinence. In the treated participants, we observed significant improvements of colposcopic findings, and there were statistically significant increases in mean maximum urethral pressure, in mean urethral closure pressure as well as in the abdominal pressure transmission ratio to the proximal urethra. Urethrocystometry showed positive but not statistically significant modifications. Conclusions Our results show that intravaginal administration of estriol may represent a satisfactory therapeutic choice for those postmenopausal women with urogenital tract disturbances who have contraindications or refuse to undergo standard hormone therapy.

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.

A low-dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins

OBJECTIVE To study the benefits of a low-dose stimulation (LDS) protocol with purified urinary follicle-stimulating hormone in patients with polycystic ovaries who have presented previously with a very high ovarian response to a standard hMG stimulation. DESIGN Cohort study. SETTING Fertility center in a university hospital. PATIENT(S) Sixty-one patients involved in an IVF/ICSI program from January 1995 to December 1996. INTERVENTION(S) The patients were first stimulated with a standard protocol using hMG and presented with a very high ovarian response. These patients were then stimulated a second time using a low-dose protocol. Cryopreserved embryos were transferred in later artificial or natural cycles until to December 1999. MAIN OUTCOME MEASURE(S) Number of gonadotropin ampules; estradiol level on the day of ovulation induction; follicles, oocytes, and cryopreserved zygotes; fertilization, implantation, and pregnancy rates; and number of ovarian hyperstimulation syndromes (OHSS). RESULT(S) The number of ampules used, the estradiol level reached, and the number of oocytes obtained were significantly lower under the LDS than the standard protocol. High implantation (21.8%) and clinical pregnancy (38.4%) rates were obtained after LDS. The cumulated deliveries per cycle started and per patient were, respectively, 41.6% and 52.5%. Five patients suffered OHSS with the standard protocol, and none with the LDS. CONCLUSION(S) The LDS protocol offers a safe and efficient treatment for patients who present with echographic polycystic ovaries and are at risk of an excessive ovarian response to standard IVF stimulation protocols.

Serological Evidence of an Early Seroconversion to Simian Virus 40 in Healthy Children and Adolescents

At present Simian virus 40 (SV40) infection in humans appears to be transmitted independently from early contaminated vaccines. In order to test the spread of SV40 infection in children, an immunologic assay employing specific SV40 synthetic peptides corresponding to its viral protein (VP) antigens was employed to estimate the seroprevalence of this polyomavirus in Italian infants and adolescents. Serum samples from 328 children and adolescents, up to 17 years, were investigated. Serum antibodies against SV40 VPs were detected by indirect enzyme-linked immunosorbent assays. The seroprevalence of this polyomavirus was calculated after stratifying the subjects by age. Anti-viral capsid protein 1-2-3 SV40 IgG antibodies were detected in 16% of the study participants. The prevalence of antibodies against SV40 VPs tended to increase with age in children, up to 10 year old (21%). Then, in the cohort of individuals aged 11–17 years, the prevalence decreased (16%). A higher prevalence rate (23%) of SV40 VP antibodies was detected in the cohorts of 1–3 year and 7–10 year old children, than in children and adolescents of the other age groups. This age corresponds to children starting nursery and primary school, respectively, in Italy. IgM antibodies against SV40 VP mimotopes were detected in 6–8 month old children suggesting that SV40 seroconversion can occur early in life. SV40 VP antibodies are present at low prevalence in Italian children (16%), suggesting that SV40 infection, although acquired early in life, probably through different routes, is not widespread. The low SV40 seroprevalence suggests that SV40 is less transmissible than other common polyomaviruses, such as BKV and JCV. Alternatively, our immunologic data could be due to another, as yet undiscovered, human polyomavirus closely related to SV40.

Procreative sex in infertile couples: the decay of pleasure?

BackgroundInfertility represents a major challenge to the emotional balance and sexual life of couples, with long-lasting and gender-specific effects. The objective of this study is to explore personality features of infertile patients and detect possible sexual disorders in couples undergoing infertility treatment.Materials and methodsIn this prospective study 60 infertile couples and 52 fertile control couples were asked to complete standardized and validated questionnaires: the Adjective Check List (ACL) to enquire about personality features and the Female Sexual Function Index (FSFI) or the International Index of Erectile Function (IIEF) to assess sexual functioning of female and male partners. The study population was divided into 3 groups: Group A (N = 30, recently diagnosed infertile couples) Group B (N = 30, infertile couples already undergoing Intrauterine Insemination) and Group C (N = 52, fertile control group).ResultsInfertile patients did not display any distinguishing personality features. Regarding sexual function, men of all the three groups scored higher in both questionnaires (sexual satisfaction, desire and orgasm) than their female partners. Comparing results between groups, Group A male partners obtained lower scores in all the subscales. Women belonging to Group A and Group B showed an impairment of sexual arousal, satisfaction, lubrification and orgasm when compared to fertile controls.ConclusionsEven if at the very first stages of infertility treatment no personality disturbances can be detected, the couples’ sexual life is already impaired with different sexual disorders according to gender.

Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids

Uterine fibroids are the most common benign tumors of the female genital tract. The management of symptomatic fibroids has traditionally been surgical; however, alternative pharmacological approaches have been proposed to control symptoms. To date, gonadotropin-releasing hormone analogs are the only available drugs for the preoperative treatment of fibroids. However, the US Food and Drug Administration recently authorized ulipristal acetate (UPA), an oral selective progesterone-receptor modulator, for the same indication. UPA is a new, effective, and well-tolerated option for the preoperative treatment of moderate and severe symptoms of uterine fibroids in women of reproductive age. According to clinical data, UPA shows several advantages: it is faster than leuprolide in reducing the fibroid-associated bleeding, it significantly improves hemoglobin and hematocrit levels in anemic patients, and it grants a significant reduction in the size of fibroids, which lasts for at least 6 months after the end of the treatment. Furthermore, UPA displays a better tolerability profile when compared to leuprolide; in fact, it keeps estradiol levels at mid follicular phase range, thereby reducing the incidence of hot flushes and exerting no impact on bone turnover. On the grounds of this evidence, the administration of 5 mg/day ulipristal acetate for 3 months is suggested for different patient categories and allows for planning a treatment strategy tailored to meet an individual patient’s needs.

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.