Francesca Papini

Infertility and pregnancy loss in euthyroid women with thyroid autoimmunity

Thyroid autoimmunity is the most prevalent autoimmune state that affects up to 5–20% of women during the age of fertility. Prevalence of thyroid autoimmunity is significantly higher among infertile women, especially when the cause of infertility is endometriosis or polycystic ovary syndrome. Presence of thyroid autoimmunity does not interfere with normal embryo implantation and have been observed comparable pregnancy rates after assisted reproduction techniques in patients with or without thyroid autoimmunity. Instead, the risk of early miscarriage is substantially raised with the presence of thyroid autoimmunity, even if there was a condition of euthyroidism before pregnancy. Furthermore the controlled ovarian hyperstimulation, used as preparation for assisted reproduction techniques, can severely impair thyroid function increasing circulating estrogen levels. Systematic screening for thyroid disorders in women with a female cause of infertility is controversial but might be important to detect thyroid autoimmunity before to use assisted reproduction techniques and to follow-up these parameters in these patients after controlled ovarian hyperstimulation and during pregnancy.

DHEA supplementation improves follicular microenviroment in poor responder patients

Objective: To analyze the effect of dehydroepiandrosterone (DHEA) supplementation on follicular microenvironment and on in vitro fertilization (IVF) outcomes among poor responder patients. Study design: We enrolled 24 patients diagnosed as poor responders based on ESHRE consensus criteria. One group received 25 mg/die three times daily of DHEA supplementation for 3 months previous to IVF cycle, while the other did not receive any treatment. COH was performed with rFSH and hMG, and a GnRH antagonist was administered according to a flexible protocol. We evaluated perifollicular vascularization of recruited follicles through power Doppler blood flow analysis and follicles were graded as described by Chui et al. Follicular fluids (FF) from F3-F4 follicles were collected, and FF levels of vascular endothelial growth factor (VEGF) and hypoxic inducible factor1 (HIF1) were measured. Results: FF levels of HIF1 were statistically significant lower in women treated with DHEA (14.76 ± 51.13 vs. 270.03 ± 262.18 pg/ml; p = 0.002). On the contrary, VEGF levels did not differ between the two groups. Concerning COH, in the DHEA-group the mean duration of treatment was significantly shorter (9.83 ± 1.85 vs. 12.09 ± 2.81; p = 0.023). Total numbers of oocytes retrieved, fertilized oocytes, good quality embryos, number of transferred embryos and clinical pregnancies tended to be higher in study group, but the results were not significant. On the other hand, considering the oocytes retrieved in selected F3-F4 follicles, there was a relation between HIF1 levels and oocytes quality. In fact, mature oocytes retrieved in selected follicles were significantly more numerous in DHEA-group (0.50 ± 0.52 vs. 0.08 ± 0.29; p = 0.018). Conclusions: The improvement of reproductive parameters after DHEA supplementation in poor responders may be explained through the effect that this pro-hormone exerts on follicular microenvironment.

Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study

This study evaluated whether heparin administration could affect IVF outcome. A total of 172 women, aged <40years, without laboratory findings of thrombophilia and undergoing their first IVF cycle, were randomly allocated to treatment (n=86) and control (n=86) groups. Patients allocated to the treatment group received low-molecular-weight heparin dalteparin sodium 2500IU s.c. daily, in addition to routine luteal phase support, from oocyte retrieval up to the day of the pregnancy test or up to the ninth week of pregnancy in the cases of positive human chorionic gonadotrophin. From the day after the oocyte retrieval, all patients began standard supplementation with vaginal progesterone 200mg twice a day. At the sixth week of pregnancy, patients underwent an ultrasound scan to assess the number/viability of gestational sacs. Implantation rates were 15% and 12% in the dalteparin and control groups, respectively. The clinical pregnancy rates/embryo transfers were 26% (19/73) and 20% (16/80), in the dalteparin and control groups, respectively, with live birth rates/embryo transfer of 21% (15/73) and 16% (13/80). Despite the lack of statistical significance, the increase in pregnancies observed in the treatment group may be considered as an important clinical point in the optimization of IVF clinical outcome.

Chromosomal abnormalities in women with premature ovarian failure

Premature ovarian failure is a complex disorder that results in the early loss of ovarian function; however this disease must be separated from early menopause because these patients can sporadically ovulate and in literature are described pregnancies. The aetiology and the patho-physiology of premature ovarian failure are still matter of debate, but is commonly accepted that genetic factors play an important role. This review is aimed to present an overview of known inherited factor implied in the pathogenesis of this disorder to help physician in the counselling of affected pregnant women.

Pharmacotherapy of ovarian hyperstimulation syndrome

Importance of the field: One of the main objectives in assisted reproduction techiques (ART) is the maturation of multiple follicles and the recovery of multiple good quality oocytes. To realize this, it is necessary to interfere with the mechanisms of selection and follicular dominance, characteristic of spontaneous mono-ovulatory cycles, by administering gonadotrophins. In 12 – 20% of the stimulation cycles, the response to ovarian stimulation in terms of follicular development is higher than expected, with the onset of the so-called ovarian hyperstimulation syndrome (OHSS). This is considered to be an exaggerated response: an iatrogenic – possibly life-threatening – complication of ovarian stimulation. Areas covered in this review: This review deals about reproductive, obstetric and gynecological aspects of OHSS. What the reader will gain: Understanding the pathophysiology of OHSS is the key to establishing a correct pharmacotherapy. However, the mechanisms underlying OHSS have not yet been completely clarified. Treatment of OHSS is empirical, so prevention is the most important aspect in its management. Several studies support the role of vascular endothelial growth factor in the development of OHSS in humans, so future studies about anti-angiogenetic molecules seem to be an important goal in ART. Take home message: Methods to prevent OHSS.

Genetic screening in Italian infertile couples undergoing intrauterine insemination and in vitro fertilization techniques: a multicentric study.

Aim of the study. To report the frequency of aberrant karyotype and mutated cystic fibrosis transmembrane conductance regulator (CFTR) gene, according to a careful application of Italian guidelines for genetic screening in infertile couple candidates for intrauterine insemination (IUI) and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Materials and methods. Two thousand and sixteen consecutive infertile couple candidates for Assisted Reproduction Techniques (ART) were screened for karyotype and 616 couples for CFTR analysis. Results. Regarding karyotype analysis, 59 chromosomal abnormalities were diagnosed in candidates for IVF/ICSI: 27 mutations in women corresponding to a frequency equal to 1.53% (27/1762; 95% confidence interval [CI], 0.96–2.1%) and 32 mutations in men corresponding to a frequency equal to 1.82% (32/1762; 95% CI, 1.2–2.44%) for men. The frequency differs according to the sperm count. In couple candidates for IUI techniques, no genetic abnormalities were found in male patients and only one aberration in a female patient with a frequency of 0.41% (1/245 CI 0.01–0.81%). Regarding CFTR analysis, excluding the 5T variant, we obtained 20 mutations in couples undergoing IVF/ICSI and 8 mutations in IUI group. Conclusion. Couples undergoing IVF/ICSI show a higher prevalence of aberrant karyotypes than general population, whereas the frequency of a mutation of the CFTR gene is similar. On the other hand, couples undergoing IUI do not differ from the general population either for karyotype or for CFTR mutations.

Ovarian response to controlled ovarian stimulation in women with different polycystic ovary syndrome phenotypes

Abstract Controlled ovarian stimulation (COH) in PCOS is a challenge for fertility expert both ovarian hyperstimulation syndrome (OHSS) and oocytes immaturity are the two major complication. Ovarian response to COH vary widely among POCS patients and while some patients are more likely to show resistance to COH, other experienced an exaggerated response. The aim of our study is to investigate a possible correlation between PCOS phenotypes and the variety of ovarian response to COH and ART outcomes in patients with different PCOS phenotypes. We retrospectively analyzed a total of 71 cycles performed in 44 PCOS infertile patients attending ART at Centre of Infertility and Assisted Reproduction of Pisa University between January 2013 and January 2016. Patientsundergoing IVF with GnRH-antagonist protocol and 150–225 UI/days of recombinant FSH; triggering was carried out using 250 mg of recombinant hCG or a GnRH analogous on the basis of the risk to OHSS. We observed that Phenotype B had a tendency to have a greater doses of gonadotropins used respect to all phenotypes. Phenotype A group showed a greater serum estrogen levels compared to all phenotypes groups, a greater number of follicles of diameter between 8–12 mm found by ultrasound on the day of triggering and a greater mean number of freeze embryo. Additionally serum AMH and antral follicles count (AFC) follow the same trend in the different phenotypes ad they were significantly higher in phenotype A and in phenotype D. In conclusion this study shows that the features of PCOS phenotypes reflect the variety of ovarian response to COH as well as the risks to develop OHSS. Serum AMH and AFC are related to the degree of ovulatory dysfunction making these ‘added values’ in identifying the different PCOS phenotypes. Phenotype A seems to be the phenotype with the higher risk to develop OHSS and the use of GnRH as a trigger seems to improve oocyte quality. To classify PCOS phenotype at diagnosis might help clinicians to identify patients at greater risk of OHSS, customize therapy and subsequently plan the trigger agent.

Comparison between GnRH agonist and antagonist protocols for severe endometriosis in assisted reproductive cycles

Purpose Endometriosis may influence different aspects of reproductive physiology including folliculogenesis, ovulation, embryo quality, and fertilization. Recent data demonstrate that patients with endometriosis-associated infertility undergoing in vitro fertilization (IVF) have a reduction of pregnancy rates compared to women with other indications for IVF. The aim of the study is to evaluate the outcomes of IVF after controlled ovarian hyperstimulation (COH) with GnRH antagonist (GnRH-ant) or GnRH agonist (GnRH-a) in severe endometriosis patients. Methods A total of 101 patients with severe endometriosis undergoing IVF cycles were retrospectively enrolled into two groups in relation to hypothalamic inhibition before COH, obtained respectively with leuprorelin and cetrorelix. We evaluated characteristics of COH and clinical outcomes (overall pregnancy rate, implantation rate, spontaneous miscarriages, ectopic pregnancies, and clinical pregnancy rates). Results The group treated with GnRH-ant presented a similar number of MII oocytes and good quality embryos while using a lower amount of gonadotropins. Outcomes of COH with both GnRH-ant and GnRH-a were similar in patients with stage III-IV endometriosis. The number of retrieved oocytes, the number of obtained embryos, the implantation rates, and the clinical pregnancy rates were similar with GnRH-ant and GnRH-a protocols. Conclusions Considering the pregnancy outcomes, COH with both GnRH-ant and GnRH-a protocols do not present statistical differences in patients with severe endometriosis, but the GnRH-ant protocol could be more convenient in term of gonadotropins amount and patient discomfort.

PCOS and pregnancy: a review of available therapies to improve the outcome of pregnancy in women with polycystic ovary syndrome

ABSTRACT Introduction: Polycystic ovary syndrome (PCOS) is a common cause of female infertility affecting multiple aspects of a women’s health. Areas covered: The aim of this review is to summarize the existing evidence on the treatment of PCOS patients and to examine the actual available therapies to overcome the problem of infertility and improve the outcome of pregnancy. We analyse different treatment strategies such as lifestyle modification, bariatric surgery, insulin sensitizing agents, inositol, clomiphene citrate (CC), aromatase inhibitors, gonadotrophins, laparoscopic ovarian drilling, and assisted reproductive techniques (ART). Expert commentary: Lifestyle modification is the best initial management for obese PCOS patients seeking pregnancy and insulin sensitizing agents seem to have an important role in treating insulin resistance. Up to now, CC maintains a central role in the induction of ovulation and it has been confirmed as the first-line treatment; the use of gonadotrophins is considered the second-line in CC resistant patients; laparoscopic ovarian drilling is an alternative to gonadotrophins in patients who need laparoscopy for another reason. However, in anovulatory patients, ART represents the only possible alternative to obtain pregnancy. Larger and well-designed studies are needed to clarify the best way to improve the outcome of pregnancy in PCOS women.

Supplementation with DHEA in Poor Responder Patients

Poor response to ovarian stimulation (POR) usually indicates a reduction in follicular response to ovarian stimulation during in vitro fertilization (IVF) cycles resulting in a reduced number of retrieved oocytes. In recent years, mainly due to the postponement of childbearing and the consequent decrease of ovarian reserve, often a POR occurs during IVF despite the high dose of gonadotropins administered. Incidence of POR has been reported from 9 to 24 % [1, 2], and even if this condition may occur unexpectedly, its prevalence increases with age, and it is >50 % in patients over 40 years [3]. Patients with POR are defined as poor responders.