Mauro Costa

Cancer and fertility preservation: International recommendations from an expert meeting

In the last years, thanks to the improvement in the prognosis of cancer patients, a growing attention has been given to the fertility issues. International guidelines on fertility preservation in cancer patients recommend that physicians discuss, as early as possible, with all patients of reproductive age their risk of infertility from the disease and/or treatment and their interest in having children after cancer, and help with informed fertility preservation decisions. As recommended by the American Society of Clinical Oncology and the European Society for Medical Oncology, sperm cryopreservation and embryo/oocyte cryopreservation are standard strategies for fertility preservations in male and female patients, respectively; other strategies (e.g. pharmacological protection of the gonads and gonadal tissue cryopreservation) are considered experimental techniques. However, since then, new data have become available, and several issues in this field are still controversial and should be addressed by both patients and their treating physicians.In April 2015, physicians with expertise in the field of fertility preservation in cancer patients from several European countries were invited in Genova (Italy) to participate in a workshop on the topic of “cancer and fertility preservation”. A total of ten controversial issues were discussed at the conference. Experts were asked to present an up-to-date review of the literature published on these topics and the presentation of own unpublished data was encouraged. On the basis of the data presented, as well as the expertise of the invited speakers, a total of ten recommendations were discussed and prepared with the aim to help physicians in counseling their young patients interested in fertility preservation.Although there is a great interest in this field, due to the lack of large prospective cohort studies and randomized trials on these topics, the level of evidence is not higher than 3 for most of the recommendations highlighting the need of further research efforts in many areas of this field. The participation to the ongoing registries and prospective studies is crucial to acquire more robust information in order to provide evidence-based recommendations.

Comparison of different ovarian stimulation protocols for gamete intrafallopian transfer in patients with minimal and mild endometriosis

Three different stimulation protocols were tested in patients affected by stage I and II endometriosis with no other causes of infertility, and scheduled for the gamete intrafallopian transfer technique. In two protocols a gonadotropin hormone-releasing hormone analog was used. The analog was started 6 months before stimulation in the former and along with the exogenous gonadotropin in the latter. Patients receiving only gonadotropin served as controls. Sixty patients were selected for this study; 55 reached laparoscopy. Whereas patients receiving either gonadotropin alone or simultaneous analog and gonadotropin had similar pregnancy rates, this was much higher in the patients undergoing a prolonged, medically induced hypoestrogenism. Prolonged analog pretreatment before ovarian stimulation may give better chances of success in endometriosis patients undergoing assisted reproduction techniques.

The duration of pituitary suppression by means of intranasal gonadotropin hormone-releasing hormone analogue administration does not influence the ovarian response to gonadotropin stimulation and success rate in a gamete intrafallopian transfer (GIFT) program

The aim of the study was to compare the ability to prevent endogenous luteinizing hormone interferences, ovarian response, and success rate between two groups of patients undergoing GIFT procedures and treated with the same stimulatory protocol but with a different timing in the administration of the gonadotropin hormone-releasing hormone analogue (GnRH-a). The former underwent a concomitant administration of gonadotropin and analogue; the latter started stimulation only after the achievement of complete hypogonadotropinism. The analogue was always given intranasally and stimulation was identical in the two groups. Our results showed that (1) prevention of premature luteinization is obtained with both approaches and (2) no significant difference in terms of length of stimulation, gonadotropin doses, ovarian response, and success rate was recorded between the two groups.

A prospective, randomized, controlled clinical study of a new subcutaneous, purified, urinary FSH preparation for controlled ovarian hyperstimulation in in vitro fertilization

The aim of this study was to evaluate the clinical efficacy and safety of a new urinary follicle stimulating hormone (FSH) preparation (Fostimon®) in patients undergoing in vitro fertilization–embryo transfer or intracytoplasmic sperm injection. Metrodin HP® was adopted as a reference drug, as its purity and therapeutic efficacy are well known. Sixty normo-ovulatory patients aged 18–38 years with normal basal FSH and body mass index < 25 kg/m2 were selected for the study. After gonadotropin releasing hormone analogue pituitary desensitization, patients were randomized to receive either Fostimon or Metrodin HP at the initial dosage of 225 IU for 6 days. Thereafter, the dosage was tailored according to the ovarian response. Both drugs were administered by the subcutaneous route. The primary end-points were: number of follicles larger than 15 mm, levels of 17β-estradiol on the day of human chorionic gonadotropin (hCG) injection and number of oocytes recovered. The secondary end-points were: number of FSH ampules used, day of hCG injection and pregnancy rate. FSH kinetic curves were calculated during the treatment period with both products. Safety was evaluated by pre- and post-treatment blood biochemistry and hematology, and recording all side-effects. Local tolerance was investigated at each visit. None of the parameters evaluated showed a statistically significant difference between the two groups. Local tolerance was always recorded as good/excellent by both the patients and the physician. In conclusion, Fostimon proved to be an effective and safe drug for assisted reproductive cycles.

Gamete intrafallopian transfer and plasma chorionic gonadotropin dynamics: Evidence of a delayed appearance

The purpose of this study was to compare early human chorionic gonadotropin secretion in two groups of pregnancies. These pregnancies were obtained, in one group, during a natural cycle, while, in the other group, they resulted from gamete intrafallopian transfers performed in hyperstimulated cycles. A logarithmic regression analysis was chosen to allow statistical comparison of serial plasmatic evaluation as hormone determinations were obtained, among patients, at different postovulatory days. The regression lines of the two groups of patients presented similar slopes. The unpairedt test performed on calculated data for 3 different days constantly revealed significantly higher levels (P<0.005) of natural vs stimulated cycles; thus a different origin on thex axis (days of the luteal phase) is deduced. These findings support the possibility of a delay in the appearance of human chorionic hormone in the patients undergoing gamete intrafallopian transfer technique.

Timing, characteristics and determinants of infertility diagnostic work up before admission to eleven second-level assisted reproductive techniques (ART) centres in Italy

OBJECTIVE To describe the time-course of infertile couples not conceiving spontaneously or with medical or surgical therapies before assisted reproductive techniques (ART). STUDY DESIGN Multicentre study of consecutive couples seen for the first time in eleven second-level infertility centres in Italy. A total of 464 couples entered the study and completed a structured questionnaire with the assistance of a clinician. Information was collected on general characteristics, reproductive and gynaecological history, and presumed causes of infertility. Further information was collected on: date of first trying for pregnancy and first consultation for infertility; doctor first consulted by the couple and who decided the diagnostic work-up; instrumental and laboratory tests performed during the diagnostic work-up. RESULTS The first medical consultation for infertility occurred after an average of 13 months of unprotected intercourse. This interval was statistically significantly longer for women with low educational level. The median interval between the first medical consultation and the consultation in a second-level infertility centre was 9.5 months. This interval was shorter when the first clinician consulted was a specialist in infertility working in a first-level public centre. Moreover, this interval was longer among women with low educational level. At the time of the consultation in a second-level infertility centre, most of the female patients had already been examined for ovarian, hypophyseal and thyroid function, but only 12% had undergone an anti-Mullerian hormone (AMH) determination: 56% had microbiological culture performed. Nearly 40% had been studied for tubal patency and karyotype. More than 50% of the male partners had not a complete semen evaluation, but 46.0% had second-level examinations. CONCLUSION Educational level is linked to a higher possibility of recognizing fertility problems. The referral process to a second-level centre is quicker in the public sector.

Abstract S5-08: Breast cancer incidence after hormonal infertility treatments: Systematic review and meta-analysis of population based studies

Background: With the increasing practice of hormonal infertility treatments in infertile women, both for ovulation induction in anovulatory women and for ovarian hyperstimulation in assisted reproductive technologies, concerns have been raised about the long-term effects of such practice on the subsequent risk of breast cancer. Sterility itself is an independent risk factor, though its effect is not yet clear. In the past years, a number of population-based studies has addressed the possible association between breast cancer incidence and infertility treatments, with inconsistent results. With these premises, we performed a systematic review and pooled analysis of the association between infertility treatments by any kind of hormonal manipulation and breast cancer incidence, based on published data. Methods: Population cohort studies, evaluating the association between BC incidence and hormonal infertility treatments were identified by literature search. Standardised Incidence Ratios (SIRs) were pooled across the studies by inverse variance weighting. Subgroup analyses were performed according to the following covariates: length of follow up ( 10 yrs), type of hormonal therapy (clomiphene vs gonadotropins) and type of control group (population based on internal control, ie infertile women). All statistical tests were two-sided. Results: Seventeen eligible studies were identified and retrieved. Data on breast cancer incidence and type of fertility treatments were available for all studies. Overall hormonal infertility treatments were associated with a 11% increase in BC incidence as compared with untreated women (SIR SIR 1.11, 95%CI 0,91-1,30). BC risk was slightly higher in clomiphene treated women (SIR 1.04; 95%CI 0.76-1.32) than in gonadotropins users (SIR 0.83; 95%CI 0.60-1.07), p for interaction 10yrs, p for interaction Conclusions: Overall hormonal infertility treatments do not appear to be consistently associated with a significant increase in breast cancer incidence. Subset analyses suggest a possible increase in BC incidence with longer FU (>10 yrs) whereas the use of gonadotropins might exert a protective effect. Finally, subset analyses according to type of controls suggest that the observed increased risk reported by several studies may be attributable to the infertility condition itself. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-08.

Abstract P6-09-01: Breast Cancer Incidence and Hormonal Infertility Treatments: A Systematic Review of Population Studies

Background: With the increasing practice of hormonal infertility treatments in infertile women, both for ovulation induction in anovulatory women and for ovarian hyperstimulation in assisted reproductive technologies, concerns have been raised about the long-term effects of such practice on the subsequent risk of breast cancer. Sterility itself is an independent risk factor, though its effect is not yet clear. In the past years, a number of population-based studies has investigated the possible association between breast cancer incidence and infertility treatments, with inconsistent results. With these premises, we performed a pooled analysis of the association between infertility treatments by any kind of hormonal manipulation and breast cancer incidence, based on published data. Methods: Population cohort studies, evaluating the association between BC incidence and hormonal infertility treatments were identified by MEDLINE search. Standardised Incidence Ratios (SIRs) were pooled across the studies by inverse variance weighting. Subgroup analyses were performed according to the following covariates: lenght of follow up ( Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-01.