The impact of letrozole administration on oocyte morphology in breast cancer patients undergoing fertility preservation.

ABSTRACT: Patients submitted to oncological fertility preservation with letrozole and gonadotropins seem to present a higher rate of immature oocytes and lower fertilization rates in comparison to infertile patients submitted to IVF cycles with gonadotropins. The aim of this study was to evaluate the influence of letrozole on oocyte morphology in patients with breast cancer submitted to fertility preservation. METHODS: Retrospective analysis performed at a public tertiary hospital in São Paulo, Brazil. The oocytes were retrieved from patients with breast cancer undergoing fertility preservation (n=69), and from infertile women undergoing in vitro fertilization (n=92). We evaluated 750 oocytes obtained from breast cancer patients submitted to ovarian stimulation with letrozole and gonadotropins, and 699 oocytes from patients without breast cancer submitted to ovarian stimulation for in vitro fertilization with gonadotropins only due to male factor infertility. The mature oocytes retrieved were analyzed for the presence of refractile bodies, ooplasm color and regularity, central granulation degree, cortical granules, zona pellucida staining and regularity, perivitelline space, presence of vacuoles or abnormal smooth-surfaced endoplasmic reticle and oocyte retraction. RESULTS: There was a higher incidence of alterations in oocyte morphology in the letrozole group when compared to the control group: increased perivitelline space (p=0.007), irregular zona pellucida (p<0.001), refractile bodies (p<0.001), dark ooplasm (p<0.001), granular ooplasm (p<0.001), irregular ooplasm (p<0.001) and dense central granulation (p<0.001). CONCLUSION: Letrozole is a risk factor for worse oocyte morphology. However, the clinical impact of ovarian stimulation protocol with combined use of gonadotropins and letrozole for fertility preservation remains unclear in this setting. These data underline the importance of establishing the predictive potential of morphological dimorphisms of human oocytes in IVF outcomes.

ANDRO-IVF: a novel protocol for poor responders to IVF controlled ovarian stimulation.

OBJECTIVE: This study aimed to assess a novel protocol designed to improve poor ovarian response through intra-ovarian androgenization. The endpoints were: number of oocytes and mature oocytes retrieved, fertilization, cancellation and pregnancy rates. METHODS: This prospective crossover study enrolled poor responders from previous ovarian stimulation cycles submitted to a novel protocol called ANDRO-IVF. The protocol included pretreatment with transdermal AndroGel(r) (Besins) 25 mg, oral letrozole 2.5 mg and subcutaneous hCG 2500 IU; cycle control was performed with estradiol valerate and micronized progesterone; ovarian stimulation was attained with gonadotropins FSH/LH 450 IU, GnRH antagonist and hCG 5000 IU. RESULTS: Fourteen poor responders were enrolled. One patient did not meet the inclusion criteria. Thirteen patients previously summited to the standard protocol were offered the ANDRO-IVF Protocol.-Standard Protocol: Mean age: 35.30 years; cancellation rate: 61.53%; mean number of MII oocytes retrieved per patient: 1.8; fertilization rate: 33.33%. Only two patients had embryo transfers, and none got pregnant.-ANDRO-IVF Protocol: Mean age: 35.83 years; cancellation rate: 7.69%; mean number of oocytes retrieved per patient: 5.58, MII oocytes: 3.91. ICSI was performed in 84.61% of the patients and a mean of 1.5 embryos were transferred per patient. Fertilization rate: 62.5%; cumulative pregnancy rate: 16.66%; mean duration of stimulation: 9.77 days. CONCLUSION: ANDRO-IVF allows intra-ovarian androgenization by increasing serum and intra-follicular androgen levels and preventing androgen aromatization. This protocol apparently improved clinical outcomes of poor responders in parameters such as number of oocytes retrieved and clinical pregnancy rates. Further randomized controlled trials are needed to confirm these findings.

Preimplantation genetic diagnosis for a patient with multiple endocrine neoplasia type 1: case report.

Preimplantation genetic diagnosis was carried out for embryonic analysis in a patient with multiple endocrine neoplasia type 1 (MEN1). This is a rare autosomal-dominant cancer syndrome and the patients with MEN1 are characterized by the occurrence of tumors in multiple endocrine tissues, associated with germline and somatic inactivating mutations in the MEN1 gene. This case report documents a successful preimplantation genetic diagnosis (PGD) involving a couple at-risk for MEN1 syndrome, with a birth of a healthy infant. The couple underwent a cycle of controlled ovarian stimulation and intracytoplasmic sperm injection (ICSI). Embryos were biopsied at the blastocyst stage and cryopreserved; we used PCR-based DNA analysis for PGD testing. Only one of the five embryos analyzed for MEN1 syndrome was unaffected. This embryo was thawed and transferred following endometrial preparation. After positive ßHCG test; clinical pregnancy was confirmed by ultrasound, and a healthy infant was born. PGD for single gene disorders has been an emerging therapeutic tool for couples who are at risk of passing a genetic disease on to their offspring.