Shai Elizur

Immature oocyte retrieval in the luteal phase to preserve fertility in cancer patients

As cancer treatment outcomes improve, the number of women with cancer seeking fertility preservation increases. Currently, embryo/oocyte cryopreservation appears to provide the best fertility preservation option. However, patients may not have sufficient time to undergo ovarian stimulation prior to chemotherapy and/or the hormones used in ovarian stimulation are contraindicated for certain tumours. In-vitro maturation has been suggested as an effective treatment for these patients. This report presents three women aged 21, 30 and 40 years, without male partners, seeking fertility preservation prior to chemotherapy. They were first seen during the luteal phase of their menstrual cycle and were to undergo gonadotoxic treatment imminently. They underwent immature oocyte retrieval in the luteal phase and seven, five and seven immature oocytes were recovered, respectively. After in-vitro maturation, five, three and five metaphase II (MII) oocytes were vitrified. Two patients later underwent one and two more retrievals, respectively, in the follicular phase of the next cycle(s) and additional oocytes were cryopreserved. These results suggest that immature oocytes recovered in the luteal phase can successfully be matured in vitro; therefore, if there is not sufficient time for conventional follicular-phase oocyte retrieval in a stimulated/unstimulated cycle prior to chemotherapy, a retrieval in the luteal phase could be considered.

A 38 h interval between hCG priming and oocyte retrieval increases in vivo and in vitro oocyte maturation rate in programmed IVM cycles.

BACKGROUND Our aim was to evaluate whether extending the interval between human chorionic gonadotrophin (hCG) priming and immature oocyte retrieval increases the oocyte maturation rate following in vitro maturation (IVM). METHODS This study was performed retrospectively. IVM was performed on 113 polycystic ovary syndrome patients (n = 120 cycles). Oocyte collection was performed either 35 h (Group 1; n = 76) or 38 h (Group 2; n = 44) after 10 000 IU of hCG priming. Following oocyte retrieval, oocyte maturity was assessed and the remaining immature oocytes were cultured in IVM medium up to Day 2. RESULTS The number of in vivo matured oocytes collected was significantly higher in Group 2 (13.6%, 114/840 versus 7.3%, 96/1312 in Group 1) (P < 0.01); the oocyte maturation rate after Day 1 was significantly higher (P < 0.01) in Group 2 (46.3 versus 36.0% in Group 1); and clinical pregnancy (40.9 versus 25%) and implantation rates (15.6 versus 9.6%) were better in Group 2 than those in Group 1. CONCLUSIONS The results suggest that extending the period of hCG priming time from 35 to 38 h for immature oocyte retrieval promotes oocyte maturation in vivo and increases the IVM rate of immature oocytes. Therefore, oocyte retrieval after 38 h of hCG priming may improve subsequent pregnancy outcome in cycles programmed for IVM treatment.

Selection of the optimal day for oocyte retrieval based on the diameter of the dominant follicle in hCG-primed in vitro maturation cycles

BACKGROUNDnThe efficiency of in vitro maturation (IVM) techniques is suboptimal compared with controlled ovarian stimulation combined with IVF cycles, and studies are needed to identify factors that predispose IVM cycles to success or failure. We compared the outcome of IVM cycles with different dominant follicle (DF) size at oocyte retrieval following hCG priming.nnnMETHODSnIVM was performed in 160 patients with polycystic ovaries (171 cycles). We administered 10,000 IU hCG s.c. 35-38 h before oocyte collection when endometrial thickness reached at least 6 mm. IVM cycles were retrospectively analyzed according to DF diameter as follows; Group 1: DF diameter <or=10 mm, Group 2: between 10 and 14 mm, Group 3: >14 mm. RESULTS A positive correlation was observed between DF size and number of in vivo matured oocytes collected (Group 1, 2 and 3 = 6.9, 10.6 and 15.1%, respectively). The rates of IVM, fertilization and embryo development were similar among the sibling immature oocytes collected from the three groups. However, clinical pregnancy rate in Group 2 (40.3%) was higher than Group 3 (17.1%) (P < 0.05). Moreover, implantation rates in Groups 1 (13.6%) and 2 (14.3%) were higher than Group 3 (4.9%) (P < 0.01).nnnCONCLUSIONSnOur results suggest that oocyte collection in IVM cycles should be performed when the DF is 14 mm diameter or less. Sibling immature oocytes may be affected detrimentally if a DF >14 mm is present at oocyte collection.

Drugs in infertility and fetal safety.

OBJECTIVEnTo evaluate the safety of drugs used in infertility treatment.nnnDESIGNnLiterature search using the keywords birth defect, congenital malformation, clomiphene, aromatase inhibitor, letrozole, gonadotropin, metformin, gonadotropin releasing hormone agonist and antagonist, progesterone, progestin, and estrogen. We conducted the search in Medline, EMBASE, and Cochrane Database of systematic reviews.nnnRESULT(S)nThe available data suggest that clomiphene treatment, especially after several cycles, might be associated with a slightly higher risk of neural tube defects and severe hypospadias in the offspring. Letrozole and metformin do not appear to be teratogenic. The existing data concerning gonadotropin preparations suggest that there is no evidence of teratogenicity, yet, information after 1991 is lacking. Micronized progesterone, which is widely used in in vitro fertilization treatment, does not appear to increase the risk of nongenital birth defects; however, there might be a possible weak association between other progestational agents and hypospadias.nnnCONCLUSION(S)nInfertility per se is a risk factor for congenital anomalies. Repeated clomiphene treatment might be associated with a slightly higher risk of hypospadias and neural tube defect. However, the overall increased risk related to various fertility drugs is only 1% to 2%.

Fertility preservation treatment for young women with autoimmune diseases facing treatment with gonadotoxic agents

OBJECTIVEnTo describe a case series of seven women with SLE and other systemic autoimmune rheumatic diseases (SARDs) who required cyclophosphamide therapy and underwent fertility preservation treatments.nnnMETHODSnOf the seven patients reported here, five women had SLE with nephritis, the sixth had immune thrombocytopenia purpura (ITP) and the seventh had microscopic polyangiitis (MPA) with renal involvement. All women were nulliparous and younger than 35 yrs.nnnRESULTSnPatients with SLE underwent in vitro maturation (IVM) of immature oocytes aspirated during a natural menstrual cycle followed by vitrification of the matured oocytes if a male partner was not available, or vitrification of embryos if one was available. The patient with ITP and the patient with MPA underwent gonadotropin ovarian stimulation followed by oocyte or embryo vitrification. All women completed fertility preservation treatment successfully and mature oocytes or embryos (36 and 13, respectively) were vitrified. No complications were associated with this treatment and cytotoxic therapy was initiated as scheduled in all cases.nnnCONCLUSIONSnOocyte or embryo cryopreservation should be considered for fertility preservation in young women with SARDs who face imminent gonadotoxic treatment. In patients, where gonadotropin ovarian stimulation is deemed unsafe, IVM of immature oocytes, aspirated during a natural menstrual cycle, followed by vitrification or fertilization of the mature oocytes, seems to be safe and feasible. For patients in whom hormonal ovarian stimulation is not contraindicated, this method may be considered depending on the urgency to start cytotoxic therapy.

Feasibility of fertility preservation in young females with Turner syndrome

Women with Turner syndrome (TS) are at risk of premature ovarian failure. The objective of this retrospective study was to identify patients with TS who could be potential candidates for fertility preservation and to determine their present reproductive and fertility status. Criteria for fertility preservation included: (i) spontaneous menarche; (ii) confirmation by ultrasound examination of the presence of at least one normal ovary; and (iii) serum FSH concentrations below 40 IU/l. Using the Montreal Childrens Hospital Cytogenetic Database from 1990 to 2006, 28 patients with complete or partial absence of one X chromosome were identified: 13 (46%) were 45,X; nine (32%) had mosaic karyotypes; and six (21%) had karyotypes containing isochromosome or ring X chromosome. Six patients (21%) had spontaneous pubertal development and four (14%) were identified as potential candidates for fertility preservation. One underwent an ovarian stimulation protocol of gonadotrophin-releasing hormone agonist down-regulation followed by recombinant FSH and human menopausal gonadotrophin stimulation. Two metaphase-II-stage oocytes were aspirated and vitrified using the McGill Cryoleaf vitrification system. Another patient conceived spontaneously at the age of 24 years. In conclusion, fertility preservation may not be feasible for most patients with TS. However, after careful consideration of increased pregnancy-associated risks, fertility preservation may be offered to young females with mosaic TS.

Fertility preservation for young women with rectal cancer--a combined approach from one referral center.

BackgroundUp to 6% of women with colorectal cancer are diagnosed in the reproductive age and are at risk for premature ovarian failure and infertility due to pelvic irradiation and chemotherapy.Study DesignBetween 1997 and 2007, six women with rectal carcinoma were referred to the McGill Reproductive Center (Montreal, Canada) for fertility preservation. Following resection of their primary tumor, they were scheduled to undergo pelvic irradiation.ResultsFive patients underwent laparoscopic ovarian lateral transposition before radiotherapy in order to relocate their ovaries outside the radiation field. A concomitant ovarian wedge resection was performed for ovarian cryopreservation. In two of these women, before dissecting the ovarian cortical tissue for cryopreservation, all visible follicles were aspirated. The sixth patient who had had low anterior resection underwent hormonal ovarian stimulation followed by oocyte retrieval and embryo vitrification.ConclusionsFertility preservation in women with rectal cancer is feasible. This includes laparoscopic ovarian transposition and cryopreservation of ovarian tissue, embryo, or oocyte.

Comparison of low-dose human menopausal gonadotropin and micronized 17β-estradiol supplementation in in vitro maturation cycles with thin endometrial lining

OBJECTIVEnA challenge of in vitro maturation (IVM) treatment in some women is insufficient development of the endometrium prior to embryo transfer.nnnDESIGNnRetrospective study.nnnSETTINGnMcGill Reproductive Center, Montreal, Canada.nnnPATIENT(S)nWomen with endometrial thickness <6 mm on days 6-10 ultrasound (US) scan of IVM treatment.nnnINTERVENTION(S)nIn the human menopausal gonadotropin (hMG) group, 150 IU/day of hMG was started and in the estradiol group, 6 to 12 mg/day of micronized 17beta-estradiol was initiated. Additional US scans were performed 2 to 3 days apart, until endometrial thickness reached > or =8 mm or a dominant follicle (>10 mm) was identified.nnnMAIN OUTCOME MEASURE(S)nEndometrial lining before oocyte retrival.nnnRESULT(S)nIn both groups endometrial lining significantly thickened following treatment. However, hMG treatment resulted in a higher number of follicles > or =7 mm compared to estradiol (7.4 +/- 4.8 vs. 3.4 +/- 2.5, respectively) and a significantly higher percentage of mature oocytes that were identified on the day of oocyte retrieval (in vivo matured oocytes) (15.1% vs. 10.5%).nnnCONCLUSION(S)nIn IVM designated cycles with a thin endometrium both low-dose hMG and micronized 17beta-estradiol supplementation significantly improve endometrial thickness. However, low-dose hMG results in larger follicles and a greater number of in vivo matured oocytes.

Cryopreservation of a mother's oocytes for possible future use by her daughter with Turner syndrome: case report

OBJECTIVEnTo report a new fertility alternative for women with Turner syndrome, who are rendered infertile, by having their mothers freeze their own oocytes for the purpose of donating to their daughters when they are adults.nnnDESIGNnCase report.nnnSETTINGnAcademic teaching hospital.nnnPATIENT(S)nA 33-year-old healthy mother of three children; and her second child, a 6-year-old daughter recently diagnosed with Turner syndrome.nnnINTERVENTION(S)nMother-to-daughter oocyte donation combined with oocyte vitrification.nnnMAIN OUTCOME MEASURE(S)nNumber of cryopreserved oocytes.nnnRESULT(S)nAfter three cycles of ovarian stimulation, 30 oocytes were cryopreserved for the daughters possible future use.nnnCONCLUSION(S)nThe treatment option presented here opens the door for the banking of a mothers oocytes as a possible donation to a young daughter with a medical condition that leads to infertility, for her possible future use.

A unique biological in-vivo model to evaluate follicular development during in-vitro maturation treatment

The aim of this study was to identify the size in which the dominant follicle acquires the ability to produce a functional corpus luteum. This observational study includes 15 women with ovulatory cycles who underwent human chorionic gonadotrophin (HCG)-primed in-vitro maturation (IVM) treatments without embryo transfer. All patients received subcutaneous injection of HCG 10,000 IU 38 h prior to oocyte retrieval. Five to seven days following retrieval, serum concentrations of progesterone and oestradiol were measured along with ultrasound scan measuring the antral follicle count. Using receiver operating characteristic curves and the Youden index (J), this study clearly shows that the diameter of the dominant follicle at the time of the LH surge is a good predictor for its ability to form a progesterone-producing corpus luteum (area under the curve 0.94). These findings revealed that the dominant follicle develops the competence to form a corpus luteum, signified by the production of more than 10 nmol/l serum progesterone at 5-7 days from oocyte retrieval, as soon as it acquires a diameter of 10.5-12.0mm. In addition, a new cohort of viable antral follicles can be identified as early as 5-7 days following IVM oocyte retrieval.