JBRA Assist. Reprod. 2022 2012;16(03):91-93
RELATO DE CASO
doi: 10.5935/1518-0557.2012.16.3.07
aConceber - Reproductive Medicine Center, Curitiba, Brazil
bFaculdade Pequeno Príncipe, Curitiba, Brazil
ABSTRACT
Objective:Show that ovarian stimulation at any stage of the cycle is an alternative for patients who need to undergo chemotherapy in an attempt to preserve fertility.
Methods:Case Report. Setting: Clinica Conceber - Reproductive Medical Center
Patient(s):Womens were diagnosed with cancer.
Intervention:Ovary stimulation, follicular aspiration and cryopreservation of oocytes or embryos. Main Outcome
Measure(s):response to ovarian stimulation, follicular growth and number of oocytes recovered at follicle aspiration
Results:for the first patient the stimulation start at ninth day whit 300IU of HMG, on the day 16th 6500 IU of rhCG was administered and the follicular aspiration was performed 35 hours later resulting in ten oocytes. The second patient starts the ovary stimulation on the 13th of the cycle and on day 22 the ovulation immediately induced with 6500 IU of rhCG and ovary aspiration performed 35 hours later and 9 oocytes was recovered and subjected to ICSI, one oocyte was successfully fertilized and cryopreserved. The third patient began stimulation on seventh day of the cycle and the aspiration was performed on the 15th day. Seven oocytes was recovered and cryopreserved.
Conclusion: This emergency protocol of ovary stimulation proved to be viable for follicular growth, fertility preservation in cancer patients
Keywords:Stimulation, Luteal phase, Follicular phase, Preservation of fertility
RESUMO
Objetivo: Demonstrar que a estimulação ovariana em qualquer estágio do ciclo é alternative para pacientes que necessitam quimioterapia e desejam preserver a fertilidade.
Material e método: relato de casos, Clinica Conceber, 03 mulheres diagnosticadas com câncer, submetidas a estimulação ovariana e criopreservação de oócitos ou embriões.
Desfecho principal: resposta à estimulação ovariana, crescimento follicular e número de oócitos recuperados na aspiração.
Resultados: na primeira paciente ao estímulo se iniciou no dia 9 do ciclo, com 300UI de HMG; no dia 16 recebeu 6500 UI de rhCG, com aspiração folicular em 35 horas, resultando 10 oócitos. A segunda iniciou a estimulação no dia 13 do ciclo, induziu a rotura no dia 22 e teve 9 oócitos recuperados, submetidos a ICSI ( um oócito foi fertilizado e criopreservado). A terceira paciente iniciou o estímulo no dia 7 e a sapiração ocorreu no dia 15, com recuperação de 7 oócitos que foram criopreservados.
Conclusão: este protocol de emergência é viável para o crecimento follicular, e assim para a preservação da fertilidade em pacientes com câncer.
Palavras-chave: Estimulação, fase lútea, fase follicular, preservação da fertilidade.
INTRODUCTION
In 2010, approximately 207.090 women were diagnosed with breast cancer in the United States, and there were 43.470 new cases of uterine cancer (American Cancer Society 2010). The national Cancer Institute of Brazil estimates that there were approximately 253.030 new cancer cases in 2010 (Instituto nacional de Câncer, 2010).
Stroud et al. (2009) reported that in 1990, the cancer survival rate for young patients (aged 15 to 45 years) was 1 in every 1,000; this rate increased to 1 in every 250 by 2010 ( Bleyer WA, 1990). However, this improved survival rate is accompanied by several types of collateral damage that cancer treatments can inflict. The ovaries are extremely sensitive to cytotoxic treatments, which can cause premature ovarian failure (POF), resulting in early menopause and functional disorders even when the ovaries are not affected by the disease (Donnez J et al, 2006). According to Sönmezer et al. (2004), the POF rate varies from 14 to 100%, and the level of damage depends on the age of the woman at the time of treatment and the type, dose and duration of the treatments used ( Sonmezer M, Oktay K., 2004). The importance of early referral for fertility preservation cannot be overestimated. Female patients who are referred to fertility specialists before undergoing cancer treatment (both chemotherapy and radiotherapy) experience better yields of oocytes and embryos (Lee S., et al, 2010). If there is insufficient time for ovarian stimulation before treatment begins, several alternatives are usually available, including less well-established approaches, such as the cryopreservation of ovarian tissue and the in vitro maturation of oocytes ( Sonmezer M, Oktay K., 2010). Recent evidence indicates that there are several opportunities for the recruitment of follicles during the normal menstrual cycle; therefore, the concept of a narrow window for follicular recruitment may not be accurate (Oktay K, Sonmezer M., 2008). Because of the current availability that GnRH antagonists offer, the utility of follicular recruitment at different stages throughout the menstrual cycle may be feasible, especially for fertility preservation, a scenario in which the development of the endometrium is irrelevant ( Sonmezer M., et al, 2011).
Based on published data, we administered emergency ovarian stimulation protocols to three patients during the follicular, late follicular and luteal phases to attempt to preserve their fertility. Here, we report the preliminary results of this new approach.
CASE REPORTS
Three patients with histories of neoplastic diseases underwent ovarian stimulation. The first patient was 23 years old and was diagnosed with adenocarcinoma of the appendix after an appendexectomy and unilateral oophorectomy. The second patient was 30 years old, was diagnosed with breast cancer and underwent a bilateral mastectomy. The third patient was 39 years old and diagnosed with breast cancer and was submitted to oophorectomy in the past, due to ovarian benign disease.
Following consultations with an oncologist, all three patients chose to pursue immediate protection of their fertility through ovarian stimulation and oocyte/embryo cryopreservation before beginning chemotherapy. Because the timing of cancer treatment plays an important role in a patient’s prognosis, the ovarian stimulation was initiated at different times from those usually used.
For the first and third patients, the stimulation occurred in the proliferative phase of the menstrual cycle; the first patient was in the late follicular phase, and the third was in the early follicular phase. The second patient was in the luteal phase.
RESULTS
For the first patient, stimulation began on the ninth day of the cycle with the administration of 300 IU of human menopausal gonadotropin (HMG Merional®), followed by 0.25 mg of a gonadotropin-releasing hormone (GnRH) antagonist (cetrorelix, Cetrotide®) and 5 mg of letrozole (Femara®). All the medications were administered daily and adjusted according to the response. The patient’s hormone levels on the sixth (d6), seventh (d7) and eighth days (d8) of stimulation were as follows: progesterone 0.5 ng/mL, 0.7 ng/mL and 1.0 ng/mL; luteinizing hormone (LH) 1.1 mIU/mL, 1.0 mIU/mL and 1.0 mIU/mL; and estradiol 555 pg/mL, 709 pg/mL and 794 pg/mL, respectively. On d16 of the cycle, the dominant follicle had reached a diameter of 18 mm, and the patient was given 6.500 IU of recombinant human chorionic gonadotropin (rhCG, Ovidrel®).. Oocyte aspiration was performed 35 hours after the administration of rhCG, and ten oocytes were retrieved and cryopreserved. Five oocytes were in metaphase II, two were in metaphase I and three were in prophase I. The second patient presented on the 11th day of her cycle, and ovulation was immediately induced with 6500 IU of rhCG because of an 18-mm follicle. Therefore, 48 hours later, the 13th day of the cycle became the first day of stimulation with the administration of 300 IU of recombinant follicle-stimulating hormone (rFSH, Gonal F), 0,25 mg of a GnRH antagonist (Cetrotide), and 5 mg of letrozole (Femara). All of the medications were administered daily and adjusted according to the response. The patient’s hormone levels on the eighth (d8) and tenth (d10) days of stimulation were as follows: progesterone 4.8 ng/mL and 1.6 ng/mL; LH 0.4 mIU/mL and 0.5 mIU/mL; and estradiol (E2) 245 pg/mL and 345 pg/mL, respectively. When the dominant follicle reached a diameter of 18 mm on 22th day of the cycle, the patient was given 6.500 IU of rhCG. Oocyte aspiration was performed 35 hours later, and nine oocytes in metaphase II were recovered and subjected to intracytoplasmic sperm injection (ICSI). One oocyte was successfully fertilized and was frozen. The third patient began stimulation on the seventh day of her cycle with 300 IU of HMG (Menopur®) and 5 mg of letrozole (Femara®), followed by 0,25 mg of a GnRH antagonist (Cetrotide®) on the tenth day onward. On the 15th day of the cycle, follicular aspiration occurred. Three metaphase II, two metaphase I and two prophase I oocytes were retrieved and subsequently cryopreserved.
DISCUSSION
The effectiveness of ovarian stimulation followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is well established, and these techniques can be practiced by any fertility center. However, fertility preservation in patients who will soon undergo cancer treatments is more complex, with some protocols requiring more than 6 weeks (for patients who are in the luteal phase) before follicular aspiration (Von Wolff M., et al, 2009).
In three cases related by Sönmezer et al. (2011), good fertilization rates were achieved, seven to ten embryos were frozen and also embryos were generated in all of the cases through the use of in vitro maturation (IVM), wherein immature oocytes are matured in the laboratory within 24-48 hours after collection (Sonmezer M., et al 2011).
In a recent study, Maman et al (2011) analyzed the results of IVM for fertility preservation in two groups of patients with neoplastic diseases: five in the luteal phase and thirteen in the follicular phase ( Maman E., et al, 2011). There were no significant differences between the two groups in the numbers of oocytes retrieved, the maturation rates, the fertilization rates, or the total numbers of oocytes and embryos that were cryopreserved (Sonmezer M., et al 2011).
The published data on COH in the late follicular or luteal phase and emergency fertility preservation are scant. Bedoschi et al. (2010) described emergency COH in two cases with breast cancer and Hodgkin lymphoma. Both patients underwent ovarian stimulation with recombinant FSH and GnRH antagonists during the luteal phase of the cycle. Twelve mature oocytes were recovered in both cases. In the first case all of the mature oocytes were subjected to ICSI, with fertilization and cleavage rates of 83.3% and 70%, respectively. In the second case, all of the mature oocytes were cryopreserved ( Bedoschi G. M., et al 2010). In contrast to the results described above, we did not achieve a good fertilization rate in the luteal phase of our second case, although a good number of eggs were retrieved. The use of GnRH antagonist to induce luteolysis in the luteal phase was described by Anderson et al. (1999) (Anderson R.A., Kinniburgh D., Baird D.T., 1999) . Two patients with histories of breast cancer who were in the luteal phase received GnRH-a, resulting in rapid drops in progesterone followed by menstruation 2-4 days later. After 4 days, ovarian stimulation was begun with 150 IU/day of hMG. The patients were stimulated for 9-11 Ovarian stimulation in the follicular, late follicular and luteal phases - Schuffner A. et all. 93 days, ovulation was induced and 6 and 8 oocytes were aspirated. Of these, 4 and 6 oocytes were successfully fertilized for IVF, respectively, resulting in an average fertilization rate of 71% (Von Wolff M., et al, 2009). It is not yet known if the frozen oocytes and embryos acquired by stimulation in the follicular or luteal phase will result in pregnancy rates comparable to those originating from conventional stimulation cycles. The existing data have been confirmed by the results of current cases, and favorable fertilization rates have been demonstrated after the ICSI of oocytes collected following ovarian stimulation with letrozole in the late follicular or luteal phase (Sonmezer M., et al 2011). Because of the young ages and consequent high ovarian reserves of the patients reported in the literature, the viability of oocytes obtained through ovarian stimulation at random phases of the menstrual cycle in older women is not known. Therefore, larger prospective studies are necessary to assess the potential of this technique in patients with lower ovarian reserves.
The effectiveness of random-start controlled ovarian stimulation has a solid scientific foundation, including the recent research on healthy volunteers by Baerwald et al. that demonstrated the presence of up to three major follicle recruitment waves during a normal menstrual cycle. Fifty women were monitored by daily ultrasound examinations and blood analyses for E2, luteinizing hormone (LH), and FSH levels. The findings showed that 34 of the 50 women exhibited two follicular waves, and 16 exhibited three waves ( Baerwald , Adams, Pierson, 2003).
There is controversy as to whether most of the oocytes that are obtained during the luteal phase are atretic. In a recent report, Bentov et al. 2010 described a patient who conceived after a GnRH antagonist-induced demise of the first cohort of follicles, followed by the emergence of a second wave of follicles and oocyte retrieval on cycle day 30 (Bentov et al, 2010). The above cases are consistent with recent scientific observations and can help bring a new perspective to the approach toward ovarian stimulation in general. As an example of a practical application of random start controlled ovarian stimulation, oocyte donors could be stimulated without any need for a delay. By the use of the random-start approach, many young donors, who often have scheduling conflicts, could be stimulated at a more convenient time. That possibility is especially exciting in light of the increased success in IVF using thawed oocytes, which is causing oocyte banks to become a reality.
In the present case series, it was demonstrated that controlled ovarian hyperstimulation (COH) can be started at any time during the menstrual cycle in the setting of urgent fertility preservation.
Most reproductive-age women suffering from cancer are not aware of the alternatives for preserving their fertility prior to undergoing cancer treatment. For this reason, it would be beneficial for the entire population to be familiar with the promising new techniques for fertility preservation. Although the recent results achieved with ovarian stimulation and oocyte cryopreservation represent significant progress, further research is needed to improve fertility preservation methods so that, in the future, the live birth rates obtained using these techniques become similar to those using fresh oocytes.
REFERENCES
American Cancer Society. Cancer facts and figures 2010. American Cancer Society, 2010.