Year : 2018 | Volume
: 1 | Issue : 1 | Page : 55--58
Oocyte cryopreservation in carcinoma breast
Richa Bansal Jagtap1, Avantika Vaze2,
1 Fellowship in Reproductive Medicine (Singapore) Clinical Director, Consultant Reproductive Medicine, Nova IVI Fertility, Chembur, India
2 Fellowship in Reproductive Medicine, Associate Consultant, Nova IVI Fertility, Mumbai, Maharashtra, India
Richa Bansal Jagtap
Nova IVI Fertility, Unit 12G and 13G, Coprorate Park, Sion Trombay Road, Chembur, Mumbai - 400 071, Maharashtra
This is a case of fertility preservation attempted at the crucial time through mature oocyte cryopreservation in a patient of breast cancer.
|How to cite this article:|
Jagtap RB, Vaze A. Oocyte cryopreservation in carcinoma breast.Onco Fertil J 2018;1:55-58
|How to cite this URL:|
Jagtap RB, Vaze A. Oocyte cryopreservation in carcinoma breast. Onco Fertil J [serial online] 2018 [cited 2019 Jul 17 ];1:55-58
Available from: http://www.tofjonline.org/text.asp?2018/1/1/55/225420
Breast cancer is the most common malignancy among woman under 50. Improvement in diagnosis and treatment has yielded a significant decrease in mortality in the past 20 years. In many cases, chemotherapy and radiotherapy have side effects on reproductive function. Therefore, before anticancer treatment impairs fertility, clinicians should offer some technique of fertility preservation for women planning motherhood in future.
Fertility preservation services are rarely offered or even discussed with the patient before starting cancer therapy. Studies have shown that infertility is a significant survival concern. Patients who received information regarding their sexual and reproductive health had lower levels of psychological distress than patients who did not receive this information. Informed decision reduces reproductive regret in these young men and women.
Multiple strategies have emerged to preserve fertility in a different type of malignancies. Currently, embryo and mature oocyte cryopreservation are the only techniques endorsed by the American Society of Assisted Reproduction and others are considered investigational. Controlled ovarian stimulation (COS) should be recommended as long as patient's medical conditions do not preclude safely performing COS or oocyte retrieval, and the patient has adequate time for the same.
A 26-year-old medical student recently diagnosed and operated case of breast carcinoma and came to us for oocyte cryopreservation on June 23, 2016.
The patient had noticed a lump in the right breast 4 months back and visited an oncosurgeon. Her mammography showed BIRADS Grade VI lesion in the right breast, and the left breast study was normal.
Positron emission tomography scan on June 6, 2016, revealed active disease in the right breast mass with low-grade metabolically active right axillary lymph nodes. Histopatholgical report was suggestive of infiltrating duct carcinoma Grade III, negative for estrogen, progesterone, HER, and neu receptors. Lumpectomy with wide excision of the lump was done on June 14, 2016. Intraoperative frozen section of all four lymph nodes was free of disease. She was advised chemotherapy 2 weeks postsurgery. On herfirst visit to us, the patient was explained and counseled regarding the procedure of oocyte cryopreservation. Since the patient was not sexually active, initial sonography was done transabdominally. She was explained about need for transvaginal scan during follicular study.
The patient came back on day 17 of her menstrual cycle. Her oncologist opined that chemotherapy can be delayed by 2 weeks considering time required for ovarian stimulation and oocyte retrieval. Consents were taken from the patient and her mother.
On the 17th day of menstrual cycle, Transvaginal sonography (TVS) showed an antral follicular count of 5 bilaterally. Her E2 was 56 pg/ml and anti-Mullerian hormone 2.1 ng/ml. Injection gonadotropin-releasing hormone (GnRH) antagonist 0.25 mg was given for 2 days and ovarian stimulation was started on the 3rd day (menstrual day 19). Stimulation was done with Letrozole (5 mg) daily along with recombinant follicle-stimulating hormone (rFSH) 225 IU daily. GnRH antagonist 0.25 mg was added on day 6 when the largest follicle reached 13 mm. On day 10 of stimulation, there were 7–8 follicles of 17–18 mm bilaterally. Oocyte retrieval was planned 35 h after agonist trigger (Decapeptyl 0.2 mg). Serum estradiol on the day of trigger was 1005 pg/ml which was much lower than expected for the number of follicles.
Fourteen mature eggs were obtained and cryopreserved using Kitazato media. Letrozole was continued, and GnRH antagonist was given to reduce serum estradiol levels postretrieval. The patient was called after 2 days for follow-up. Her ovarian size on transabdominal scan was 6–6.5 cm. There was no free fluid. The patient was comfortable with no complaints. Her estradiol levels on that day (postovum pick up day 2) had dropped to 300. She was given GnRH agonist depot a week after retrieval as decided by her oncologist before planned chemotherapy
Response to ovarian stimulation in cancer patients
In cancer patients, both the specific malignancy and the patient's multisystem condition may have an impact on the response to ovarian stimulation. The increased catabolic state, malnutrition, and increased stress hormone levels associated with the malignancy may affect the hypothalamic–gonadal axis and decrease fertility. Possible adverse association between the presence of a neoplastic process and ovarian reserve or oocyte quality is also suggested. There are mixed reports about how cancer patients respond to the in vitro fertilization (IVF) stimulation protocols: Some reporting no significant change and others demonstrating worse ovarian response in cancer patients compared with age-matched healthy women., In a meta-analysis conducted on seven retrospective studies, women with malignancies had lower numbers of total oocytes (11.7 7.5 vs. 13.5 8.4) and mature oocytes retrieved (9.0 6.5 vs. 10.8 6.8) after COS for fertility preservation compared with healthy age-matched patients. Moreover, the relative risk of poor response leading to cycle cancellation was higher in cancer patients than in the control group.
How to avoid delay in the start of treatment?
In oncology, patients are not advised to delay the start of COS. It is, therefore, usual to begin the stimulation outside days 2–3 of the menstrual cycle. The strategy varies according to the time of the cycle. In the early proliferative phase, when there is still no dominance follicular, stimulation starts even if the patient is not on days 2–3 of the cycle.
When the patient is in the secretory phase of the cycle, the ovulation is confirmed by ultrasound along with the analytical determination of estradiol and progesterone. The GnRH antagonist is administered for luteolysis, and then, stimulation is begun. The objective of the antagonists of GnRH is to achieve estradiol levels <60 pg/ml and not to delay treatment until the start of a new physiological cycle.
Ovarian stimulation protocols
A conventional IVF cycle requires approximately 10–12 days of COS with gonadotropins to achieve multifollicular development. This results in an elevation of the serum estradiol, up to 10 times higher than physiological levels. To avoid this elevation of estradiol in patients with breast cancer, many protocols have been developed for stimulation with gonadotropins associated with tamoxifen or aromatase inhibitors (letrozole). The peak of estradiol in the protocols of ovarian stimulation with tamoxifen or with letrozole is slightly higher than the levels achieved in a natural cycle, around 300–350 pg/ml.
The most widely used protocol to stimulate patients with breast cancer is the oral administration of letrozole 5 mg from day 2 to day 3 of the cycle, in conditions of ovarian quiescence ([FSH] <13 IU/L/E2 <60 pg/ml). After 2 days of treatment with letrozole, a variable dose of rFSH between 150 and 300 IU/day is added. When the concentration of serum estradiol exceeds 250 pg/ml or the follicles reach a size >13 mm in diameter, administration of GnRH antagonists is started to avoid the premature peak of luteinizing hormone (LH). Follicular growth is monitored until at least two of the follicles reach 20 mm in diameter, and at that moment, ovulation is triggered with the agonists of GnRH. By comparing the use of GnRH agonists versus human chorionic gonadotropin (hCG) trigger ovulation, it was found that the agonists achieved a greater and faster decline of the estradiol levels without reducing the number of mature oocytes collected or the fertilization rate.
This protocol has been implemented in an extended form, independent of the molecular phenotype of breast cancer.
Conventional start protocol
Gonadotropin stimulation starts on day 2 of their menstrual cycle. GnRH antagonist is added to prevent premature ovulation when the lead follicle measured 12 mm and is continued until the day of trigger.
The late follicular phase is defined as after menstrual cycle day 7 with emergence of a dominant follicle (>13 mm) and progesterone level <2 ng/mL. The luteal phase was determined by progesterone level >3 ng/mL.
In the late follicular phase, ovarian stimulation without GnRH antagonist is started if the follicle cohort following the lead follicle is <12 mm and stayed <12 mm before a spontaneous LH surge. After the LH surge, GnRH antagonist was started when the secondary follicle cohort reached 12 mm to prevent premature secondary LH surge. If the follicle cohort following the lead follicle has reached 12 mm before the spontaneous LH surge, pituitary suppression with GnRH antagonist is initiated and continued until triggering final oocyte maturation.
Ovulation can be induced with GnRH agonist when the dominant follicle reaches 18 mm in diameter. Ovarian stimulation can be started in 2–3 days after the trigger.
Luteal phase start
If the patient presented in the luteal phase or ovulation is induced as above, ovarian stimulation is started in the absence of GnRH antagonist. Similarly, to conventional COS, GnRH antagonist administration is initiated later in the cycle when the follicle cohort reaches 12 mm, to prevent premature secondary LH surge, and is continued until the hCG or GnRH agonist trigger.
In patients who presented in the early- to mid-luteal phase, the use of GnRH antagonists has been explored as a method to induce corpus luteum regression and to expedite the time to follicular phase so that ovarian stimulation could be initiated sooner. Those studies showed that after the administration of GnRH antagonist in the luteal phase, serum progesterone levels decreased and menses ensued 2–4 days later.
Studies have demonstrated that both late follicular- and luteal-phase random start COS protocols were as effective as conventional early follicular-phase start COS in fertility preservation. The number of total and mature oocytes retrieved, oocyte maturity rate, mature oocyte yield, and fertilization rates are similar across protocols. In addition, the use of letrozole in patients with estrogen-sensitive cancers did not adversely affect COS outcomes, including oocyte maturity or competence, in either random- or conventional-start protocol
Ovarian hyperstimulation: Selecting the appropriate ovarian stimulation regimen can be challenging in embryo/oocyte cryopreservation because it is important to balance the risk of OHSS and obtaining sufficient number of oocytes or embryos to maximize the chance of a successful pregnancy in the future. The impact of OHSS can be profound in cancer patients because it may result in delaying or complicating planned life-saving cancer therapy. GnRH agonist trigger in GnRH antagonist-based protocols dramatically reduces the risk of OHSS, owing to the short half-life of GnRH agonist-induced endogenous LH surge.
Delays in starting chemotherapy and thromboembolic phenomenon are the other complications. Neutropenia increasing risk of pelvic infections and thrombocytopenia (bone marrow involvement, and liver metastasis) causing bleeding during retrieval are the possible complications; hence, blood counts need to be checked before planning stimulation. Respiratory disturbance due to cancer may cause anesthesia-related complications.
Neither the cancerous nor the normal cells in the breast react to the gonadotropins (FSH, LH) or to hCG. Conversely, there is cellular proliferation and an increase in cancer cell lines ER+ (estrogen receptor) with exposure to estrogen, and it is dose-dependent. Exposure to progesterone or clomiphene citrate shows a decline in cellular proliferation in the ER line, with a mutation of BRCA1. On the other hand, the hCG shows a tendency to protect. These findings support the idea that COS with minimal elevation in levels of estradiol does not present an added risk for breast cancer.
Two main developments led to the revival of mature oocyte freezing. First, reappraisal of the effects of freezing on the oocyte structure gave a more optimistic outlook. At least 60% of surviving oocytes had normal spindles and chromosome, with no evidence of an increased frequency of freezing-associated aneuploidy by fluorescence or cytogenetics. The second major change was the introduction of ICSI to fertilize in vitro cryopreserved oocytes with the same success rates as those obtained with control oocytes. It has been reported cryopreserved oocyte survival and pregnancy rates similar to those of frozen embryos with a modified oocyte cryopreservation regimen.
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Conflicts of interest
There are no conflicts of interest.
|1||Munoz E, Gonzalez N. Ovarian Stimulation in patients with breast cancer. Ecancermedicalsciences 2015;9:504.|
|2||Mahajan N. Fertility preservation in female cancer patients – An overview. J Reprod Sci 2015;8:3-13.|
|3||Cakmak H, Rosen MP. Ovarian stimulation in cancer patients. Fertil Steril 2013;99:1476-84.|
|4||Agarwal A, Said TM. Implications of systemic malignancies on human fertility. Reprod Biomed Online 2004;9:673-9.|
|5||Robertson AD, Missmer SA, Ginsburg ES. Embryo yield after in vitro fertilization in women undergoing embryo banking for fertility preservation before chemotherapy. Fertil Steril 2011;95:588-91.|
|6||Friedler S, Koc O, Gidoni Y, Raziel A, Ron-El R. Ovarian response to stimulation for fertility preservation in women with malignant disease: A systematic review and meta-analysis. Fertil Steril 2012;97:125-33.|
|7||Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: Random-start controlled ovarian stimulation. Fertil Steril 2013;100:1673-80.|
|8||Humaidan P, Bungum L, Bungum M, Hald F, Agerholm I, Blaabjerg J, et al. Reproductive outcome using a GnRH antagonist (cetrorelix) for luteolysis and follicular synchronization in poor responder IVF/ICSI patients treated with a flexible GnRH antagonist protocol. Reprod Biomed Online 2005;11:679-84.|
|9||Cooley A, Matthews L, Zelivianski S, Hardy A, Jeruss JS. Effect of infertility treatment and pregnancy-related hormones on breast cell proliferation in vitro. Hum Reprod 2012;27:146-52.|