Pankaj Talwar1 , Puneet Rana Arora2 and Nalini Mahajan3
ART Centre, Research and Referral Hospital, New Delhi, New Delhi, 10010, India
Reproductive Medicine and Infertility, Nova IVI Fertility, B2/1A Safdarjung Enclave, Africa Avenue, New Delhi, New Delhi, 110029, India
Department of Reproductive Medicine, Nova IVI Fertility, B2/1A Safdarjung Enclave, Africa Avenue, New Delhi,, New Delhi, 110029, India
Puneet Rana Arora (Corresponding author)
Established fertility preservation options in the postpubertal female patient with cancer include embryo and oocyte cryopreservation. Controlled ovarian hyperstimulation (COH) is required for both of these procedures, which may (conventional) or may not (random start) coincide with the menstrual cycle. Understanding of the folliculogenesis has led to establishment for random-start protocols that are now being extensively utilized prior to embryo or oocyte cryopreservation. Correct identification of the phase of the menstrual cycle is essential prior to using random-start protocols.
CryopreservationFertility preservationGonadotropinsInfertilityNeoplasmsOvarian stimulation
33.1 Cancer and Fertility
Improvement in cancer therapies has led to improvement in cancer survival rates. This has not only led to increase in life expectancy but also highlighted issues affecting long-term survivors. The toxic effects of some of the chemotherapeutic agents like alkylating agents (e.g., cyclophosphamide, busulfan, and ifosfamide), which are common components of chemotherapy for breast cancer, lymphomas, leukemia, and sarcomas, are well documented. Pelvic radiation therapy is also known to cause follicular destruction, and exposure to 5–10 Gy pelvic radiation appears to be toxic to oocytes, resulting in premature ovarian insufficiency in many women. These effects are dependent on age of the women at the time of treatment and the baseline ovarian reserve prior to starting the treatment for cancer. The potential adverse effect of the disease process itself remains unknown.
33.2 Options of Fertility Preservation in Cancer Patients
There is importance of reproduction for many cancer patients especially those who are young. In a survey conducted on young women affected by breast cancer , more than half of respondents were concerned with infertility as a side effect. As a part of cancer care and counseling, patient should be made aware of the possible long-term consequences of cancer therapy in the form of impairment of fertility. Available fertility preservation options should be discussed as a part of cancer counseling. On the other hand, the discussion with regard to fertility preservation might not be taken that well and can pose a challenge accommodating this treatment in between the treatment of cancer. This should be done in a best possible way jointly with treating oncologist. The time interval available between the diagnosis and the initiation of the cancer therapy is an important aspect as to which available option to be utilized prior to starting cancer treatment. Embryo cryopreservation and oocyte cryopreservation are the standard options available at present. Embryo cryopreservation and oocyte cryopreservation both need ovarian stimulation prior to oocyte recovery. Other options such as cortical tissue cryopreservation, in vitro maturation of the immature oocytes, and ovarian cryopreservation are very promising but at this stage are experimental and need further trials. Use of medical therapies like gonadotropin-releasing hormone (GnRH agonist) is controversial and needs further robust randomized controlled trials.
33.3 Effect of Cancer on Ovarian Stimulation
Controlled ovarian hyperstimulation (COH) is essential for embryo and oocyte cryopreservation. This can be achieved with either conventional methods of ovarian stimulation or with random-start ovarian stimulation protocols. Recent studies [2, 3] have demonstrated no significant change in ovarian reserve or response to gonadotropins in patients with different cancers who are undergoing IVF treatment. By contrast others [4, 5] have found a decline in ovarian response in cancer patients who are undergoing ovarian stimulation protocols to preserve their fertility prior to cancer therapy. A recent meta-analysis  found a reduced number of oocytes in patients with malignancies undergoing COH for fertility preservation. One of the theories behind this varied response to ovarian stimulation is put down to fact that cancer is typically a catabolic state increasing stress hormone levels and altering the hypothalamic pituitary axis, thereby impairing reproductive capacity. Another study  to evaluate COH in women with cancer compared with healthy women found no significant differences in the number of oocytes retrieved, number of mature oocytes retrieved, and the number of oocytes fertilized. However, the patients with cancer had longer duration of stimulation and higher total dose of gonadotropin, which could be explained by some element of hypothalamic dysfunction. There is also varied stimulation response seen in cancer patients positive for BRCA mutations. Mutations in BRCA genes are associated with an increased risk of breast and ovarian cancers. A low response to ovarian stimulation in BRCA mutation positive breast cancer patients was seen in another study .
33.4 Ovarian Stimulation Protocols in Cancer Patients
Proper understanding of the reproductive endocrinology is essential when planning ovarian stimulation protocols for such group of women as they may present in any part of their menstrual cycle, and achieving optimal reproductive outcome is of paramount importance in such group of women as they may not get another chance of considering their reproductive potential. Protocols for ovarian stimulation can be broadly divided into conventional and random-start ovarian stimulation protocols.
33.4.1 Conventional Ovarian Stimulation Protocols (COS)
Conventional methods of ovarian stimulation are related with onset of menstrual cycle. It involves initiation of the gonadotropins for ovarian stimulation in the follicular phase of the menstrual cycle, as this has been thought to improve the clinical outcomes. The suppression of LH surge for spontaneous ovulation has been successfully achieved either with gonadotropin-releasing hormone (GnRH) agonist started in the preceding luteal phase or with gonadotropin-releasing hormone (GnRH) antagonist started when the dominant follicle has attained diameter of 14 mm or on day 6 of ovarian stimulation. GnRH antagonist may offer advantage in ovarian stimulation for cancer patients by shortening the time frame from patient presentation to embryo/oocyte cryopreservation, but this protocol still requires onset of menses before initiating ovarian stimulation. Awaiting for onset of menstrual cycle prior to starting ovarian stimulation for fertility preservation prior to initiation of cancer treatment can increase the stress and anxiety of patient and treating oncologist with regard to outcome of cancer therapies and hence prevent patients from forgoing fertility preservation treatment. This has been overcome by random-start ovarian stimulation protocols.
33.4.2 Random-Start Ovarian Stimulation Protocols (ROS)
With better understanding of the reproductive physiology, endocrinology, and ovarian folliculogenesis, random-start ovarian stimulation protocols have been developed to minimize the time interval needed for initiation of ovarian stimulation and hence with a hope to increase the uptake of these fertility-preserving strategies. It is no longer felt that there is a single wave of folliculogenesis initiating in the follicular phase but there are two to three waves in one interovulatory cycle. Studies on changes in ovarian follicular dynamics during the human menstrual cycle have now well documented that there are wavelike changes in follicle number rather than a single cohort of antral follicles occurring only during the follicular phase of menstrual cycle. This concept has been used in providing ovarian stimulation in any part of menstrual cycle and has been extrapolated to providing ovarian stimulation prior to cancer therapies as this subgroup of women can present in any part of menstrual cycle. The rest of the pattern of stimulation with regard to dose and type of gonadotropins is very much similar as in conventional protocols.
Depending on the timing of presentation in relation to menstrual cycle, random-start protocols can be divided into starting controlled ovarian stimulation in early follicular phase, late follicular phase, early luteal phase, and late luteal phase (Fig. 33.1) . Early follicular phase is defined as presentation within first 7 days of onset of menstruation. Late follicular phase is primarily defined as presentation after 7 days of onset of menstrual cycle or the presence of dominant follicle of >12 mm diameter or progesterone level <2 ng/ml. Early luteal phase is defined as presentation within first 7 days after ovulation. Late luteal phase is presentation within last 7 days of the last menstrual cycle. Late follicular phase and early luteal phase are the most challenging time for random-start ovarian stimulation protocols.
Conventional and random-start antagonist IVF protocols for cancer patients undergoing fertility preservation. COS can be started with spontaneous menses (a) or with menses following luteolysis induced by GnRH antagonist (b). COS can also be initiated in the late follicular (c) or luteal phase following spontaneous LH surge (d) or after ovulation induction with hCG or GnRH agonist (e) (From Cakmak and Rosen )
188.8.131.52 Early Follicular Phase Protocol
Presentation in early follicular phase can very similarly be treated like convention stimulation regimens with GnRH antagonist protocol provided there is no dominant follicle more than 12 mm. If there is already dominant follicle more than 12 mm, it can then be treated as being in late follicular phase, which will be discussed subsequently (Fig. 33.1).
184.108.40.206 Late Follicular Phase Protocol
Late follicular ovarian stimulation involves assessment of the ovaries for the presence or absence of dominant follicles. If the ovary contains dominant follicle more than 12 mm, further management would involve luteolysis of the dominant follicle with either GnRH antagonist or progesterone followed by stimulation for the rest of the follicles. Prior to luteolysis, triggering of the already grown follicle by HCG or GnRH agonist may be considered. This can then be followed 36–40 h later by luteolysis with GnRH antagonist for 3–4 days. Depending on the ovarian reserve of the patient, ovarian stimulation can then be started by appropriate gonadotropins based on age and ovarian reserve parameters (AMH, antral follicular count) (Fig. 33.1).
220.127.116.11 Early and Late Luteal Phase Protocol
Early luteal phase is defined as the completion of spontaneous LH surge and the presence of corpus luteum in the ovaries. Early and late luteal phase can be essentially treated in the same way. Luteolysis of the corpus luteum can be achieved by GnRH antagonist 3 mg stat or in multiple doses of 0.25 mg. This can be followed by gonadotropin stimulation in conventional way preferably with recombinant FSH avoiding exogenous LH activity, which might prevent luteolysis. Pituitary suppression for LH surge by GnRH antagonist can be initiated in usual way when the dominant follicle reaches 14 mm and use of either HCG or GnRH agonist for trigger of the final maturation of the oocyte. (Fig. 33.1)
The dose of gonadotropin should be individualized depending on age, ovarian reserve, and weight of the patient. Using higher doses of gonadotropins can be one of the strategies to increase the embryo and oocyte yield per cycle. In a study comparing a low-dose antagonist IVF protocol (150 IU FSH) and a higher-dose antagonist IVF protocol (>150 UI) in cancer patients, although the number of follicles > 17 mm was greater in the higher-dose group, there was no difference in the number of oocytes generated between the two groups . That study suggests that the use of higher doses of gonadotropins may not necessarily result in higher oocyte/embryo yield consistent with the theory that higher doses of gonadotropins may stimulate the recruitment of chromosomally abnormal or incompetent oocytes . However, in patients with decreased ovarian reserve as assessed with the use of AFC and/or AMH, higher doses of gonadotropins may be required.
The studies have suggested that these protocols have been able to provide reasonable number of mature eggs able to fertilize but the exact implantation potential and subsequent pregnancy rates of embryos and oocytes retrieved through these protocols are still unanswered. Being relatively new and being tried mainly in cases in cancer patients, these have been reported in very few studies.
18.104.22.168 Controlled Ovarian Stimulation with Estrogen-Sensitive Tumors
Controlled ovarian stimulation in women with estrogen-sensitive tumors is another challenge and should be dealt with caution. This can be achieved with addition of letrozole or tamoxifen to the above protocols to nullify the effect of rising estradiol levels during stimulation. Study by Oktay et al.  concluded that stimulation protocols using letrozole alongside gonadotropins are currently preferred over tamoxifen protocols as treatment with letrozole results in a higher number of oocytes obtained and fertilized when compared to tamoxifen protocols.
There has been case report by Reichamn et al.  of using these ovarian stimulation protocols for oocyte vitrification in prepubertal girls diagnosed with cancer that have not yet attained menarche and hence got no gonadotropin recruitable follicles. This has been reported as having successful ovarian stimulation and oocyte retrieval. This approach needs further robust evidence before it can be widely applicable to such group of cancer-affected females.
The goal of superovulation for this group of patients represents a compromise between obtaining a relatively large number of oocytes for vitrification, to maximize chances of later pregnancy, and the absolute need for avoidance of ovarian hyperstimulation in a patient who will shortly begin chemotherapy.
33.5 Complications of Controlled Ovarian Stimulation in Cancer Patients
The patients referred for fertility preservation may not necessarily represent the typical population of subfertile patients treated in IVF units. Cancer may affect multiple tissues throughout the body and can result in variety of complications during ovarian stimulation. Cancer may induce hypercoagulable state, and when this is combined with increased serum estradiol levels, it may put cancer patients undergoing controlled ovarian stimulation at an increased risk of thromboembolic events. Therefore, consideration should be given for commencement of anticoagulation therapy around the time of ovarian stimulation. The other strategy of preventing thromboembolic events is to use letrozole during ovarian stimulation as in women undergoing ovarian stimulation with estrogen-sensitive malignancies to keep estradiol levels close to <500 pg/ml. Letrozole at 2.5 or 5 mg/day can be started with ovarian stimulation and can be titrated up to 10 mg/day depending on the estradiol levels. Letrozole or GnRH antagonist should be continued even after oocyte retrieval for up to a week depending on the estradiol levels at the time of ovulation induction.
Some blood-borne malignancies may alter the hemostatic function and may create a tendency toward bleeding during oocyte retrieval owing to thrombocytopenia, platelet dysfunction, or defective coagulation factor synthesis. Collaborative team approach involving hematologist and anesthetist should be preferred to prevent complication of bleeding in these patients. Pelvic infection after oocyte retrieval can be a problem especially in neutropenic patients. In the case of neutropenia, consultation from the patient’s oncologist for the use of granulocyte colony-stimulating factor to increase the neutrophil count should be obtained, and prophylactic antibiotics should be given before oocyte retrieval to decrease the risk of infection. Cancers involving tracheal compression, or large pleural effusion, may preclude safe administration of anesthesia for oocyte pickup. This should be discussed with anesthetists prior to starting ovarian stimulation.
In cancer patients, antagonist protocols should be preferred and where possible trigger for final maturation to be planned with GnRH agonist to prevent the risk of OHSS. The impact of OHSS can be profound and all measures should be taken to prevent it. In cancer patients, its effect can be more profound as it may result in delaying or complicating planned life-saving cancer therapy.
Another aspect of ovarian stimulation, which needs further consideration, is the fact that success in vitrification has been seen in nonmalignant healthy infertile population, and little information is obtained about vitrification in cancer patients though studies have shown no difference in oocytes and embryos derived from patients with cancer and in nonmalignant conditions.
Successful implementation of fertility preservation services requires establishing liaisons with reproductive specialists and oncology colleagues. While survival is clearly the most important issue facing a young woman with cancer, it is clear that future fertility is also important. A rapid and efficient referral system with minimal delay can bring good results, and this can be established in close collaboration and effective communication with colleagues in medical, surgical, and radiation oncology.
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