Department of Obstetrics and Gynaecology, IVF Centre, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi, Delhi, India
Ovarian stimulation in cancer patients is a relatively new and challenging concept. A large number of cancer patients in the reproductive-age group are now expected to survive and lead a normal life. However, various therapies responsible for this markedly improved prognosis can also cause a significant detrimental effect on the reproductive ability. It is important that all young patients diagnosed with cancer are fully informed and offered the option of various fertility preservation strategies. Ovarian stimulation followed by either embryo or mature oocyte cryopreservation is currently the most successful option. Special considerations are required while performing ovarian stimulation in cancer patients. A detailed pretreatment assessment, counseling, and proper selection of ovarian stimulation protocol within the available short time period with minimum side effects are crucial to maximize the success of fertility preservation.
Ovarian stimulationCancer patientCurrent cancerPrevious/past history of cancer
With significant improvement in survival rates for various types of malignancies, mainly due to the recent advancements in early diagnosis and treatment, more and more patients with either current or past diagnosis of cancer are now seeking infertility treatment.
The other important reason for assisted reproduction specialists to come across these patients more often is that infertile patients are reported to have higher incidence of cancer .
The infertile nulliparous women especially those with unexplained infertility have been associated with an increased risk of developing ovarian and uterine cancers (standardized incidence ratio [SIR] 2.64 [95 % CI 1.10–6.35] and 4.59 [95 % CI 1.91–11.0] respectively) .
Several confounding factors such as infertility itself rather than the medications may well be the reason for the increased incidence of cancer among infertile women .
Infertility practitioners can be faced with two different subgroups of cancer patients. The first group consists of those women recently diagnosed with cancer and have been recommended either surgery or chemotherapy/radiotherapy with potential to cause significant compromise to their reproductive ability. These women may not have had subfertility issues as such, but they wish to preserve their chance of having a child in the future. The treatment of this group presents several unique challenges. Cancer may affect multiple tissues throughout the body and can result in a variety of complications during controlled ovarian stimulation . A multidisciplinary approach including the oncologist, psychologist, and reproductive medicine specialist is imperative to counsel and help the patient to make an informed choice. The task is especially difficult as the patient and family are still going through the shock and acute distress of being diagnosed with cancer and their maximum focus is to get the treatment started at the earliest.
Multiple strategies have emerged in the recent times aiming to preserve fertility in such women. These include embryo and oocyte (both mature and immature) cryopreservation, cortical and whole ovary cryopreservation, ovarian transplantation, ovarian transposition, and GnRH agonist protection . Recent advances in the technology of vitrification of human oocytes and embryos have increased the opportunities for this group of women . Current statistics of chances of live birth from cryopreserved ovarian tissue are depressingly poor, with a handful of births reported worldwide . Currently, embryo and mature oocyte cryopreservation following in vitro fertilization (IVF) are the only techniques endorsed by the American Society of Reproductive Medicine, and all other methods are still considered to be investigational [6, 7]. Ovarian stimulation for these patients in order to retrieve good quality sufficient number of oocytes under the time pressure with minimum side effects is extremely important and remains a challenging task.
The second group of patients is those who had suffered and survived the cancer either during their childhood or reproductive age. More than 7,90,000 new female cancer cases were estimated to be diagnosed in 2012 in the United States . Substantial improvements in cancer treatment have greatly increased 5-year survival rates in these women. From 2002 to 2012, 83 % of women younger than 45 years diagnosed with cancer survived . The treatment for most of the cancer types in reproductive-age women involves either removal of the reproductive organs or cytotoxic treatment (chemotherapy and/or radiotherapy that may partially or definitively affect reproductive function) . Infertility is reported to be a major concern as a long-term effect of these treatments, especially in female cancer survivors [11, 12].
Quantification of the risk of reproductive dysfunction after cancer treatment (radiotherapy to pelvic organs and chemotherapy regimens containing alkylating agents) is a major challenge . Menstruation is not a sensitive way to identify the gonadotoxic effects of treatment . Barton et al  noted an increased risk of infertility in cancer survivors at very young ages, even though many resumed menstruation, showing that the menstrual function does not equate to normal fecundity. The fertility preservation should be considered in these cancer survivors if they are not ready to attempt conception .
34.2 Pre-ovarian Stimulation Assessment and Counseling
Controlled ovarian stimulation (COS) is the key step for embryo or mature oocyte cryopreservation. The number of oocytes retrieved and their quality are imperative factors to predict the potential efficacy of the fertility preservation program .
The antral follicle count (AFC) and measurement of anti-Mullerian hormone (AMH) are the two most important tests to assess the ovarian reserve and counsel the patient about predicted response. This information is also valuable to decide the COS protocol and starting dose of gonadotropins. The ovarian response will also be influenced by the patient-specific factors, most importantly female age. A detailed clinical history including previous pregnancies and menstrual and gynecological history and a physical examination to assess pelvic anatomy as in any other case for ovarian stimulation are important and must be carried out. A complete medical assessment of patient’s health and professional counseling are essential prerequisites for the treatment in cancer patients. Many women may be systemically unwell with contraindications to anesthesia or surgical oocyte collections .
There are mixed reports about the response of cancer patients to COS protocols: some reporting no significant change [15–17] and others demonstrating worse ovarian response in cancer patients compared with age-matched healthy women [18–20]. Both the malignancy and the patient’s multisystemic condition may have an impact on the response to ovarian stimulation . It has been reported that in patients with BRCA-1 mutations, oocytes may be more prone to DNA damage, clinically manifesting as diminished ovarian reserve or earlier menopause . These patients should be informed that the expected number of oocytes retrieved after COS may be lower compared with healthy patients of similar age. However, more studies are needed to confirm these findings .
In one study, AMH was found to be significantly lower in patients with lymphoma before chemotherapy compared with healthy control subjects . Ebbel et al.  demonstrated that women with cancer before gonadotoxic therapy may have significantly lower AFC compared with healthy women aged 25–40 years.
Some women may have estrogen-sensitive tumors, which may be stimulated during superovulation with gonadotropins . The question of the possible posthumous utilization of their gametes or embryos needs to be addressed in a sensitive but clear manner, with a written declaration of intent .
34.3 Ovarian Stimulation Protocols for the Cancer Patients
The main objective of COS in women with current cancer is to retrieve sufficient number of good quality oocytes within the shortest possible time with minimal risks. There is absolute need for avoidance of ovarian hyperstimulation syndrome (OHSS) in a patient who will shortly begin chemotherapy . The choice of the protocol is influenced by the time frame available, potential side effects, tumor biology, and the menstrual cycle phase.
There is a potential risk that the supraphysiological E2 levels during COS with gonadotropins may promote the growth of estrogen-sensitive tumors such as endometrial and estrogen receptor-positive breast cancers . The rise in E2 is directly proportional to the number of follicles recruited to grow. Therefore, alternative and potentially safer protocols have been suggested for this group of patients.
34.3.1 Choice of COS Protocols for Cancer Patients
· Natural-cycle protocol
· Tamoxifen alone
· Tamoxifen combined with gonadotropins
· Aromatase inhibitors (letrozole)
· Aromatase inhibitors combined with gonadotropins
· Long agonist protocol
· Short agonist protocol
· Antagonist protocol
· Conventional-start protocol
· Random-start/any phase stimulation protocol
34.3.2 Natural-Cycle IVF/ICSI Protocol
Since the elevation of estradiol levels is undesirable in estrogen receptor-positive cancer women, these patients have been offered natural-cycle IVF, which resulted in a single embryo in approximately 60 % of the preservation cycles .
However, for those patients diagnosed with current cancer, they usually have a single cycle opportunity owing to the time constraints. Maximizing the number of oocytes and embryos is extremely important; therefore, natural-cycle IVF giving only one or two oocytes and high rate of cycle cancelation is ineffective and not recommended for the purpose of fertility preservation .
It is a nonsteroidal triphenylethylene compound related to clomiphene and known to have an antiestrogenic action on breast tissue. This acts by inhibiting the growth of breast tumors by competitive antagonism of estrogen at its receptor site and accepted as first-line drug in hormonal prevention and treatment of estrogen receptor-possible breast cancer . The selective antagonist action of tamoxifen on the estrogen receptors in the central nervous system (similar to that of clomiphene) leads to an increase in GnRH secretion from the hypothalamus and a subsequent release of FSH from the pituitary, resulting in the stimulation of ovarian follicular development .
Tamoxifen can be used for COS alone starting on day 2–5 of the menstrual cycle in doses of 20–60 mg/day or in combination with gonadotropins, similar to the use of clomiphene . Its usage has been suggested in estrogen receptor-positive breast cancer patients and shown to increase the mature oocyte and embryo yield compared with natural-cycle IVF (1.6 vs. 0.7 and 1.6 vs. 0.6, respectively) and reduce cycle cancelations . When combined with gonadotropins, there is further increase in the number of oocytes (5.1 vs. 1.5) and embryos (3.8 vs. 1.3) . As tamoxifen has stimulatory effect on the endometrium, it cannot be used in women with endometrial cancer for ovarian stimulation.
34.3.4 Aromatase Inhibitors: Letrozole
The third-generation aromatase inhibitors such as letrozole significantly reduce the risk of recurrence in postmenopausal women with hormone receptor-positive breast cancer. Centrally, these release the hypothalamic-pituitary axis from estrogenic negative feedback, increase the secretion of FSH by pituitary gland, and thereby stimulate follicle growth . Stimulation protocols using letrozole with gonadotropins are currently preferred over tamoxifen protocols due to higher number of oocytes obtained and fertilized when compared to tamoxifen protocols . The main advantage of adding daily letrozole to gonadotropins COS protocols is to decrease serum E2 levels to be closer to that observed in natural cycle which is <500 pg/ml, without affecting oocyte or embryo yield [30, 31].
In a study  comparing the letrozole plus gonadotropin protocol in breast cancer patients and the standard IVF protocols in age-matched noncancer patients with tubal-factor infertility, letrozole 5 mg/day was started on day 2 or 3 of cycle, and FSH 150–300 IU/ day was added 2 days later. All medications were discontinued on the day of hCG trigger. The letrozole was reinitiated after oocyte retrieval and continued until E2 level fell to <50 pg/ml. The results were similar in terms of the number of total oocytes retrieved and length of COS in both groups . The recommended dosage of letrozole is 2.5–10 mg/day . Oktay et al.  demonstrated that the best maturity and fertilization results are achieved when hCG is given at 19.5–20.5 mm rather than traditional criteria of 17–18 mm.
220.127.116.11 GnRH Agonist Protocols
Traditional long downregulation GnRH agonist-based COS protocol requires 3–4 weeks preparation before oocyte retrieval. As there is usually considerable time constrains and patient would like to start chemo- or radiotherapy at the earliest possible, the long protocol is not a preferred option in the cancer patients.
Short “flare-up” protocol using GnRH agonist from day 1 of the cycle and gonadotropins from day 2 or 3 of the cycle can be used if these patients present at the appropriate phase of the menstrual cycle. No significant difference in pregnancy rates has been reported between short “flare-up” and antagonist cycles .
18.104.22.168 GnRH Antagonist Based COS Protocols
The majority of patients are treated with a GnRH antagonist-based protocol, which allows the shortest deferral of the initiation of radio-/chemotherapy .
Conventional-Start Antagonist-Based COS Protocol
Gonadotropins are started on day 2 of the menstrual cycle. As GnRH antagonists immediately suppress the pituitary release of FSH and LH and thereby prevent premature LH surge, these are initiated when the size of the lead follicle reaches 12–14 mm or from day 6 of gonadotropins stimulation.
This approach still requires awaiting menses before initiating gonadotropins, but it decreases the interval to oocyte retrieval compared to conventional long agonist protocols.
22.214.171.124 Random-Start/Any Phase COS Protocol
Random-start protocols are stimulation protocols, which can start on any day of the cycle as these patients do not have much time before chemotherapy (See Fig. 33.1)
· Luteal phase-start protocol. The use of GnRH antagonists during the preceding luteal phase was explored originally for cancer patients and then for poor IVF responders as a method to improve ovarian stimulation by inducing corpus luteum breakdown and synchronizing the development of the next wave of follicles . If a GnRH antagonist (single dose of 3 mg cetrorelix) or 250 mcg once daily for 2–3 days subcutaneously) is given during the midluteal phase, menses ensues a few days later . This would minimize the potential delay in oocyte retrieval and thereafter starting the cancer treatment.
· Late follicular phase protocol. The late follicular phase has been defined as after day 7 of the menstrual cycle with emergence of a dominant follicle (>13 mm) and/or progesterone level < 2 ng/ml. In a study reported by Cakmak et al. , if the cancer patient presented in the late follicular phase, then one of the following treatment plans were employed:
· COS started without GnRH antagonist after the LH surge. GnRH antagonist was started later in the cycle when the secondary follicle cohort reached 12 mm.
· Ovulation was induced with hCG or GnRH antagonist followed by start of the COS in 2–3 days in the luteal phase.
The authors reported that the numbers of total and mature oocytes retrieved and fertilization rates were similar between groups. However, the length of COS was 2 days longer, and therefore, the total dose of gonadotropin used was significantly higher in late follicular and luteal phase-start groups compared with the conventional-start group .
This approach overall provides a significant advantage by decreasing total time for the IVF cycle . This is consistent with a newer concept of ovarian physiology, which indicates that there are multiple waves of follicle recruitment during each menstrual cycle . Further clinical studies are needed to assess the efficacy of this strategy.
34.4 Final Oocyte Maturation and Prevention of OHSS
Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of COS; it is important to balance the risk of OHSS and obtain sufficient number of oocytes or embryos to maximize the chances for a successful pregnancy in the future . The impact of OHSS can be even more serious in cancer patients as it would further delay or complicate their planned cancer treatment.
As hCG trigger is well known to be associated with risk of including OHSS, it has been suggested to use GnRH agonist instead in GnRH antagonist-based cycles. The dosage between 1 and 4 mg leuprolide acetate has been recommended in the studies [3, 35].
Intracytoplasmic sperm injection (ICSI) on retrieved oocytes rather than simple IVF is recommended to avoid risk of failed fertilization. Depending on the patient’s age, a survival rate of the embryos following thawing of 35–90 %, an implantation rate of up to 30 %, and a cumulative pregnancy rate of 30–40 % can be achieved [36, 37]. With vitrification freeze-thaw protocols, promising results with more than 60 % of mature oocytes surviving after thawing and subsequent fertilization have been reported [38, 39].
With significant improvement in the survival rates, quality of life issues- especially the reproduction has become an important aspect. A detailed and professional counseling regarding fertility preservation is an essential part of comprehensive cancer care . Assessment of ovarian reserve and prediction of ovarian response to COS are important to decide right COS protocol. While the main objective is to retrieve maximum number of good quality oocytes, the potential risks must be avoided. Letrozole plus gonadotropins COS protocol is an effective and safe option in patients with estrogen-sensitive cancers undergoing fertility preservation . A random-start or any phase protocol is an emerging new strategy. Further studies with long-term follow-up to evaluate the pregnancy and live birth rates are necessary to prove the efficiency of newer protocols.
Louis SL, Saso S, Ghaem-Maghami S, Abdalla H, Smith RJ. The relationship between infertility treatment and cancer including gynaecological cancers. Obstet Gynaecol. 2013;15(3):177–83.
Venn A, Watson L, Bruinsma F, Giles G, Healy D. Risk of cancer after use of fertility drugs with in-vitro fertilization. Lancet. 1999;354(9190):1586–90.CrossRefPubMed
Cakmak H, Rosen MP. Ovarian stimulation in cancer patients. Fertil Steril. 2013;99(6):1476–84.CrossRefPubMed
Anderson RA, Wallace WH. Fertility preservation in girls and young women. Clin Endocrinol (Oxf). 2011;75(4):409–19.CrossRef
Koch J, Ledger W. Ovarian stimulation protocols for onco-fertility patients. J Assist Reprod Genet. 2013;30(2):203–6.PubMedCentralCrossRefPubMed
Ethics Committee of the American Society for Reproductive Medicine. Fertility preservation and reproduction in cancer patients. Fertil Steril. 2005;83(6):1622–8.CrossRef
Practice Committees of American Society for Reproductive Medicine; Society for Assisted Reproductive Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril. 2013;99(1):37–43.CrossRef
American Cancer Society. Cancer facts and figures 2012. American Cancer Society, Atlanta; 2012 (Available at: http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2012. (Accessed 06 Aug 2014).
Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, et al. editors. SEER cancer statistics review, 1975–2009 (vintage 2009 populations). Bethesda: National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2009_pops09/. Accessed 06 Aug 2014.
Rodriguez-Wallberg KA, Oktay K. Options on fertility preservation in female cancer patients. Cancer Treat Rev. 2012;38(5):354–61.CrossRefPubMed
Connell S, Patterson C, Newman B. Issues and concerns of young Australian women with breast cancer. Support Care Cancer. 2006;14(5):419–26.CrossRefPubMed
Peate M, Meiser B, Hickey M, Friedlander M. The fertility-related concerns, needs and preferences of younger women with breast cancer: a systematic review. Breast Cancer Res Treat. 2009;116(2):215–23.CrossRefPubMed
Barton SE, Najita JS, Ginsburg ES, Leisenring WM, Stovall LL, Diller L. Infertility, infertility treatment and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Study cohort. Lancet Oncol. 2013;14(9):873–81.CrossRefPubMed
Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update. 2001;7(6):535–43.CrossRefPubMed
Das M, Shehata F, Moria A, Holzer H, Son WY, Tulandi T. Ovarian reserve, response to gonadotropins, and oocyte maturity in women with malignancy. Fertil Steril. 2011;96(1):122–5.CrossRefPubMed
Knopman JM, Noyes N, Talebian S, Krey LC, Grifo JA, Licciardi F. Women with cancer undergoing ART for fertility preservation: a cohort study of their response to exogenous gonadotropins. Fertil Steril. 2009;91(4):1476–8.CrossRefPubMed
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(2):588–91.CrossRefPubMed
Pal L, Leykin L, Schifren JL, Isaacson KB, Chang YC, Nikruil N, et al. Malignancy may adversely influence the quality and behaviour of oocytes. Hum Reprod. 1998;13(7):1837–40.CrossRefPubMed
Klock SC, Zhang JX, Kazer RR. Fertility preservation for female cancer patients: early clinical experience. Fertil Steril. 2010;94(1):149–55.CrossRefPubMed
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(1):125–33.CrossRefPubMed
Oktay K, Kim JY, Barad D, Babayev SN. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol. 2010;28(2):240–4.PubMedCentralCrossRefPubMed
Lawrenz B, Fehm T, von Wolff M, Soekler M, Huebner S, Henes J, et al. Reduced pretreatment ovarian reserve in premenopausal female patients with Hodgkin lymphoma or non-Hodgkin-lymphoma—evaluation by using antimüllerian hormone and retrieved oocytes. Fertil Steril. 2012;98(1):141–4.CrossRefPubMed
Ebbel E, Katz A, Kao CN, Cedars M. Reproductive aged women with cancer have a lower antral follicle count than expected. Fertil Steril. 2011;96 Suppl 3:S199–200.CrossRef
Reddy J, Oktay K. Ovarian stimulation and fertility preservation with the use of aromatase inhibitors in women with breast cancer. Fertil Steril. 2012;98(6):1363–9.CrossRefPubMed
Oktay K, Buyuk E, Davis O, Yermakova I, Veeck L, Rosenwaks Z. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod. 2003;18(1):90–5.CrossRefPubMed
Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1992;339(8785):71–85.
Rodriguez-Wallberg KA, Oktay K. Fertility preservation in women with breast cancer. Clin Obstet Gynecol. 2010;53(4):753–62.PubMedCentralCrossRefPubMed
Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol. 2005;23(19):4347–53.CrossRefPubMed
Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril. 2001;75(2):305–9.CrossRefPubMed
Testart J, Frydman R, Nahoul K, Grenier J, Feinstein MC, Roger M, et al. Steroids and gonadotropins during the last pre-ovulatory phase of the menstrual cycle. Time relationships between plasma hormones levels and luteinizing hormone surge onset. J Steroid Biochem. 1982;17(6):675–82.CrossRefPubMed
Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A, et al. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab. 2006;91(10):3885–90.CrossRefPubMed
Anderson RA, Kinniburgh D, Baird DT. Preliminary experience of the use of a gonadotrophin-releasing hormone antagonist in ovulation induction/in-vitro fertilization prior to cancer treatment. Hum Reprod. 1999;14(10):2665–8.CrossRefPubMed
Cakmak H, Zamah AM, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian hyperstimulation. Fertil Steril. 2013;100(6):1673–80.CrossRefPubMed
Baerwald AR, Adams GP, Pierson RA.Characterization of ovarian follicular wave dynamics in women. Biol Reprod. 2003;69(3):1023–31.CrossRefPubMed
McArdle CA, Franklin J, Green L, Hislop JN. Signalling, cycling and desensitisation of gonadotrophin-releasing hormone receptors. J Endocrinol. 2002;173(1):1–11. Review.CrossRefPubMed
Ata B, Chian RC, Tan SL. Cryopreservation of oocytes and embryos for fertility preservation for female cancer patients. Best Pract Res Clin Obstet Gynaecol. 2010;24(1):101–12.CrossRefPubMed
Sonmezer M, Oktay K. Fertility preservation in female patients. Hum Reprod Update. 2004;10(3):251–66.CrossRefPubMed
Noyes N, Knopman JM, Melzer K, Fino ME, Friedman B, Westphal LM. Oocyte cryopreservation as a fertility preservation measure for cancer patients. Reprod Biomed Online. 2011;23(3):323–33.CrossRefPubMed
Yoon TK, Lee DR, Cha SK, Chung HM, Lee WS, Cha KY. Survival rate of human oocytes and pregnancy outcome after vitrification using slush nitrogen in assisted reproductive technologies. Fertil Steril. 2007;88(4):952–6.CrossRefPubMed