What is the Future for Fertility Preservation in Girls with Cancer?

The article by Lawrenz et al. in this issue of Klinische Pädiatrie reviews the literature for fertility preservation in girls and adolescents with cancer. Long-term survival has increased considerably in these patients. Chemotherapy as well as radiation therapy have contributed to these remarkable results [10].

Gonadal dysfunction and infertility are early as well as late effects concerning long-term survivors of malignancies treated during childhood, adolescence and adulthood. Preservation of fertility is an important issue to all these patients, their parents or guardians when infertility is one of the possible long-term sequelae of treatment [4]. Oncologists should be prepared to discuss possible fertility preservation methods before treatment with the patient/parents and/or refer them to a reproductive specialist [1] [24].

A number of different methods are listed and commented in this article. They have been developed to preserve fertility in the adult patient. Preliminary data are reported in the pediatric age group. Most of the procedures are experimental for pediatric and adolescent patients. They include protection of the ovaries by gonadotropin-releasing hormone analogues [3], transposition of the ovaries away from the radiation field prior to abdominal irradiation [18], embryo or oocyte cryopreservation [15], cryopreservation of ovarian tissue or ovarian cortex with subsequent orthotopic or heterotopic re-transplantation [9]. The authors of the article “Fertility preservation in girls and adolescents before chemotherapy and radiotherapy – review of the literature” recommend that “the effects of cancer treatment on ovarian function and later fertility should be discussed at the start of treatment. This discussion should also imply that parenthood in later life is realistic”.

It is the oncologist, who informs the parents and the adolescent about the effects and side effects of different chemotherapies and radiation treatments including their effects on ovarian function. These effects depend on the chemotherapeutic agent, their single or cumulative dose, the age and the fertility status of the patient. The effects of radiation therapy on ovarian function depend on the location of the radiation field, the total dose of direct or scattered irradiation. After the patients/parents have obtained this information including their presumed effect on ovarian function they have to decide which of the several fertility preservation options they should choose.

Chemotherapy alone seems to be less toxic to the ovaries of young girls when compared to the ovaries of older women since their ovaries contain a higher number of follicles [8]. For most treatment protocols the information on ovarian toxicity is limited or not available. Some information can be obtained from previous similar treatment protocols. Thus, data on ovarian function and/or fertility from different treatment protocols should be collected in the long-term follow-up of patients who have remained in first continuous complete remission after cancer therapy. It will be important to have data not only on the effects of different chemotherapeutic agents but also on the “threshold” dose of the substance that causes ovarian failure.

Radiation therapy causes ovarian failure in 88–100% of patients receiving total body or pelvic irradiation. The incidence is around 40–50% in patients treated with irradiation to one ovary. Scattered abdominal and spinal irradiation also affects ovarian function depending on the cumulative ovarian dose [25] [26] [28]. In addition, uterine function is impaired depending on the total radiation dose [5] [12]

Chemotherapeutic agents can affect ovarian function transiently or cause early or premature ovarian failure. With early ovarian failure the ovaries are so severely damaged that puberty does not start or progress. Generally, an estrogen/gestagen substitution therapy will be necessary until the age of menopause.

If premature ovarian failure is the consequence of chemo- or radiotherapy puberty would be completed spontaneously and regular menses would occur. Ovarian dysfunction, premature ovarian failure and infertility would become manifest only later in life [8]. It would be important to know when ovarian function fails in the forthcoming years, so that ovarian function should be carefully followed in cancer survivors who undergo normal pubertal development and experience regular menstrual cycles. If there is a risk that chemotherapy and/or radiotherapy might affect ovarian function ultrasonography and serum parameters are available to diagnose incipient ovarian failure. Ovarian volume and the number of antral follicles can be determined by ultrasonography. Smaller ovarian volumes and reduced number of antral follicles indicate impaired ovarian function. Similarly, high levels of Follicle Stimulating Hormone (FSH), low levels of inhibin B and Anti-Müllerian Hormone (AMH) are suggestive of incipient premature ovarian failure [11] [14]. Serum concentrations of AMH and inhibin B decline during the reproductive years and are undectable by menopause. The true place of ultrasonography, FSH, inhibin B and especially AMH in evaluating ovarian function is still unknown. These parameters should be evaluated in long-term prospective studies of survivors of childhood malignancies since there is a lack of information confirming the utility of these tests. Until these data have been presented the young women should be advised to attempt a pregnancy early in her reproductive life since her years of normal ovarian function might be shorter than expected.

GnRH agonists reduce ovarian toxicity by diminishing ovarian activity. The effect is reversible when chemotherapy and GnRH treatment are discontinued [3]. A possible protective role has been demonstrated in some human trials, but not in others [2]. Therefore, the effectiveness of GnRH agonists awaits further proof in larger prospective randomized trials. GnRH analogue treatment should therefore not be used in pediatric patients until further evidence is presented or prospective randomized controlled studies have been initiated.

Ovarian transposition can be used in patients receiving pelvic irradiation [20] [21]. Since there is a risk of remigration of the ovaries the operation should be performed close to the radiation treatment and the ovaries be marked by a metal clip so that they can be located any time during radiotherapy. Scatter radiation and vascular compromise can affect ovarian function. The success rates vary from 16 to 90 percent [18]. Transposition of the ovaries can be performed laparoscopically and should be recommended prior to pelvic irradiation.

The following fertility preservation methods depend on the patient's age, her pubertal development and in some cases on her partner status. The procedures should be performed in prospective clinical trials in the pediatric and adolescent age group.

Embryo cryopreservation is a proven and effective technique to preserve fertility in adult women as it has been used to store surplus embryos after successful in vitro fertilization (IVF) with partner or donor sperm [7] [22]. As most adolescents are not in a stable partnership and embryo cryopreservation in Germany is possible only with the consent of both partners this option of fertility preservation is generally not available to the adolescent.

Cryopreservation of unfertilized oocytes is another technique for fertility preservation. It is especially suitable when a partner or a sperm donor is not available. Oocytes are obtained by ovarian stimulation which usually requires a delay in cancer treatment by 2 or more weeks. In the pubertal female with a higher number of primordial follicles there is a considerable risk of the ovarian hyperstimulation syndrome so that lower doses of gonadotropins should probably be used. During ovarian stimulation oocyte development is followed by abdominal ultrasound in the sexually inactive adolescent. After stimulation, oocytes are collected under sedation or general anesthesia and cryopreserved until needed. Over 900 babies have born after oocyte cryopreservation [17].

Surgical removal of one ovary or a portion of one ovary with subsequent cryopreservation and heterotopic or orthotopic retransplantation is available for adult patients as well as for prepubertal and pubertal girls. The ovary or the ovarian tissue is removed laparoscopically and frozen. There is no major delay in cancer treatment since the time required for this procedure is <1 day. At the request of the patient the tissue is thawed and reimplanted into the pelvis or into a heterotopic site such as the forearm. Oocytes are collected after spontaneous ovulation or stimulation with exogenous gonadotropins for in vitro fertilization. One major concern with reimplanting ovarian tissue is the reintroduction of tumor cells especially in patients with systemic malignant diseases such as leukemia. At least 13 pregnancies have been reported worldwide after orthotopic reimplantation [6]. No pregnancies have been reported in prepubertal girls [27].

Some additional topics must be addressed before widespread use of the suggested fertility preservation methods can be implemented into general use in pediatric patients.

Several of the presently available procedures of fertility preservation are still in its infancy 23. There are only a few studies addressing the fertility preservation methods in the pediatric age group. Therefore, oocyte and ovarian cryopreservation and orthotopic or heterotopic transplantation procedures should be performed only in centers with the necessary expertise under protocols that include follow-up for later pregnancies and for recurrent, perhaps cryopreservation associated cancer. The pediatric patient cannot legally provide informed consent, but she has to assent to the procedure after age-appropriate information has been provided. This information can best be presented to the child by a counselor with experience in child development as well as expertise in the pros and cons of the different fertility preservation methods 19. Prior to the collection of oocytes or ovarian tissue informed written consent should be obtained about the use of the child's gametes if the child dies or spontaneous pregnancies occur. What do we know about the fate of the remaining ovary? Is the loss of one or part of an ovary associated with decreased ovarian function 13 16? Theoretically, the loss of a completely normal gonad decreases the hormonal and fertility potential by 50%. What are the risks of infertility for the pediatric patient in her treatment protocol? Among the survivors of the Childhood Cancer Survivor Study 6.3% developed acute ovarian failure, 8% premature nonsurgical menopause 8. Ovarian dysfunction in this study is reported with a total frequency of 14.3%. At the same time this demonstrates that the majority of patients i. e., 85.7% had normal ovarian function at the time of the study. Risk factors for premature ovarian failure included increasing doses of radiation to the ovaries, increasing alkylating scores and a diagnosis of Hodgkin lymphoma. Thus, the majority of cancer survivors can generally be assured that ovarian function is not impaired especially in those patients who do not belong to the aforementioned risk groups.

In summary, more information is needed to guide parents, pediatric patients and oncologists through this difficult, but promising field of fertility preservation in patients with childhood and adolescent malignancies.

Literatur

• 1 Anderson RA, Weddell A, Spoudeas HA. et al . Do doctors discuss fertility issues before they treat young patients with cancer?.  Hum Reprod. 2008;  23 2246-2251
• 2 Behringer K, Wildt L, Mueller H. et al . No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group.  Ann Oncol. 2010;  21 2052-2060
• 3 Blumenfeld Z, von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy.  Hum Reprod Update. 2008;  14 543-552
• 4 Burns KC, Panepinto JA. Attitudes regarding fertility preservation in female adolescent cancer patients.  J Pediatr Hematol Oncol. 2006;  28 350-354
• 5 Critchley HOD, Wallace WHB. Impact of Cancer Treatment on Uterine Function.  J Natl Cancer Inst Monogr. 2005;  34 64-68
• 6 Donnez J, Silber S, Andersen CY. et al . Children born after autotransplantation of cryopreserved ovarian tissue. A review of 13 live births.  Ann Med. 2011 Jan 13;  [Epub ahead of print]
• 7 Gook DA, Edgar DH. Human oocyte cryopreservation.  Hum Reprod Update. 2007;  13 591-605
• 8 Green DM, Sklar JA, Boice JD. et al . Ovarian Failure and Reproductive Outcomes After Childhood Cancer Treatment: Results From the Childhood Cancer Survivor Study.  J Clin Oncol. 2009;  27 2374-2381
• 9 Jadoul P, Dolmans M-M, Donnez J. Fertility preservation in girls during childhood: is it feasible, efficient and safe and to whom should it be proposed?.  Hum Reprod Update. 2010;  16 617-630
• 10 Jemal A, Siegel R, Xu J. et al . Cancer Statistics, 2010.  CA: Cancer J Clin.. 2010;  60 277-300
• 11 Knauff EA, Eijkemans MJ, Lambalk CB. et al . Anti-Mullerian hormone, inhibin B, and antral follicle count in young women with ovarianfFailure.  J Clin Endocrinol Metab. 2009;  94 786-792
• 12 Larsen EC, Schmiegelow K, Rechnitzer C. et al . Radiotherapy at a young age reduces uterine volume of childhood cancer survivors.  Acta Obstet Gynecol Scand. 2004;  83 96-102
• 13 Lass A. The fertility potential of women with a single ovary.  Hum Reprod Update. 1999;  5 546-550
• 14 Ledger WL. Clinical utility of measurement of anti-Mullerian hormone in reproductive endocrinology.  J Clin Endocrinol Metab. 2010;  95 5144-5154
• 15 Lee SJ, Schover LR, Partridge AH. et al . American Society of Clinical Oncology Recommendations on Fertility Preservation in Cancer Patients.  J Clin Oncol. 2006;  24 2917-2931
• 16 Levitas E, Furman B, Shoham-Vardi I. et al . Treatment outcome in women with a single ovary versus patients with two ovaries undergoing in vitro fertilization and embryo transfer (IVF/ET).  Eur J Obstet Gynecol Reprod Biol. 2000;  88 197-200
• 17 Noyes N, Porcu E, Borini A. Over 900 oocyte cryopreservation babies born with no apparent increase in congenital anomalies.  Reprod Biomed Online. 2009;  18 769-776
• 18 Sonmezer M, Oktay K. Fertility preservation in female patients.  Hum Reprod Update. 2004;  10 251-266
• 19 Stegmann BJ. Unique ethical and legal implications of fertility preservation research in the pediatric population.  Fertil Steril. 2010;  93 1037-1039
• 20 Stroud JS, Mutch D, Rader J. et al . Effects of cancer treatment on ovarian function.  Fertil Steril. 2009;  92 417-427
• 21 Terenziani M, Piva L, Meazza C. et al . Oophoropexy: a relevant role in preservation of ovarian function after pelvic irradiation.  Fertil Steril. 2009;  91: 935 e15-e16
• 22 Veeck LL, Bodine R, Clarke RN. et al . High pregnancy rates can be achieved after freezing and thawing human blastocysts.  Fertil Steril. 2004;  82 1418-1427
• 23 von Wolff M, Donnez J, Hovatta O. et al . Cryopreservation and autotransplantation of human ovarian tissue prior to cytotoxic therapy – A technique in its infancy but already successful in fertility preservation.  Eur J Cancer. 2009;  45 1547-1553
• 24 Wallace WH. Fertility preservation for young people treated with cancer: What are the attitudes and knowledge of clinicians?.  Pediatric Blood & Cancer. 2007;  48 2-3
• 25 Wallace WHB, Shalet SM, Crowne EC. et al . Ovarian failure following abdominal irradiation in childhood: natural history and prognosis.  Clin Oncol. 1989;  1 75-79
• 26 Wallace WH, Thomson AB, Saran F. et al . Predicting age of ovarian failure after radiation to a field that includes the ovaries.  Int J Radiat Oncol Biol Phys. 2005;  62 738-744
• 27 Wallace WHB, Barr RD. Fertility preservation for girls and young women with cancer: what are the remaining challenges?.  Hum Reproduct Update. 2010;  16 614-616
• 28 Wallace WHB, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte.  Hum Reprod. 2003;  18 117-121

Korrespondenzadresse