Abstract
For all patients affected by a disease that could impair fertility before or during the reproductive lifespan, strategies to preserve their fertility and the ability to bear their own children is likely to be of utmost importance. While fertility preservation is a promising option, most of the technologies currently used are far from being well-established or are still experimental. Patients should be aware that no method guarantees success. Psychological and ethical impacts of fertility preservation are major concerns and should be included in the multidisciplinary approach to the patients.
Over the past 25 years, major advances in diagnostic modalities, chemotherapy, radiotherapy and supportive care have markedly improved cure rates for many childhood and adult cancers [1]. Current data suggest that approximately 80% of children with cancer will stay alive 5 years from diagnosis [2]. As a consequence, the number of long-term survivors is increasing, and fertility preservation has become a major issue for a young patient about to start treatment for cancer. Whether the only established opinion to preserve male fertility is cryopreservation of spermatozoa, the female condition provides significantly different challenges. Indeed, the emergence of mature oocyte cryopreservation and more recently ovarian cortical tissue freezing offers new opportunities not only in young adults but also in prepubertal young women. Therefore, patients included in a fertility preservation program, as well as their families and medical staff, are confronted with a unique and challenging situation that demands special considerations with regard to the psychological impact. In this article, we outline the current fertility preservation strategies in young female patients who are at risk for gonadal failure, and discuss the psychological and ethical questions raised by this activity.
Effect of chemotherapy/radiotherapy on ovarian function
This article will focus on cancer requiring cytotoxic therapy but we have to be aware that in gynecologic oncology, effective treatments to achieve cancer survival can also compromise the ability to subsequently conceive and/or carry a child. However, there are now more conservative surgical procedures for selected early-stage ovarian and cervical cancers that could lead to the discussion of fertility preservation.
The gonadotoxic effect of chemotherapeutic agents is well documented, although the prevailing mechanisms are not fully understood. Overall, alkylating agents such as cyclophosphamide, which are non-cell-cycle specific, are more cytotoxic to the ovaries than cell-cycle-specific agents such as methotrexate and fluorouracil, whose major effect is on ovarian follicle growth and maturation [3]. Thus, cyclophosphamide is the agent most commonly implicated in causing damage to oocytes and granulosa cells in a dose-dependent manner [4]. Follicular destruction following chemotherapy can present with a variety of symptoms that reflect varying degrees of damage, culminating in premature ovarian failure (POF).
Abdominal ionizing radiation associated with alkylating agents often induces POF, rendering patients infertile in almost 100% of cases. Indeed, for radiotherapy, it has been stated that a dose of 5–20 gray (Gy) administered to the ovary is sufficient to completely impair gonadal function [5], whatever the age of the patient. The dose of radiation required to destroy 50% of the oocyte reserve has been found to be <2 Gy [6]. Moreover, uterine irradiation at a young age reduces adult uterine volume [7]. Furthermore, radiation doses between 14 and 30 Gy have also been reported to result in uterine dysfunction, with increased risk of miscarriage [8]. Even though it is not within the scope of this article, ovarian transposition procedures are worth mentioning. Ovarian transposition, which involves the fixation of the ovaries outside of the radiation field, can only be used when pelvic radiotherapy is used alone. However, this procedure has a variable success rate, ranging from 16 to 90%, owing to scatter radiation and vascular compromise, and depending on the age of the patient, dose of radiation and whether intracavitary brachytherapy or pelvic external beam irradiation is used [9].
Although regular menstrual cycles may serve as a convenient marker for ovarian function, a normal menstrual cycle is not synonymous with fertility. Similarly, irregular menses or amenorrhoea do not always imply infertility, as shown in a retrospective series of women ≤35 years with breast cancer, who received chemotherapy with 5-fluorouracil, anthracycline and cyclophosphamide. In this study, 33 pregnancies occurred in 25 patients (21%), of whom only 64% continued to menstruate regularly during and after chemotherapy [10].
It is noteworthy that POF is not only drug-type specific but also age dependent. Indeed, it is well-established that younger women having undergone systemic therapy resume menstrual cycles more frequently compared to older patients. This phenomenon may be explained by a better ovarian reserve of follicles in younger women [11–16].
Finally, depending on the type of cancer, fertility might be impaired by the disease itself, or through gonadal damage as a consequence of aggressive chemotherapy and/or radiotherapy regimens, as well as bone marrow transplantation. Therefore, at present it is impossible to predict the functional life span of the chemo-/radio-therapeutically damaged ovary and the reproductive potential of patients with cancer.
Option for preserving female fertility
Ovarian suppression
Ovarian suppression with a GnRH-a as a method of diminishing the toxic effects of chemotherapy on the ovarian follicles is a controversial issue. Based upon the belief that the fertility of prepubertal girls is not affected by gonadotoxic treatment, the effect of creating a prepubertal hormonal environment through the use of GnRH-a has been investigated for preserving fertility. Theoretically, suppression of pituitary gonadotropins with a GnRH-a can only impact on follicles that have already reached the gonadotropin-dependant stage of follicular growth and are destined to ovulate in the next 90–120 days. However, by diminishing ovarian perfusion [17] or activating GnRH receptors on ovarian granulosa cells inhibiting apoptosis [18], the ovary might receive additional protective benefits from the GnRH-a. However, the questionable presence of GnRH receptors on human primordial follicles challenges the plausible mechanism of action [19]. In addition, more than half of prepubertal children who received high-dose chemotherapy had ovarian failure [20].
Following encouraging findings in animal models [21], nonrandomized studies with short term follow-up have suggested a protective role for GnRH-a co-treatment [22]. A recent study in Hodgkin's lymphoma patients, who were retrospectively sorted into three different groups according to the cytotoxicity of the chemotherapy regimen, demonstrated a significant advantage in terms of normal FSH levels in patients receiving ovarian suppression compared with those who did not [23]. In the only prospective, randomized study, 20 men and eight women were given a GnRH-a prior to and during chemotherapy [23–25]. There was no difference in the rate of amenorrhea 3 years following treatment in the eight women treated with the GnRH-a (4/8) compared with the control group (6/9). All men were profoundly oligospermic in both the treatment and control group. This study concluded that there was no evidence for a beneficial effect of GnRH-a, in the dosage or schedule used, to conserve gonadal function during intensive chemotherapy for advanced Hodgkin's lymphoma disease. However, recent reviews still pointed the discrepancies on a possible effect of ovarian suppression using GnRH-a [26,27]. Some possible reasons are suggested for this discrepancy between various studies. In the negative study, GnRH-a was not administered intramuscularly, which is less effective in suppressing ovarian function [28]. In addition, some studies had inadequate intervals for desensitization between GnRH administration and the initiation of chemotherapy [29]. Combination of GnRH antagonist and agonist may solve this delay [30]. Finally, further clinical trials are required to determine the overall effect of GnRH-a on protecting the ovaries from the toxic effects of chemotherapy.
Embryo freezing
Embryo fertilization requires controlled ovarian hyperstimulation that can delay the start of the cancer treatment of 2–6 weeks. In addition, embryo cryopreservation has others significant drawbacks. First, it requires that the female patient has a male partner or uses donor sperm to fertilize retrieved eggs. Second, ovarian stimulation that must precede oocyte retrieval necessitates a delay sometimes unacceptable in the case of a cancer patient requiring rapid initiation of chemo- or radiotherapy. Third, because conventional ovarian stimulation entails exogenous gonadotropin administration to induce multiple follicular developments, which is associated with a remarkable increase in serum estradiol (E2) levels, conventional ovarian stimulation protocols are contraindicated in breast cancer patients. To avoid the potential risks of rising of E2 levels during controlled ovarian hyperstimulation, a protocol using aromatase inhibitor was recently developed [40–41].
Oocyte cryopreservation
Cryopreservation of oocytes is an emerging option suitable for young adolescents, women without partners or women who do not wish to have their oocytes fertilized by sperm from a partner or anonymous donor. Cryopreservation of mature oocytes requires in most cases controlled ovarian hyperstimulation (10–14 days) but also can be performed after
Ovarian tissue cryopreservation
Cryopreservation of ovarian tissue is a promising experimental technology, presenting with several advantages. As it does not require ovarian stimulation and ovarian tissue can be harvested laparoscopically without any preparation, at any time of the menstrual cycle, ovarian cryopreservation may be the main option for fertility preservation in cancer patients who have contraindication or do not have time to undergo ovarian stimulation for oocyte or embryo cryopreservation. Thus, the storage of a large number of primordial and primary follicles can be rapidly performed [44–54]. Although the freezing–thawing procedure of ovarian tissue is now relatively well established, the use of the cryopreserved ovarian cortex in order to restore fertility remains a challenge. Orthotopic or heterotopic transplantation is currently the only available option to restore fertility using cryopreserved ovarian tissue. Alternatives such as
One of the major concerns in transplanting ovarian tissue from cancer patients is the risk for reseeding cancer cells. Previous studies demonstrated that most of the occult metastases belong to the infiltrating lobular histological subtype, which constitutes <15% of all breast cancers and more commonly occurs in postmenopausal women [63]. It should also be remembered that patients with
Psychological aspects of fertility preservation in cancer patients
This is a new and original form of consultation that is ideally conducted simultaneously by a gynecologist and a psychologist. The presence of both professionals in the consultation enables them to share the clinical situation, and witness together the affects evoked and the representations that exist in the mind of the patient. This consultation aims at informing the patient of the options available to preserve her fertility. It is therefore often long and strenuous for all concerned. The consultation follows the delivery of the diagnosis to the patient by her physician, which may have occurred as recently as a few hours to a few days prior to this meeting. The patient often does not fully comprehend the goal of this consultation, suggested by the oncologist. The news of the diagnosis has interfered with the patient's ability to process the information because of the profound distress it has generated. Therefore the gynecologist has to explain the possible effects of the chemotherapy on the patient's fertility.
However, advances in medical treatment compel physicians to adapt their practices to the new techniques available. The speed of this progress doesn't give the clinicians the opportunity to think through the implications of this new medical procedure on the patient's psychological capacity to react. Physicians are themselves ambivalent regarding the advances of some techniques. They often have to use these techniques without any evidence on their potential efficacy. Clinicians are confronted with a discrepancy between scientific progress and its application, and will therefore have to inform the patient how experimental the treatment remains.
Women suffering from cancer are brutally confronted with a traumatic and paradoxical situation: they simultaneously learn that they have cancer and that the treatment will in most cases decrease if not destroy their fertility, at the same time as they are told that a new medical technique could nevertheless enable them to preserve their fertility. Given the emotional impact of being diagnosed with cancer, the patients' knowledge that their fertility potential might be preserved might help them cope with and overcome this serious disease.
This new development raises many questions. Once the diagnosis of cancer has been made, the chemotherapy or/and radiotherapy must start on a timely basis. In spite of the shock incurred by the patient upon hearing the news, the patient must almost immediately make a decision on fertility preservation. This leaves little time to think, dream and formulate an answer. The patient has to deal with two very different and conflicting thoughts about herself: she suffers from a potentially fatal illness but must project herself as a fertile woman, a future mother. According to their testimonies, the fertility preservation procedure has been considered as a ‘real hope’ to become a genetic mother and an opportunity to project themselves in a future life after their disease. She is given an opportunity to repress or deny for a moment the death threat to which she is submitted.
“The worst thing isn't having cancer, but never having children”. Patients often utter these words during the consultation of fertility preservation, as if not giving birth made them sadder and more anxious than having cancer. This can be seen as a defense mechanism to ward off and repress the death threat to which they are confronted. Thus, patients concentrate on their sterility in order to avoid thinking about their illness. However, repression is also accompanied by the genuine grief stemming from the inability to procreate and therefore to perpetuate the lineage. The line of descent is a way to immortality [64].
Interview with the psychologist
The psychological interview is an opportunity to rekindle thinking and the ability to daydream, and a setting in which the multiple meanings of the decision can be explored. With the help of the psychologist, the patient can find a way to work through her fantasies and make use of herself and her psychic fertility, as a shield against mental breakdown and psychic death. Listening to the patient enables the emergence of death anxieties that are triggered both by the threat to the patients life and the specter of possible sterility. The patient is given room to express her depression. The psychologist has to invest some time to listen to what the patient absorbed during the consultation with the gynecologist in order to rephrase the information so that the patient can fully understand her choices. The patient, and sometimes her family, are helped to think differently about her prognosis in view of the imminence of the massive and castrating treatment which emphasizes the emergence of death anxieties.
The question of temporality
The time frame in which the physician has to inform the patient of the ovarian toxicity of treatment and the possibility to undergo fertility preservation is often short. Thus, both the patient and the gynecologist are held hostage to this time frame. The psychological repercussions of this situation are worth considering. In addition, questions regarding the thawing process and the time lapse before using the cryopreserved ovocytes, embryos or ovarian tissue are often raised. Indeed, although time will stop for the frozen organ, the woman's temporality continues.
Temporality is also involved in the preservation technique. Cryopreservation can also be seen as a suspension of the life of a living tissue. During the freezing period, the tissue will be in a kind of ‘no man's land’, neither completely alive, nor totally dead, only suspended, until the patient is ready to ask for the fulfillment of their desire to have a child.
Ethical issues raised by the preservation of fertility in cancer patients
Application of ovarian cryopreservation and transplantation raises a number of potential legal and ethical issues including clinical indications, issues of experimental versus established therapies, age limits, time limit for storage, the ability of minors to give consent and posthumous reproduction [65,66].
One of the major ethical issues for the young women who wish to preserve their fertility with a partner centers on the question of to whom the embryo ‘belongs’. The couple may disagree about the decision to have a child at this time, or about the future of the cryopreserved embryos. Then, the embryos will become unusable. The cooperation of both partners is necessary to constitute an embryo, however, the deadly risk facing the patient, the possibility of the couple not surviving the pressures of the harsh treatments and ultimately separating as a result, should be kept in mind. In addition, what about the ethical dilemma of women requesting the use of her preserved ovarian tissue after she has reached the usual age of menopause in her culture or has exceeded a designated age? Such questions have been the object of previous ethical debates [65,66].
Is it possible to refuse fertility preservation?
As a consequence of the limited time given to the patients to make a decision, some patients do not have the capacity to imagine themselves as a future mother and are prone to refuse the fertility preservation proposal. Indeed, it is established that medical practices can alter the thought process, possibly leading to defense mechanisms that result in a rejection of something new [67]. Therefore, the underlying reasons of such a decision may be pondered. Why do they refuse? Could it be considered as a self-destructive move, a way of killing off their lineage and killing themselves? Furthermore, could we hypothesize the refusal as a desire to let nature go its way, and not force a different outcome? Another alternative could be viewing the decision as a reaction against the medical decision, a fantasy of regressing to the infantile omnipotence against the physician. Refusing thus becomes the only means of affirmation.
Conclusion
The decision regarding using fertility preservation typically must be made simultaneously with other decisions about treatment of a life-threatening diagnosis. Ethical, religious and other implications of preserving fertility confront the patient before cancer treatment can even start. The trauma that such technologies potentially create highlights the importance of a multidisciplinary management involving not only physicians but also psychologists. Therefore, we consider that all patient suffering from cancer should, before any treatment, be counseled by a reproductive endocrinology specialist on the possible consequences of chemo- and radiotherapy on their fertility and the possibility to preserve it.
Although some patients, perceive stored embryos and oocytes as ‘frozen hope’ [68], it would be interesting to study whether the preservation of fertility, with the expectations it creates, influences the healing process of the cancer.
The technologies used to preserve women fertility can be fantasized as the congealed guardian of their urge to give life, in the hope of one day they may see their desire to have a child become true.
Future perspective
During the past decade, fertility preservation in women diagnosed with cancer has become a major concern. However, current technologies performed to achieve this issue have many drawbacks.
Footnotes