Female Fertility Issues After HSCT
Normal Ovarian Function
Oocytogenesis is a limited process, which is completed before or shortly after birth. The number of primary oocytes (primordial follicle) peaks at the 5 months of gestational life with several million of primary oocytes. From this moment there is a progressive decline. At puberty 200,000–500,000 primary oocytes are present, and at menopause less the 1000 remain. Following puberty, during each menstrual cycle, pituitary gonadotrophin, the lutenizing hormone (LH), stimulates completion into secondary oocyte. During her normal reproductive lifespan, a woman will have about 450 ovulatory monthly cycles. The progressive decline of the primordial follicles is attributed to follicle death by apoptosis. The main cause of the decline of primordial follicles is age of the female, which account for more than 80%. Other factors are smoking, body mass index, parity and stress. Only a few oocytes will undergo ovulation during the reproductive years. The majority of the oocytes will be lost due to atresia.
Clinical infertility is defined as the inability to conceive after one or more years of intercourse without contraception during the fertile phase of the menstrual cycle. In a general female population, incidence of sterility is estimated at 8% for women aged 16−26 years, and 18% for women aged 35−39 years.
Female Fertility After Cancer Treatment & HSCT
Cancer treatment with multi-agent chemotherapy and radiotherapy may damage the ovaries and lead to premature ovarian failure. The degree of ovarian impairment due to gonadotoxic treatment is closely related with the number of remaining oocytes at time of the treatment. Therefore, because the number of oocytes is decreasing with advancing age, the age of the patient at time of treatment plays a relevant role. The ovarian damage occurring during HSCT is mainly due to the gonadotoxic effects of the conditioning regimen. However, some patients may already have a reduced number of oocytes before transplantation because of the previous treatment received for a malignant disorder.
Ovarian tissue is particularly susceptible to radiation therapy. Radiation dose at which 50% human oocytes are lost has been estimated to be less than 2 Gy.[8,9] The effective sterilizing dose related to the age of the woman at time of treatment has been estimated to be 20.3 Gy at birth, 18.4 Gy at 10 years, 16.5 Gy at 20 years and 14.3 Gy at 30 years. Total body irradiation (TBI) plays an important role in the post-transplant infertility. The majority of female patients treated with TBI experience gonadal failure. Recovery of gonadal function occurs in 10−14% of these women, and the number of pregnancies observed after HSCT is lower than 2%. From a cohort of 532 females conditioned with TBI (≥10 Gy), 10% showed ovarian recovery and 1.3% had a pregnancy. Doses of 6 Gy are sufficient to cause irreversible ovarian injury in most patients treated after the age of 40, while two- to three-times this dose is required to precipitate ovarian failure in irradiated children. When administrated before puberty, TBI is less gonadotoxic. Around 40−60% of the girls conditioned with TBI and transplanted before the onset of puberty retain adequate gonadal function, experiencing spontaneous puberty and menarche. However, based on measures of anti-Müllerian hormone (AMH) concentration, it appears that the proportion of ovarian failure in prepubertal girls conditioned with TBI is much higher, despite these girls do not present clinical signs.
Ovarian damage due to chemotherapy is dependent on the type and dose of the drug as well as the patient's age at time of treatment. The ovary is particularly susceptible to alkylating agents such as cyclophosphamide, busulfan or melphalan, all of them commonly used in HSCT with myeloablative conditioning. Childhood cancer survivors treated with alkylating agents have a two to fivefold risk of premature menopause before age 40 years. Cyclophosphamide used alone for conditioning is compatible with recovery of gonadal function in younger women, but premature ovarian failure occurs in women older than 30 years. In a single center study of patients conditioned with cyclophosphamide alone for severe aplastic anemia, ovarian recovery occurred in all women younger than 26 years at time of transplantation, but only in five of 16 women older than 26 years. In a retrospective multicenter study on 138 female recipients transplanted in childhood or adolescence, fertility impairment was suspected in 83%. Start of treatment at age of 13 years or more, and the conditioning with busulfan based preparative regimen were the major risk factors for impaired fertility.
The impact of reduced intensity conditioning on ovarian function remains uncertain. Initially, reduced intensity conditioning has been mainly applied to elder patients with poor health condition, where fertility preservation was not in focus. However, in recent years a considerable number of young patients have received transplants with reduced intensity conditioning. So far, recovery of ovarian function and single cases of successful pregnancy outcome has been reported. However, more data are required to draw definitive conclusions.
In addition to ovarian injury, irradiation also may cause uterine damage, with impaired growth and blood flow, leading to reduced uterine volume with decreased endometrial thickness and loss of distensibility. The extent of the impact of radiation on uterus appears to be more pronounced when applied before puberty.[19,20] Young women exposed to TBI during childhood may also suffer from impaired uterine growth and blood flow. In a group of 12 women transplanted for leukemia or lymphoma during childhood, 4 to 10.9 years after TBI and HSCT the average uterine volume was reduced to 40% that of normal adult size, despite spontaneous pubertal development or hormone replacement therapy. Hormone replacement therapy, when indicated was insufficient to establish normal uterine growth and development.
Screening for Infertility & Fertility Preservation
There are several clinical and biological indicators of gonadal failure in women. Clinical indicators include failure to go through puberty, absent menstruation (primary or secondary) and menopausal symptoms. Biologic indicators include elevated serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), low level of anti-Müllerian hormone and reduced or absent antral follicles on ultrasound. Two FSH levels in the menopausal range measured at least one month apart and associated with amenorrhea/oligomenorrhea and low estradiol levels are strongly suggestive of ovarian failure. However, there is no method completely reliable for the evaluation of the fertility. The presence of menstruation is not necessarily indicative of oocyte reserve and quality. The definite proof of fertility can only be established by the spontaneous occurrence of a pregnancy.
After HSCT, women should have annual gynecologic evaluation as part of general health screening. Monitoring tests for gonadal function in females are FSH and LH that should be performed at one year post HSCT, and subsequently based on menopausal status. Hormone replacement therapy may be required to maintain libido, sexual function and bone density and should therefore be discussed with young women who have estrogen deficiency after HSCT. Concerns about hormonal replacement have been reported by the Women's Health Initiative Study relating on the increased risk of breast cancer, coronary heart disease, stroke and pulmonary embolism. Since this publication, the negative message of hormonal replacement therapy has been tempered. In a recent position paper, the North American Menopause Society supports the initiation of hormone therapy around the time of menopause to treat menopause-related symptoms and to prevent osteoporosis in women at high risk of fractures.
The risk of premature ovarian failure after HSCT is very high. Therefore, fertility preservation methods should be discussed with all young women in childbearing age and parents of children facing HSCT. Fertility preservation options for females treated with HSCT are summarized in (Table 1). An algorithm for fertility preservation options according to the pubertal age of female patients at time of HSCT is presented on (Figure 1A). Hormone replacement treatment in long-term survivors with ovarian failure improves vasomotor and urogenital menopausal symptoms and increases measures of psychological well-being, but has no effect on fertility. The choice of a less gonadotoxic conditioning regimen may have a sparing effect on ovarian function. Reduced intensity conditioning, with low or no dose of TBI, lower dose of busulfan or melphalan may cause less ovarian damage after HSCT.[26,27] However, more studies are needed to determine whether non-myeloablative or some reduced intensity regimens are as effective as myeloablative regimens in controlling (curing) the underlying disease and whether these regimens will result in less gonadal failure.
Algorithm for fertility preservation options according to the pubertal age of the patient at time of hematopoietic stem cell transplantation. (A) Options for female patients and (B) options for male patients.†Experimental, only performed as part of a clinical study.Adapted with permission from [92,93].
So far, embryo cryopreservation is the most common way for female fertility preservation. Embryo cryopreservation requires that the woman receives hormones timed to her menstrual cycle to stimulate development of eggs which can then be collected and fertilized in vitro. The approach involves a 2−5-week delay in treatment of the patients to allow maturation of oocytes. Thereafter the mature oocytes have to be extracted and fertilized in vitro with sperms. Therefore, embryo cryopreservation requires male sperm source thus precluding its use in children and women without a partner willing to donate sperm. For this procedure, the woman has to be treated with supraphysiologic levels of hormones. Despite these limitations, embryo cryopreservation remains the most used and most successful method of fertility preservation for female cancer patients. Approximately 75% of embryos survive the freeze and thaw process, with reported pregnancy rates of 30% per cycle, depending on the women's age and to total number of embryos transferred. While embryo cryopreservation for a female under 18 may be ethically questionable, in some countries the use of donor sperm is acceptable with permission.
With the development of the vitrification technique, oocyte cryopreservation is becoming a very attractive, routine practice and should no longer be considered experimental. Using this method, clinical pregnancy rates and live birth rates are now comparable to those obtained with fresh cycles, and children born from vitrified oocytes do not present higher rates of congenital abnormalities. For postpubertal women who lack a partner or for those who do not accept donor sperm and have moral concerns about embryo cryopreservation, cryopreservation of unfertilized oocytes is the strategy to follow. As for embryo cryopreservation, prerequisites for the collection of unfertilized oocytes include the necessity to postpone for a minimum of 2−3 weeks cancer treatment or HSCT and absence of a contraindication for ovarian stimulation. Likewise, ovarian stimulation is performed by administering exogenous hormones, resulting in the generation of several mature oocytes from a single treatment cycle. However, unlike embryo cryopreservation, the oocytes are not fertilized with sperm prior cryopreservation.
Whenever treatment cannot be delayed, it may be possible to obtain ovarian tissue for freezing. Ovarian tissue banking is a promising technique. It does not involve stimulation of the ovaries and provides the opportunity for preserving gonadal function not only in adults but also in prepubertal girls. In young, prepubertal girls, it is the only option of fertility preservation and should be offered when there is a high risk of premature ovarian insufficiency.[31,32] Cryopreservation of ovarian tissue is also a valid option for postpubertal women excluded as candidates for other fertility preservation options. Ovarian tissue is harvested, usually laparoscopically and cryopreserved for later use. Additionally, this method secures the re-establishment of the women's own endogenous hormone production after transplantation. In adult cancer patients, cryopreservation of ovarian tissue before gonadotoxic chemotherapy has been shown to restore the menstrual cycles and lead to the birth of healthy children. In a series of 72 transplanted female patients under the age of 42 years, 33 were offered assisted reproduction technology and 12 of them proceeded to do so: eight of the women had stored embryos, four oocytes and two ovarian tissue (two patients had stored oocytes in addition to either embryos or ovarian tissue).
In order to prevent impairment of oocyte quality by chemotherapy, international guidelines have supported an early intervention before anticancer therapy. However, in patients with malignant hematological disease, this procedure can be called into question. Indeed, ovarian material collected at time of overt leukemia has a high probability of being contaminated by malignant cells. Postponing the fertility preservation measure to the time of leukemia remission results in less or no leukemia contamination in the ovarian tissue. Further studies are needed to balance between the risk of residual ovarian contamination and impairment in ovarian function, depending on the timing of ovarian tissue collection.
Although infertility is common after HSCT, contraception counseling is recommended in female survivors after HSCT. Contraception is advisable in fertile women or if fertility status is not known and pregnancy not desired. Recommendation concerning protection against sexually transmitted infections should be included independent of fertility status. According to the new international recommended screening and preventive practices, spontaneous or assisted pregnancies should be delayed for at least 2 years after HSCT valuing that this is the time frame where highest risk of relapse is also highest.
Expert Rev Hematol. 2013;6(4):375-388. © 2013 Expert Reviews Ltd.