rate of 90% [2,3]. Chemotherapy has a central role in the management of both these and most other cancers. But it is associated with a risk of infertility after completion of treatment. With improved long‐term survival, there has been a shift in focus to quality of life issues of which fertility is a major concern for the patient. Onco‐fertility counseling now should be an integral part of multidisciplinary cancer management but can be challenging in the absence of comprehensive information about the gonadotoxicity of specific drug regimens currently administered. Fertility after chemotherapy is also influenced by other factors such as age and ovarian reserve, making it difficult to accurately predict the risk of infertility after treatment. Discussion about fertility prognosis at diagnosis and provision of fertility preservation is improving, but timely follow‐up after completion of cancer therapy to advise about future fertility and early detection of ovarian insufficiency could be improved.
Effects of chemotherapy
Fertility potential relates to the total number and quality of oocytes in the primordial follicles in the ovary, and the ability of those follicles to respond to stimulation from the pituitary or exogenous hormonal stimulation. Chemotherapeutic agents act on the ovary directly by inducing apoptotic cell death and accelerated loss of primordial follicles, as well as indirectly by effects of reduced vascularity and fibrosis. Loss of follicles results in a decreased ovarian reserve and, if severe, in premature ovarian failure. The degree and rate of loss of follicles will determine whether ovarian failure is immediate or delayed, and whether temporary or permanent. Reversible amenorrhea results when only maturing follicles are destroyed; premature ovarian failure will result when all of the primordial follicles are destroyed.
The important predictors for women who will ultimately experience chemotherapy‐induced ovarian failure are: age of the woman, her ovarian reserve at the time of treatment, the type of chemotherapeutic agent used, the dose and duration of chemotherapy [4]. The risk of infertility increases in women over the age of 30 as there is a concomitant natural age‐related decline in ovarian reserve.
Early stage lymphoma treated with ABVD regimens has been shown to have a successful treatment outcome, and with similar birth rates compared to the general population [5–7]. However, regimens such as FEC (5‐fluorouracil, epirubicin, cyclophosphamide) administered for breast cancer, and BEACOPP for relapsed or refractory cases of HL contain the alkylating agent cyclophosphamide which carries a much higher risk of infertility [8,9].
Ovarian function after chemotherapy
It is not uncommon for women to experience menstrual irregularities or amenorrhea during, and up to 2 years after cancer treatment. Young women with long term drug‐induced amenorrhea may still regain menstruation at the end of treatment. It should be remembered that there is a natural decline in fertility with age, and that although regular menstrual cycles may serve as a marker of ovarian function, they are not synonymous with maintenance of fertility potential as there may still be ovulatory dysfunction. Similarly, irregular menses do not necessarily imply infertility. In young women spontaneous conception can occur despite a very low ovarian reserve and even in the presence of significant oligomenorrhea. However, even where there is apparent ovarian recovery, the ovarian reserve could still be reduced, and the degree of reduction will determine the window of reproductive opportunity that remains.
Failure to resume ovarian function by two years following cessation of chemotherapy is most likely to indicate ovarian failure. However, in some young women recovery may occur several years later and can even occur following a stem cell transplant for relapsed HL which generally has a high risk of ovarian failure.
Timing to conception after chemotherapy
It is generally not recommended for conception to be attempted immediately after completion of chemotherapy. The decision about when to start trying should be made jointly with the oncologist and the gynecologist in discussion with the patient, taking into account the following factors:
1 There is a higher risk of recurrences in the first two or three years after cancer diagnosis, influenced by the stage of the disease and nodal involvement, and in the case of breast cancer, the receptor status.
2 An adequate interval needs to be provided after the cessation of chemotherapy for ovarian function to recover, and to avoid any deleterious toxic effects of the chemotherapy on developing oocytes. Given that it takes approximately six months for the primordial germ cells to develop to the stage of primary oocyte, a safety margin of at least a year is suggested.
3 However, women who have been treated with highly toxic regimens such as FEC and BEACOPP, and older women should be made aware of the higher risk of developing premature ovarian failure and may need to start as soon as deemed safe.
Taking all these factors into account, a minimum delay of at least 2–3 years following completion of chemotherapy is conventionally recommended which should take the woman past the period of greatest risk of recurrence. In estrogen‐receptor (ER) positive breast cancer this will also allow her to have completed the minimum required exposure to endocrine adjuvant therapy [10] before taking a break for pregnancy. Following cessation of tamoxifen women are advised to delay attempting conception for at least three months to minimize the risk of birth defects [11,12]. The patient should resume tamoxifen following the pregnancy.
Management options
Timely return for a fertility review after completion of treatment will enable the woman to receive appropriate advice about future fertility and discuss her fertility options particularly when there is a limited window for conception. Symptomatic patients with amenorrhea may be referred earlier and further follow up will confirm whether ovarian failure is temporary or permanent and whether or not hormone replacement therapy should be recommended and commenced [13].
Assessment of ovarian reserve
It is good practice to assess gonadal status and ovarian reserve irrespective of menstrual function about a year after completion of chemotherapy. A significantly reduced ovarian reserve may be identified even in young women in the presence of regular menstrual cycles. Ovarian reserve can be assessed by measuring serum anti‐Müllerian hormone (AMH) levels and the antral follicle count (AFC) on ultrasound.
Follicle stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, and estradiol should be assessed in the early part of the menstrual cycle, but are of dubious value in oligomenorrhea and are generally less accurate predictors of ovarian reserve than AMH and AFC.
Early recourse to assisted reproduction techniques (ART)
If natural conception fails to occur despite simple interventions (as in Case History 1), there should be a low threshold to move to assisted conception if appropriate. Although the number of oocytes recovered might be low thus limiting the chance of a successful outcome, a woman may wish to take this opportunity particularly if she was unable to have prior fertility preservation. In the case described, the woman was taking a limited break after 5 years on tamoxifen. As she had not conceived after a year of trying, and already had embryos cryopreserved, she should proceed to replace her frozen embryos and preferably one at a time to avoid multiple pregnancy and maximize her overall chances of conception from the cryopreserved cycle.
IVF and replacement of frozen embryos require the use of exogenous hormones. In women with ER positive breast cancer the data currently available do not show that women undergoing ART have an increased risk of recurrence of their breast cancer [14,15]
In Case History 2, given the chemotherapy regimens the patient was administered and her irregular menstrual cycles she is likely to have a significantly reduced ovarian reserve and unlikely to conceive naturally nor have an appropriate response to ovarian stimulation. IVF using donated oocytes would be her best option. When her treatment was escalated to BEACOPP with a high risk of ovarian failure, there was a small window between cancer treatment cycles for freezing ovarian tissue for fertility preservation. This would have given her the option