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 of having ovarian tissue transplantation (OTT) at a future date and a chance of natural conception. OTT in patients with lymphoma and breast cancer was not previously advised due to the risk of reintroducing malignant cells and inducing a recurrence of the primary cancer. Recent published series have demonstrated a successful outcome of OTT in women with these cancers after appropriate screening, with no evidence of recurrence in a follow up period of 3–5 years [16,17]. Unfortunately, in Case History 2 the persistence of a mediastinal mass increasing the anesthetic risk made this patient unsuitable for a laparoscopy to cryopreserve ovarian tissue.
In the event of ovarian failure, the option of donated oocytes or adoption remains. For those women who have received pelvic irradiation as well as chemotherapy, surrogacy can be considered.
Prepregnancy counseling
Certain chemotherapeutic agents are known to increase the risk of later systemic problems. Both anthracycline in ABVD and supra‐diaphragmatic radiotherapy can lead to later cardiac toxicity. In the presence of subclinical cardiac disease, physiological changes that occur in pregnancy including the increase in cardiac output can precipitate cardiac symptoms for the first time. In Case History 2, the patient should be advised to have an echocardiogram prior to conception and cardiology review if indicated [18,21].
Case History 2 will need be advised a CT scan prior to ART to confirm the absence of any breast cancer recurrence before embarking on fertility treatment.
Pregnancy after chemotherapy
The chance of pregnancy after chemotherapy will depend on the age of the patient and her diagnosis. In the presence of the high estrogen and progesterone milieu of pregnancy, there have been concerns that pregnancy after breast cancer could stimulate micro‐metastases and increase the risk of disease recurrence, particularly in women with hormone receptor positive breast cancer. Current data have not shown an adverse impact on survival for those women who became pregnant regardless of the hormone receptor status of the primary tumor [15]. Interestingly, several studies have shown a better survival in women who achieved a pregnancy compared with those who did not, perhaps due to a “healthy mother effect” (i.e. women who achieve a pregnancy being a better cancer prognosis group [19,22]).
Prevention
Early referral at the time of diagnosis gives the patient the opportunity to discuss fertility and to avail themselves of the best option for fertility preservation through cryopreservation of oocytes or embryos (see Chapter 10). For example, in Case History 2, although the ABVD regimen for HL is thought not to significantly affect fertility, the patient would have benefitted from fertility preservation prior to treatment as her ovarian reserve of 12.5 pmol/L was low for her age and will reduce her window of reproductive opportunity. Her treatment was then escalated to BEACOPP which is more gonadotoxic than ABVD, and with an already reduced pretreatment ovarian reserve, this patient would likely develop premature ovarian failure. In general, women older than 35 years undergoing treatment with ABVD would benefit from early fertility discussion as it has now been shown that they have a diminished ovarian reserve recovery when assessed a year after completion of chemotherapy [13].
Sadly, there is still no treatment that will remove the risk of ovarian compromise after chemotherapy. Both case histories had concomitant gonadotropin releasing analogue (GnRHa) during chemotherapy and despite recent studies suggesting some benefit in reducing the risk of ovarian failure, improvement in pregnancy rates is yet to be demonstrated [20,21]. However, it still has an important use in avoiding the heavy menstrual loss and irregular bleeding that occurs during chemotherapy in hematological malignancies, particularly in those with leukemia and clotting defects [22].
Key points
Challenge: Female fertility after chemotherapy.
Background:
Chemotherapy will often result in infertility and premature ovarian failure.
The risk of loss of fertility is difficult to predict as comprehensive information about the gonadotoxicity of current cancer drug regimens do not exist.
The loss of fertility is influenced by the age of the patient, pretreatment ovarian reserve, and the type and duration of chemotherapy administered.
Return of menstrual function after chemotherapy does not always imply the return of fertility, nor does oligomenorrhea always indicate ovarian insufficiency.
When there is a return of ovarian function, the reduced ovarian reserve that occurs after chemotherapy may limit the window of reproductive opportunity.
Management options:
Onco‐fertility counseling and management requires a multidisciplinary service.
Management is influenced by the age of the patient, her ovarian reserve after chemotherapy and whether she had fertility preservation before cancer treatment.
Early referral for fertility discussion and assessment of ovarian reserve.
There should be a low threshold to move to assisted reproduction techniques.
Oocyte donation, surrogacy and adoption could be relevant management options.
Appropriate prepregnancy counseling depending upon type of chemotherapy administered.
