reported till 2017 [5], OTC has moved from being experimental to a more established method of fertility preservation in various countries [6,7,8]. However, it should only be offered by specialized centers with relevant clinical and laboratory expertise, facilities and appropriate accreditation, such as Human Tissue Authority (HTA) licensing in the UK.
Generally, no more than 50% of one of the ovaries is removed in a day‐case laparoscopic procedure (Figure 10.1), and the cortical tissue is prepared to a thickness of approximately 1mm, cut into small pieces and then cryopreserved [4]. If the woman becomes menopausal following her cancer treatment, she may have the ovarian cortical tissue transplanted as and when she decides to try to conceive a pregnancy.
There is a theoretical risk of transplantation resulting in the reintroduction of cancer cells. This risk can be mitigated by the use of in vitro maturation (IVM). The first live birth achieved using IVM in a woman with cancer has been reported in 2020 [9], and this could become an important option for fertility management. Nevertheless, a recent systematic review of all peer‐reviewed published reports of women receiving ovarian tissue transplantation has found no evidence of reseeding malignant cells present in the frozen ovarian tissue in sufficient numbers to cause recurrence of cancer [8].
Figure 10.1 Laparoscopic removal of part of an ovary. Stay suture to stabilize the ovary (a). Removal of 1/3‐1/2 of the cortex without the use of energy (b,c).
Images courtesy of Mr. Yousri Afifi, Birmingham Women’s Hospital, Birmingham, UK.
Controlled ovarian stimulation and cryopreservation of oocytes or embryos
This is the most established female fertility preservation method. However, it requires approximately 2 weeks to complete the treatment to the oocyte retrieval stage. Ovarian stimulation can be started at any stage of the menstrual cycle, which is called random start protocol (Figure 10.2); however, if it is started in the late follicular phase or luteal phase, it is essential that:
A follicle stimulating hormone (FSH) only preparation is used, rather than human menopausal gonadotropin (hMG), which contains human chorionic gonadotropin (hCG) driven luteinizing hormone (LH) activity that can induce luteinization); and,Figure 10.2 Controlled ovarian stimulation at various stages in menstrual cycle. FSH, follicle stimulating hormone; GnRH, gonadotropin releasing hormone; HMG, human menopausal gonadotropin.
A gonadotropin releasing hormone (GnRH) antagonist is started at the same time as the FSH injections (to prevent luteinization if a late follicular phase start, or to induce luteolysis if a luteal phase start).
GnRH agonist should be used, unless contraindicated, to induce final follicular maturation as it significantly reduces the risk of ovarian hyperstimulation syndrome [10]. GnRH agonist trigger also has an additional value in hormone dependent breast cancer patients as it reduces the estrogen levels in the luteal phase following the trigger with no negative impact on the number of mature oocytes available for storage (see Chapter 51) [11].
For the patients in Case Histories 1 and 2, controlled ovarian stimulation and oocyte retrieval should be offered, as long as approximately 2 weeks delay in cancer therapy is acceptable. For the woman in Case History 1, cryopreservation of oocytes and/or embryos should be offered. However, with embryos there could always be a risk that she would not be able to use them if her partner withdraws consent to the use of embryos (see Chapter 108). One way of addressing this risk is to divide the lot of oocytes in half, and store half as embryos and the other half as oocytes; alternatively, the woman may decide to cryopreserve oocytes, rather than create any embryos with her partner’s sperm. Two additional issues are worth considering for the woman in Case History 1:
1 As she has an estrogen receptor positive breast cancer, the co‐administration of 5 mg of letrozole daily, commencing on Day 2 and continued throughout COS, is recommended as it reduces peak estradiol concentrations without significantly decreasing oocyte yield (see Chapter 51) [12].
2 As a pregnancy will be associated with very high levels of estrogen, gestational surrogacy may need to be considered [13].
For the girl in Case History 2, oocyte cryopreservation should be offered. The success rate of oocyte cryopreservation has risen, and the increasing use of vitrification has improved outcomes, with IVF pregnancy rates now similar to those achieved with fresh oocytes [14]. There is no evidence that babies born from cryopreserved eggs have an increased risk of congenital abnormalities [15].
GnRH agonist co‐treatment during chemotherapy
Administration of GnRH analog (GnRHa) during chemotherapy has been proposed to protect ovarian reserve and fertility. One hypothesis is that GnRHa may protect the ovary by shutting down the hypothalamic–pituitary–ovarian axis, thus mimicking a prepubertal state when ovaries may be less vulnerable to the effects of chemotherapy [16]. Another hypothesis is that GnRHa may provide protection via reduced ovarian blood flow, resulting in reduced amounts of chemotherapeutic agents reaching the follicles [16]. Research evidence on the effects of GnRHa co‐treatment during chemotherapy has yielded conflicting results [16–19]. However, a 2019 Cochrane review concluded that GnRH agonist appears to be effective in protecting the ovaries during chemotherapy, in terms of maintenance and resumption of menstruation, treatment‐related premature ovarian failure and ovulation. However, evidence for protection of fertility was insufficient and needs further investigation [20]. Until more evidence is available, it would be reasonable to offer women GnRHa treatment during chemotherapy.
Sperm banking
The most common cancers in men during their reproductive years are leukemia, Hodgkin lymphomas and testicular germ cell tumors [21]. Semen analysis may be abnormal in men with germ cell tumors. Furthermore, there is evidence that the integrity of sperm DNA is affected even before initiation of cancer therapy in men with Hodgkin lymphomas and testicular cancers [13]. Chemotherapeutic agents, particularly alkylating agents such as cyclophosphamide, can have profound gonadotoxic effects. Radiotherapy, even at low doses, is toxic to sperm [13]. Thus, the man in Case History 3 should be offered the opportunity of sperm banking. Men with testicular cancer who cannot produce a sample or are azoospermic can undergo surgical sperm retrieval (see Chapter 91).
Key points
Challenge: Fertility preservation in patients with cancer.
Background:
Young patients with many cancers have excellent survival prognosis and should be promptly referred to explore their fertility preservation options.
The effect of chemotherapy on ovarian function and fertility will depend on drug(s) used, dosage, duration of treatment, age of the patient and baseline ovarian reserve.
Radiotherapy, particularly if directed to the pelvis, can affect fertility.
Management options:
Multidisciplinary team approach.