Fertility and effect of cancer treatment in women
Infertility is defined as the failure to achieve pregnancy after more than one year of regular sexual intercourse without contraception. Fertility in women presupposes normal anatomy and normal functioning of the sexual organs. Gonatropin-releasing hormone (GnRH) is secreted by the hypothalamus and stimulates secretion of follicle-stimulating hormone (FSH) and luteinising hormone (LH) from the hypophysis. In the ovaries, these gonadotropins stimulate follicle development and cause further maturation of the oocytes. Despite recent hypotheses to the effect that oocytes are also developed post-natally, the theory that a woman is born with a more or less fixed reservoir of immature oocytes still prevails
(4). The reduction in the number of immature oocytes in the ovaries takes place through apoptosis, and proceeds both before and after birth. From puberty, the loss of oocytes is assumed to be between 500 and 1 000 in each menstrual cycle (5). Oocyte quality declines with increasing age, and is more pronounced from the age of about 35. By menopause the ovarian reserve is almost empty.
Women who have been treated for cancer become infertile after surgical operations, cytostatics treatment or radiation of the cervix, uterus or ovaries (table 1)
(6). High-dose cytostatics treatment, particularly with alkylating cytostatics, and full body radiation as part of the conditioning regimen prior to haematopoietic stem cell transplantation may induce apoptosis in the follicles of the ovaries and result in a reduction of the oocyte reserve. The result may be premature menopause (menopause before the age of 40) (7). Radiation of the central nervous system with doses of ≥ 40 Gy may harm the hypothalamus and hypophysis and result in hypogonadotropic hypogonadism.
Risk of amenorrhoea/premature ovarian failure after cancer treatment of girls and women
High risk (≥ 80 %)
Radiation treatment of whole abdomen or pelvis with ≥ 6 Gy in adult women, ≥ 15 Gy in prepubertal girls and > 10 Gy in post-pubertal girls.
Full body radiation
Alkylating chemotherapy (including cyclophosphamide ≥ 7.5 g/m² women < 20 years old
High-dose melphalan chemotherapy with stem cell support (HMAS)
Protocols for treating lymphoma that contain procarbazine: BEACOPP¹, cyclo-phosphamide, vincristine, procarbazine, prednisone-dacarbazine (COPP), nitrogen mustard, vincristine, procarbazine, prednisone (MOPP)
Radiation of the brain ≥ 40 Gy
Intermediate risk (30 – 70 %)
Cyclophosphamide, epirubicin, fluorouracil (FEC): 30 – 39 years old
Radiation treatment of whole abdomen or pelvis at 10 – 15 Gy in prepubertal girls, 5 – 10 Gy in post-pubertal girls
Cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)
Radiation of the central nervous system ≥ 25 Gy
Low risk (< 20 %)
Doxorubicin and/or cyclophosphamide in women aged 30 – 39
Cyclophosphamide, epirubicin, fluorouracil (FEC) in women aged < 30
Doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD)
Continued menstruation after cancer treatment is no guarantee that fertility has been preserved. The oocyte reserve may be severely reduced even if menstruation continues immediately after treatment. The oocyte reserve can be predicted by measuring the volume of the ovaries, number of antral follicles, FSH level, inhibin B, oestradiol and anti-Müller hormone (AMH). Follow-up studies of young cancer survivors show that the AMH level in the serum, as an indicator of the number of small pre-antral follicles in the ovaries, is not affected by the menstrual cycle or use of oral contraceptives and appears to be a better marker of the residual activity of the ovaries than the FSH or inhibin B-level
Fertility-preserving treatment of children is still experimental, as the technical aspects are under development and there is less experience of these methods, also worldwide. This treatment should only be carried out at specialised clinics and with parental consent
(9). Some serious benign diseases in children, such as aplastic anaemia, thalassaemia, sickle cell anaemia, Langerhans cell histiocytosis, haemophagocytic lymphohistiocytosis, Wegener’s granulomatosis and Turner’s syndrome may also cause infertility, due either to the disease itself or to gonadotoxic treatment of the underlying disease. Consequently, fertility-preserving measures may also be relevant with these diseases (10). Today this is an option only for patients who receive gonadotoxic treatment for the underlying disease, not for those whose fertility has been reduced by the underlying disease itself.
Figs 1 and 2 provide an overview of currently available fertility-preserving treatments for girls and women.
Figure 1 Schematic overview of fertility-preserving methods for prepubertal girls and women who cannot postpone cancer treatment
Figure 2 Schematic overview of fertility-preserving methods for adult women who cannot postpone cancer treatment