Factors of importance for implantation and problems after treatment for childhood cancer.

The uterus is of fundamental importance to reproduction; it nourishes the early embryo and accommodates growth and differentiation of the developing fetus. It is thus possible that the modalities employed to treat childhood cancer, that is; chemotherapeutic agents, and particularly irradiation, may result in damage to the uterine structure (musculature and local vasculature), with potential impairment of normal uterine function and thus increased risk of subsequent defective implantation. This may result in an impaired reproductive outcome (increased risk of spontaneous abortion, preterm labour, and low-birth-weight infants). Thus the reproductive problems foreseen following treatment of childhood cancer will be 1) ovarian failure or impaired ovarian activity and 2) uterine/endometrial structural and functional damage. The mode of treatment and age at its administration will be the major determinants of residual ovarian and uterine function. To understand the mechanisms that may be responsible for potential problems in reproductive function after treatment, it is essential to consider the mechanisms governing normal early pregnancy. Ovarian estradiol (E) and progesterone (P) secreted in a cyclical manner orchestrate the spatial and temporal morphological and functional changes in the endometrium required for implantation. In the absence of sex steroids, the endometrium is inactive. Implantation takes place in the midsecretory phase, that is, 5-9 days postovulation. E and P act sequentially to regulate cellular concentrations of their respective receptors and in turn gene transcription events are initiated to prepare the endometrium for implantation. A complex interaction exists between the network of uterine cells (epithelial, stroma, vascular, haemopoietic) and the endocrine system. Several key factors implicated in the implantation process will be addressed. There is published evidence that reports the risk of pubertal failure and early menopause after treatment for childhood cancer and, in those women who continue with ovarian activity and achieve pregnancy, a risk of poor reproductive outcome. It is likely that radiation damage to the uterus will adversely effect pregnancy potential. Our own group has reported impaired uterine characteristics in women after abdominal irradiation. More recently, we have shown that lower doses of radiotherapy (as with total-body irradiation) may be associated with a potential for improved uterine characteristics in response to physiological sex steroid replacement. The outlook after chemotherapy alone may be more optimistic; our early data support a normal uterine morphological response. Reproductive outcome in these patients remains unpredictable, so simple noninvasive assessment of uterine characteristics may provide data of predictive value with respect to future fertility potential.