Ovarian function following radiation and chemotherapy for cancer

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Abstract

High-dose chemotherapy and radiotherapy have increased the long-term survival of young patients with cancer; nevertheless, the toxic effects on ovarian function causing amenorrhoea, premature menopause and infertility, are still severe.

Introduction

Advances in the management of cancer have significantly improved cure rates especially in the case of haematological malignancies and some solid tumours in young patients (Table 1)

Cancer patients today realistically hope for cure or long-term survival. However, damage to other body cells may occur, and the germinative epithelium of the ovary is a target organ for antiproliferative treatments. Young patients treated with chemo- or radiotherapy that can today expect a normal life span, may suffer significant damage to the ovary. Normal life span does not imply normal reproductive life span.

Unlike men, women only have a finite number of germ cells at birth, and the total diminishes with age. At puberty 200,000 follicles are present and functioning in the ovary, progressively declining with age to 400 at the time of menopause. With chemotherapy and radiotherapy, the rate at which the germ cells and primordial follicles, diminish is high and this brings forward the onset of menopause. Premature menopause is the commonest toxic effect experienced in women undergoing both chemotherapy and radiotherapy, and hormone replacement therapy should be considered where necessary.

Ovarian damage and ovarian failure are important and common long-term effects of chemotherapy. Infertility and premature menopause in young women have a strong impact on self-esteem and quality of life. After chemotherapy, the amenorrhea rate varies from 40 to 68%. The patients that recover a normal menstrual cycle after antitumoral therapy are more likely to experience premature menopause because of the reduced follicular reserve. These side effects of chemotherapy are a serious problem for the patients, as some of them are relatively young and wish to have a normal reproductive life.

Chemotherapy, however, damages the growth and maturation of ovarian follicles more than it alters male gonadal function and normally, the first lesions which are histologically detected at an ovarian level are fibrosis and destruction of follicles. In particular, Himelstein-Braw et al. [11], through extensive study carried out at autopsy, have shown, in patients with leukaemia treated with chemotherapy, a considerable reduction of secondary type follicles, while he did not see a statistically important difference in the number of primary follicles.

Moreover, the follicle seems to be more sensitive during the proliferative stage of the cycle and it seems that the reduction of the tissue concentration of oxygen and low temperature have a protective effect on the irradiated gonad. Another protective factor seems to be the thickening of chromatin. The importance of the dose of radiation is clear because a low dose can save many follicles and repair the damage induced in some of them.

Section snippets

Chemotherapy

Chemotherapy has an adverse effect on ovarian tissue. The damage will depend on the agent used, the dose, and the age of the patient (Fig. 1, Fig. 2, Fig. 3, Fig. 4). Younger patients tolerate higher doses and ovarian function starts again once the treatment is suspended, though the latent period before the reappearance of normal menstruation is widely variable.

Although the adverse effect of chemotherapy on ovarian function is well known, there is insufficient evidence from the literature on

Radiotherapy

Radiotherapy has an adverse affect on ovarian tissue (Fig. 5, Fig. 6, Fig. 7). The damage will depend on the dose, the irradiation field and the age of the patient.

Every patient has a different sensitivity to radiation damage, which is probably genetically pre-determinated; but in women the age factor is most important, as younger patients, because of the greater primordial follicle reserve, are more likely to preserve residual ovarian function.

Ovarian follicle radio sensitivity is higher

Condensation

Review of the experience of various authors on the effects of chemotherapy and radiotherapy on ovarian function.

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