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Ovarian failure due to anticancer drugs and radiation

Authors
Corrine K Welt, MD
Charles L Shapiro, MD
Section Editors
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD

INTRODUCTION

Several toxins can cause primary hypogonadism. Some are lifesaving therapies, such as anticancer drugs and radiation therapy. Others include cigarette smoke, chemicals, pesticides, viruses, and radioactivity. Anticancer drugs and radiation therapy are the most common of the known ovarian toxins, and will become an increasingly frequent cause of ovarian failure. It is estimated that up to 1 in 1000 persons under age 20 years will have been cured of cancer by these treatments by the year 2000, and many of them will have forgotten their treatment by the time they seek care for reproductive dysfunction. As an example, in a survey of 1928 adult survivors of childhood cancer, 14 percent denied having had cancer and 18 percent misclassified their treatment [1]. Ovarian failure due to anticancer drugs and radiation will be reviewed here. Other causes of premature ovarian failure, an overview of fertility in cancer survivors, and options for fertility preservation in patients undergoing gonadotoxic therapy are discussed elsewhere. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Overview of infertility and pregnancy outcome in cancer survivors" and "Fertility preservation in patients undergoing gonadotoxic treatment or gonadal resection".)

CHEMOTHERAPEUTIC DRUGS

Ovarian effects — Most anticancer drugs affect dividing cells and, therefore, would be expected to affect the granulosa and theca cells of the ovary more than the nondividing oocytes. However, the effect of these drugs on ovarian function varies widely, some having no effect and others causing permanent hypogonadism (table 1). Typically, the ovaries of women who received chemotherapy have normal to mildly decreased numbers of primordial follicles and a greater decrease in the numbers of larger maturing follicles [2,3], indicating a greater effect on follicular development than on oocytes.

Consistent with these histology findings are the clinical observations that many women, especially under 40 years of age, develop amenorrhea during chemotherapy, often with high serum gonadotropin concentrations, but menstrual function and, in some cases, fertility, may return several months to years after the cessation of therapy [4-6].

Individual agents — Alkylating drugs, such as cyclophosphamide, are the best documented and most potent at inducing ovarian failure. They alter base pairs, leading to DNA cross-links, and introduce single-strand DNA breaks [7]. As a result, they can theoretically affect both resting cells, such as oocytes, and dividing cells. The effects are age, dose, and drug-dependent. Younger women are affected less often than older women, presumably because they have more remaining oocytes. In one study, as an example, all women over age 40 years had amenorrhea after receiving more than 5.2 g of cyclophosphamide, whereas the dose required to cause amenorrhea in younger women was 9.5 g [8].

Variable susceptibility to ovarian dysfunction — However, there is considerable variation in susceptibility, with some women having normal ovarian function but others of the same age having permanent primary hypogonadism after high doses of a single drug. (See "Acute side effects of adjuvant chemotherapy for early stage breast cancer" and "Patterns of relapse and long-term complications of therapy in breast cancer survivors" and "General toxicity of cyclophosphamide in rheumatic diseases".)

              

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Literature review current through: Nov 2016. | This topic last updated: Tue Aug 25 00:00:00 GMT+00:00 2015.
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