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Reproductive Issues for Cancer Patients/Survivors

Children's Hospital-Boston, Brigham and Women's Hospital, Boston, MA

SUCCESSFUL OUTCOMES in the treatment of cancer result in long-term survival. One aspect of quality of life for cancer survivors is the preservation of reproductive endocrine function and fertility. As has the field of medical oncology, the field of reproductive medicine has rapidly expanded over the past 20 years. We now have a better understanding of reproductive function and increased options for interventions to achieve pregnancies. The specific effects of cancer therapy on reproductive function are not as well understood; increased and continued long-term outcomes research by oncologists and reproductive specialists will further advance our ability to improve long-term quality of life, including fertility.

In this issue of the Journal of Clinical Oncology, Brewer et al¹ present a study of the "Outcome and Reproductive Function after Chemotherapy for Ovarian Dysgerminoma." This study presents follow-up data on reproductive function in a population of young women treated with therapy aimed at preserving ovarian function. This information is most helpful as we aim to counsel our patients newly diagnosed with cancer and provide options for reproductive function for long-term survivors.

When analyzing data regarding reproductive function following chemotherapy and/or radiation therapy, it is important to define and standardize the outcomes measures to be addressed. It is essential to differentiate between sex steroid production and fertility or reproductive function. The ovary functions to make hormones and oocytes; the fact that hormones are produced is not necessarily predictive that the patient will make an oocyte that is fertilizable. Thus, when evaluating studies that look at reproductive function, we need to evaluate end points that are specific to ovarian function. Cancer survivors treated with chemotherapy and/or radiation can have a complete spectrum of menstrual disorders and ovarian function ranging from normal to premature ovarian failure. If she is amenorrheic, then this may result from premature ovarian failure, gonadal dysgenesis, or hypothalamic amenorrhea. If she is having irregular periods, then she is most likely having hormonal production with or without normal ovulation. If she is having regular periods, then she is most likely having cyclic hormonal production with ovulation. All of these hormonal situations can be evaluated with gonadotropin (luteinizing hormone, follicle-stimulating hormone) and sex steroid (estradiol, progesterone) testing. However, there is no test for fertility except for a resulting pregnancy proving that fertility exists.

As the average age of menopause is approximately 52 years in the United States, there are many women in their late 40s and early 50s who are still having regular periods with normal levels of gonadotropins and sex steroids. These women are having regular ovarian function from a sex steroid standpoint, but they rarely produce an oocyte that is fertilizable. During this perimenopausal time period, the ovary is still functional (producing sex steroids), but the woman is not fertile. This is an important concept for cancer patients/survivors and their health care providers. Many cancer survivors and their health care providers assume that because menstrual bleeding is occurring there is normal ovarian function. This can be misleading. In addition, if there is normal menstrual function on oral contraceptive pills (or other exogenous hormones), no comment can be made about the state of ovarian function. These are also important concepts for us as we evaluate the medical literature and try to counsel cancer patients/survivors regarding fertility options after specific cancer treatment.

Studies have shown that the effects of chemotherapy and radiation therapy are both dose dependent and sensitive to the age at the time of exposure. It is thus more likely that a younger woman (younger than 30 years of age) exposed to cytotoxic agents will have a "better" chance of maintaining reproductive function than someone receiving the same drugs and dosages who is over the age of 30.^2-5 It is important to remember that fertility rates decrease in the general population at age 40 and that female survivors of childhood malignancies have been found to undergo premature ovarian failure at an advanced rate compared with their nontreated sisters.⁶ It is thus important to counsel long-term cancer survivors that, even if they have regular menses and ovulatory function, they may undergo a premature menopause. Cancer patients/survivors need to be aware of this increased risk of premature ovarian failure as they plan the timing of their careers and families.

When counseling a woman about reproductive function and fertility in cases of dysgerminoma, it is important to know the baseline endocrine and chromosomal state because there are associations with pure gonadal dysgenesis, androgen insensitivity (testicular feminization), and hermaphroditism.^7-11 In cases of gonadal dysgenesis, the patient may have a 46,XY karyotype (as reported in at least two of the patients in Brewer et al's study). Individuals with dysgenetic gonads are at risk for gonadoblastoma and dysgerminoma and thus should have both gonads removed, even if only one is involved with dysgerminoma, because the other is usually a streak and nonfunctional. Patients with dysgenetic gonads may not make Müllerian inhibiting substance and will thus have a uterus that functions normally. These women are excellent candidates for the later use of donor oocytes because their uterus will function normally for gestation.

With impaired or absent ovarian function, the adolescent may experience no secondary sexual development or may have some development and subsequently present with primary or secondary amenorrhea. Replacement therapy with estrogen and progestin can result in normal secondary sexual development.¹²

For those cancer survivors who retain their fertility after treatment, the complications of pregnancy, spontaneous abortions, or congenital abnormalities are not believed to be increased compared with pregnancies in the general population. The results of reports that have addressed pregnancy outcome and health in offspring of survivors of childhood cancer are encouraging.^13-19

The options of fertility interventions for cancer survivors with gonadal dysfunction include controlled ovarian hyperstimulation, intrauterine inseminations, assisted reproductive technologies, embryo cryopreservation, and ovum donation. These advances in fertility therapies have greatly increased options for cancer survivors, although little actual data are available as to patient and health care worker knowledge or utilization of these options. In addition, the specific success rates of the assisted reproductive technologies in the cancer survivor population are not known. Some data from the use of assisted reproductive techniques, such as ovulation induction, ovum donation, and in vitro fertilization, for cancer survivors with infertility are available,^20-25 but additional data need to be generated and evaluated.

With the increasingly successful treatment of cancers, women have been confronted with the issues of survivorship. Evaluation of long-term follow-up data of specific cancer therapies helps to progress the field of oncology for the selection of treatment regimens that save lives and improve quality of life, including reproductive endocrine function and fertility.

REFERENCES

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