Female Reproductive Health

The effects of children’s cancer therapy on female reproductive function depend on many factors, including the person’s age at the time of cancer therapy, the specific type and location of the cancer, and the treatment that was given. It is important to understand how the ovaries and female reproductive organs function and how they may be affected by therapy given to treat cancer during childhood.

At birth, a girl’s ovaries contain all the eggs they will ever have. When it is time for a girl to begin pubertal development, the pituitary gland in the brain signals the ovaries by releasing two hormones: FSH and LH. The ovaries secrete the female hormones, estrogen and progesterone, necessary for reproductive function. During each menstrual cycle, at least one egg usually matures and is released from the ovaries. If the egg is not fertilized, menstruation begins. The cycle then repeats itself about every 28 days. With each menstrual cycle, the supply of eggs decreases. When most of the eggs are depleted from a woman’s ovaries, menopause begins. During menopause, the menstrual cycles stop, the ovaries stop making hormones, and the woman is no longer able to become pregnant.

Effect of Cancer Therapy on Ovaries

Certain chemotherapy drugs, radiation therapy, and surgery can sometimes damage the ovaries, reducing the reserve supply of eggs. When the ovaries are not able to produce eggs or hormones, this is called ovarian failure.

Causes of Ovarian Failure

Chemotherapy of the “alkylator” type (such as cyclophosphamide, nitrogen mustard, and busulfan) is most likely to affect ovarian function. The total dose of alkylators used during cancer treatment is important in determining the likelihood of ovarian damage. With higher total doses, the likelihood of damage to the ovaries increases. If treatment for children’s cancer included a combination of both radiation and alkylating chemotherapy, the risk of ovarian failure may be increased.

Radiation therapy can affect ovarian function in two ways:

• Primary (direct) failure of the ovaries can be caused by radiation that is aimed directly at or near the ovaries. The age of the person at the time of radiation and the total radiation dose can affect whether or not ovarian failure occurs. Generally, younger girls tend to have less damage to the ovaries than people who received equal doses but who were teenagers or young adults at the time of radiation. However, doses of 10-20 Gy (1000 – 2000 cGy/rads) or higher usually cause the ovaries to stop functioning in most females regardless of age.
• Secondary (indirect) failure of the ovaries can occur as a result of radiation therapy to the brain. The pituitary gland, located in the center of the brain, regulates the production of two hormones (FSH and LH) needed for proper ovarian function. Radiation to the brain, especially at doses of 30 Gy (3000 cGy/rads) or higher can damage the pituitary gland, leading to low levels of these hormones.

Cancer Treatments that Increase the Risk of Ovarian Failure

Radiation therapy to any of the following areas:

• Abdomen (including para-aortic)
• Pelvis (including iliac/inguinal)
• Spine
• “Inverted Y” or total lymphoid radiation
• TBI (total body irradiation)
• Cranial radiation at doses of 30 Gy (3000 cGy/rads) or higher

Chemotherapy – the class of drugs called “alkylators” can cause ovarian failure when given in high doses. Examples of these drugs include:

• Cyclophosphamide (Cytoxan®)
• Ifosfamide
• Nitrogen mustard
• Procarbazine
• Melphalan
• Busulfan
• Chlorambucil
• Lomustine (CCNU)
• Carmustine (BCNU)
• Thiotepa
• Dacarbazine (DTIC®)
• Temozolamide
• Carboplatin
• Cisplatin

Effects of Children’s Cancer Treatment on the Female Reproductive

• Failure to enter puberty. Pre-pubertal girls who received cancer therapy that resulted in ovarian failure will need hormonal therapy (hormones prescribed by a doctor) in order to progress through puberty. It is important for young girls who had cancer treatment that can affect ovarian function to have their hormone levels checked before the expected onset of puberty. If a problem is detected, they should be referred to an endocrinologist (hormone doctor) for further evaluation and management.
• Temporary cessation of menstrual cycles. Many females who were already menstruating will stop having monthly periods during their cancer therapy. In most cases, menstrual cycles will resume sometime after cancer treatment ends, although the timing of this is unpredictable. In some cases, it may take up to several years to restart menstruation. Since eggs are released before the menstrual cycle, pregnancy can occur before the menstrual periods resume.
• Permanent cessation of menstrual cycles (premature menopause). Menopause (the permanent cessation of menstrual cycles) generally occurs in women between the ages of 45 and 55. Females who were already menstruating prior to their cancer therapy sometimes develop ovarian failure as a result of their cancer treatment and never resume menstrual cycles. Others may resume menstrual cycles, but then stop menstruating much earlier than would normally be expected. If a woman who received alkylating chemotherapy agents or abdominal radiation during her cancer treatment is currently having menstrual periods, she may still be at risk for entering menopause at an early age.
• Lack of female hormones. Females with ovarian failure do not make enough estrogen. Estrogen isn’t just needed for reproduction – it is also an important hormone necessary for maintaining strong healthy bones, a healthy heart, and overall well-being. Young women with ovarian failure should see an endocrinologist (hormone specialist) for hormone replacement therapy, which will be necessary until they reach middle age.
• Infertility. Infertility is the inability to achieve a pregnancy after at least one year of unprotected intercourse. In women, infertility occurs when the ovaries cannot produce eggs (ovarian failure), or when the reproductive organs are unable to sustain a pregnancy. Infertility may be the result of surgery, radiation therapy, chemotherapy, or any combination of these. There may also be other reasons for infertility that are unrelated to cancer therapy.
• If a woman has regular monthly menstrual periods and normal hormone levels (FSH, LH, and estradiol), she is likely to be fertile and able to have a baby.
• If a woman does NOT have monthly menstrual periods, or if she has monthly menstrual periods ONLY with the use of supplemental hormones, or if she had to take hormones in order to enter or progress through puberty, she is likely to be infertile.
• Women who had surgical removal of both ovaries will be infertile.
• Women who had surgical removal of the uterus (hysterectomy) will also be unable to bear a child.
• Pregnancy risks. Certain therapies used during treatment for childhood cancer can sometimes increase the risk of problems that a woman may experience during pregnancy, labor, and childbirth. The following women may be at increased risk:
• Women who had radiation to the abdomen (including para-aortic areas), pelvis (including iliac/inguinal areas), or total body (TBI) may have an increased risk of miscarriage, premature delivery, or problems during labor.
• Women who received anthracycline chemotherapy (such as doxorubicin or daunorubicin), and women who received radiation to the left side of the abdomen or to the chest may be at risk for heart problems that can worsen with pregnancy and labor.
• A small percentage of women who had a diagnosis of Wilms tumor may have an increased risk of problems with the uterus during pregnancy.

Women with these risk factors should be followed closely by an obstetrician who is qualified to care for women with high-risk pregnancies.

Females who have had any cancer treatments that may affect ovarian function should have a yearly check-up that includes careful evaluation of menstrual history, hormonal status, and progression through puberty. Blood may be tested for hormone levels (FSH, LH, and estradiol). If any problems are detected, a referral to an endocrinologist (hormone specialist) and/or other specialists may be recommended. For women with ovarian failure, a bone density test (special type of X-ray) to check for thinning of the bones (osteoporosis) may also be recommended.