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Late Effects



Ovarian Damage


Any cytotoxic therapy such as radiation therapy (RT) and chemotherapy can damage the ovaries and deplete the oocyte pool, causing:

  • Primary ovarian failure:
    • If pre-pubertal at the time of therapy this will lead to:
      • Impaired development of secondary sexual characteristics
      • Primary amenorrhea
    • If post-pubertal at the time of therapy:
      • Menstrual irregularities and secondary amenorrhea (absence of menstruation)
      • Infertility
      • Premature menopause and symptoms of estrogen deficiency
      • Early onset of significant osteoporosis
      • night sweats, hot flashes
      • vaginal dryness (atrophy)


RT induced ovarian damage

RT to the abdomen, pelvis, whole body radiotherapy (TBI) or craniospinal RT can significantly damage the ovaries.

Radiation causes:

  • Decrease in ovarian follicles
  • Impaired follicular maturation
  • Cortical fibrosis and atrophy
  • Generalized hypoplasia
  • Hyalinization of the capsule

Females treated before puberty (pre-pubertal) have a greater number of oocytes than after puberty (post-pubertal) females; therefore, girls treated in the prepubertal stage have a better change at retaining fertility.


Effect on fertility depends on:

  • Dose of RT received by ovaries:
    • The dose of RT needed to destroy 50% of the oocytes = LD50
    • Oocytes are very sensitive with an LD 50 of < 2 Gy4
  • Number of follicles present at the time of treatment (therefore the age of the patient at the time of therapy is important)
    • The number of primordial follicles at the time of treatment and the dose of RT will determine the “window of fertility” and the age at which menopause will occur
    • Mathematical models can be used to predict when menopause will occur
    • Teenagers are more at risk than younger children


Doses of 10-20 Gy will halt ovarian function at any age


Chemotherapy induced ovarian damage:

Table: Gonadotoxic chemotherapeutic agents in females

High risk

Moderate risk

Alkylating agents
    • Procarbazine
    • Cyclophosphamide
    • Ifosfamide
    • Nitrosoureas (CCNU, BCNU)
    • Melphalan
    • Busulphan

Platinum agents






Non-classical alkylators:

  • Dacarbazine
  • Temazolamide



The effect of chemotherapy on ovarian function is dependent on the agent and the dose.

The effects of chemotherapy are more pronounced in post-pubertal females.

Therapy with both RT and chemotherapy increases the risk of infertility.


The Childhood Cancer Survivor Study (CCSS) looked at the fertility rates of 5-year survivors (female) of childhood cancer and compared them with a cohort of randomly selected siblings using a survey5. There were 5,149 female CCSS participants.

  • The overall relative risk (RR) for survivors of ever being pregnant was 0.81
  • Patients were much less likely ever to have been pregnant if they received:
    • An ovarian/uterine RT dose greater than 5 Gy.
    • A summed alkylating agent dose (AAD) score of three or four.
    • Treated with lomustine or cyclophosphamide.

This large study demonstrated that fertility is decreased among female survivors of childhood cancer.

After TBI (low dose whole body RT) combined with alkylating chemotherapy prior to bone marrow transplant leads to infertility in at least 90% of patients.


Surgery induced ovarian damage:

Removal of both ovaries (bilateral oophorectomy) always leads to ovarian failure.

Removal of one ovary is associated with a risk of early menopause.




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