COSA:AYA cancer fertility preservation/Impact of cancer treatments on fertility/Female reproductive and hormonal functions
Impact of cancer treatments on female reproductive and hormonal functions
In females future reproductive function can be compromised by any treatment that:
- decreases the number of primordial follicles
- interferes with the functioning of the ovaries, fallopian tubes, uterus or cervix
- changes the anatomic or vascular function of the uterus, cervix or vagina 
The therapies posing the greatest threat to ovarian function are alkylating agents and pelvic irradiation.
Effects of chemotherapy
Many alkylating agents (in particular cyclophosphamide and procarbazine) cause follicular atresia and destruction of the follicular pool, leading to premature menopause and infertility.
Chemotherapy may result in:
- acute/temporary ovarian failure
- permanent ovarian failure
- return or persistence of normal menses but subsequent development of premature ovarian failure much earlier than would be otherwise expected
- fragile or poor ovarian function despite normal menses.
The impact of chemotherapy treatment on an individual’s ovarian function is related to:
- the patient’s age at the time of diagnosis. This is the most critical factor, as the number of oocytes declines with advancing age, therefore the ovaries of older women are more vulnerable to gonadal toxins 
- the type of drug/s used (especially the use of alkylating agents)
- frequency of administration (cyclic/pulse or chronic daily use).
Effects of radiation therapy
- Radiation to the ovaries damages both the germ cell and endocrine components of ovarian tissue. It may cause immediate permanent sterility, temporary amenorrhea or lead to premature menopause. The risk of infertility increases with age and concurrent use of chemotherapy.
- Whole abdominal or pelvic radiation can cause serious damage to the uterus, particularly the endometrium and the myometrium, increasing the risk of vascular insufficiency. Irradiation doses of 20-30 Gy to the uterus increase the risk of miscarriage.
- Cranial radiation may affect pituitary hormone production and release, impairing pubertal development and long-term reproductive function. However the hormonal deficiency can usually be replaced by exogenous hormone administration to restore function.
- Total body irradiation may result in ovarian failure.
Table 1 illustrates the range of risks associated with chemotherapy and radiotherapy treatment of the most common cancers in adolescents and young adults.
Table 2 summarises the effects of common cancer treatment regimens on development of amenorrhea.
Estimating the risk of ovarian damage from chemotherapy for patients with different types of cancers is hampered by several factors, including the lack of long–term follow up of ovarian function in survivors, poor discrimination between the more acute, temporary ovarian failure and more long-term, permanent ovarian failure and the common use of menstrual history as a measure of ovarian function, rather than more objective and reliable measures. (See Long term follow up for more information about measures of ovarian function).
Table 1: Representative rates of ovarian failure after treatment of common childhood and young adult cancers *
|Disease||Likelihood of premature ovarian failure|
|Breast cancer (treated with chemotherapy)|
|Age <30 years||< 10%|
|Age 30–40 years||20 – 40%|
|Sarcoma||< 10 – 40%|
|Hodgkin lymphoma||≥ 5% unless intensive therapy (However the risk of later onset of premature ovarian failure is 19%; average 9 years after treatment, onset of permanent ovarian failure at mean age 33.5 years) 
|non-Hodgkin lymphoma||10 – 40%|
|High-dose therapy and stem-cell transplantation||> 70 – 90%|
Modified from Stern CJ, Toledo MG, Good DA, Seymour JF. Fertility preservation in female oncology patients. Aust NZ J Obstet Gynaecol 2006; 46(1): 15-23. http://www.ncbi.nlm.nih.gov/pubmed/16441687
* This table presents representative rates of ovarian failure after treatment (average >2 years after treatment), but does not consider any additional established risk of later premature ovarian failure.
Table 2: Effect of cancer treatment on development of amenorrhea
This table is an updated and amended version of the table by Levine et al (2010). Given the complexities of different regimens and scarcity of data, it presents only a summary of the effects of common cancer treatment regimens. If you need more comprehensive information, we recommend these recent reviews:
- Effects of cancer treatment on ovarian function.
- Toxicity of chemotherapy and radiation on female reproduction.
- Fertility after allogeneic haematopoietic stem cell transplantation in childhood and adolescence.
- Breast cancer in young women and its impact on reproductive function.
- Ovarian function, reproduction and strategies for fertility preservation after breast cancer.
|Degree of Risk||Treatment Protocol||Common Usage|
|High risk: > 80% of women develop amenorrhea after treatment||Whole abdominal or pelvic radiation doses ≥ 6 Gy in adult women||Multiple cancers|
|Whole abdominal or pelvic radiation doses; ≥ 15 Gy in prepubertal girls and ≥ 10 Gy in postpubertal girls||Wilms tumor, neuroblastoma, sarcoma, Hodgkin lymphoma|
|Total body irradiation (TBI) radiation doses (83% risk) ||Bone marrow transplantation, Stem cell transplantation (BMT/SCT)|
|CMF, CEF, or CAF × 6 cycles in women age 40+||Breast cancer|
|Cyclophosphamide 5 g/m2 in women age 40+||Multiple cancers|
|Cyclophosphamide 7.5 g/m2in females age < 20||NHL, neuroblastoma, ALL, sarcoma|
|Alkylating chemotherapy (eg, cyclophosphamide, busulfan, melphalan) conditioning for transplantation||BMT/SCT|
|Any alkylating agent (eg, cyclophosphamide, ifosfamide, busulfan, BCNU, CCNU) + TBI or pelvic radiation||BMT/SCT, ovarian cancer, sarcoma, neuroblastoma, Hodgkin lymphoma|
|Protocols containing procarbazine (51% risk) : MOPP, MVPP, COPP, ChIVPP, ChIVPP/EVA, MOPP/ABVD, COPP/ABVD||Hodgkin lymphoma|
|Cranial/brain radiation ≥ 40 Gy||Brain tumour|
|Intermediate risk: approximately 30%-70% of women develop amenorrhea after treatment||CMF, CEF, or CAF × 6 cycles in women age 30-39||Breast cancer|
|AC in women age 40+||Breast cancer|
|BEACOPP protocol||Hodgkin lymphoma|
|Whole abdominal or pelvic radiation 10 to < 15 Gy in prepubertal girls||Wilms tumour, neuroblastoma|
|Whole abdominal or pelvic radiation 5 to 10 Gy in postpubertal girls, spinal radiation ≥ 25 Gy||Spinal tumour, brain tumour, neuroblastoma, relapsed ALL or NHL|
|Low risk: < 20% of women develop amenorrhea||AC in women age 30-39||Breast cancer|
|CMF, CEF, or CAF × 6 cycles in women age < 30||Breast cancer|
|Lower dose alkylating chemotherapy: ABVD (5% risk) , CHOP(q21), COP (in women aged 30-35)||Hodgkin lymphoma, NHL|
|Anthracycline + cytarabine||AML|
|Very low/no risk: negligible effect on menses||Methotrexate + fluorouracil||Breast cancer|
|Vincristine (used in multiagent therapies)||Leukaemia, Hodgkin lymphoma, NHL, neuroblastoma, rhabdomyosarcoma, Wilms tumour, Kaposi's sarcoma|
|Radioactive iodine||Thyroid cancer|
|Unknown risk||Paclitaxel, docetaxel (taxanes used in AC protocols)||Breast cancer|
|Bevacizumab||Colon, non–small-cell lung cancer|
|Cetuximab||Colon, head and neck cancer|
|Erlotinib||Non–small-cell lung, pancreatic cancer|
|Imatinib||Chronic myeloid leukemia, GI stromal tumor|
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