COSA:AYA cancer fertility preservation/Impact of cancer treatments on fertility/Female reproductive and hormonal functions

From Cancer Guidelines Wiki
Fertility preservation for AYAs diagnosed with cancer: Guidance for health professionals. > 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 [1]

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 [2][3]
  • the type of drug/s used (especially the use of alkylating agents)
  • dose
  • duration
  • 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.[4]
  • Cranial radiation may affect pituitary hormone production and release, impairing pubertal development and long-term reproductive function.[5] However the hormonal deficiency can usually be replaced by exogenous hormone administration to restore function.
  • Total body irradiation may result in ovarian failure.

Back to top


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.[6] (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) [7]


40 – 60% if escalated therapy

non-Hodgkin lymphoma 10 – 40%
Leukaemia < 10%
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.

Back to top

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).[6] 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.[8]
  • Toxicity of chemotherapy and radiation on female reproduction.[9]
  • Fertility after allogeneic haematopoietic stem cell transplantation in childhood and adolescence.[10]
  • Breast cancer in young women and its impact on reproductive function.[11]
  • Ovarian function, reproduction and strategies for fertility preservation after breast cancer.[12]


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) [10] 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) [13]: 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) [14], CHOP(q21), COP (in women aged 30-35) Hodgkin lymphoma, NHL
Anthracycline + cytarabine AML
Multiagent therapies ALL
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
Oxaliplatin Ovarian cancer
Irinotecan Colon cancer
Bevacizumab Colon, non–small-cell lung cancer
Cetuximab Colon, head and neck cancer
Trastuzumab Breast cancer
Erlotinib Non–small-cell lung, pancreatic cancer
Imatinib Chronic myeloid leukemia, GI stromal tumor

Source: Levine J, Canada A, Stern CJ. Fertility preservation in adolescents and young adults with cancer J Clin Oncol 2010 Nov 10;28(32):4831-41 [Available at http://www.ncbi.nlm.nih.gov/pubmed/20458029].

Back to top

References

  1. Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006 Jun 20;24(18):2917-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16651642.
  2. Sklar CA, Mertens AC, Mitby P, Whitton J, Stovall M, Kasper C, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 2006 Jul 5;98(13):890-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16818852.
  3. Petrek JA, Naughton MJ, Case LD, Paskett ED, Naftalis EZ, Singletary SE, et al. Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study. J Clin Oncol 2006 Mar 1;24(7):1045-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16476708.
  4. Royal College of Physicians, The Royal College of Radiologists, Royal College of Obstetricians and Gynaecologists. The effects of cancer treatment on reproductive functions: Guidance on management. Report of a Working Party. 2007;London: RCP; Accessed March 2011. Abstract available at http://www.rcog.org.uk/resources/public/pdf/EffectCancerRepro.pdf.
  5. Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate G, Sutton ML. Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med 1989 Feb;70(262):145-60 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2594955.
  6. 6.0 6.1 Levine J, Canada A, Stern CJ. Fertility preservation in adolescents and young adults with cancer. J Clin Oncol 2010 Nov 10;28(32):4831-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20458029.
  7. De Bruin ML, Huisbrink J, Hauptmann M, Kuenen MA, Ouwens GM, van't Veer MB, et al. Treatment-related risk factors for premature menopause following Hodgkin lymphoma. Blood 2008 Jan 1;111(1):101-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17890454.
  8. Stroud JS, Mutch D, Rader J, Powell M, Thaker PH, Grigsby PW. Effects of cancer treatment on ovarian function. Fertil Steril 2009 Aug;92(2):417-27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18774559.
  9. Meirow D, Biederman H, Anderson RA, Wallace WH. Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol 2010 Dec;53(4):727-39 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21048440.
  10. 10.0 10.1 Borgmann-Staudt A, Rendtorff R, Reinmuth S, Hohmann C, Keil T, Schuster FR, et al. Fertility after allogeneic haematopoietic stem cell transplantation in childhood and adolescence. Bone Marrow Transplant 2011 Apr 11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21478918.
  11. Hickey M, Peate M, Saunders CM, Friedlander M. Breast cancer in young women and its impact on reproductive function. Hum Reprod Update 2009;15(3):323-39 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19174449.
  12. Tomao F, Spinelli GP, Panici PB, Frati L, Tomao S. Ovarian function, reproduction and strategies for fertility preservation after breast cancer. Crit Rev Oncol Hematol 2010 Oct;76(1):1-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20185328.
  13. Behringer K, Breuer K, Reineke T, May M, Nogova L, Klimm B, et al. Secondary amenorrhea after Hodgkin's lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin's Lymphoma Study Group. J Clin Oncol 2005 Oct 20;23(30):7555-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16234521.
  14. Leader A, Lishner M, Michaeli J, Revel A. Fertility considerations and preservation in haemato-oncology patients undergoing treatment. Br J Haematol 2011 May;153(3):291-308 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21391973.

Back to top