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Fertility preservation for people with cancer

Ovarian function

Clinical Question

Is the ovarian function of women and girls who received cancer treatment reduced in comparison to women and girls in the general population?

It is generally accepted that some chemotherapeutic agents and radiotherapy treatment have a gonadotoxic effect, including a reduction in ovarian reserve which can impact fertility and long-term bone, cardiovascular and cognitive health.[1] Ovarian reserve is an indirect measure of the primordial follicle pool within the ovary, and an indicative marker of the temporal risk of an early menopause. Ovarian reserve is assessed by the serum marker anti-mullerian hormone (AMH) which is routinely used in fertility practice. Ovarian reserve can also be assessed by measuring the small, antral follicles within the ovary, or less commonly by the ovarian volume or surface area[2] in post pubertal patients.

The strongest evidence of the impact of cancer treatment on ovarian function comes from prospective cohort studies. Studies that are part of the "Ovarian Reserve After Cancer: Longitudinal Effects (ORACLE)" (NCT02467231) study, reported young patients with cancer experienced more symptoms of menopause after treatment compared to similar age-matched controls.[3] Another cohort study also found that reproductive-aged women with a history of cancer were more likely to experience menopausal symptoms such as vaginal dryness than their similar-aged peers.[4]

The ORACLE study also found that decreased AMH levels were associated with an increase in menopausal symptoms in women [3], however the rate of change of AMH after cancer treatment was not significantly different than similar-aged controls.[5] Late reproductive-aged patients with breast cancer also had significantly lower AMH compared with age-matched controls, particularly in menstruating patients who subsequently developed chemotherapy-related amenorrhea.[6] Newer AMH assays are available that are a highly sensitive measure of ovarian activity and may better predict future menses or amenorrhoea.[7][8]

The fact that women are more likely to have reduced ovarian reserve after cancer treatment is sufficient evidence to prompt the discussion of the impact of cancer treatment on fertility with all women diagnosed with cancer. It is important to state that ovarian reserve (as measured by serum AMH) is not a predictor of oocyte quality or the chance of conception, it is purely a measure of the pool of remaining follicles.

In the interpretation of the serum AMH concentration, it should be conveyed to the patient that a ‘high’ or ‘low’ concentration is not a predictor of the chance of having a healthy baby. Should IVF be required, a ‘higher’ concentration of serum AMH is more predictive of a better response to ovarian stimulation, than a woman with a ‘low’ serum AMH.[9] Additionally, AMH in the immediate post chemotherapy phase, and in patients on treatments such as GnRHa may be difficult to asses. Therefore follow up for ovarian reserve should be delayed for at least 6-12 months.

Evidence Summary

Evidence summaryLevelReferences
Women who receive cancer treatment may be more likely to have reduced ovarian reserve, compared to those who have not undergone cancer treatment.II[3], [5], [4], [6]

Recommendation

Evidence-based recommendationGrade
Health professionals should advise patients prior to cancer treatment of the risk of a reduction in their ovarian reserve after treatment. Patients of any age with a risk of infertility (or their families in the case of children) should be given the opportunity to discuss fertility preservation before cancer treatment.A

References

  1. Hart R. Preservation of fertility in adults and children diagnosed with cancer. BMJ 2008 Oct 27;337:a2045 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18955375.
  2. Podfigurna A, Lukaszuk K, Czyzyk A, Kunicki M, Maciejewska-Jeske M, Jakiel G, et al. Testing ovarian reserve in pre-menopausal women: why, whom and how? Maturitas 2018 Mar;109:112-117 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29292013.
  3. Cameron KE, Kole MB, Sammel MD, Ginsberg JP, Gosiengfiao Y, Mersereau JE, et al. Acute Menopausal Symptoms in Young Cancer Survivors Immediately following Chemotherapy. Oncology 2018;94(4):200-206 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29393227.
  4. Chemerinski A, Cameron K, Sammel M, Ginsberg J, Carlson C, Gracia C. Relationship of menopausal symptoms and ovarian reserve in reproductive-aged cancer survivors. J Cancer Surviv 2020 Apr 22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/32323140.
  5. Cameron K, Sammel MD, Prewitt M, Gracia C. Differential Rates of Change in Measures of Ovarian Reserve in Young Cancer Survivors Across the Reproductive Lifespan. J Clin Endocrinol Metab 2019 May 1;104(5):1813-1822 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30566616.
  6. Su HI, Sammel MD, Green J, Velders L, Stankiewicz C, Matro J, et al. Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer 2010 Feb 1;116(3):592-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19918920.
  7. Anderson RA, Mansi J, Coleman RE, Adamson DJA, Leonard RCF. The utility of anti-Müllerian hormone in the diagnosis and prediction of loss of ovarian function following chemotherapy for early breast cancer. Eur J Cancer 2017 Dec;87:58-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29117576.
  8. Chai J, Howie AF, Cameron DA, Anderson RA. A highly-sensitive anti-Müllerian hormone assay improves analysis of ovarian function following chemotherapy for early breast cancer. Eur J Cancer 2014 Sep;50(14):2367-74 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25027307.
  9. Fleming R, Seifer DB, Frattarelli JL, Ruman J. Assessing ovarian response: antral follicle count versus anti-Müllerian hormone. Reprod Biomed Online 2015 Oct;31(4):486-96 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26283017.

Body of evidence

Is the ovarian function of female cancer survivors who had cancer treatment, more adversely affected than females in the general population, as measured by markers of their ovarian reserve after treatment?

CitationLevel of EvidenceQuality of EvidenceSize of EffectNumber of PatientsRelevance of Evidence
Cameron K, Sammel MD, Prewitt M, Gracia C. Differential Rates of Change in Measures of Ovarian Reserve in Young Cancer Survivors Across the Reproductive Lifespan. J Clin Endocrinol Metab 2019 May 1;104(5):1813-1822 Available from:http://www.ncbi.nlm.nih.gov/pubmed/30566616IIMediumN/AN/AN/A
Cameron KE, Kole MB, Sammel MD, Ginsberg JP, Gosiengfiao Y, Mersereau JE, et al. Acute Menopausal Symptoms in Young Cancer Survivors Immediately following Chemotherapy. Oncology 2018;94(4):200-206 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29393227IIMediumN/A124N/A
Chemerinski A, Cameron K, Sammel M, Ginsberg J, Carlson C, Gracia C. Relationship of menopausal symptoms and ovarian reserve in reproductive-aged cancer survivors. J Cancer Surviv 2020 Apr 22 Available from:http://www.ncbi.nlm.nih.gov/pubmed/32323140IIMediumN/A170N/A
Gracia CR, Sammel MD, Freeman E, Prewitt M, Carlson C, Ray A, et al. Impact of cancer therapies on ovarian reserve. Fertil Steril 2012 Jan;97(1):134-40.e1 Available from:http://www.ncbi.nlm.nih.gov/pubmed/22137491IVMediumN/A120N/A
Larsen EC, Müller J, Schmiegelow K, Rechnitzer C, Andersen AN. Reduced ovarian function in long-term survivors of radiation- and chemotherapy-treated childhood cancer. J Clin Endocrinol Metab 2003 Nov;88(11):5307-14 Available from:http://www.ncbi.nlm.nih.gov/pubmed/14602766III-3MediumN/A100N/A
Lie Fong S, Laven JS, Hakvoort-Cammel FG, Schipper I, Visser JA, Themmen AP, et al. Assessment of ovarian reserve in adult childhood cancer survivors using anti-Müllerian hormone. Hum Reprod 2009 Apr;24(4):982-90 Available from:http://www.ncbi.nlm.nih.gov/pubmed/19153092III-3MediumN/A227N/A
Morarji K, McArdle O, Hui K, Gingras-Hill G, Ahmed S, Greenblatt EM, et al. Ovarian function after chemotherapy in young breast cancer survivors. Curr Oncol 2017 Dec;24(6):e494-e502 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29270058IVMediumN/A100N/A
Su HI, Sammel MD, Green J, Velders L, Stankiewicz C, Matro J, et al. Antimullerian hormone and inhibin B are hormone measures of ovarian function in late reproductive-aged breast cancer survivors. Cancer 2010 Feb 1;116(3):592-9 Available from:http://www.ncbi.nlm.nih.gov/pubmed/19918920IIMediumN/A127N/A
Thomas-Teinturier C, Allodji RS, Svetlova E, Frey MA, Oberlin O, Millischer AE, et al. Ovarian reserve after treatment with alkylating agents during childhood. Hum Reprod 2015 Jun;30(6):1437-46 Available from:http://www.ncbi.nlm.nih.gov/pubmed/25801499III-3LowN/A105N/A
van den Berg MH, Overbeek A, Lambalk CB, Kaspers GJL, Bresters D, van den Heuvel-Eibrink MM, et al. Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve. Hum Reprod 2018 Jul 6 Available from:http://www.ncbi.nlm.nih.gov/pubmed/29982673III-3LowN/A564N/A
Yu B, Douglas N, Ferin MJ, Nakhuda GS, Crew K, Lobo RA, et al. Changes in markers of ovarian reserve and endocrine function in young women with breast cancer undergoing adjuvant chemotherapy. Cancer 2010 May 1;116(9):2099-105 Available from:http://www.ncbi.nlm.nih.gov/pubmed/20187091IIMediumN/AN/AN/A
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Cancer Council Australia