Key messages
• In women with breast cancer, temporarily stopping the function of the ovaries by using hormone therapy might result in a reduction in ovarian insufficiency caused by chemotherapy. This means that the treatment may keep the ovaries working properly, but our certainty in this evidence is low.
• We cannot reach conclusions on what method to use to preserve fertility (the ability to get pregnant) in premenopausal women with breast cancer treated with chemotherapy.
• More research on this topic is needed.
What is fertility preservation, and why is it important?
Women with cancer are often treated with chemotherapy. Chemotherapy can harm the ovaries, reducing fertility or causing infertility. For women with cancer, preserving fertility (their ability to get pregnant) is important for their future family plans. Two methods are commonly used.
1. Stimulating the ovaries and using medication to protect them, followed by freezing eggs or embryos for later use (controlled ovarian hyperstimulation with gonadotropins and a protective agent)
2. Temporarily stopping the ovaries from working by using hormone therapy (ovarian suppression using gonadotropin-releasing hormone agonists (GnRH agonists)).
What did we want to find out?
We wanted to find out the effects of the two main methods used for preserving fertility in women with cancer, including whether they were associated with any unwanted effects. As breast cancer is the most common cancer in women worldwide, it is the primary focus of this review.
What did we do?
We searched for studies that looked at premenopausal women (women with a regular period) with cancer being treated with chemotherapy.
We investigated studies for three different comparisons.
Comparison 1: stimulating the ovaries and using medication to protect them and then freezing eggs or embryos for later use versus placebo, usual care, no treatment or another protective agent
Comparison 2: temporarily stopping the ovaries from working by using hormone therapy versus placebo, usual care, no treatment or another hormone therapy
Comparison 3: stimulating the ovaries and using medication to protect them and then freezing eggs or embryos for later use versus temporarily stopping the ovaries from working by using hormone therapy
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 23 studies; two studies for comparison 1 and 23 studies for comparison 2. We found no studies for comparison 3.
The studies involved 2647 premenopausal women with cancer treated with chemotherapy; 2366 of the women had breast cancer and 311 of the women had other cancers.
Comparison 1
We are very uncertain about the effect of stimulating the ovaries and using medication to protect them on the number of oocytes retrieved in breast cancer patients. Two studies compared two different protective medications (letrozole versus tamoxifen) and found that there is probably no difference between them in terms of the number of eggs obtained.
We found no evidence about the effects of stimulating the ovaries and using medication to protect them on our other outcomes of interest (e.g. ovary failure, live births, survival and adverse events).
Comparison 2
In women with breast cancer, temporarily stopping the function of the ovaries using hormone therapy may result in a large reduction in ovarian insufficiency. This means that the treatment may keep the ovaries working properly.
Temporarily stopping ovary function using hormone therapy for may make little to no difference to disease-free (without signs or symptoms of breast cancer) survival or overall survival over 10 years in women with breast cancer. The effect on the rate of live births to women with breast cancer is very uncertain.
We are also very uncertain about the effect of temporarily stopping ovary function using hormone therapy on pregnancy-related adverse events, including induced abortion, miscarriage, preterm delivery, delivery complications and elective termination.
Both chemotherapy-related adverse events (e.g. fatigue, nausea, leukopenia (increased risk of infection due to low white blood cell count) and non-pregnancy-related adverse events (e.g. sweating, hot flush, headache) were experienced by women in the studies. Temporarily stopping ovary function by using hormone therapy likely increased non-pregnancy-related adverse events.
Comparison 3
We found no evidence for this comparison.
Women with cancers other than breast cancer
For women with other cancers, it is not possible to draw any conclusions because we have very low certainty about the evidence.
What are the limitations of the evidence?
For comparison 1, we have moderate to little confidence in the evidence because there were not enough studies and the studies were very small.
For comparison 2, we are not at all confident in the evidence for women with breast cancer because the studies were very small and there were only a few cases of pregnancy and live birth. In addition, some studies did not provide information about everything that we were interested in, and some studies stopped earlier than planned.
How up to date is this evidence?
The evidence is up to date to November 2023.
Read the full abstract
Anti-cancer drugs can be toxic to healthy cells in the body and have the potential to cause irreversible damage to ovarian tissue. This may lead to premature ovarian insufficiency. There are two main strategies to preserve fertility in women undergoing chemotherapy treatment for cancer. One is controlled ovarian hyperstimulation with gonadotropins and a protective agent for safety, followed by freezing of oocytes or embryos; the other is ovarian suppression using gonadotropin-releasing hormone agonists (GnRH agonists).
This review aims to gain an understanding of the best way to support women with cancer to preserve their fertility. As breast cancer is the most common cancer in women worldwide, it is the primary focus of this review.
Objectives
To determine the effectiveness and safety of the two main fertility preservation strategies used in premenopausal women with cancer undergoing chemotherapy. One strategy is controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos, and the other is ovarian suppression using GnRH agonists.
Search strategy
We searched the Cochrane Gynaecology and Fertility (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO on 27 November 2023. To identify additional studies, we also checked reference lists and contacted study authors and experts in the field.
Selection criteria
We included randomised controlled trials (RCTs) that evaluated protective agents used in combination with controlled ovarian hyperstimulation with gonadotropins and followed by freezing of oocytes or embryos, and RCTs that evaluated the use of GnRH agonists to suppress the ovaries. The comparator could be placebo, usual care, no treatment or another agent in the same group (e.g. ovarian suppression using goserelin versus using leuprolide acetate). We also looked for studies that compared the two main fertility preservation methods against each other.
Data collection and analysis
We used the standard methodological procedures recommended by Cochrane. The primary review outcomes were ovarian insufficiency, live birth and overall survival. We had a number of secondary outcomes, including non-pregnancy-related adverse events.
Main results
We included 23 RCTs (2647 women analysed). We judged the certainty of the evidence to be very low to moderate. The main limitations in the evidence were serious risk of bias in multiple domains for several studies, publication bias due to early termination of three studies and very serious imprecision.
Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients
There was no evidence available for our primary outcomes: ovarian insufficiency, live birth and overall survival. Nor was there any evidence for disease-free survival, pregnancy-related adverse events or non-pregnancy-related adverse events.
Compared to standard controlled ovarian hyperstimulation, the evidence is very uncertain about the effect of controlled ovarian hyperstimulation with gonadotropins plus a protective agent on the number of oocytes retrieved (letrozole: mean difference (MD) 0.70 (95% confidence interval (CI) −2.60 to 4.00; 1 study, 108 women); tamoxifen: MD 0.70 (95% CI −3.05 to 4.45; 1 study, 109 women) (both very low-certainty evidence). There is probably little to no difference between the use of letrozole or tamoxifen as the protective agent added to controlled ovarian hyperstimulation with gonadotropins (MD −0.04, −2.72 to 2.64; 2 studies, 203 women; I² = 0%; moderate-certainty evidence).
Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients
Ovarian suppression using GnRH agonists may result in a large reduction in ovarian insufficiency (relative risk (RR) 0.43, CI 0.31 to 0.59; P < 0.001; 5 studies, 811 women; I² = 0%; low-certainty evidence).
The evidence is very uncertain about the effect of ovarian suppression using GnRH agonists on live birth (RR 1.60, CI 0.89 to 2.87; P = 0.12; 3 studies, 599 women; I² = 0%; very low-certainty evidence). Ovarian suppression using GnRH agonists may have little to no effect on overall survival over 10 years (hazard ratio (HR) 1.17, CI 0.67 to 2.04; P = 0.58; 1 study, 281 women) and disease-free survival over 10 years (HR 1.16, CI 0.76 to 1.77; P = 0.5; 1 study; 281 women), but the evidence is of low certainty.
Only evidence that we judged to have very low certainty was available for pregnancy-related adverse events (4 studies, 648 women), including induced abortion, miscarriage, preterm delivery, delivery complications and elective termination.
Moderate-certainty evidence was available for non-pregnancy-related adverse events (4 studies; 744 women), which showed that study participants in both groups experienced chemotherapy-related adverse events (e.g. fatigue, nausea, leukopenia) and non-pregnancy-related adverse events (e.g. sweating, hot flushes, headache); however, ovarian suppression might increase the likelihood of non-pregnancy-related adverse events.
Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos versus ovarian suppression using GnRH agonists
No evidence was available for this comparison.
Women with cancers other than breast cancer
For women with other cancers, the evidence is inconclusive and of very low certainty, and it is not possible to draw conclusions and implications for practice.
Authors' conclusions
In women with breast cancer being treated with chemotherapy, the evidence is very uncertain about controlled ovarian hyperstimulation using gonadotropins plus a protective agent (letrozole or tamoxifen) compared to controlled ovarian hyperstimulation with gonadotropins in terms of the number of oocytes obtained. When comparing letrozole versus tamoxifen used as the protective agent, there is probably little to no difference in the number of oocytes retrieved.
There is no evidence available for the long-term implications of controlled ovarian hyperstimulation protocols, such as their effects on live births or overall survival of women with breast cancer.
In women with breast cancer, ovarian suppression using GnRH agonists may result in a large reduction in ovarian insufficiency caused by chemotherapy, but the certainty of the evidence is low. Evidence for other outcomes is of low or very low certainty.
We are not able to reach any conclusions concerning the choice of controlled ovarian hyperstimulation versus ovarian suppression because there are no data available comparing these fertility preservation interventions.
