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Adjuvant gonadotropin-releasing hormone analogues for the
prevention of chemotherapy-induced premature ovarian failure in
premenopausal women (Review)
Chen H, Xiao L, Li J, Cui L, Huang W
Chen H, Xiao L, Li J, Cui L, Huang W.

Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in
premenopausal women.
Cochrane Database of Systematic Reviews 2019, Issue 3. Art. No.: CD008018.
DOI: 10.1002/14651858.CD008018.pub3.
www.cochranelibrary.com

Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature
ovarian failure in premenopausal women (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.

Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 9
OBJECTIVES.................................................................................................................................................................................................. 10
METHODS..................................................................................................................................................................................................... 10
RESULTS........................................................................................................................................................................................................ 12
Figure 1.................................................................................................................................................................................................. 13
Figure 2.................................................................................................................................................................................................. 15
Figure 3.................................................................................................................................................................................................. 16
DISCUSSION.................................................................................................................................................................................................. 19
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 22
ACKNOWLEDGEMENTS................................................................................................................................................................................ 22
REFERENCES................................................................................................................................................................................................ 23
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 27
DATA AND ANALYSES.................................................................................................................................................................................... 48
Analysis 1.1. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 1: Menstruation recovery 50
or maintenance.....................................................................................................................................................................................
Analysis 1.2. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 2: Premature ovarian 51
failure (POF)...........................................................................................................................................................................................
Analysis 1.3. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 3: Pregnancy................... 51
Analysis 1.4. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 4: Ovulation.................... 51
Analysis 1.5. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 5: Antral follicle count...... 51
Analysis 1.6. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 6: FSH (mUI/L)................ 52
Analysis 1.7. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 7: FSH < 20 mIU/mL........ 52
Analysis 1.8. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 8: LH (mUI/L)................... 52
Analysis 1.9. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 9: LH < 20 mIU/L.............. 52
Analysis 1.10. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 10: AMH (pmol/L).......... 53
Analysis 1.11. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 11: Inhibin B.................. 53
Analysis 1.12. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 12: Estradiol.................. 53
Analysis 1.13. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 13: Estradiol > 20 pg/mL... 53
Analysis 1.14. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 14: Adverse effects: hot 54
flush........................................................................................................................................................................................................
Analysis 1.15. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 15: Adverse effect: 54
vaginal dryness.....................................................................................................................................................................................
urogenital symptoms............................................................................................................................................................................
sweating.................................................................................................................................................................................................
headache...............................................................................................................................................................................................
Analysis 1.19. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 19: Adverse effect: mood 55
swings....................................................................................................................................................................................................
fatigue....................................................................................................................................................................................................
Analysis 1.21. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 21: Adverse effect: joint 56
pain........................................................................................................................................................................................................
Analysis 1.22. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 22: Adverse effect: muscle 56
pain........................................................................................................................................................................................................
decrease in lipid....................................................................................................................................................................................
thromboembolism................................................................................................................................................................................
Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in i
Informed decisions.

agitation.................................................................................................................................................................................................
anxiety....................................................................................................................................................................................................
depression.............................................................................................................................................................................................
insomnia................................................................................................................................................................................................
Analysis 2.1. Comparison 2: Agonist-antagonist cotreatment plus chemotherapy versus chemotherapy alone, Outcome 1: 58
Menstruation recovery or maintenance..............................................................................................................................................
Analysis 2.2. Comparison 2: Agonist-antagonist cotreatment plus chemotherapy versus chemotherapy alone, Outcome 2: 58
Pregnancy..............................................................................................................................................................................................
ADDITIONAL TABLES.................................................................................................................................................................................... 58
APPENDICES................................................................................................................................................................................................. 59
WHAT'S NEW................................................................................................................................................................................................. 62
HISTORY........................................................................................................................................................................................................ 62
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 63
DECLARATIONS OF INTEREST..................................................................................................................................................................... 63
SOURCES OF SUPPORT............................................................................................................................................................................... 63
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 63
INDEX TERMS............................................................................................................................................................................................... 63
Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in ii
Informed decisions.

[Intervention Review]
Adjuvant gonadotropin-releasing hormone analogues for the prevention

of chemotherapy-induced premature ovarian failure in premenopausal
women
Hengxi Chen1,2, Li Xiao1, Jinke Li1,2, Ling Cui3, Wei Huang1,2
1Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China. 2Key
Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, China. 3Department of
Gynaecological Oncology, Sichuan Cancer Hospital & Institute, Chengdu, China
Contact: Wei Huang, weihuang64@163.com.
Editorial group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group.

Publication status and date: Stable (no update expected for reasons given in 'What's new'), published in Issue 8, 2021.
Citation: Chen H, Xiao L, Li J, Cui L, Huang W. Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-
induced premature ovarian failure in premenopausal women. Cochrane Database of Systematic Reviews 2019, Issue 3. Art. No.:
CD008018. DOI: 10.1002/14651858.CD008018.pub3.
ABSTRACT
Background
This is an update of the original review published in the Cochrane Database of Systematic Reviews 2011, Issue 11, and updated in 2015,
Issue 4.
Chemotherapy has significantly improved prognosis for women with malignant and some non-malignant conditions. This treatment,
however, is associated with ovarian toxicity. The use of gonadotropin-releasing hormone (GnRH) analogues, both agonists and antagonists,
may have a protective effect on the ovaries. The primary mechanism of action of GnRH analogues is to suppress the gonadotropin levels to
simulate pre-pubertal hormonal milieu and subsequently prevent primordial follicles from maturation and therefore decrease the number
of follicles that are more vulnerable to chemotherapy.
Objectives
To assess the efficacy and safety of GnRH analogues given before or in parallel to chemotherapy to prevent chemotherapy-related ovarian
damage in premenopausal women with malignant or non-malignant conditions.
Search methods
The search was run for the original review in July 2011, and for the first update in July 2014. For this update we searched the
following databases in November 2018: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the Chinese
Biomedicine Database (CBM).
Selection criteria
Randomised controlled trials (RCTs), in all languages, which examined the effect of GnRH analogues for chemotherapy-induced ovarian
failure in premenopausal women, were eligible for inclusion in the review.
Data collection and analysis

Two review authors independently extracted data and assessed trial quality using the Cochrane 'Risk of bias' tool. We analysed binary
data using risk ratios (RRs) with 95% confidence intervals (CI) and for continuous data, we used the standardized mean difference (SMD)
to combine trials. We applied the random-effects model in our analyses. We used the GRADE approach to produce a 'Summary of findings'
table for our main outcomes of interest.
Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in 1
Informed decisions.

Main results
We included 12 RCTs involving 1369 women between the ages of 12 and 51.1 years. Participants were diagnosed with breast malignancy,
ovarian malignancy, or Hodgkin's lymphoma, and most of them received alkylating, or platinum complexes, based chemotherapy. The
included studies were funded by a university (n = 1), research centres (n = 4), and pharmaceutical companies (n = 1). Trials were at high
or unclear risk of bias.
Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone

The incidence of menstruation recovery or maintenance was 178 of 239 (74.5%) in the GnRH agonist group and 110 of 221 (50.0%) in the
control group during a follow-up period no longer than 12 months (RR 1.60, 95% CI 1.14 to 2.24; 5 studies, 460 participants; I2 = 79%; low-
certainty evidence), with an overall effect favouring treatment with GnRH agonist (P = 0.006). However, we observed no difference during
a follow-up period longer than 12 months between these two groups (P = 0.24). In the GnRH agonist group, 326 of 447 participants had
menstruation recovery or maintenance (72.9%) in comparison to the control group, in which 276 of 422 participants had menstruation
recovery or maintenance (65.4%) during a follow-up period longer than 12 months (RR 1.08, 95% CI 0.95 to 1.22; 8 studies, 869 participants;
I2 = 56%; low-certainty evidence).
The incidence of premature ovarian failure was 43 of 401 (10.7%) in the GnRH agonist group and 96 of 379 (25.3%) in the control group
(RR 0.44, 95% CI 0.31 to 0.61; 4 studies, 780 participants; I2 = 0%; moderate-certainty evidence), with an overall effect favouring treatment
with GnRH agonist (P < 0.00001).
The incidence of pregnancy was 32 of 356 (9.0%) in the GnRH agonist group and 22 of 347 (6.3%) in the control group (RR 1.59, 95% CI
0.93 to 2.70; 7 studies, 703 participants; I2 = 0%; low-certainty evidence), with no difference between groups (P = 0.09). However, we are
cautious about this conclusion because there were insufficient data about whether the participants intended to become pregnant.
The incidence of ovulation was 29 of 47 (61.7%) in the GnRH agonist group and 12 of 48 (25.0%) in the control group (RR 2.47, 95% CI 1.43
to 4.26; 2 studies, 95 participants; I2 = 0%; low-certainty evidence) with an overall effect favouring treatment with GnRH (P = 0.001).
The most common adverse effects of GnRH analogues included hot flushes, vaginal dryness, urogenital symptoms, and mood swings. The
pooled analysis of safety data showed no difference in adverse effects between GnRH agonist group and control group.
Comparison 2: GnRH agonist-antagonist cotreatment plus chemotherapy versus chemotherapy alone

Only one RCT discussed GnRH agonist-antagonist cotreatment. The limited evidence showed the incidence of menstruation recovery
or maintenance was 20 of 25 (80%) in both cotreatment group and control group during a 12-month follow-up period (RR 1.00, 95% CI
0.76 to 1.32; 50 participants; very low-certainty evidence), with no difference between groups (P = 1.00). In the cotreatment group, 13 of
25 participants had menstruation recovery or maintenance (52.0%) in comparison to the control group, in which 14 of 25 participants
had menstruation recovery or maintenance (56.0%) during a follow-up period longer than 12 months (RR 0.93, 95% CI 0.56 to 1.55; 50
participants; very low-certainty evidence), with no difference between groups (P = 0.78). The incidence of pregnancy was 1 of 25 (4.0%) in
the cotreatment group and 0 of 25 (0%) in the control group (RR 3.00, 95% CI 0.13 to 70.30; 50 participants; very low-certainty evidence),
with no difference between groups (P = 0.49).
Authors' conclusions
GnRH agonist appears to be effective in protecting the ovaries during chemotherapy, in terms of maintenance and resumption of
menstruation, treatment-related premature ovarian failure and ovulation. Evidence for protection of fertility was insufficient and needs
further investigation. Evidence was also insufficient to assess the effect of GnRH agonist and GnRH antagonist cotreatment on ovarian
protection against chemotherapy. The included studies differed in some important aspects of design, and most of these studies had no
age-determined subgroup analysis. Large and well-designed RCTs with longer follow-up duration should be conducted to clarify the effects
of GnRH analogues in preventing chemotherapy-induced ovarian failure, especially on different age groups or different chemotherapy
regimens. Furthermore, studies should address the effects on pregnancy rates and anti-tumour therapy.
PLAIN LANGUAGE SUMMARY
Gonadotropin-releasing hormone analogues for women with ovarian cancer undergoing chemotherapy
Review question
This is the first update of a review published in the Cochrane Database of Systematic Reviews (2011, Issue 11).
Chemotherapy has improved the prognosis for people with cancer and some non-cancerous conditions, however, this treatment, in women
can be associated with ovarian function failure. A hormone called gonadotropin-releasing hormone (GnRH), both agonists and antagonists,
may make ovaries less sensitive to the effects of chemotherapy drugs. We conducted this review to establish whether GnRH analogues
can prevent damage to ovaries caused by chemotherapy in premenopausal women undergoing chemotherapy treatment for cancer or
other diseases.
Study characteristics
Informed decisions.

We searched the medical literature up to November 2018 and selected randomised controlled trials (RCTs), where women were randomly
assigned to two (or more) groups, to test if GnRH analogues given before or alongside chemotherapy could prevent the damage to women's
ovaries caused by chemotherapy. Included studies were funded by universities, research centres, or pharmaceutical companies. However,
the trials were of low methodological quality.
Key results
We included 12 RCTs involving 1369 women undergoing chemotherapy. The studies examined women given GnRH agonist plus
chemotherapy compared with chemotherapy alone (Group 1) or women given GnRH agonist-antagonist cotreatment plus chemotherapy
compared with chemotherapy alone (Group 2).
For Group 1, we found GnRH agonist had a protective effect on ovarian function, which could reduce the rate of premature ovarian
failure (moderate-certainty evidence) and increase the rate of ovulation (low-certainty evidence). The incidence of menstruation (periods)
recovery or maintenance during 12-month follow-up period in the GnRH agonist group was higher than that in the control group, but
we observed no difference when women were followed up for more than 12 months (low-certainty evidence). There was no difference in
pregnancy rates between groups (low-certainty evidence); however, it was not clear if the women were trying to get pregnant. There was
no difference in side effects including hot flushes, vaginal dryness, headaches, and depression between groups (very low- to moderate-
certainty evidence).
One RCT gave limited evidence for Group 2 and showed that GnRH agonist-antagonist cotreatment had no protective effect on the ovaries
in respect of menstruation recovery or maintenance and pregnancy rate (very low-certainty evidence).
Conclusions
GnRH agonist appears to be effective in protecting the ovaries during chemotherapy, in terms of menstruation recovery or maintenance,
premature ovarian failure and ovulation. Evidence for rates of pregnancy was insufficient and needs further investigation. Evidence was
also insufficient to assess the effect of GnRH agonist-antagonist cotreatment on ovarian function with chemotherapy.
SUMMARY OF FINDINGS

Summary of findings 1. GnRH agonist plus chemotherapy versus chemotherapy alone for the prevention of chemotherapy-induced premature
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ovarian failure in premenopausal women
GnRH agonist plus chemotherapy versus chemotherapy alone for the prevention of chemotherapy-induced premature ovarian failure in premenopausal women
Patient or population: premenopausal women with malignant conditions, receiving GnRH agonist before or in parallel to chemotherapy
Settings: hospital
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Trusted evidence.
Intervention: GnRH agonist plus chemotherapy
Comparison: chemotherapy alone
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of partici- Certainty of Comments
(95% CI) pants the evidence
Assumed risk Corresponding risk (studies) (GRADE)
Control: chemothera- GnRH agonist plus chemotherapy

py alone
Menstruation re- Study population RR 1.60 460 ⊕⊕⊝⊝

covery or main- (1.14 to 2.24) (5 studies) Low 1,2
tenance: 498 per 1000 796 per 1000
(567 to 1000)
Follow-up ≤ 12
months
Moderate
496 per 1000 794 per 1000

(565 to 1000)
Menstruation re- Study population RR 1.08 869 ⊕⊕⊝⊝

covery or main- (0.95 to 1.22) Low 3,4
(8 studies)

tenance: 654 per 1000 706 per 1000
(621 to 798)
Follow-up > 12
months
Moderate
681 per 1000 735 per 1000

(647 to 831)
Premature ovar- Study population RR 0.44 780 ⊕⊕⊝⊝ We defined prema-

ian failure (0.31 to 0.61) (4 studies) Moderate 5 ture ovarian failure
253 per 1000 111 per 1000 as amenorrhoea after
chemotherapy with
4

(79 to 155) postmenopausal FSH
levels.
Moderate Follow-up periods were
≥ 12 months
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249 per 1000 110 per 1000
(77 to 152)
Pregnancy Study population RR 1.59 703 ⊕⊕⊝⊝ Follow-up periods were

(0.93 to 2.70) (7 studies) Low 6,7 ≥ 18 months
63 per 1000 101 per 1000
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(59 to 171)
Moderate
95 per 1000 151 per 1000

(88 to 257)
Ovulation Study population RR 2.47 95 ⊕⊕⊝⊝ Follow-up periods

Low 8,9 ranged from 8 months to
250 per 1000 618 per 1000 (1.43 to 4.26) (2 studies) > 3 years
(357 to 1000)
Moderate
239 per 1000 590 per 1000
(342 to 1000)
Adverse effects: Study population RR 1.49 731 ⊕⊝⊝⊝ Follow-up periods

hot flush (0.16 to 13.60) (4 studies) Very low ranged from 1 year to > 7
390 per 1000 580 per 1000 10,11,12 years
(62 to 1000)

Moderate
245 per 1000 365 per 1000

(39 to 1000)
Adverse effects: Study population RR 1.18 488 ⊕⊕⊕⊝ Follow-up periods

vaginal dryness (0.68 to 2.04) (2 studies) Moderate 13 ranged from 5 months to
88 per 1000 104 per 1000 > 7 years
(60 to 180)
5

Moderate
88 per 1000 104 per 1000
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(60 to 180)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is
based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; FSH: follicle-stimulating hormone; RR: risk ratio
Better health.
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Trusted evidence.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
1Downgraded by one level due to concern about risk of bias (unclear random sequence generation in three out of five studies, unclear allocation concealment in two studies,
unclear blinding in four studies, no blinding in one study, and selective reporting in one study).
2Downgraded one level due to substantial heterogeneity among results of included studies (I2= 79%).
3Downgraded by one level due to concern about risk of bias (unclear random sequence generation in four out of eight studies, unclear allocation concealment in five studies,
unclear blinding in six studies, no blinding in two studies, selective reporting in two studies, and other biases in two studies).
4Downgraded one level due to substantial heterogeneity among results of included studies (I2= 56%).
5Downgraded by one level due to concern about risk of bias (unclear random sequence generation and unclear allocation concealment in one out of four studies, unclear blinding
in all studies, and other bias in one study).
6Downgraded by one level due to concern about risk of bias (unclear random sequence generation in four out of seven studies, unclear allocation concealment in five studies,
unclear blinding in all studies, incomplete outcome data in one study, selective reporting in two studies and other bias in four studies).
7Downgraded by one level due to concern about indirectness (insufficient data about the participants' intention of pregnancy).
8Downgraded by one level due to concern about risk of bias (unclear allocation concealment in one out of two studies, unclear random sequence generation and unclear blinding
in all studies, and other bias in one study).
9Downgraded by one level due to imprecision (small sample size).
10Downgraded by one level due to concern about risk of bias (unclear random sequence generation, allocation concealment and other bias in three out of four studies; unclear
blinding in all studies).

11Downgraded one level due to considerable heterogeneity among results of included studies (I2= 99%).
12Downgraded by one level due to imprecision (wide confidence interval crossing the line of no effect).
13Downgraded by one level due to concern about risk of bias (unclear random sequence generation and unclear allocation concealment in one out of two studies, unclear blinding
in both two studies, and other bias in one study).

Summary of findings 2. GnRH agonist-antagonist cotreatment plus chemotherapy versus chemotherapy alone for the prevention of chemotherapy-
induced premature ovarian failure in premenopausal women
GnRH agonist-antagonist cotreatment plus chemotherapy versus chemotherapy alone for the prevention of chemotherapy induced premature ovarian failure in
premenopausal women
6

Patient or population: premenopausal women with malignant conditions, receiving GnRH agonist before or in parallel to chemotherapy
Settings: hospital
Intervention: GnRH agonist-antagonist cotreatment plus chemotherapy
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Comparison: chemotherapy alone
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of partici- Certainty of Comments
(95% CI) pants the evidence
Assumed risk Corresponding risk (studies) (GRADE)
Better health.
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Trusted evidence.
Control: Agonist-antagonist cotreatment
chemotherapy plus chemotherapy
alone
Menstruation recov- Study population RR 1.00 50 ⊕⊝⊝⊝

ery or maintenance: (0.76 to 1.32) (1 study) Very low 1,2
800 per 1000 800 per 1000
Follow-up ≤ 12 (608 to 1000)
months
Moderate
800 per 1000 800 per 1000

(608 to 1000)
Menstruation recov- Study population RR 0.93 50 ⊕⊝⊝⊝

ery or maintenance: (0.56 to 1.55) (1 study) Very low 1,2
560 per 1000 521 per 1000
Follow-up > 12 (314 to 868)
months
Moderate
560 per 1000 521 per 1000

(314 to 868)

Premature ovarian - - Not estimable 0 - No data.
failure
We defined prema-
ture ovarian failure
as amenorrhoea
after chemother-
apy with post-
menopausal FSH
levels
7

Pregnancy Study population RR 3.00 50 ⊕⊝⊝⊝ Follow-up: 18
(0.13 to 70.30) (1 study) Very low 1,2 months
0 per 1000 0 per 1000
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(0 to 0)
Moderate
0 per 1000 0 per 1000

(0 to 0)
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Trusted evidence.
Ovulation - - Not estimable 0 - No data
Adverse events - - Not estimable 0 - No data
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is
based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; FSH: follicle-stimulating hormone; RR: risk ratio
GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
1 Downgraded by one level due to concern about risk of bias (unclear blinding, and high risk of selective reporting).
2 Downgraded by one level due to serious imprecision (single RCT with small sample size).


8

Informed decisions.

BACKGROUND Description of the intervention

This review is an update of a previously published review in Gonadotropin-releasing hormone (GnRH), also known as
the Cochrane Database of Systematic Reviews (2011, Issue 11) luteinizing-hormone-releasing hormone (LHRH), is a peptide
on 'Adjuvant gonadotropin-releasing hormone analogues for the hormone responsible for the release of gonadotropins (FSH and
prevention of chemotherapy induced premature ovarian failure in LH). GnRH is synthesized and released from the hypothalamus, and
premenopausal women' (Chen 2011). carried by the hypophyseal portal system to the pituitary gland,
where it activates GnRH receptors and stimulates synthesis and
Description of the condition secretion of LH and FSH. GnRH activity, critical for reproductive
function, is very low during childhood and is activated at puberty.
Chemotherapy has significantly improved the prognosis in people The frequency of the pulses varies during the menstrual cycle.
with malignancies, including breast cancer, lymphoma and Low-frequency GnRH pulses lead to FSH release, whereas high-
gynaecological cancers, and in some non-malignant conditions, frequency GnRH pulses stimulate LH release.
such as rheumatoid arthritis and systemic lupus erythematosus.
This treatment, however, is associated with significant physical GnRH analogues are synthetic peptide drugs modelled on GnRH
and psychological effects as more and more young people become that are designed to interact with the GnRH receptors and modify
long-term survivors. Of these, ovarian toxicity has been under the release of gonadotropins. Two types of analogues have been
wider scrutiny. Animal studies have shown that chemotherapy developed: GnRH agonists and GnRH antagonists, with specific
agents, such as cyclophosphamide, busulphan, and 5-fluorouracil, amino acid substitutions, typically in positions 6 and 10 (goserelin
cause follicular atresia in the ovaries (Tan 2014). Oocyte death by and leuprorelin), or only a single substitution at position 6
apoptosis is one of the main mechanisms responsible for loss of (triptorelin). GnRH agonists do not degrade rapidly and do not
germ cells (Soleimani 2011). Focal fibrosis of the ovarian cortex dissociate from the GnRH receptor quickly. As a result, they trigger
and damage to blood vessels are other mechanisms involved an initial increase in FSH and LH secretion ('flare-up' effect),
in the direct chemotherapy-related ovarian injury (Bedoschi followed by a profound hypogonadal effect through receptor down-
2016). In addition, chemotherapy causes an increase in follicular regulation (Maggi 2016). The 'flare-up' effect lasts for about one
recruitment, resulting in indirect depletion of primordial follicles week (Guenther 2017), and down-regulation of gonadotrophins
and consequently ovarian failure (Kalich-Philosoph 2013; Morgan can take up to two weeks after administration of GnRH agonists
2012). Ovarian damage caused by chemotherapy is not an 'all (Hasky 2015). Triptorelin, leuprolide, goserelin and buserelin are
or none' phenomenon. The impact ranges from partial damage among the mostly used GnRH agonists. GnRH antagonists are
resulting in irregular menses and reduced fertility up to full derivatives of the natural GnRH decapeptide with multiple amino
damage with total loss of primordial follicles and ovarian atrophy, acid substitutions. Competing with GnRH for its receptor, GnRH
which ultimately lead to amenorrhoea, permanent infertility antagonists decrease or block GnRH action to shut down the output
and premature ovarian failure (Dayangan Sayan 2018; Kano of FSH and LH rapidly without triggering the undesirable 'flare-up'
2017; Levine 2015; Trivers 2014). Regular menses shortly after effect (Maggi 2016). The combination of GnRH antagonist and GnRH
chemotherapy does not rule out the development of premature agonist combines the quick onset of action of GnRH antagonist with
ovarian failure, which may occur subsequently, and restoration the long-lasting effects of GnRH agonist. Side effects of the GnRH
of menstruation after chemotherapy-related amenorrhoea is also analogues are similar to those of hypoestrogenaemia, including hot
possible (Lutchman-Singh 2005). Women might have regular flushes, headaches and bone loss.
menses for several years after chemotherapy, but may have
reduced fertility due to a significant reduction in ovarian reserve. How the intervention might work
Ultrasonographic (ovarian volume, antral follicle count) and
Several proposed mechanisms have been put forward on how
biochemical markers (serum levels of follicle-stimulating hormone
GnRH analogues may work.
(FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH),
inhibin, estradiol, and progesterone) might suggest varying levels 1. Suppression of gonadotropin levels to stimulate pre-pubertal
of ovarian reserve damage before complete ovarian failure in hormonal milieu and subsequently prevent primordial follicles
women with preserved menstrual cycles (Bedoschi 2016). Other from maturation and therefore decrease the number of follicles
premature ovarian failure-related symptoms such as increased that are more vulnerable to chemotherapy (Blumenfeld 2008b;
cardiovascular risk and osteoporosis may also significantly affect a Hasky 2015)
woman's overall well-being and quality of life.
2. Decrease in utero-ovarian perfusion, resulting in a decreased
Factors that may affect the risk of chemotherapy-induced ovarian exposure of the ovaries to the chemotherapeutic agents
damage include age, type and dose of chemotherapy agents, (Blumenfeld 2007; Meirow 2004)
chemotherapy agents' association and length of treatment. 3. Direct activation of GnRH receptors on ovaries (Blumenfeld
Leonard and colleagues found a higher incidence of amenorrhoea 2007; Imai 2007)
after chemotherapy in women aged over 40 years diagnosed with 4. Regulation of the expression of intra-gonadal anti-apoptotic
breast cancer when compared with younger women (Leonard molecules, such as sphingosine-1-phosphate, Bcl-2 and
2017). Similar results were also found by D'avila 2015, indicating caspases-3 (Blumenfeld 2007; Huang 2009)
that ovaries become more sensitive to chemotherapeutic agents in 5. Protection of the undifferentiated germline stem cells
older women. (Blumenfeld 2007)
Informed decisions.

Why it is important to do this review if insufficient information was available. Where data extraction was
not possible, we included studies as awaiting classification.
For adolescents and young adults taking chemotherapeutic
agents, premature ovarian failure causing oestrogen deficiency Types of participants
symptoms and loss of fertility can significantly affect quality of
life and self-esteem. GnRH analogues are easily accessible drugs, Inclusion criteria
administration is simple and there are few side effects. The Premenopausal women (confirmed by age, menstrual history,
possibility of administering an adjuvant GnRH analogue, which may ovarian sonography and/or hormone levels, such as FSH and
minimize the ovarian damage caused by an otherwise successful estradiol) with malignant or non-malignant conditions, receiving
chemotherapy, is therefore a good clinical option. GnRH analogues supplementation before or in parallel to
chemotherapy.
Animal studies have been conducted to investigate the protective
effect of GnRH analogues on the ovaries. Li 2013 found that the Exclusion criteria
percentage of normal cyclicity in rats treated with or without
GnRH analogues increased from 0% with cisplatin alone to 25.0%, Premenopausal women who had taken oral contraceptive pills or
33.3%, 66.7% and 41.7%, in the GnRH agonist plus cisplatin, hormone replacement therapy after chemotherapy.
GnRH antagonist plus cisplatin, GnRH agonist and GnRH antagonist
Types of interventions
cotreatment plus cisplatin groups, respectively. Pretreatment with
GnRH agonist, GnRH antagonist and combination of GnRH agonist 1. GnRH agonists or antagonists or both versus placebo or other
and antagonist significantly protected the primordial follicles interventions, before or in parallel to chemotherapy
from destruction by preserving 57.6%, 63.4%, 87.1% and 60.4% 2. Combination of GnRH agonists and antagonists versus GnRH
of the follicles, respectively. GnRH antagonists have also been agonists or antagonists alone, before or in parallel to
found to decrease ovarian damage caused by cyclophosphamide chemotherapy
in mice (Meirow 2004), and to deplete primordial follicles in a 3. GnRH agonists or antagonists or both plus other interventions
murine model in a prospective primary research study (Danforth versus GnRH agonists or antagonists or both, or other methods
2005). However, some other studies found contradictory results. alone, before or in parallel to chemotherapy (where 'other
Horicks 2018 found that cyclophosphamide induced a significant interventions' indicate alternatives to GnRH analogues to
follicular loss of more than 50% in mice, regardless of previous preserve ovarian function, such as oral contraceptive pills or
treatment with gonadotropins, and observed no difference in cell cryopreservation of embryo etc., and are the same in each arm
proliferation or apoptosis. Horicks 2015 found that GnRH agonist of the RCT comparison)
and antagonist failed to inhibit follicular development, irrespective
of the doses and injection sites. They still observed a depletion Types of outcome measures
of primordial follicles after chemotherapy. Peng 2007 showed
that GnRH antagonists had no protective effect on ovaries from Primary outcomes
cyclophosphamide in rats. 1. Menstruation recovery or maintenance: maintenance or
recovery of menstruation (normal or oligomenorrhoea) with or
In clinical studies, the protection effect of GnRH analogues on
without clear evidence of ovulation
ovaries is still under debate. Although some guidelines and expert
opinions support the use of GnRH analogues to preserve ovarian 2. Premature ovarian failure: no resumption of menstrual activity
function for women with breast cancer (AGO 2017; Lambertini with postmenopausal FSH levels at least one year after the end
2016), the administration of GnRH analogues during chemotherapy of chemotherapy
is considered an experimental strategy to preserve ovarian function 3. Pregnancy
and fertility as a whole due to inconsistency of results in the
literature. Secondary outcomes
1. Ovulation (confirmed by, for example, ovarian sonography or
OBJECTIVES serum progesterone levels)
To assess the efficacy and safety of GnRH analogues given before 2. Ovarian sonography (antral follicle count, size of ovary, etc.)
or in parallel to chemotherapy to prevent chemotherapy-related 3. Hormone levels (FSH, LH, AMH, inhibin, estradiol, progesterone,
ovarian damage in premenopausal women with malignant or non- etc.)
malignant conditions. 4. Anti-cancer efficacy (five-year survival rate, etc.)
5. Adverse effects (symptoms of hypoestrogenaemia, such as hot
METHODS flashes, headaches and osteoporosis, etc.)
Criteria for considering studies for this review Search methods for identification of studies
Types of studies We sought papers in all languages and carried out translations
Randomised controlled trials (RCTs) in all languages that examined where necessary.
the effect of GnRH analogues for chemotherapy-induced ovarian
Electronic searches
failure in premenopausal women were eligible for inclusion in the
review. We included studies published in abstract form, if extraction The search was run for the original review in July 2011 and
of data was possible, and treated these as being at high risk of bias, subsequent searches were run in July 2014.
Informed decisions.

For this update we searched the following databases in November indicating low risk of bias, 'No' indicating high risk of bias and
2018: 'Unclear' indicating unclear or unknown risk of bias (Appendix 6).
We resolved differences by discussion among the review authors
1. the Cochrane Central Register of Controlled Trials (CENTRAL; or by consulting Cochrane Gynaecological, Neuro-oncology and
2018, Issue 11), in the Cochrane Library; Orphan Cancers.
2. MEDLINE via Ovid (July 2014 to November week 2 2018);
3. Embase via Ovid (July 2014 to 2018 week 47); Measures of treatment effect
4. Chinese Biomedicine Database (CBM), (July 2014 to November We analysed data using Review Manager 5 (Review Manager 2014).
2018). We compared outcome measures for binary data using risk ratios
(RRs) with 95% confidence intervals (CI). For continuous data,
We identified all relevant articles found on PubMed and using the we used the standardized mean difference (SMD) to combine
'related articles' feature, carried out a further search for newly trials because all trials used different scales. Due to substantial
published articles. heterogeneity in terms of different chemotherapy agents, we used
random-effects models in our analyses.
We formulated comprehensive search strategies in order to identify
all relevant studies regardless of language or publication status. We Unit of analysis issues
have provided the search strategies in, Appendix 1 for CENTRAL,
Appendix 2 for MEDLINE, Appendix 3 for Embase, and Appendix 4 The included studies recruited and analysed all of the participants
for CBM. individually.
Searching other resources Dealing with missing data
We searched the following databases for ongoing We tried to contact study authors for additional or missing data, but
studies and conference abstracts in November 2018: we received no response.
www.who.int/ictrp/en/; www.clinicaltrials.gov; www.controlled-
Assessment of heterogeneity
trials.com/; www.trialscentral.org/; www.asco.org/meetings;
www.isiwebofknowledge.com. We tested heterogeneity using the Cochrane Q test (Deeks 2017),
with significance at a P value of less than 0.10. We used the I2
We searched clinical study results for clinical trial results statistic (Higgins 2003), to estimate the percentage of heterogeneity
of marked pharmaceuticals (www.clinicalstudyresults.org). For between trials that could not be ascribed to sampling variation.
grey literature, we searched OpenGrey database (http://
www.opengrey.eu/) and Google (www.google.com). 1. 0% to 40%: might not be important;
2. 30% to 60%: may represent moderate heterogeneity;
We also searched reference lists of relevant trials and reviews.
3. 50% to 90%: may represent substantial heterogeneity;
Data collection and analysis 4. 75% to 100%: considerable heterogeneity.
Selection of studies If there was evidence of substantial heterogeneity, we investigated
Two review authors (HC and JL) independently examined titles and and reported the possible reasons for this.
abstracts from the initial search in order to identify studies that
Assessment of reporting biases
met the inclusion criteria. We retrieved the full text of those studies
thought to fulfil the inclusion criteria and those without abstracts. We assessed study reports, and protocols where available, to
We have detailed reasons for excluding trials in Characteristics of assess whether study authors reported all prespecified outcomes.
excluded studies. In future updates of this review, if there are 10 or more studies in
the meta-analysis, we will investigate reporting biases using funnel
Data extraction and management plots.
Two review authors (HC and JL) independently extracted
Data synthesis
data on study characteristics including methods, study quality,
participants, interventions, outcomes and duration of follow-up We combined the data using the random-effects model. For
(Appendix 5). We resolved differences by discussion between the dichotomous outcomes, we calculated the RR for each trial and
review authors. Review authors were blinded to the trial authors, then pooled these RRs. When there were no events in one of
their institutions, the source of funding and acknowledgments. HC the groups for RR, we used the default zero-cell correction. For
conducted a double data entry. continuous data, we calculated and then pooled the SMD.
Assessment of risk of bias in included studies Assessing the certainty of the evidence
Two review authors (HC and JL) independently assessed risk of We used the GRADE system to rate the certainty of the evidence
bias according to the guidelines stated in the Cochrane Handbook for the seven most important outcomes. We downgraded certainty
for Systematic Reviews of Interventions (Higgins 2017). The 'Risk of for inconsistency, design limitations (risk of bias), imprecision,
bias' tables in the Characteristics of included studies consist of six indirectness and other factors, such as publication bias, where
domains, including sequence generation; allocation concealment; appropriate (Higgins 2011a). Two review authors (HC and JL)
blinding; incomplete outcome data addressed; free of selective conducted the grading, resolving differences by discussion and, if
reporting bias; and free of other bias, with a judgement of 'Yes' necessary, by involving a third review author (WH).
Informed decisions.

We downgraded the evidence from 'high' certainty by one level for RESULTS
serious (or by two for very serious) concerns for each limitation:
Description of studies
1. High-certainty: we are very confident that the true effect lies
close to that of the estimate of the effect. Results of the search
2. Moderate-certainty: we are moderately confident in the effect The original literature search identified 2122 articles, of which we
estimate: the true effect is likely to be close to the estimate of the excluded 2113 as they were animal studies, reviews, and repeated
effect, but there is a possibility that it is substantially different. reports etc. Of the remaining nine studies, we excluded another
3. Low-certainty: our confidence in the effect estimate is limited: two studies with reasons (Bernhard 2007; Sverrisdottir 2009). In
the true effect may be substantially different from the estimate the end, we included four studies; two studies are still awaiting
of the effect. classification (Behringer 2007; Ismail-Khan 2008), and one is still
4. Very low-certainty: we have very little confidence in the effect ongoing (Manger 2006).
estimate: the true effect is likely to be substantially different
For this update the Cochrane Gynaecological, Neuro-Oncology and
from the estimate of effect.
Orphan Cancer's Information Specialist ran electronic searches in
Subgroup analysis and investigation of heterogeneity November 2018.
We intended to explore the following potential sources of 1. The November 2018 search produced a list of 462 references.
heterogeneity using subgroup analyses. Subgroup analyses may This list was reduced to 417 by removing duplicates. Two
be based on the following: the participant's age at treatment; review authors (HC and JL) independently screened the 417
types of diseases; types of chemotherapy agents; chemotherapy references by title and abstract, leading to the identification of
regimen (types, dose, and duration); onset of GnRH analogues 16 references for classification. We excluded four studies with
supplementation; types of GnRH analogues; regimen of GnRH reasons (Demeestere 2016; Mina 2013; Regan 2017; Zhang 2018)
analogues; and follow-up periods. and included nine references; these were references related to
eight RCTs. Another three studies are awaiting classification
Sensitivity analysis (Anderson 2016; Karimi-Zarchi 2011; Rossi 2015).
We performed sensitivity analysis to assess the robustness of 2. The Internet databases search produced a list of 247 references.
the meta-analyses by comparing the results using all trials and Two review authors (HC and JL) independently screened
then excluding trials of lower methodological quality or those we the references by title, abstract, or protocol, leading to the
considered to be at a higher risk of bias. identification of five ongoing RCTs.
The review therefore comprises 12 included studies (involving 13

articles) (Characteristics of included studies), six ongoing studies
(Characteristics of ongoing studies), and five studies awaiting
classification (Characteristics of studies awaiting classification). We
have included the study selection as a flow chart (Figure 1).

Informed decisions.

Figure 1. Flow diagram

Included studies Settings
We attempted to contact authors of 10 included studies by email for Of the 12 studies identified for inclusion in the review, two studies
additional or missing data, but received no replies (Badawy 2009; were conducted in Egypt (Badawy 2009; Elgindy 2013), two in
Elgindy 2013; Gerber 2011; Giuseppe 2007; Karimi-Zarchi 2014; England (UK) (Leonard 2017; Waxman 1987), two in Italy (Giuseppe
Lambertini 2015a; Leonard 2017; Moore 2015; Munster 2012; Song 2007; Lambertini 2015a), and two in Iran (Gilani 2007; Karimi-Zarchi
2013). 2014); one each in China (Song 2013), Germany (Gerber 2011), and
the USA (Munster 2012); and one international, multi-centre trial in
Population Australia, Switzerland, Peru and USA (Moore 2015).
The total number of randomised participants was 1369. Lambertini
Intervention and comparators
2015a contributed the largest sample of 281, while Waxman
1987 recruited only 18 participants. All included studies recruited All included studies compared GnRH agonist plus chemotherapy
women menstruating normally and between the ages of 12 and versus chemotherapy alone. Elgindy 2013 also compared combined
51.1 years. Women were diagnosed with breast cancer (Badawy GnRH agonist and GnRH antagonist plus chemotherapy versus
2009; Elgindy 2013; Gerber 2011; Karimi-Zarchi 2014; Lambertini chemotherapy alone.
2015a; Leonard 2017; Moore 2015; Munster 2012; Song 2013),
ovarian cancer (Gilani 2007), or Hodgkin's lymphoma (Giuseppe Follow-up
2007; Waxman 1987). Women in most included studies received Women in all studies were followed up for more than 12 months
alkylating- or platinum complexes-based chemotherapy (Badawy except in three studies (Badawy 2009; Gilani 2007; Karimi-Zarchi
2009; Elgindy 2013; Gerber 2011; Gilani 2007; Giuseppe 2007; 2014). Participants in seven studies were followed up for no less
Karimi-Zarchi 2014; Lambertini 2015a; Leonard 2017; Munster 2012; than two years (Gerber 2011; Giuseppe 2007; Lambertini 2015a;
Song 2013). Leonard 2017; Moore 2015; Munster 2012; Waxman 1987). The mean
time of follow-up in Giuseppe 2007 was 4.2 years and the median
Informed decisions.

long-term follow-up was 7.3 and 4.1 years in Lambertini 2015a and Munster 2012), and one by a pharmaceutical company (Gerber
Moore 2015 respectively. 2011). Six of the included studies did not mention the funding
sources (Badawy 2009; Gilani 2007; Giuseppe 2007; Karimi-Zarchi
Outcomes 2014; Song 2013; Waxman 1987).
Primary outcome
Further information is available in the Characteristics of included
Eleven studies reported the rates of menstruation recovery or studies table.
maintenance (Badawy 2009; Elgindy 2013; Gerber 2011; Gilani
2007; Giuseppe 2007; Karimi-Zarchi 2014; Lambertini 2015a; Excluded studies
Leonard 2017; Munster 2012; Song 2013; Waxman 1987). Four We excluded six studies. Bernhard 2007 gave the intervention
studies measured treatment-related premature ovarian failure (goserelin) after chemotherapy; the women received hormone
using combination of amenorrhoea and postmenopausal FSH replacement therapy during chemotherapy in Demeestere 2016;
levels (Lambertini 2015a; Leonard 2017; Moore 2015; Song 2013 Mina 2013 did not discuss the primary outcomes of this review; not
). Seven studies reported the rates of pregnancy (Elgindy 2013; all women in treatment group received GnRH analogues in Regan
Gerber 2011; Giuseppe 2007; Lambertini 2015a; Moore 2015; 2017; not all women received chemotherapy in Sverrisdottir 2009;
Munster 2012; Waxman 1987). and all included women received sequential or simultaneous GnRH
Secondary outcomes analogues in Zhang 2018. For further details please refer to the
Characteristics of excluded studies table.
Badawy 2009 and Waxman 1987 reported ovulation rates. Elgindy
2013, Gerber 2011 and Giuseppe 2007 reported ultrasound antral Risk of bias in included studies
follicle count. Hormone levels were reported outcomes in ten listed
studies (Badawy 2009; Elgindy 2013; Gerber 2011; Gilani 2007; We judged seven included RCTs as unclear risk of bias due to one
Giuseppe 2007; Karimi-Zarchi 2014; Lambertini 2015a; Leonard or more criteria assessed being unclear (Badawy 2009; Gilani 2007;
2017; Munster 2012; Song 2013). Lambertini 2015a and Moore 2015 Giuseppe 2007; Karimi-Zarchi 2014; Lambertini 2015a; Leonard
reported disease-free survival. Five studies reported adverse events 2017; Song 2013), while another five included RCTs were at high
(Elgindy 2013; Gerber 2011; Lambertini 2015a; Moore 2015; Song risk of bias due to one or more criteria assessed being high
2013). (Elgindy 2013; Gerber 2011; Moore 2015; Munster 2012; Waxman
1987). Random sequence generation, allocation concealment and
Funding sources blinding in most studies were unclear. Please see Figure 2 and
Figure 3. Detailed information is available in the Characteristics of
One included study was funded by a university (Elgindy 2013), four included studies table.
by research centres (Lambertini 2015a; Leonard 2017; Moore 2015;

Informed decisions.

Figure 2. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study
Blinding (performance bias and detection bias): All outcomes

Incomplete outcome data (attrition bias): All outcomes
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Selective reporting (reporting bias)

Other bias
Badawy 2009 ? + ? + + ?
Elgindy 2013 + + - + - ?
Gerber 2011 ? ? - + + ?
Gilani 2007 ? ? ? + + ?
Giuseppe 2007 ? ? ? + + ?
Karimi-Zarchi 2014 ? ? ? + + ?
Lambertini 2015a + + ? + + +
Leonard 2017 + + ? + + +
Moore 2015 ? ? - + + -
Munster 2012 + ? ? + - -
Song 2013 ? ? ? + + ?
Waxman 1987 ? ? ? + + -

Informed decisions.

Figure 3. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies
Random sequence generation (selection bias)

Allocation concealment (selection bias)
Blinding (performance bias and detection bias): All outcomes
Incomplete outcome data (attrition bias): All outcomes
Selective reporting (reporting bias)
Other bias
0% 25% 50% 75% 100%
Low risk of bias Unclear risk of bias High risk of bias

Allocation follow-up period: one woman in each group except the GnRH
agonist plus delayed chemotherapy group, in which two women
We rated four studies at low risk of bias for randomisation because
died. In Gerber 2011, the risk of bias in the primary outcomes
they used computer-generated lists of random numbers (Elgindy
is low as only two women (6.7%) in each group withdrew due
2013; Lambertini 2015a; Leonard 2017; Munster 2012).
to adverse events, progression of disease and being unwilling to
We rated eight studies at unclear risk of bias for randomisation; continue to participate. All women were followed up in Gilani 2007,
none provided details of the generation of the randomisation Giuseppe 2007 and Karimi-Zarchi 2014. In the 12-month follow-
sequence (Badawy 2009; Gerber 2011; Gilani 2007; Giuseppe 2007; up of Lambertini 2015a, six women (4.5%) in the chemotherapy
Karimi-Zarchi 2014; Moore 2015; Song 2013; Waxman 1987). alone group did not receive chemotherapy and six (4.5%) were
lost to follow-up, while two women (1.4%) in the GnRH agonist
We rated four studies at low risk of bias for allocation concealment plus chemotherapy group did not receive chemotherapy and seven
because they reported using unbiased methods of concealment. (4.7%) were lost to follow-up. At the study cut-off date for long
Methods included: using a clinical trials centre to keep the follow-up (median follow-up was 7.3 years), 18 (13.5%) and 17
randomisation code, or sealed envelopes (Badawy 2009; Elgindy (11.5%) women were lost to follow-up in the chemotherapy-
2013; Lambertini 2015a; Leonard 2017). alone group and chemotherapy plus triptorelin group respectively.
In Leonard 2017, three women (2.8% in GnRH group and 2.4%
We rated eight studies at unclear risk of bias for allocation in control group) in each arm had died within 24 months of
concealment; none provided information on how they had randomisation. For a further 19 women (11 in the control arm and
achieved allocation concealment (Gerber 2011; Gilani 2007; 8 in the intervention arm), menstrual status during the interval
Giuseppe 2007; Karimi-Zarchi 2014; Moore 2015; Munster 2012; between the 12-month follow-up visit and the 24-month follow-up
Song 2013; Waxman 1987). visit could not be determined from the data available. Moore 2015
collected data on pregnancy and survival in 93.6% women. Attrition
Blinding was mainly due to withdrawal, loss to follow-up and non-response.
We rated nine studies at unclear risk of bias for blinding; none Munster 2012 reported that one woman (3.7%) in the GnRH agonist
mentioned whether participant/personnel/outcome assessment group withdrew consent before the first treatment. Another woman
was blinded or not (Badawy 2009; Gilani 2007; Giuseppe 2007; (4.5%), in the control arm, was found to have residual disease
Karimi-Zarchi 2014; Lambertini 2015a; Leonard 2017; Munster 2012; after neoadjuvant chemotherapy and was treated with additional
Song 2013; Waxman 1987). chemotherapy not permitted by protocol. Song 2013 reported that
16 (14.5%) in the chemotherapy-alone group (two women failed to
We rated three studies at high risk of bias for blinding; these studies complete at least one cycle of chemotherapy and 14 women were
were open-label trials without blinding (Elgindy 2013; Gerber 2011; lost to follow-up), and 21 (19.1%) in the chemotherapy plus GnRH
Moore 2015). agonist group (four women failed to complete at least one cycle
of chemotherapy and 17 women were lost to follow-up), were not
Although most studies did not indicate whether they had included in the evaluation. Waxman 1987 reported that one woman
implemented blinding, the impact on primary outcomes, including (5.6%) was not included in the evaluation because she died during
menstruation recovery or maintenance, premature ovarian failure treatment.
and pregnancy was limited, because the primary outcomes were
objective indicators. Selective reporting
Incomplete outcome data We found protocols for five studies (Gerber 2011; Lambertini 2015a;
Leonard 2017; Moore 2015; Munster 2012) and all these studies
We assessed all studies at low risk of attrition bias because loss to except Munster 2012 reported all the outcomes mentioned in their
follow-up was balanced across these groups with rational reasons. protocol. Protocols were not available for seven included studies.
Badawy 2009 reported that only one woman (2.5%) in each group We compared the methods and results sections of each study and
dropped out. In Elgindy 2013, five women (5%) died during the found consistent reporting between sections in six studies (Badawy
Informed decisions.

2009; Gilani 2007; Giuseppe 2007; Karimi-Zarchi 2014; Song 2013; Comparison 1: GnRH agonist plus chemotherapy versus
Waxman 1987). Elgindy 2013 mentioned adverse events as an chemotherapy alone
outcome measurement but did not report the results. Thus, we
Primary outcomes
assessed ten studies in this review at low risk of reporting bias
(Badawy 2009; Gerber 2011; Gilani 2007; Giuseppe 2007; Lambertini Menstruation recovery or maintenance
2015a; Karimi-Zarchi 2014; Leonard 2017; Moore 2015; Song 2013; Subgroup analysis based on follow-up period of 12 months or less
Waxman 1987) and two studies at high risk (Elgindy 2013; Munster
2012). Based on results from five included studies (Badawy 2009; Elgindy
2013; Gilani 2007; Karimi-Zarchi 2014; Lambertini 2015a), the
Other potential sources of bias incidence of menstruation recovery or maintenance was 178 of
239 (74.5%) in the GnRH agonist plus chemotherapy group and
We assessed Lambertini 2015a at low risk of other potential bias
110 of 221 (50.0%) in the chemotherapy alone group during a
because there was no clear violation of the protocol and no
follow-up period no longer than 12 months. The RR was 1.60
significant difference in baseline characteristics between groups.
The original protocol of Leonard 2017 restricted the entry of women (95% CI 1.14 to 2.24; I2 = 79%; Analysis 1.1), with an overall effect
to those with oestrogen receptor (ER)-negative tumours only, but favouring treatment with GnRH agonist (P = 0.006). We detected
women with ER-positive tumours, for whom the investigator did heterogeneity among results of included studies (I2 = 79%; P =
not deem ovarian suppression necessary as part of the treatment, 0.0007), then we performed sensitivity analysis excluding one study
were subsequently allowed entry to the study after a protocol that was at high risk of bias (Elgindy 2013). When this study was
amendment. There was no other violation of the protocol and no excluded, the result of the meta-analysis was unchanged (RR 1.82,
significant difference in baseline characteristics between groups. 95% CI 1.23 to 2.67; 4 studies, 410 participants; P = 0.002; I2 = 75%).
We also assessed this study at low risk of other potential bias. We downgraded the evidence for this outcome to low certainty, for
risk of bias and inconsistency (Summary of findings 1).
There was no significant difference in baseline characteristics
between groups in another seven studies (Badawy 2009; Elgindy Subgroup analysis based on follow-up period of more than 12 months
2013; Gerber 2011; Gilani 2007; Giuseppe 2007; Karimi-Zarchi 2014; Based on results from eight studies (Elgindy 2013; Gerber 2011;
Song 2013). However, the protocols were not mentioned. Thus, we Giuseppe 2007; Lambertini 2015a; Leonard 2017; Munster 2012;
assessed these studies at unclear risk of other potential bias. Song 2013; Waxman 1987), in the GnRH agonist plus chemotherapy
group, 326 of 447 participants had menstruation recovery or
We assessed three studies at high risk of other potential bias (Moore
maintenance (72.9%) in comparison to the chemotherapy alone
2015; Munster 2012; Waxman 1987). Moore 2015 closed early owing
group, in which 276 of 422 participants had menstruation recovery
to loss of funding for study-drug distribution. Munster 2012 initially
or maintenance (65.4%) during a follow-up period longer than
planned to enrol 124 women, but the trial was stopped for futility
12 months. The RR was 1.08 (95% CI 0.95 to 1.22; 8 studies, 869
after 49 women were enrolled. The planned follow-up time was five
participants; I2 = 56%; Analysis 1.1), with no difference between
years but was stopped early because no difference between the two
groups (P = 0.24). We detected statistical heterogeneity among
groups was identified. In Waxman 1987, women in the treatment
groups tended to be younger than those in the control groups the results of the included studies (I2 = 56%; P = 0.02), then we
and the low dose of buserelin used could have led to incomplete performed sensitivity analysis excluding four included studies that
pituitary downregulation, which might have affected the results. were at high risk of bias (Elgindy 2013; Gerber 2011; Munster 2012;
Waxman 1987). When these four studies were excluded, the result
Effects of interventions of meta-analysis was unchanged (RR 1.20, 95% CI 0.98 to 1.46; 4
studies, 695 participants; P = 0.08; I2 = 66%). We downgraded the
See: Summary of findings 1 GnRH agonist plus chemotherapy evidence for this outcome to low certainty, for risk of bias and
versus chemotherapy alone for the prevention of chemotherapy- inconsistency (Summary of findings 1).
induced premature ovarian failure in premenopausal women;
Summary of findings 2 GnRH agonist-antagonist cotreatment Subgroup analysis based on age
plus chemotherapy versus chemotherapy alone for the
Two studies reported data regarding different age subgroups
prevention of chemotherapy-induced premature ovarian failure in
(Karimi-Zarchi 2014; Leonard 2017), with inconsistent results.
premenopausal women
Leonard 2017 reported a protective effect of GnRH agonist on
See Summary of findings 1 and Summary of findings 2. We obtained menses in women aged 40 years or older, while the effect was
all data from published literature. We attempted to contact authors no different in women younger than 40 years (Table 1). However,
of included studies by email for additional or missing data, but Karimi-Zarchi 2014 found that GnRH agonist had a protective effect
received no replies (Badawy 2009; Elgindy 2013; Gerber 2011; regarding menstruation in women aged 35 years and older, and the
Giuseppe 2007; Karimi-Zarchi 2014; Lambertini 2015a; Leonard effect was no different in women younger than 35 years (Table 2).
2017; Moore 2015; Munster 2012; Song 2013). For those data that
Premature ovarian failure
were incomplete and could not be analysed in the meta-analysis,
we tried to report them narratively or in additional tables wherever Combining results from four studies (Lambertini 2015a; Leonard
possible. 2017; Moore 2015; Song 2013), the incidence of treatment-related
premature ovarian failure was 43 of 401 (10.7%) in the GnRH
agonist plus chemotherapy group and 96 of 379 (25.3%) in the
chemotherapy alone group. The RR was 0.44 (95% CI 0.31 to 0.61;
4 studies, 780 participants; I2 = 0%; Analysis 1.2), with an overall
effect favouring treatment with GnRH (P < 0.00001). We performed
Informed decisions.

sensitivity analysis for this outcome as one included study was at Hormone levels
high risk of bias (Moore 2015). When this study was excluded, the Ten included studies reported hormone levels (Badawy 2009;
result of meta-analysis was unchanged (RR 0.45, 95% CI 0.31 to 0.65; Elgindy 2013; Gerber 2011; Gilani 2007; Giuseppe 2007; Karimi-
3 studies, 645 participants; P < 0.0001; I2 = 9%). We downgraded Zarchi 2014; Lambertini 2015a; Leonard 2017; Munster 2012; Song
the evidence for this outcome to moderate certainty for risk of bias 2013), however, most data were not presented in a form that
(Summary of findings 1). could be meta-analysed. We tried to report these data narratively
Subgroup analysis based on age
wherever possible.
Leonard 2017 reported a protective effect of GnRH agonist on FSH/LH

ovaries in respect of premature ovarian failure rates in women Pooled results of Giuseppe 2007 and Karimi-Zarchi 2014 found that
aged 40 years or older, while the effect was no different in women there was no difference in FSH/LH levels between chemotherapy
younger than 40 years (Table 1). However, Song 2013 reported plus GnRH agonist group and chemotherapy alone group (for FSH:
no difference in premature ovarian failure rates in different age SMD 0.26, 95% CI −0.80 to 1.31, P = 0.63; 2 studies, 71 participants;
subgroups (women aged 35 years and older, and women younger I2 = 79%; Analysis 1.6; for LH: SMD −0.62, 95% CI −1.28 to 0.03; P
than 35 years) between the chemotherapy plus GnRH agonist group
= 0.06; I2 = 45%; Analysis 1.8). Three other studies found the same
and the chemotherapy alone group (Table 3).
results (Elgindy 2013; Lambertini 2015a; Munster 2012). However,
Pregnancy Gilani 2007 reported protective effects by GnRH agonist on ovaries
in respect of FSH and LH levels (RR 1.48, 95% CI 1.02 to 2.13; 30
Based on results from seven included studies (Elgindy 2013; Gerber participants; P = 0.04; Analysis 1.7 ; Analysis 1.9). This conclusion
2011; Giuseppe 2007; Lambertini 2015a; Moore 2015; Munster 2012; was consistent with Badawy 2009 (P < 0.009 for FSH levels and P <
Waxman 1987), the incidence of pregnancy was 32 of 356 (9.0%) in 0.004 for LH levels), Gerber 2011 (P = 0.015 for LH levels), and Song
the GnRH agonist plus chemotherapy group and 22 of 347 (6.3%) 2013 (P < 0.05 for FSH levels).
in the chemotherapy alone group. The RR was 1.59 (95% CI 0.93
to 2.70; 7 studies, 703 participants; I2 = 0%; Analysis 1.3), with no AMH
difference between groups (P = 0.09). The follow-up periods were Giuseppe 2007 found there was no difference in AMH levels
no less than 18 months. Five of the included studies were at high between groups (SMD −0.05, 95% CI −0.78 to 0.68; 29 participants; P
risk of bias (Elgindy 2013; Gerber 2011; Moore 2015; Munster 2012; = 0.89; Analysis 1.10). This result was consistent with Elgindy 2013.
Waxman 1987). Sensitivity analysis excluding these five studies Gerber 2011 reported data regarding AMH incompletely and so we
gave the same result (RR 1.04, 95% CI 0.11 to 10.06; 310 participants; could not analyse them.
P = 0.97; I2 = 54%). We downgraded the evidence for this outcome
to low certainty for risk of bias for risk of bias and indirectness Inhibin B
(Summary of findings 1).
Giuseppe 2007 found no difference in inhibin B levels between
Secondary outcomes chemotherapy plus GnRH agonist group and chemotherapy alone
groups (SMD 0.06, 95% CI -0.67 to 0.78; 29 participants; P =
Ovulation 0.88; Analysis 1.11). Gerber 2011 and Munster 2012 reported data
Based on results from two included studies (Badawy 2009; Waxman regarding inhibin B levels incompletely and we could not analyse
1987), the incidence of ovulation was 29 of 47 (61.7%) in the GnRH them.
agonist plus chemotherapy group and 12 of 48 (25.0%) in the
Estradiol
chemotherapy alone group. The RR was 2.47 (95% CI 1.43 to 4.26;
2 studies, 95 participants; I2 = 0%; Analysis 1.4), with an overall Karimi-Zarchi 2014 reported that GnRH agonist had a protective
effect favouring treatment with GnRH (P = 0.001). Follow-up periods effect on ovaries in respect of estradiol levels (SMD 1.35, 95% CI 0.67
ranged from eight months to more than three years. We performed to 2.02; 42 participants; P < 0.0001; Analysis 1.12). Gilani 2007 found
sensitivity analysis for this outcome excluding one study with high the same conclusion (RR 3.44, 95% CI 1.57 to 7.58; 30 participants;
risk of bias (Waxman 1987). Only one trial remained and the result P = 0.002; Analysis 1.13). Five other studies found no difference
was the same (RR 2.70, 95% CI 1.52 to 4.79; 78 participants; P in estradiol levels between groups (Badawy 2009; Elgindy 2013;
= 0.0007). We downgraded the evidence for this outcome to low Gerber 2011; Lambertini 2015a; Song 2013).
certainty for risk of bias and imprecision.
Survival rate
Antral follicle count
Lambertini 2015a reported that five-year disease-free survival was
Three studies reported ultrasound antral follicle count (Elgindy 80.5% (95% CI 77.2% to 90.5%), in chemotherapy plus GnRH
2013; Gerber 2011; Giuseppe 2007). Giuseppe 2007 found there was agonist group and 83.7% (95% CI 76.1% to 89.1%), in chemotherapy
no difference in antral follicle count between chemotherapy plus alone group. Moore 2015 reported that the four-year Kaplan-Meier
GnRH agonist and chemotherapy alone (SMD 1.11, 95% CI 0.32 to estimate of the rate of disease-free survival was 89% in the GnRH
1.90; 1 study, 29 participants; P = 0.006; Analysis 1.5). Elgindy 2013 agonist group and 78% in the control group (P = 0.04), while the
did not provide data that could be meta-analysed; however, this four-year Kaplan-Meier estimate of the rate of overall survival was
study came to the same conclusion, that there was no difference in 92% and 82% respectively (P = 0.05).
antral follicle count between groups. Data regarding antral follicle
Adverse effects
count in Gerber 2011 were incomplete and could not be analysed.
Based on results from four included studies (Gerber 2011;
Lambertini 2015a; Moore 2015; Song 2013), the incidence of
Informed decisions.

hot flush was 172 of 369 (46.6%) in the GnRH agonist plus result was the same (RR 0.99, 95% CI 0.81 to 1.22; 2 studies, 214
chemotherapy group and 141 of 362 (39.0%) in the chemotherapy participants; P = 0.95).
alone group. The RR was 1.49 (95% CI 0.16 to 13.60; 731 participants;
I2 = 99%; Analysis 1.14), with no difference between groups (P = Meta-analyses also found no difference between chemotherapy
0.73) . We performed sensitivity analysis for this outcome as Gerber plus GnRH agonist groups and chemotherapy alone groups in rates
2011 and Moore 2015 were at high risk of bias. When these two of fatigue (RR 2.16, 95% CI 0.20 to 23.42; 1 study, 214 participants; P
studies were excluded, the result was unchanged (RR 1.21, 95% = 0.53; Analysis 1.20 Moore 2015), joint pain (RR 0.22, 95% CI 0.01 to
CI 0.17 to 8.72; 2 studies, 457 participants; P = 0.85; I2 = 98%). We 4.43; 1 study, 214 participants; P = 0.32; Analysis 1.21 Moore 2015),
downgraded the evidence for this outcome to very low certainty for muscle pain (RR 0.54, 95% CI 0.05 to 5.85; 1 study, 214 participants;
risk of bias, inconsistency and imprecision (Summary of findings 1). P = 0.61; Analysis 1.22 Moore 2015), decrease in lipid (RR 1.62, 95%
CI 0.60 to 4.38; 1 study, 214 participants; P = 0.35; Analysis 1.23;
Based on results from two included studies (Lambertini 2015a; Moore 2015), thromboembolism (RR 3.23, 95% CI 0.13 to 78.43;
Moore 2015), the incidence of vaginal dryness was 26 of 250 (10.4%) 1 study, 214 participants; P = 0.47; Analysis 1.24; Moore 2015),
in the GnRH agonist plus chemotherapy group and 21 of 238 (8.8%) agitation (RR 1.29, 95% CI 0.41 to 4.11; 1 study, 214 participants; P
in the chemotherapy alone group. The RR was 1.18 (95% CI 0.68 = 0.44; Analysis 1.25; Moore 2015), anxiety (RR 2.42, 95% CI 0.77 to
to 2.04; 488 participants; I2 = 0%; Analysis 1.15), with no difference 7.63; 1 study, 214 participants; P = 0.13; Analysis 1.26 Moore 2015),
between groups (P = 0.55). We performed sensitivity analysis for depression (RR 3.23, 95% CI 0.90 to 11.61; 1 study, 214 participants;
this outcome excluding one included study with high risk of bias P = 0.07; Analysis 1.27 Moore 2015), and insomnia (RR 5.00, 95 % CI
(Moore 2015). Only one trial remained and the result was the same 0.62 to 40.28; 1 study, 60 participants; P = 0.13; Analysis 1.28 Gerber
(RR 1.01, 95% CI 0.48 to 2.10; 1 study, 274 participants; P = 0.98). We 2011).
downgraded the evidence for this outcome to moderate certainty
Comparison 2: GnRH agonist-antagonist cotreatment plus
for risk of bias (Summary of findings 1).
chemotherapy versus chemotherapy alone
Based on results from two included studies (Gerber 2011; Song Only one included RCT discussed GnRH agonist-antagonist
2013), the incidence of urogenital symptoms was 95 of 119 (79.8%) cotreatment (Elgindy 2013).
in the GnRH agonist plus chemotherapy group and 95 of 124 (76.6%)
in the chemotherapy alone group. The RR was 2.37 (95% CI 0.01 Primary outcome
to 448.16; 2 studies, 243 participants; I2 = 96%; Analysis 1.16), with Menstruation recovery or maintenance
no difference between groups (P = 0.75). We performed sensitivity
analysis for this outcome excluding one included study with high The limited evidence from Elgindy 2013 showed the incidence
risk of bias (Gerber 2011). Only one trial remained and the result of menstruation recovery or maintenance was 20 of 25 (80%)
was the same (RR 1.00, 95% CI 0.98 to 1.02; 1 study, 184 participants; in both the GnRH agonist plus chemotherapy group and the
P = 1.00). chemotherapy alone group during the 12-month follow-up period.
The RR was 1.00 (95% CI 0.76 to 1.32; 1 study, 50 participants;
Based on results from two included studies (Lambertini 2015a; Analysis 2.1), with no difference between groups (P = 1.00). In the
Moore 2015), the incidence of sweating was 31 of 250 (12.4%) in the GnRH agonist plus chemotherapy group, 13 of 25 participants had
GnRH agonist plus chemotherapy group and 18 of 238 (7.6%) in the menstruation recovery or maintenance (52.0%) in comparison to
chemotherapy alone group. The RR was 1.65 (95% CI 0.93 to 2.80; 2 the chemotherapy alone group, in which 14 of 25 participants had
studies, 488 participants; I2 = 0%; Analysis 1.17), with no difference menstruation recovery or maintenance (56.0%) during follow-up
between groups (P = 0.09). We performed sensitivity analysis for period longer than 12 months. The RR was 0.93 (95% CI 0.56 to 1.55;
this outcome excluding one included study with high risk of bias 1 study, 50 participants; Analysis 2.1) with no difference between
(Moore 2015). Only one trial remained and the result was the same groups (P = 0.78). We downgraded the evidence for this outcome to
(RR 1.65, 95% CI 0.83 to 3.29; 1 study, 274 participants; P = 0.16). very low certainty for risk of bias and serious imprecision (Summary
of findings 2).
Based on results from two included studies (Lambertini 2015a;
Moore 2015), the incidence of headache was 40 of 250 (16.0%) in Pregnancy
the GnRH agonist plus chemotherapy group and 20 of 238 (8.4%)
The limited evidence from Elgindy 2013 showed the incidence
in the chemotherapy alone group. The RR was 2.54 (95% CI 0.54
of pregnancy rate was 1 of 25 (4.0%) in the GnRH agonist plus
to 11.92; 2 studies, 488 participants; I2 = 75%; Analysis 1.18), with chemotherapy group and 0 of 25 (0%) in the chemotherapy
no difference between groups (P = 0.24). We performed sensitivity alone group. The RR was 3.00 (95% CI 0.13 to 70.30; 1 study, 50
analysis for this outcome excluding one study with high risk of bias participants; Analysis 2.2), with no difference between groups (P
(Moore 2015). Only one trial remained and the result was the same = 0.49). We downgraded the evidence for this outcome to very
(RR 1.34, 95% CI 0.78 to 2.31; 1 study, 274 participants; P = 0.29). low certainty for risk of bias and serious imprecision (Summary of
findings 2).
Based on results from three included studies (Gerber 2011;
Lambertini 2015a; Song 2013), the incidence of mood swings was DISCUSSION
107 of 266 (40.2%) in the GnRH agonist plus chemotherapy group
and 111 of 251 (44.2%) in the chemotherapy alone group. The RR Summary of main results
was 1.00 (95% CI 0.98 to 1.02; 3 studies, 517 participants; I2 = 0%;
Analysis 1.19), with no difference between groups (P = 0.99). We The review included 12 RCTs involving 1369 participants to evaluate
performed sensitivity analysis for this outcome excluding one study the effect of GnRH analogues on the prevention of chemotherapy-
with high risk of bias (Gerber 2011). Two studies remained and the induced premature ovarian failure in premenopausal women.
Informed decisions.

The participants were diagnosed with breast malignancy, lower and ovulation was more prevalent in GnRH agonist plus
ovarian malignancy, or Hodgkin's lymphoma. Most women of chemotherapy groups than that in chemotherapy-alone groups.
included studies received alkylating- or platinum complexes-based
chemotherapy. Elgindy 2013 found that some women who menstruated in the
12-month follow-up period developed amenorrhoea later in both
Protection of GnRH agonist against chemotherapy-induced chemotherapy plus GnRH agonist groups and chemotherapy alone
premature ovarian failure groups; while Lambertini 2015a found substantial restoration of
menstruation after chemotherapy-related amenorrhoea in long-
Pooled results showed that the incidence of menstruation recovery
term follow-up. Researchers believed that regular menses shortly
or maintenance in chemotherapy plus GnRH agonist groups was
after chemotherapy completion does not rule out the development
higher than that in chemotherapy alone groups during the 12-
of premature ovarian failure at a later date, and restoration of
month follow-up period, but we observed no difference during
menstruation after chemotherapy-related amenorrhoea is also
follow-up periods longer than 12 months (low-certainty evidence;
possible (Lutchman-Singh 2005). Thus, the protective effect of
Summary of findings 1). Treatment-related premature ovarian
GnRH agonist on menstruation is complex and needs more
failure, which was defined as no resumption of menstrual activity
research.
with postmenopausal FSH levels at least one year after the
completion of chemotherapy, occurred less often when GnRH Most oncologists recommend waiting two to five years after
agonist was given with chemotherapy compared to chemotherapy concluding cancer treatments before trying to achieve pregnancy
alone (moderate-certainty evidence; Summary of findings 1). because the majority of cancers recur during this time frame and
Evidence on the effects of GnRH agonist in the age subgroup was due to concerns that exposure to chemotherapy or radiotherapy
little and inconsistent. (or both) may have genetically damaged maturing ovaries. Pooled
results in this review demonstrated no difference in pregnancy rates
GnRH agonist had a protective effect on ovulation rates (low-
between groups. However, these studies did not give details on the
certainty evidence; Summary of findings 1), however, there was
length of time after the end of chemotherapy before pregnancy was
no difference in pregnancy rates between chemotherapy plus
achieved, nor the use of contraception.
GnRH agonist groups and chemotherapy groups (low-certainty
evidence; Summary of findings 1). We are cautious about this FSH and LH levels are commonly used hormone markers for
conclusion because there were insufficient data about whether the premature ovarian failure. There were discrepancies in the results
participants intended to become pregnant. relating to FSH/LH levels. Five included studies reported protective
effects by GnRH agonist on ovaries in respect of FSH/LH levels
Although most included studies discussed hormone levels, most
(Badawy 2009; Gerber 2011; Gilani 2007; Karimi-Zarchi 2014; Song
results were not presented in a form that we could meta-analyse
2013), whereas the other four studies (Elgindy 2013; Giuseppe
and the results were discrepant. Evidence of ultrasound antral
2007; Lambertini 2015a; Munster 2012), found that there was no
follicle count and survival rate was very sparse overall, and often
difference in FSH/LH levels between GnRH agonist-chemotherapy
not presented in a form that we could meta-analyse, making
groups and chemotherapy-alone groups. Anti-Mullerian hormone
interpretation difficult.
(AMH) is also a valid and valuable marker of ovarian follicle
Most common adverse effects of GnRH analogues include reserve. Two studies found that there was no difference regarding
vasomotor symptoms, hot flushes, vaginal dryness, urogenital AMH between groups. Inhibin A is secreted by dominant follicles
symptoms, headaches, sleep disturbance, sweating, depression and corpus lutea, while inhibin B is secreted by developing pre-
and mood swings. The pooled analyses of safety data showed no antral and small antral follicles. Low levels of inhibin are typical
difference in adverse effects between GnRH agonist groups and in postmenopausal women (De Koning 2000; Luborsky 2000;
control groups. The certainty of evidence ranged from very low to Shelling 2000). Levels of inhibin may be an alternative indicator for
moderate (Summary of findings 1). premature ovarian failure than the currently used FSH/LH levels,
for which there are cyclical changes and inter-patient variability.
Protection of GnRH agonist-antagonist cotreatment against However, only one study provided data regarding inhibin B levels
chemotherapy-induced premature ovarian failure and found that there was no difference between groups (Giuseppe
2007). Other commonly measured hormone markers include
A combination of GnRH antagonist and GnRH agonist appears to estradiol and progesterone. Five out of seven studies reported
be useful because it combines the quick onset of action of GnRH no differences in estradiol levels between groups (Badawy 2009;
antagonist with the long-lasting effects of GnRH agonist. However, Elgindy 2013; Gerber 2011; Lambertini 2015a; Song 2013). On the
we only included one RCT involving GnRH agonist-antagonist whole, most data were incompletely reported and we could not
cotreatment (Elgindy 2013). The limited evidence from this study meta-analyse them. The limited opportunities for meta-analysis
showed cotreatment had no protective effect on the ovaries in might give an incomplete picture of the effects of GnRH agonist on
respect of menstruation recovery or maintenance, regardless of the hormone levels.
follow-up periods. There was also no difference in pregnancy rates
between groups (Summary of findings 2). Ovaries become more sensitive to chemotherapeutic agents in
older women (Hickman 2018; Leonard 2017). Chemotherapy-
Overall completeness and applicability of evidence induced ovarian damage may be drastically different in women
Despite most included studies being at unclear risk of bias, we under the age of 35 than in those between 35 and 40 and over 40. We
found evidence to support a conclusion that the GnRH agonist found very little evidence on the effects of GnRH for age subgroup.
was effective in protecting ovarian function during chemotherapy. Even where data were available, it was often incompletely reported
Incidence of treatment-related premature ovarian failure was and the results were totally different (Karimi-Zarchi 2014; Leonard
2017; Song 2013). Leonard 2017 found a protective effect of
Informed decisions.

goserelin on both the rate of amenorrhoea alone and on premature the impact on primary outcomes, including menstruation recovery
ovarian failure in women aged 40 or older; while the effect was or maintenance, premature ovarian failure and pregnancy, were
less clear in women over 40 years. However, Song 2013 reported limited, as the primary outcomes were objective indicators.
no difference between different age subgroups (women ≤ 35 years
and younger and women older than 35 years) regarding premature For comparisons between GnRH agonist plus chemotherapy versus
ovarian failure between chemotherapy plus GnRH-agonist groups chemotherapy alone, we judged the certainty of evidence on
and chemotherapy alone groups. Karimi-Zarchi 2014 found that premature ovarian failure as moderate due to risk of bias caused by
GnRH agonist had a protective effect in woman over 35 years unclear study methodology or study design limitations. Evidence
instead of woman under 35 years. The limited opportunities for that we rated as low certainty included evidence on menstruation
meta-analysis made it difficult to know the effect of GnRH agonist recovery or maintenance, pregnancy, and ovulation. Evidence was
on different age subgroups. often undermined by risk of bias and inconsistency (I2 > 50%).
Additional reasons for downgrading the certainty of evidence
Chemotherapeutic agents are often used in combination and included imprecision (small sample size) and indirectness (the
therefore it is difficult to evaluate the risk of ovarian damage of population should be restricted to women who intended to become
each individual agent. Some reports concluded that alkylating pregnant for the outcome of pregnancy rate). Hormone levels as
agents, cisplatin and adriamycin are among the most toxic agents secondary outcomes were reported in almost all studies; however,
(Blumenfeld 1999; Falcone 2005). Almost all recruited women in most data were incompletely reported and could not be meta-
this review underwent treatment with chemotherapeutic agents analysed. The limited opportunities for meta-analysis might give
that are considered to be the most toxic towards ovarian function, an incomplete picture of the effects of GnRH agonist on hormone
treatment durations were usually above six courses, and the levels. Ultrasound antral follicle count and survival rate were
administration of agents were usually via the intravenous route. seldom reported. The evidence was generally of moderate to very
However, it was not possible to get an understanding of the low certainty for adverse effects, and often undermined by unclear
relationship between effects of GnRH analogues and treatment study methodology or study design limitations, inconsistency, and
regimen for cumulative dose, dose-intensity, duration and the imprecision (wide confidence interval crossing the line of no effect).
route of administration in this review.
Only one included RCT, with a small sample size, compared
Four included studies reported data regarding adverse effects GnRH agonist-antagonist cotreatment plus chemotherapy versus
of GnRH agonist injection, such as hot flushes, vaginal dryness, chemotherapy alone. Thus, the evidence was very low certainty due
urogenital symptoms, headaches, sleep disturbance, sweating, to concern about risk of bias and serious imprecision (single RCT
depression and mood swings (Gerber 2011; Lambertini 2015a; with small sample size).
Moore 2015; Song 2013). We did not detect any difference in
respect of adverse effects between groups. Since GnRH analogues Potential biases in the review process
could decrease utero-ovarian perfusion and exposure of ovaries
We prepared this review using Cochrane methodology, and were
to chemotherapy, administration of GnRH analogues before or
guided by both the Cochrane Handbook for Systematic Reviews
in parallel to chemotherapy may affect anti-tumour effects of
of Interventions (Higgins 2011b), and the standard methods of
chemotherapy, especially for uterine or ovarian malignancies.
Cochrane Gynaecological, Neuro-Oncology and Orphan Cancers.
However, evidence on survival rate was very sparse, and
We strictly followed the review protocol in study selection, data
often not presented in a form that could be meta-analysed,
extraction and data analysis. Two review authors independently
making interpretation difficult. Lambertini 2015a reported five-
performed study selection, data extraction and assessment of risk
year disease-free survival and Moore 2015 reported the four-
of bias. We used standardized data extraction forms.
year Kaplan-Meier estimate of the rate of disease-free survival.
Those two studies included participants with breast cancer. Neither However, this review had limitations. Some important information
studies found any difference between groups. from studies was unclear and this could result in bias. The included
studies differed in some important aspects of design, namely the
Quality of the evidence definition of menstruation recovery or maintenance and premature
We rated the certainty of the evidence and have presented our ovarian failure, and time to follow-up, which could lead to biases
findings in Summary of findings 1 and Summary of findings 2 for key relating to information and misclassification. We tried to contact
outcomes. The review included 12 RCTs involving 1369 participants. the authors of included studies for additional or missing data and
individual patient data, but no one replied. Thus, we extracted all
Most included studies were single-centre trials with small numbers data from published articles. We used the random-effects model
of participants. We made explicit judgements about whether these for analyses. The limitations of this approach were down-weighting
studies were at high risk of bias, according to the criteria given large studies when statistical heterogeneity was present, and giving
in the Cochrane Handbook for Systematic Reviews of Interventions more equal weighting to the studies combined. Women recruited
(Higgins 2017). We judged seven included RCTs as unclear risk in this review were between the ages of 12 and 51.1 years; however,
of bias due to one or more criteria assessed being unclear most studies had no age-determined subgroup analysis. This could
(Badawy 2009; Gilani 2007; Giuseppe 2007; Karimi-Zarchi 2014; also introduce bias due to the fact that chemotherapy-induced
Lambertini 2015a; Leonard 2017; Song 2013), while another five ovarian damage may be drastically different in women of different
were at high risk of bias due to one or more criteria assessed ages. Moreover, the default zero-cell correction could potentially
being high (Elgindy 2013; Gerber 2011; Moore 2015; Munster bias the result of the meta-analysis towards no difference between
2012; Waxman 1987). Random sequence generation, allocation the two groups, as the RR was calculated when there were no events
concealment and blinding in most studies were unclear. Although (pregnancy) in GnRH group.
most studies did not indicate whether blinding was implemented,
Informed decisions.

There are five studies awaiting classification because we were terms of menstruation recovery or maintenance, treatment-related
unable to obtain the full texts. This could generate information bias premature ovarian failure and ovulation. Evidence for protection of
and publication bias within the methodology and processes of the fertility was insufficient and needs further investigation. Evidence
systematic review. was also insufficient to assess the effect of GnRH agonist and
GnRH antagonist cotreatment on ovarian protection against
Agreements and disagreements with other studies or chemotherapy.
reviews
Implications for research
Several recently published systematic reviews and meta-analyses
have discussed the protective effects of GnRH agonist on ovaries. Large and well-designed randomised controlled trials should
Hickman 2018 and Lambertini 2015b found that GnRH agonists be conducted to clarify the effects of GnRH analogues in
had a protective effect against chemotherapy-related premature preventing chemotherapy-induced ovarian failure, especially for
ovarian failure. Although this conclusion was consistent with ours, the use of GnRH antagonists. We suggest that further studies
one major problem with these two reviews was that the review on the protective effect of GnRH analogues supplementation on
authors simply classified un-recovered menstruation during the different age groups or different chemotherapy regimens should
follow-up period as premature ovarian failure and analysed real be conducted. Furthermore, studies should have longer follow-up
premature ovarian failure and amenorrhoea together. Munhoz duration and address the effects on pregnancy rates, anti-tumour
2016 found that GnRH agonist given with chemotherapy was therapy (including five-year-survival) and direct adverse effects
associated with increased rates of menstruation recovery after a (symptoms of hypoestrogenaemia such as hot flashes, headaches
minimum of six months after the last cycle of chemotherapy. This and osteoporosis).
result was partially consistent with ours, which demonstrated that
menstruation recovery or maintenance after chemotherapy plus ACKNOWLEDGEMENTS
GnRH agonist was higher than for chemotherapy alone during a
The authors wish to thank the Cochrane Gynaecological, Neuro-
12-month follow-up period, but no difference was observed during
oncology and Orphan Cancers editorial team: Jo Morrison (Co-
follow-up longer than 12 months. Lambertini 2015b and Munhoz
ordinating Editor) for clinical and editorial advice, Clare Jess
2016 found that GnRH agonist seemed to increase the pregnancy
(Managing Editor) and Tracey Harrison (Assistant Managing Editor)
rate, whereas our results demonstrated no difference in pregnancy
for their editorial support, and Jo Platt (Information Specialist) for
rates between groups. Discrepancies might be due to differences in
her assistance with the search.
the studies and the included population (it included only women
with breast cancer) and absence of subgroup analyses at different This project was supported by the National Institute for Health
follow-up periods. Research, via Cochrane Infrastructure funding to the Cochrane
Gynaecological, Neuro-oncology and Orphan Cancer Group. The
AUTHORS' CONCLUSIONS
views and opinions expressed therein are those of the authors
Implications for practice and do not necessarily reflect those of the Systematic Reviews
Programme, NIHR, NHS or the Department of Health.
Gonadotropin-releasing hormone (GnRH) agonist appears to be
effective in protecting the ovaries during chemotherapy, in
Informed decisions.

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Zhang 2018 {published data only} breast cancer. www.clinicaltrials.gov/ct2/show/NCT00090844?
term=chemotherapy&recrs=abdefghm&type=Intr&intr=GnRH&gndr=Female
Zhang Y, Ji Y, Li J, Lei L, Wu S, Zuo W, et al. Sequential versus
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hormone agonist (GnRHa) among estrogen receptor (ER)-
NCT00380406. Protecting ovaries and fertility during
positive premenopausal breast cancer patients: effects on
chemotherapy - the proof trial: a randomized controlled
ovarian function, disease-free survival, and overall survival.
trial of gonadotropin releasing hormone agonist
Breast Cancer Research and Treatment 2018;168(3):1-8.
(GnRHa) for fertility preservation in oncology patients.
www.clinicaltrials.gov/ct2/show/NCT00380406?
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Anderson 2016 {published data only} NCT02483767 {published data only}

Anderson R, Yellowlees A, Dunlop J, Thomas G, Leonard R. NCT02483767. Gonadotropin-releasing hormone
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Behringer 2007 {published data only} NCT02856048 {published data only}

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Targeted anti-apoptosis activity for ovarian protection against

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Badawy 2009
Methods Study design: single-centre RCT
Study duration: not mentioned
Participants Inclusion criteria: women diagnosed with unilateral adenocarcinoma of the breast, with positive or
negative lymph node status, and with no metastasis who had undergone modified radical mastecto-
my or breast-conserving surgery plus full axillary lymph node dissection. All women were menstruating
normally and aged 18 to 40 years (basal FSH levels < 10 mU/mL)
• Country: Egypt
• Number: GnRH agonist + chemotherapy (n = 40); chemotherapy (n = 40)
• Age (mean ± SD)
◦ GnRH-agonist + chemotherapy: 30 ± 3.51 years
◦ Chemotherapy: 29.2 ± 2.93 years
Exclusion criteria: women with macroscopic metastatic spread of the disease
Interventions Treatment group
• GnRH-agonist + chemotherapy
• Women received subcutaneous goserelin at a dose of 3.6 mg 2 weeks before the initiation of
chemotherapy then every 28 days for 6 months
Informed decisions.

Badawy 2009 (Continued)
Control group
• Chemotherapy
• Women received chemotherapy alone. Chemotherapy included FAC, TP, VAC and BEP
Outcomes Women were followed up monthly for up to 8 months after completion of treatment:
• Menstruation recovery or maintenance

• Ovulation: confirmed by serial ultrasound
• Hormone levels: FSH, LH, estradiol and progesterone
Notes • Funding source: not mentioned

• Declarations of interest: not mentioned
• We contacted Badawy 2009 [pers comm] for additional data
• There was no difference between groups regarding age, body weight, height, number of dissected
lymph nodes and serum LH levels. The chemotherapy dose of 2 groups were not significantly different
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Not mentioned

tion (selection bias)
Allocation concealment Low risk Quote: "sealed, dark envelopes" were used
(selection bias)
Blinding (performance Unclear risk Not mentioned whether participant/personnel/outcome assessment was
bias and detection bias) blinded or not
All outcomes
Incomplete outcome data Low risk Only 1 woman in each group dropped out. Reasons not mentioned
(attrition bias)
All outcomes
Selective reporting (re- Low risk Results of all outcomes mentioned in Methods section were reported in Re-
porting bias) sults section
Other bias Unclear risk Protocol was not mentioned. There was no difference between groups regard-
ing age, body weight, height, number of dissected lymph nodes, serum LH,
and chemotherapy dose

Elgindy 2013
Methods Study design: 2-centre, 4-armed, open-label RCT
Study duration: December 2009 to August 2011
Participants Inclusion criteria: women (18 to 40 years old) with primary hormone insensitive breast cancer (stage
I–IIIa) scheduled for cyclophosphamide-based chemotherapy; and with a history of regular menstrual
periods, transvaginal ultrasound-confirmed presence of both ovaries, and absence of ovarian tumours
or cysts > 40 mm
• Country: Egypt
Informed decisions.

Elgindy 2013 (Continued)
• Number: GnRH agonist + GnRH antagonist + early chemotherapy (n = 25); GnRH agonist + delayed
chemotherapy (n = 25); early chemotherapy (n = 25); delayed chemotherapy (n = 25)
• Age (mean ± SD):
◦ GnRH agonist + GnRH antagonist + early chemotherapy: 33.28 ± 3.3 years
◦ GnRH agonist + delayed chemotherapy: 33 ± 3.8 years
◦ Early chemotherapy: 32.32 ± 3.99 years
◦ Delayed chemotherapy: 32.84 ± 4.3 years
Exclusion criteria: women with advanced breast cancer (stage IIIb–IV), primary ovarian cancer or
pelvic metastases, history of chemotherapy or abdominal or pelvic radiation; women receiving or plan-
ning to receive hormone therapy; and pregnant and nursing women
• Intervention 1: GnRH agonist + GnRH antagonist + early chemotherapy

• Women received chemotherapy after downregulation by a combined GnRH antagonist and agonist
cotreatment. The GnRH antagonist (cetrorelix 0.25 mg daily; Merck Serono) and GnRH agonist (trip-
torelin 3.75 mg; Ferring) were administered until downregulation (estradiol < 50 pg/mL) was con-
firmed. Then, women were instructed to discontinue the GnRH antagonist and to continue using the
GnRH agonist every 4 weeks until the end of chemotherapy
• Intervention 2: GnRH agonist + delayed chemotherapy
• Women received chemotherapy after downregulation by GnRH agonist, which was continued every 4
weeks until the end of chemotherapy
Control group
• Intervention 3: early chemotherapy

• women receive early chemotherapy alone (chemotherapy within 1 week of enrolment). The standard
regimen of intravenous 5-fluorouracil (500 mg/m2), adriamycin (50 mg/m2), and cyclophosphamide
(500 mg/m2) every 21 days for 6 cycles was used in all participants
• Intervention 4: delayed chemotherapy
• women received delayed chemotherapy alone (chemotherapy at least 10 days after study inclusion)
Outcomes Women were followed up on a 6-month basis for 18 months

• Pregnancy
• Hormone levels: FSH, LH, AMH and estradiol
• Antral follicle count
• Adverse events
Notes • This study took place in 2 university-affiliated oncology centres in Egypt (Medical Oncology Depart-
ments, Zagazig University School of Medicine and National Cancer Institute, Cairo University)
• Funding source: funded by the School of Medicine Zagazig University and the Alexandria Regional
Centre for Women's Health
• Declarations of interest: none
• We contacted Elgindy 2013 [pers comm] for missing and additional data
• Surgical intervention and lymph node dissection were performed on a case-by-case basis. Regional
adjuvant radiotherapy was allowed if indicated by the managing oncologist
• Baseline characteristics were comparable between each intervention group and its respective control
groups
Risk of bias
Informed decisions.

Elgindy 2013 (Continued)
Random sequence genera- Low risk Quote: "computer-generated block randomisation scheme with variable block
tion (selection bias) sizes" was used
Allocation concealment Low risk Quote: "The randomisation list was produced by a statistician not involved
(selection bias) with patient recruitment. Allocation concealment was achieved with sequen-
tially numbered, dark, opaque, sealed envelopes"
Blinding (performance High risk Quote: It's an "open-label trial"

bias and detection bias)
All outcomes
Incomplete outcome data Low risk Five women died during the follow-up period: one woman in each group
(attrition bias) except the GnRH agonist plus delayed chemotherapy group, in which two
All outcomes women died
Selective reporting (re- High risk Adverse events as outcomes were not reported
porting bias)
Other bias Unclear risk Protocol was not mentioned. There was no significant difference in baseline
characteristics between groups

Gerber 2011
Methods Study design: randomised, open-label, controlled, multi-centre phase II study
Study duration: March 2005 to December 2007
Participants Inclusion criteria: premenopausal women (aged 18 to 45 years) with primary hormone-insensitive
breast cancer. They had to have had regular and spontaneous menstrual periods before study entry,
with FSH < 15 mlU/mL in the follicular phase of the menstrual cycle. Women had to use adequate non-
hormonal contraceptive measures during study treatment. Treatment with sex hormones was not al-
lowed
• Country: Germany
• Age (median, range):
◦ GnRH-agonist + chemotherapy: 35 (26 to 44) years
◦ Chemotherapy: 38.5 (29 to 47) years
Exclusion criteria: women were excluded for known hypersensitivity reaction to the investigational
compounds, prior cytotoxic treatment for any reason, and distant metastases and if (primary or sec-
ondary) ovarian insufficiency was suspected
• Intervention: GnRH agonist + chemotherapy

• Women received their first injection of 3.6 mg goserelin at least 2 weeks before start of chemothera-
py independently from the day of menstrual cycle and then every 4 weeks until the end of the last
chemotherapy cycle. Before the first administration of chemotherapy, ovarian suppression had to be
proven. Otherwise, start of chemotherapy was postponed until proven ovarian suppression
Control group
• Intervention: chemotherapy
Informed decisions.

Gerber 2011 (Continued)
• Women received chemotherapy alone. Chemotherapy regimen including at least an anthracycline
and cyclophosphamide with > 500 mg/m2 per cycle and > 2400 mg/m2 in total per regimen, adminis-
tered every 3 weeks for 6 or 8 cycles
Outcomes Women were followed up on a 6-month basis for at least 24 months

• Pregnancy
• Hormone levels: FSH, LH, AMH, inhibin B, estradiol, progesterone and sexual hormone-binding glob-
ulin
• AFC
• Adverse events
Notes • Funding source: funded by companies including Novartis and AstraZeneca

• Declarations of interest (Honoraria): Bernd Gerber, AstraZeneca, Roche, Sanofi-Aventis, Novartis,
GlaxoSmithKline; Olaf Ortmann, Novartis, Pfizer, AstraZeneca; Tanja Fehm, Roche, Novartis
• We contacted Gerber 2011 [pers comm] for additional data
Risk of bias

Allocation concealment Unclear risk Not mentioned

(selection bias)
Blinding (performance High risk Quote: it's an "open-label trial"

All outcomes
Incomplete outcome data Low risk The risk of bias in the primary outcomes is low as only two women in each
(attrition bias) group withdrew due to adverse event, progression of disease and unwilling-
All outcomes ness to participate. Antral follicle count was only measured in 10 women, thus
the risk of bias for this secondary outcome was high
Selective reporting (re- Low risk Results of all outcomes mentioned in protocol were reported
porting bias)
Other bias Unclear risk There was no significant difference in baseline characteristics between groups

Gilani 2007
Methods Study design: RCT
Participants Inclusion criteria: post-menarchal women aged 12 to 40 years with ovarian malignancy; history of nor-
mal menstrual rhythm; women who had 1 or 2 ovaries and normal laboratory tests after surgery; alky-
lating or alkylating-like metronomic chemotherapy; different histological ovarian tumours and any FI-
GO stage
• Country: Iran
Informed decisions.

Gilani 2007 (Continued)
• Age (median, range ):
◦ GnRH-agonist + chemotherapy: 22 years (15 to 35 years)
◦ Chemotherapy: 21 years (13 to 33 years)
Exclusion criteria: < 12 or > 40 years; had received radiotherapy; had received > 6 months' chemother-
apy, single agent chemotherapy or non-alkylating or alkylating-like metronomic chemotherapy

• women were given the GnRH analogue (intramuscular depot injection of 3.75 mg diphereline) each
month before and during treatment with chemotherapy. The first dose was administered 7 days be-
fore starting chemotherapy
Control group
• Women received chemotherapy alone. The chemotherapy included TC, TP, VAC.
Outcomes Women were followed up for 6 months after chemotherapy

• Hormone levels: FSH, LH and estradiol

• There was no difference between groups regarding age, body weight, height, number of dissected
lymph nodes and serum LH. The chemotherapy dose of the 2 groups were not significantly different
Risk of bias


(selection bias)
All outcomes
Incomplete outcome data Low risk All women were followed up to the end of the trial
(attrition bias)
All outcomes

Informed decisions.

Giuseppe 2007
Methods Study design: single-centre, RCT
Study duration: 1996 to 2002
Participants Inclusion criteria: female cancer survivors previously affected by Hodgkin's lymphoma, aged 20 to 38
years, treated with the same standardized chemotherapeutic schedule
• Country: Italy
• Age (mean ± SD)
◦ GnRH agonist + chemotherapy: 21.3 ± 5.3 years
Exclusion criteria: not mentioned

• Women received GnRH agonist (triptorelin monthly 3.25 mg or 11.25 mg depot) before starting
chemotherapy, then monthly depot was administered every 3 months during the chemotherapy
Control group
• Women only received chemotherapy
Outcomes Women were followed up every 6 months after cessation of chemotherapy (mean follow-up time was
4.2 ± 2.8 years)

• Pregnancy
• Hormone levels: FSH, LH, AMH and inhibin B

• We contacted Giuseppe 2007 [pers comm] for additional data
• The study took place in the Haematology Dept, University of Bari
• 13 women were treated with ABVD; another 13 women with ABVD, alternating with CMOPP; while an-
other 3 women were treated with CMOPP and DHAP. 24 women received supradiaphragmatic radio-
therapy for a total dosage of 2900 to 6300 Gy. No women had pelvic radiotherapy
Risk of bias


(selection bias)
All outcomes
Informed decisions.

Giuseppe 2007 (Continued)
Incomplete outcome data Low risk All women were followed up and included in the analyses
(attrition bias)
All outcomes

Karimi-Zarchi 2014
Study duration: 2010 to 2011
Participants Inclusion criteria: women with breast cancer aged 25 to 45 years; oestrogen receptor-negative and
progesterone receptor-negative breast cancer; primary Stages to Stage II (T2N/M0); candidate for
chemotherapy
• Country: Iran
• Age (mean ± SD): 37 ± 5 years
Exclusion criteria: advanced stages of breast cancer; low complaint cases in receiving diphereline
monthly; oestrogen receptor-positive and progesterone receptor-positive breast cancer; concurrent
malignancies; FSH ≥ 30 IU/L

• Women received 3.75 mg intramuscular diphereline every 28 days for 6 months simultaneous with
chemotherapy
Control group
• Women received chemotherapy alone (600 mg/m2 cyclophosphamide; 60 mg/m2 adriamycin; 75 mg/
m2 taxotere)
Outcomes Women were followed up at the end of months 3 and 6 after cessation of chemotherapy

• Hormone levels: FSH, LH and estradiol

• We contacted Karimi-Zarchi 2014 [pers comm] for additional data
• The study took place in Shahid Sadoughi Hospital
Risk of bias
Informed decisions.

Karimi-Zarchi 2014 (Continued)

(selection bias)
Blinding (performance Unclear risk Not mentioned

All outcomes
Incomplete outcome data Low risk All women were followed up

(attrition bias)
All outcomes
Other bias Unclear risk Protocol was not mentioned. There was no mention of baseline characteristics
between groups

Lambertini 2015a
Methods Study design: multi-centre, randomised phase 3 trial
Study duration: October 2003 to January 2008
Participants Inclusion criteria: histologically proven stage I, II, or III breast cancer; aged 18 to 45 years, pre-
menopausal
• Country: Italy
◦ GnRH agonist + chemotherapy: 39 (24 to 45) years
◦ Chemotherapy: 39 (25 to 45) years
Exclusion criteria: previous chemotherapy, radiotherapy, for both cancer or nonneoplastic diseases;
evidence of distant metastases; other malignancies in the previous 5 years, except basal or squamous
cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix; and pregnancy or lacta-
tion

• Women received 3.75 mg intramuscular triptorelin at least 1 week before starting chemotherapy and
then every 4 weeks during the treatment (the last dose was given before the last cycle of chemother-
apy)
Control group
• Women received chemotherapy alone (100 mg/m2 of oral cyclophosphamide on days 1 to 14 or 600
mg/m2 of intravenous cyclophosphamide on days 1 and 8; 40 mg/m2 of methotrexate on days 1 and
8; and 600 mg/m2 of fluorouracil on days 1 and 8)
Outcomes Women were followed up every 12 months (the median long-term follow-up was 7.3 years)
Informed decisions.

Lambertini 2015a (Continued)
• POF: no resumption of menstrual activity and postmenopausal levels of both FSH and estradiol for 1
year after the end of chemotherapy
• Pregnancy
• Hormone levels: FSH and estradiol
• Disease-free survival
• Adverse events
Notes • This study took place in 16 Italian centres

• Funding source: sponsored by the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy and the
Associazione Italiana per la Ricerca sul Cancro, Italy. The triptorelin used in the study was provided
by Ipsen, Milan, Italy
• Declarations of interest: Dr Del Mastro reported receiving honoraria for speaking activity from Ipsen.
Dr Garrone reported receiving payment for lectures from AstraZeneca
• We contacted Lambertini 2015 [pers comm] for additional data
• All of the women with hormone-sensitive tumours (ER-positive, PR-positive, or both) received 20 mg/d
of tamoxifen for 5 years starting from the end of chemotherapy. In both study groups, women who re-
sumed their ovarian function during the 12-month period of observation after the end of chemother-
apy or at any time during the following 5 years of follow-up were allowed to receive GnRH agonists
for at least 2 years
• Baseline characteristics were comparable between groups
Risk of bias
Random sequence genera- Low risk Quote: "Randomisation lists were prepared with the use of permuted blocks of
tion (selection bias) different sizes and a 1:1 ratio"
Allocation concealment Low risk Quote: "Randomisation was performed centrally by faxing the Clinical Trials
(selection bias) Unit of the National Cancer Research Institute in Genoa (Italy)"
All outcomes
Incomplete outcome data Low risk In 12-month follow-up, 6 women in chemotherapy-alone group did not receive
(attrition bias) chemotherapy and 6 were lost to follow-up, while 2 women in chemother-
All outcomes apy plus triptorelin group did not receive chemotherapy and 7 were lost to
follow-up. At the study cut-off date of long follow-up period (median fol-
low-up was 7.3 years), 18 and 17 women were lost to follow-up in chemothera-
py-alone group and chemotherapy plus triptorelin group respectively
Selective reporting (re- Low risk All outcomes mentioned in the Protocol were reported
porting bias)
Other bias Low risk No information specified. There was no significant difference in baseline char-
acteristics between groups

Leonard 2017
Methods Study design: multi-centre RCT
Informed decisions.

Leonard 2017 (Continued)
Study duration: August 2004 to December 2009
Participants Inclusion criteria: premenopausal women (defined as regular menses in the 12 months prior to
chemotherapy) with histologically confirmed breast cancer who were to receive adjuvant or neo-ad-
juvant chemotherapy; women with estradiol receptor-negative tumours; women with estradiol recep-
tor-positive tumours for whom the investigator did not deem ovarian suppression necessary as part of
the treatment; the breast cancers could be up to stage IIIB (T1-T4 with N0-2) and complete excision of
the tumour before adjuvant chemotherapy or planned after neoadjuvant therapy
• Country: England, UK
◦ GnRH agonist + chemotherapy: 37.9 (25.9 to 50.0) years
◦ Chemotherapy: 38.8 (24.8 to 51.1) years
Exclusion criteria: women who had prior chemotherapy or endocrine therapy

• Women received 3.6 mg goserelin implant or nothing starting at least 1week, and preferably 2 weeks,
prior to the start of the chemotherapy treatment, and continuing goserelin 3 to 4 weekly until the end
of the chemotherapy treatment
Control group
• Women received chemotherapy alone. Chemotherapy regimens included 6 to 8 cycles of cyclophos-
phamide and/or anthracycline-containing regimens with or without a taxane. Chemotherapy had to
start within 8 weeks of definitive surgery
Outcomes Women were followed up 6-monthly for 24 months

• POF: no menses between 12 and 24 months after randomisation, combined with FSH > 25 IU/L
• Hormone levels: FSH, LH, AMH and estradiol
Notes • Funding source: the study was funded by Cancer Research UK. Roche Diagnostics provided the
reagents for AMH analysis
• Declarations of interest: RL has undertaken consultancy work for Amgen, Pfizer, Novartis, Roche, Te-
va, Caris; GB has undertaken consultancy work for Eisai, Genomic Health, Pfizer, Novartis; JM has un-
dertaken consultancy work for Puma biotechnology; AY has undertaken consultancy work for Kyowa
Kirin, Emergent, Galderma, Immodulan, Ipsen, Leica, Pharmagenesis, ReNeuron, Shield, Tokai; RC re-
ceived research funding from Bayer, Amgen to his institution; RAA has undertaken consultancy work
for Roche Diagnostics. The other authors have no conflicts to disclose
• We contact Leonard 2017 [pers comm] for additional data
Risk of bias
Random sequence genera- Low risk Quote: "Randomisation was centrally performed by telephone to the trial cen-
tion (selection bias) tre, eligibility was confirmed verbally, and treatment was allocated by com-
puter-generated lists"
Informed decisions.

Leonard 2017 (Continued)
Allocation concealment Low risk Quote: "Randomisation was centrally performed by telephone to the trial cen-
(selection bias) tre, eligibility was confirmed verbally, and treatment was allocated by com-
puter-generated lists"
All outcomes
Incomplete outcome data Low risk Three in each arm had died within 24 months of randomisation. For a further
(attrition bias) 19 women (11 in the control arm and 8 in the intervention arm), menstrual
All outcomes status during the interval between the 12-month follow-up visit and the 24-
month follow-up visit could not be determined from the data available
Selective reporting (re- Low risk All outcomes mentioned in Protocol were reported
porting bias)
Other bias Low risk The original protocol restricted the entry of women to those with estradiol re-
ceptor-negative tumours only, but women with estradiol receptor-positive tu-
mours for whom the investigator did not deem ovarian suppression necessary
as part of the treatment were subsequently allowed entry to the trial after a
protocol amendment. There was no significant difference in baseline charac-
teristics between groups

Moore 2015
Methods Study design: open-label, international multi-centre, randomised phase 3 trial
Study duration: February 2004 to May 2011
Participants Inclusion criteria: premenopausal women, 18 to 49 years of age were eligible if they had operable
stage I-IIIA estradiol receptor-negative and progesterone receptor-negative breast cancer. Eligible par-
ticipants had taken no oestrogens, antioestrogens, selective estradiol receptor modulators, aromatase
inhibitors, or hormonal contraceptives within the month before inclusion
• Country: Australia, Switzerland, Peru, USA

◦ GnRH agonist + chemotherapy: 37.6 (26.1 to 48.6) years
◦ Chemotherapy: 38.7 (25.1 to 49.9) years
Exclusion criteria: Exceptions were made for the use of hormonal contraception in women < 35 years
of age that was discontinued before randomisation and for hormonal treatment for up to 2 months for
the purposes of in vitro fertilization and cryopreservation of embryos or oocytes before randomisation

• Women were given 3.6 mg subcutaneous goserelin 1 week before the initial chemotherapy dose and
then every 4 weeks for the duration of the chemotherapy (the last dose was given 2 weeks before or
after the final chemotherapy dose)
Control group
Informed decisions.

Moore 2015 (Continued)
• Women received chemotherapy alone. A total of 91% women received anthracycline-based
chemotherapy
Outcomes Women were followed up annually (the median follow-up time at the time of the end-point analysis
was 4.1 years)
• POF: amenorrhoea for the preceding 6 months and FSH levels in the postmenopausal range at 2 years
• Pregnancy
• Disease-free survival and overall survival
• Adverse events
Notes • Funding source: grants from National Cancer Institute at the National Institutes of Health
• Declarations of interest: Dr. Albain reports her institution received accrual credits for the women en-
rolled on this study and funding as a U10 institution during the conduct of this study. Dr. Fabian reports
grant support from the Oregon Health and Science University during the conduct of the study. Dr. Gel-
ber reports grant support from the NIH and non-financial support from AstraZeneca during the con-
duct of the study. Dr. Hortobagyi reports grant support and personal fees from Novartis and person-
al fees from Peregrine Pharmaceuticals, Pfizer, Galena Biopharma, Genentech, Amgen, AstraZeneca,
Allergan, and Sanofi-Aventis outside the submitted work. Dr. Lombard reports non-financial support
from AstraZeneca outside the submitted work.
• We contacted Moore 2015 [pers comm] for missing and additional data
Risk of bias


(selection bias)
Blinding (performance High risk Quote: it's an "open-label trial"

All outcomes
Incomplete outcome data Low risk Data on pregnancy and survival were collected in 218 women, and data on ad-
(attrition bias) verse events were collected in 214 women. Attrition mainly due to withdrawal,
All outcomes loss to follow-up and non-response. The attrition bias for these outcomes were
at low risk. Data on POF were available for only 88 and 69 women in treatment
group and control group respectively. Attrition was due to incomplete data on
menstruation or FSH levels. The attrition bias for POF was at high risk
Selective reporting (re- Low risk All outcomes mentioned in Protocol were reported
porting bias)
Other bias High risk The study closed early owing to loss of funding for study-drug distribution.
ClinicalTrials.gov Identifier: NCT00196846

Munster 2012
Informed decisions.

Munster 2012 (Continued)
Study duration: July 2003 to January 2007
Participants Inclusion criteria: premenopausal women (< 45 years of age with a FSH level < 40 mIU/mL and ≥ 2
menstrual periods in the preceding 6 months) with newly diagnosed early-stage breast cancer (stages I-
III) and planned adjuvant or neoadjuvant chemotherapy
• Country: USA
◦ GnRH agonist + chemotherapy: 39 (21 to 44) years
◦ Chemotherapy: 38 (26 to 44) years
Exclusion criteria: pregnancy or lactation, prior chemotherapy, or bilateral oophorectomy or ovarian

irradiation before enrolment; history of other cancers; personal or familial (first-degree relative) prema-
ture ovarian failure; plan to undergo an oophorectomy/hysterectomy within 2 years; and oral contra-
ceptive administration

• Women received triptorelin (3.75 mg) every 28 to 30 days by intramuscular injection starting no sooner
than 4 weeks and at least 7 days before the first cycle of chemotherapy and continued throughout
chemotherapy duration
Control group:
• Women did not receive GnRH agonist as co-treatment
Outcomes Women were followed up for at least 2 years after the last cycle of chemotherapy (median follow-up
time was 18 months from completion of last chemotherapy)

• Pregnancy
• Hormone levels: FSH and inhibin B
Notes • Funding source: National Cancer Institute Award

• We contacted Munster 2012 [pers comm] for missing and additional data
• 20 women in treatment group and 16 women in control group received tamoxifen. The chemotherapy
regimen included doxorubicin plus cyclophosphamide; fluorouracil plus doxorubicin plus cyclophos-
phamide and fluorouracil plus epirubicin plus cyclophosphamide
Risk of bias
Random sequence genera- Low risk Quote: "computerized randomisation" was used

(selection bias)
All outcomes
Incomplete outcome data Low risk 1 participant in the triptorelin arm withdrew consent before first treatment.
(attrition bias) Another, in the control arm, was found to have residual disease after neoad-
Informed decisions.

Munster 2012 (Continued)
All outcomes juvant chemotherapy and was treated with additional chemotherapy not per-
mitted by protocol
Selective reporting (re- High risk Protocol was mentioned in the published article. Levels of serum inhibin A
porting bias) were not reported
Other bias High risk The study initially planned to enrol 124 women, but the trial was stopped for
futility after 49 women were enrolled. The planned follow-up time was 5 years
but was stopped early because no difference between the 2 groups was seen

Song 2013
Methods Study design: single-centre, prospective randomised phase II study
Study duration: February 2010 to March 2012
Participants Inclusion criteria: premenopausal women, 18 to 45 years; proven histological stage I–III breast cancer;
received primary surgical therapy before adjuvant chemotherapy; no history of prior chemotherapy or
hormone therapy; no distant metastases or localized cancer relapse; no prior or concomitant malig-
nancy; no history of primary or secondary ovarian insufficiency; and no pregnancy or nursing
• Country: China
• Age (mean ± SD):
◦ GnRH agonist + chemotherapy: 40.3 ± 6.5 years

• Women received subcutaneous injection of 3.75 mg leuprolide. If ovarian suppression was confirmed,
women started to receive chemotherapy; otherwise, chemotherapy was not started until ovarian sup-
pression was proved. During chemotherapy, women were given leuprolide at same dosage every 4
weeks
Control group
• Women received chemotherapy alone. All women received cyclophosphamide-doxorubicin-based
chemotherapy as determined by oncologist before randomisation
Outcomes Women were followed up for 12 months after the end of chemotherapy

• POF: FSH level > 40 mIU/mL and estradiol < 20 pg/mL in the absence of resumption of menstrual ac-
tivity within 12 months after the end of chemotherapy
• Hormone levels: FSH and estradiol
• Adverse events
Notes • This study took place at Jiangyin Hospital Affiliated to Nanjing University of Traditional Chinese Med-
icine
• Funding source: not mentioned
• We contacted Song 2013 [pers comm] for additional data
Informed decisions.

Song 2013 (Continued)
Risk of bias


(selection bias)
All outcomes
Incomplete outcome data Low risk Sixteen in chemotherapy-alone group (2 women failed to complete at least
(attrition bias) one cycle of chemotherapy and 14 women were lost to follow-up) and 21 in
All outcomes chemotherapy plus GnRH agonist group (4 women failed to complete at least
one cycle of chemotherapy and 17 women were lost to follow-up) were not in-
cluded in the evaluation
Other bias Unclear risk There was no significant difference in baseline characteristics between groups

Waxman 1987
Participants Inclusion criteria: women aged 17 to 46 years old with Hodgkin's disease
• Country: England, UK
• Age (mean, range):
◦ GnRH agonist + chemotherapy: 28.5 (17 to 34) years
◦ Chemotherapy: 25.9 (17 to 46) years

• Women received buserelin (200 μg 3 times daily intranasally) 1 week prior to and on day 1 of each
cycle of chemotherapy and for a further 3 days after its completion. Each woman was treated with ≤
6 cycles of standard MVPP.
Control group:
• Women only received chemotherapy
Informed decisions.

Waxman 1987 (Continued)
Outcomes Women were followed up for 3 years after completing treatment

• Pregnancy
• Ovulation: confirmed by progesterone levels

Risk of bias


(selection bias)
All outcomes
Incomplete outcome data Low risk One woman died during treatment
(attrition bias)
All outcomes
Other bias High risk Control groups included women who were > 45 years old while GnRH-agonist
group included women less than 34 years old. Besides, low dose of busere-
lin used in the study could have led to incomplete pituitary downregulation,
which might have affected the results
ABVD: Doxorubicin, Bleomycin, Vinblastine, Dacarbazine; AMH: anti-Mullerian hormone; BEP: Bleomycin, Etoposide, Cisplatin; CMOPP:
Cyclophosphamide, Mitoxantrone, Vincristine, Prednisone, Procarbazine; DHAP: Rituximab, Dexamethasone, Ara-C-cytarabine, Platinol;
FAC: 5-Fluorouracil, Doxorubicin, Cyclophosphamide; FIGO: International Federation of Gynaecology and Obstetrics; FSH: follicle-
stimulating hormone; GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; MVPP: Mustine, Vinblastine, Procarbazine,
Prednisone; POF: premature ovarian failure; RCT: randomised controlled trial; TC: Paclitaxel, Carboplatin; TP: Paclitaxel, Cisplatin;
VAC:Vincristine, Actinomycin, Cyclophosphamide; VAC: Vincristine, Actinomycin, Cyclophosphamide

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Bernhard 2007 Not intervention of interest
Demeestere 2016 Wrong population
Mina 2013 Not outcome of interest
Regan 2017 Not intervention of interest
Sverrisdottir 2009 Wrong population
Informed decisions.

Study Reason for exclusion
Zhang 2018 Wrong population

Characteristics of studies awaiting classification [ordered by study ID]

Anderson 2016
Methods Prospective, multi-centre, open-label RCT
Participants 227 premenopausal women with early or locally advanced breast cancer where adjuvant or neoad-
juvant chemotherapy was indicated were included
Interventions • Intervention group: GnRH agonist (3.6 mg goserelin was given 1 to 2 weeks before chemotherapy
and continued every 4 weeks until the end of chemotherapy) + chemotherapy (6 to 8 cycles of
cyclophosphamide and/or anthracycline-containing regimens)
• Control group: chemotherapy
Outcomes • Amenorrhoea
• Hormone levels: AMH
Notes It's a conference abstract. It did not report the number of women in both groups

Behringer 2007
Methods RCT
Participants Women (18 to 40 years) with advanced-stage HL, including stage II with B symptoms and 1 of the
following risk factors: extranodal disease and/or large mediastinal mass, stage III, and IV
Interventions • Intervention group: GnRH analogue (Zoladex) + chemotherapy

• Control group: Oral contraceptive (Microgynon) + chemotherapy
Outcomes • Hormone levels: FSH, LH, inhibin A, inhibin B, AMH, estradiol, progesterone, prolactin, testos-
terone, dehydroepiandrosterones, sex hormone binding globulin
Notes The recruitment of the trial was stopped early and only 23 women included in the final analysis.
Unclear whether GnRH was administered before or in parallel to chemotherapy and the data were
not presented in the abstract

Ismail-Khan 2008
Methods RCT
Participants Premenopausal (age < 44 years, FSH < 40 mIU/mL) women receiving (neo)adjuvant chemotherapy
for breast cancer
Interventions • Intervention group: GnRH agonist (triptorelin) + chemotherapy

Outcomes • Menstruation recovery or maintenance
Informed decisions.

Ismail-Khan 2008 (Continued)
• Hormone levels: FSH, LH, estradiol
Notes It's a conference abstract. Unclear whether GnRH was administrated before or in parallel to
chemotherapy. It did not report the number of women in both groups

Karimi-Zarchi 2011
Methods Double-blinded RCT
Participants 44 young women with Hodgkin lymphoma during cyclophosphamide chemotherapy were included
Interventions • Intervention group: GnRH agonist + chemotherapy


• Hormone levels: FSH, LH
chemotherapy. It did not report the number of women in both groups

Rossi 2015
Methods Phase III randomised study
Participants 88 women with breast cancer undergoing (neo)adjuvant chemotherapy were included

Outcomes • Hormone levels: FSH, AMH, and estradiol
chemotherapy
AMH: anti-Mullerian hormone; FSH: serum levels of follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone; LH: luteinizing
hormone; RCT: randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

Manger 2006
Study name The PREGO-Study
Methods Prospective randomised study
Participants Young women with Systemic Lupus Erythematosus undergoing cyclophosphamide treatment
Interventions Monthly injection of depot GnRH agonist was administered before and continued throughout the
chemotherapy
Outcomes Not known
Informed decisions.

Manger 2006 (Continued)
Starting date Not known
Contact information Karin.manger@rzmail.uni-erlangen.de
Notes None

NCT00090844
Study name Triptorelin for preserving ovarian function in premenopausal women receiving chemotherapy for
early-stage breast cancer
Methods randomised phase II trial
Participants Women ≤ 44 years of age with breast cancer
Interventions • Intervention group: beginning within 1 to 4 weeks before the start of chemotherapy, women re-
ceive intramuscular triptorelin once monthly for 4to6 months during neoadjuvant or adjuvant
systemic chemotherapy
• Control group: women receive neoadjuvant or adjuvant systemic chemotherapy only. Quality of
life is assessed at baseline, monthly during treatment, every 6 months for 2 years, and then annu-
ally for 3 years
Outcomes • Amenorrhoea
• Hormone levels: inhibin A, inhibin B
• Disease-free survival
Starting date Completed
Contact information Not known
Notes Early closure due to low accrual.
Other study ID numbers: CDR0000374991; P30CA076292 (U.S. NIH Grant/Contract ); MCC-0203 (oth-
er identifier: Moffitt CCOP Research Base); NCI-7031 (other identifier: National Cancer Institute Divi-
sion of Cancer Prevention)

NCT00380406
Study name NCT00380406
Methods Double-blind RCT
Participants Women aged 18 to 38 years
Interventions • Intervention group: GnRH agonist (leuprolide) + chemotherapy

• Control group: placebo + chemotherapy
Outcomes • Ovarian failure

• Sonographic and biochemical markers of ovarian reserve
Starting date January 2007
Informed decisions.

NCT00380406 (Continued)
Notes Other study ID numbers: 2006603-01H

NCT02483767
Study name Gonadotropin-releasing hormone agonist for the preservation of ovarian function during
chemotherapy in premenopausal breast cancer (POF)
Methods Prospective randomised control clinical trial
Participants Women aged 18 to 45 years with breast cancer

• Triptorelin administration starts at the inclusion visit and at least 72 days before chemotherapy
with alkylating agents until 1 month after end of chemotherapy (mean duration: 12 months).
Outcomes • Ovarian failure and ovarian dysfunction

• Pregnancy
• Hormone levels: AMH, FSH, estradiol
• Disease-free survival and overall survival
Starting date Completed on 17 October 2017
Notes Other study ID numbers: PUMCH-BC-ovarian suppression

NCT02856048
Study name Co-treatment with GnRH analogues on the ovarian reserve in young women treated with alkylating
agents for cancer (PRESOV)
Methods Multicentre, open-liable RCT
Participants Female participants aged 12 to 25 years with cancer (sarcoma, Ewing, osteosarcoma, lymphoma)


• Pregnancy
• Hormone levels: AMH, FSH, estradiol
• Adverse events
Starting date Active, not recruiting (27 February 2018)
Informed decisions.

NCT02856048 (Continued)
Notes Other study ID numbers: P140932; 2015-001121-17 (EudraCT number)

NCT03444025
Study name Prospective phase II randomised trial of evaluating the effect of adding LHRH analogue to the
neoadjuvant chemotherapy treatment of triple negative breast cancer on pathologic complete re-
sponse (pCR) rates
Methods Open-label RCT
Participants Premenopausal women aged 18 to 60 years with invasive carcinoma of breast
Interventions • Intervention group: GnRH agonist (goserelin) + chemotherapy

• Goserelin 3.6 mg depot injection will be administered subcutaneously every month along with
standard chemotherapy regimen
• Control group: placebo + chemotherapy
Outcomes • Ovarian failure

• Relapse-free survival
• Adverse events
Starting date Not yet recruiting (23 February 2018)
Notes Other study ID numbers: B2017-11
AMH: anti-Mullerian hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone;
LHRH: luteinizing Hormone Releasing Hormone

DATA AND ANALYSES

Comparison 1. GnRH agonist plus chemotherapy versus chemotherapy alone
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1.1 Menstruation recovery 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only
or maintenance
1.1.1 Follow-up time ≤ 12 5 460 Risk Ratio (M-H, Random, 95% CI) 1.60 [1.14, 2.24]
months
1.1.2 Follow-up time > 12 8 869 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.95, 1.22]
months
1.2 Premature ovarian fail- 4 780 Risk Ratio (M-H, Random, 95% CI) 0.44 [0.31, 0.61]
ure (POF)
1.3 Pregnancy 7 703 Risk Ratio (M-H, Random, 95% CI) 1.59 [0.93, 2.70]
Informed decisions.

pants
1.4 Ovulation 2 95 Risk Ratio (M-H, Random, 95% CI) 2.47 [1.43, 4.26]
1.5 Antral follicle count 1 Std. Mean Difference (IV, Random, Totals not selected
95% CI)
1.6 FSH (mUI/L) 2 71 Std. Mean Difference (IV, Random, 0.26 [-0.80, 1.31]
95% CI)
1.7 FSH < 20 mIU/mL 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.8 LH (mUI/L) 2 71 Std. Mean Difference (IV, Random, -0.62 [-1.28, 0.03]
95% CI)
1.9 LH < 20 mIU/L 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.10 AMH (pmol/L) 1 Std. Mean Difference (IV, Random, Totals not selected
95% CI)
1.11 Inhibin B 1 Std. Mean Difference (IV, Random, Totals not selected
95% CI)
1.12 Estradiol 1 Std. Mean Difference (IV, Random, Totals not selected
95% CI)
1.13 Estradiol > 20 pg/mL 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.14 Adverse effects: hot 4 731 Risk Ratio (M-H, Random, 95% CI) 1.49 [0.16, 13.60]
flush
1.15 Adverse effect: vaginal 2 488 Risk Ratio (M-H, Random, 95% CI) 1.18 [0.68, 2.04]
dryness
1.16 Adverse effect: urogen- 2 243 Risk Ratio (M-H, Random, 95% CI) 2.37 [0.01, 448.16]
ital symptoms
1.17 Adverse effect: sweat- 2 488 Risk Ratio (M-H, Random, 95% CI) 1.61 [0.93, 2.80]
ing
1.18 Adverse effect: 2 488 Risk Ratio (M-H, Random, 95% CI) 2.54 [0.54, 11.92]
headache
1.19 Adverse effect: mood 3 517 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.98, 1.02]
swings
1.20 Adverse effect: fatigue 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.21 Adverse effect: joint 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
pain
1.22 Adverse effect: muscle 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
pain
1.23 Adverse effect: de- 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
crease in lipid
Informed decisions.

pants
1.24 Adverse effect: throm- 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
boembolism
1.25 Adverse effect: agita- 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
tion
1.26 Adverse effect: anxiety 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.27 Adverse effect: depres- 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
sion
1.28 Adverse effect: insom- 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
nia

Analysis 1.1. Comparison 1: GnRH agonist plus chemotherapy versus
chemotherapy alone, Outcome 1: Menstruation recovery or maintenance
GnRH-a plus chemotherapy chemotherapy alone Risk Ratio Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
1.1.1 Follow-up time ≤ 12 months

Badawy 2009 35 39 13 39 18.1% 2.69 [1.71 , 4.25]
Elgindy 2013 21 25 20 25 23.2% 1.05 [0.81 , 1.36]
Gilani 2007 15 15 10 15 20.5% 1.48 [1.02 , 2.13]
Karimi-Zarchi 2014 19 21 7 21 14.1% 2.71 [1.46 , 5.05]
Lambertini 2015a 88 139 60 121 24.2% 1.28 [1.02 , 1.59]
Subtotal (95% CI) 239 221 100.0% 1.60 [1.14 , 2.24]
Total events: 178 110
Heterogeneity: Tau² = 0.11; Chi² = 19.20, df = 4 (P = 0.0007); I² = 79%
Test for overall effect: Z = 2.72 (P = 0.006)
1.1.2 Follow-up time > 12 months

Elgindy 2013 14 25 13 25 4.9% 1.08 [0.65 , 1.80]
Gerber 2011 28 30 29 30 22.1% 0.97 [0.86 , 1.08]
Giuseppe 2007 14 14 8 15 5.7% 1.82 [1.14 , 2.91]
Lambertini 2015a 116 148 96 133 20.7% 1.09 [0.95 , 1.24]
Leonard 2017 74 107 66 95 17.2% 1.00 [0.83 , 1.20]
Munster 2012 23 26 19 21 16.4% 0.98 [0.80 , 1.19]
Song 2013 53 89 39 94 10.9% 1.44 [1.07 , 1.93]
Waxman 1987 4 8 6 9 2.1% 0.75 [0.33 , 1.72]
Subtotal (95% CI) 447 422 100.0% 1.08 [0.95 , 1.22]
Test for subgroup differences: Chi² = 4.58, df = 1 (P = 0.03), I² = 78.2% 0.01 0.1 1 10 100
GnRH-a plus chemotherapy chemotherapy alone

Informed decisions.


chemotherapy alone, Outcome 2: Premature ovarian failure (POF)

Lambertini 2015a 11 139 31 121 26.5% 0.31 [0.16 , 0.59]

Leonard 2017 12 107 23 95 26.7% 0.46 [0.24 , 0.88]
Moore 2015 5 66 15 69 12.0% 0.35 [0.13 , 0.90]
Song 2013 15 89 27 94 34.8% 0.59 [0.33 , 1.03]
Total (95% CI) 401 379 100.0% 0.44 [0.31 , 0.61]

Total events: 43 96
Heterogeneity: Tau² = 0.00; Chi² = 2.44, df = 3 (P = 0.49); I² = 0% 0.01 0.1 1 10 100
Test for overall effect: Z = 4.91 (P < 0.00001) GnRH-a plus chemotherapy chemotherapy alone
Test for subgroup differences: Not applicable

Analysis 1.3. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 3: Pregnancy

Elgindy 2013 1 25 1 25 3.8% 1.00 [0.07 , 15.12]

Gerber 2011 1 30 1 30 3.8% 1.00 [0.07 , 15.26]
Giuseppe 2007 0 14 2 15 3.2% 0.21 [0.01 , 4.09]
Lambertini 2015a 8 148 3 133 16.5% 2.40 [0.65 , 8.85]
Moore 2015 22 105 12 113 66.5% 1.97 [1.03 , 3.78]
Munster 2012 0 26 2 21 3.2% 0.16 [0.01 , 3.22]
Waxman 1987 0 8 1 10 3.0% 0.41 [0.02 , 8.84]
Total (95% CI) 356 347 100.0% 1.59 [0.93 , 2.70]

Total events: 32 22
Test for overall effect: Z = 1.71 (P = 0.09) GnRH-a plus chemotherapy chemotherapy alone

Analysis 1.4. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 4: Ovulation

Badawy 2009 27 39 10 39 89.9% 2.70 [1.52 , 4.79]

Waxman 1987 2 8 2 9 10.1% 1.13 [0.20 , 6.24]
Total (95% CI) 47 48 100.0% 2.47 [1.43 , 4.26]

Total events: 29 12

Analysis 1.5. Comparison 1: GnRH agonist plus chemotherapy
versus chemotherapy alone, Outcome 5: Antral follicle count
GnRH-a plus chemotherapy chemotherapy alone Std. Mean Difference Std. Mean Difference
Study or Subgroup Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI
Giuseppe 2007 3.35 2.8 14 0.33 2.5 15 1.11 [0.32 , 1.90]
-10 -5 0 5 10
Informed decisions.


Analysis 1.6. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 6: FSH (mUI/L)
Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI
Giuseppe 2007 6.54 5.6 14 11.15 20.25 15 48.4% -0.30 [-1.03 , 0.44]
Karimi-Zarchi 2014 48.09 29.67 21 29.64 14.11 21 51.6% 0.78 [0.15 , 1.41]
Total (95% CI) 35 36 100.0% 0.26 [-0.80 , 1.31]

Test for overall effect: Z = 0.48 (P = 0.63) -10 -5 0 5 10
Test for subgroup differences: Not applicable GnRH-a plus chemotherapy chemotherapy alone

versus chemotherapy alone, Outcome 7: FSH < 20 mIU/mL

Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI
Gilani 2007 15 15 10 15 1.48 [1.02 , 2.13]
0.01 0.1 1 10 100


Analysis 1.8. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 8: LH (mUI/L)
Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI
Karimi-Zarchi 2014 11.7 6.35 21 22.64 14.98 21 53.7% -0.93 [-1.57 , -0.29]
Giuseppe 2007 5.16 3.19 14 7.6 12.02 15 46.3% -0.27 [-1.00 , 0.47]
Total (95% CI) 35 36 100.0% -0.62 [-1.28 , 0.03]

Test for overall effect: Z = 1.87 (P = 0.06) -10 -5 0 5 10
Test for subgroup differences: Not applicable GnRH-a plus chemotherapy chemotherapy alone

versus chemotherapy alone, Outcome 9: LH < 20 mIU/L

Gilani 2007 15 15 10 15 1.48 [1.02 , 2.13]
0.01 0.1 1 10 100


Informed decisions.


versus chemotherapy alone, Outcome 10: AMH (pmol/L)
Giuseppe 2007 8.01 9.5 14 8.58 11.47 15 -0.05 [-0.78 , 0.68]
-10 -5 0 5 10

Analysis 1.11. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 11: Inhibin B
Giuseppe 2007 62.25 61.53 14 58.23 78.65 15 0.06 [-0.67 , 0.78]
-10 -5 0 5 10

Analysis 1.12. Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 12: Estradiol
Karimi-Zarchi 2014 81 19.35 21 40.14 37.35 21 1.35 [0.67 , 2.02]
-10 -5 0 5 10

versus chemotherapy alone, Outcome 13: Estradiol > 20 pg/mL

Gilani 2007 15 15 4 15 3.44 [1.57 , 7.58]
0.01 0.1 1 10 100


Informed decisions.


versus chemotherapy alone, Outcome 14: Adverse effects: hot flush

Gerber 2011 16 30 10 30 24.8% 1.60 [0.87 , 2.94]

Lambertini 2015a 34 147 20 127 25.0% 1.47 [0.89 , 2.42]
Moore 2015 33 103 17 111 24.9% 2.09 [1.24 , 3.52]
Song 2013 89 89 94 94 25.3% 1.00 [0.98 , 1.02]
Total (95% CI) 369 362 100.0% 1.49 [0.16 , 13.60]

Heterogeneity: Tau² = 5.04; Chi² = 405.96, df = 3 (P < 0.00001); I² = 99% 0.01 0.1 1 10 100

chemotherapy alone, Outcome 15: Adverse effect: vaginal dryness

Lambertini 2015a 14 147 12 127 55.6% 1.01 [0.48 , 2.10]

Moore 2015 12 103 9 111 44.4% 1.44 [0.63 , 3.27]
Total (95% CI) 250 238 100.0% 1.18 [0.68 , 2.04]

Total events: 26 21

chemotherapy alone, Outcome 16: Adverse effect: urogenital symptoms

Gerber 2011 6 30 1 30 48.1% 6.00 [0.77 , 46.87]

Song 2013 89 89 94 94 51.9% 1.00 [0.98 , 1.02]
Total (95% CI) 119 124 100.0% 2.37 [0.01 , 448.16]

Total events: 95 95
Heterogeneity: Tau² = 13.79; Chi² = 26.06, df = 1 (P < 0.00001); I² = 96% 0.01 0.1 1 10 100

Informed decisions.


versus chemotherapy alone, Outcome 17: Adverse effect: sweating

Lambertini 2015a 21 147 11 127 64.4% 1.65 [0.83 , 3.29]

Moore 2015 10 103 7 111 35.6% 1.54 [0.61 , 3.89]
Total (95% CI) 250 238 100.0% 1.61 [0.93 , 2.80]

Total events: 31 18

versus chemotherapy alone, Outcome 18: Adverse effect: headache

Lambertini 2015a 28 147 18 127 59.5% 1.34 [0.78 , 2.31]

Moore 2015 12 103 2 111 40.5% 6.47 [1.48 , 28.20]
Total (95% CI) 250 238 100.0% 2.54 [0.54 , 11.92]

Total events: 40 20

chemotherapy alone, Outcome 19: Adverse effect: mood swings

Gerber 2011 2 30 2 30 0.0% 1.00 [0.15 , 6.64]

Lambertini 2015a 16 147 15 127 0.1% 0.92 [0.47 , 1.79]
Song 2013 89 89 94 94 99.9% 1.00 [0.98 , 1.02]
Total (95% CI) 266 251 100.0% 1.00 [0.98 , 1.02]


versus chemotherapy alone, Outcome 20: Adverse effect: fatigue

Moore 2015 2 103 1 111 2.16 [0.20 , 23.42]
0.01 0.1 1 10 100


Informed decisions.


versus chemotherapy alone, Outcome 21: Adverse effect: joint pain

Moore 2015 0 103 2 111 0.22 [0.01 , 4.43]
0.01 0.1 1 10 100


versus chemotherapy alone, Outcome 22: Adverse effect: muscle pain

Moore 2015 1 103 2 111 0.54 [0.05 , 5.85]
0.01 0.1 1 10 100


chemotherapy alone, Outcome 23: Adverse effect: decrease in lipid

Moore 2015 9 103 6 111 1.62 [0.60 , 4.38]
0.01 0.1 1 10 100


chemotherapy alone, Outcome 24: Adverse effect: thromboembolism

Moore 2015 1 103 0 111 3.23 [0.13 , 78.43]
0.01 0.1 1 10 100


versus chemotherapy alone, Outcome 25: Adverse effect: agitation

Moore 2015 6 103 5 111 1.29 [0.41 , 4.11]
0.01 0.1 1 10 100


Informed decisions.


versus chemotherapy alone, Outcome 26: Adverse effect: anxiety

Moore 2015 9 103 4 111 2.42 [0.77 , 7.63]
0.01 0.1 1 10 100


versus chemotherapy alone, Outcome 27: Adverse effect: depression

Moore 2015 9 103 3 111 3.23 [0.90 , 11.61]
0.01 0.1 1 10 100


versus chemotherapy alone, Outcome 28: Adverse effect: insomnia

Gerber 2011 5 30 1 30 5.00 [0.62 , 40.28]
0.01 0.1 1 10 100


Comparison 2. Agonist-antagonist cotreatment plus chemotherapy versus chemotherapy alone
pants
2.1 Menstruation recovery or 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only
maintenance
2.1.1 Follow-up time ≤ 12 1 50 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.76, 1.32]
months
2.1.2 Follow-up time > 12 1 50 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.56, 1.55]
months
2.2 Pregnancy 1 50 Risk Ratio (M-H, Random, 95% CI) 3.00 [0.13, 70.30]

Informed decisions.

Analysis 2.1. Comparison 2: Agonist-antagonist cotreatment plus chemotherapy

versus chemotherapy alone, Outcome 1: Menstruation recovery or maintenance
cotreatment+chemotherapy chemotherapy alone Risk Ratio Risk Ratio
2.1.1 Follow-up time ≤ 12 months

Elgindy 2013 20 25 20 25 100.0% 1.00 [0.76 , 1.32]
Subtotal (95% CI) 25 25 100.0% 1.00 [0.76 , 1.32]
Total events: 20 20
Heterogeneity: Not applicable
2.1.2 Follow-up time > 12 months

Elgindy 2013 13 25 14 25 100.0% 0.93 [0.56 , 1.55]
Subtotal (95% CI) 25 25 100.0% 0.93 [0.56 , 1.55]
Total events: 13 14
Heterogeneity: Not applicable
Test for subgroup differences: Chi² = 0.06, df = 1 (P = 0.80), I² = 0% 0.01 0.1 1 10 100
cotreatment+chemotherapy chemotherapy alone

Analysis 2.2. Comparison 2: Agonist-antagonist cotreatment plus
chemotherapy versus chemotherapy alone, Outcome 2: Pregnancy
cotreatment+chemotherapy chemotherapy alone Risk Ratio Risk Ratio

Elgindy 2013 1 25 0 25 100.0% 3.00 [0.13 , 70.30]
Total (95% CI) 25 25 100.0% 3.00 [0.13 , 70.30]

Total events: 1 0
Heterogeneity: Not applicable 0.01 0.1 1 10 100
Test for overall effect: Z = 0.68 (P = 0.49) cotreatment+chemotherapy chemotherapy alone

ADDITIONAL TABLES

Table 1. Leonard 2017: amenorrhoea and premature ovarian failure in age subgroups
Age (years) Percentage of women with amenorrhoea/POF P value
Chemotherapy+GnRH agonist Chemotherapy group

group
Amenorrhoea ≤ 40 10% 25.4% 0.032
> 40 42.9% 54.2% 0.376
POF ≤ 40 2.6% 20.0% 0.038
> 40 42.3% 47.2% 0.798
POF: premature ovarian failure; GnRH: gonadotropin-releasing hormone

Informed decisions.

Table 2. Karimi-Zarchi 2014: menstruation recovery or maintenance at six months after chemotherapy in age
subgroups
Age (years) Number of participants with menstruation recovery or RR 95% CI P value
maintenance/total number of participants

group
< 35 13/13 3/15 1.5 0.15 to 15.46 0.73
> 35 6/8 4/6 96.43 4.51 to 0.003

2059.53
GnRH: gonadotropin-releasing hormone; CI: confidence interval; RR: risk ratio

Table 3. Song 2013: premature ovarian failure in age subgroups
Age (years) Number of participants with POF/ total number of partic- RR 95% CI P value
ipants

group
≤ 35 5/43 10/41 0.48 0.18 to 1.28 0.14
> 35 10/46 17/43 0.55 0.28 to 1.07 0.08
POF: premature ovarian failure; GnRH: gonadotropin-releasing hormone; CI: confidence interval; RR: risk ratio

APPENDICES
Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Ovarian Failure, Premature explode all trees
#2 ovar* and (failure or function or damage)
#3 MeSH descriptor Fertility explode all trees
#4 fertility
#5 (#1 OR #2 OR #3 OR #4)
#6 chemotherap*
#7 gonadal toxicity or gonadotoxic*
#8 MeSH descriptor Antineoplastic Agents explode all trees
#9 MeSH descriptor Antineoplastic Combined Chemotherapy Protocols explode all trees
#10 (#6 OR #7 OR #8 OR #9)
#11 MeSH descriptor Gonadotropin-Releasing Hormone explode all trees
#12 GnRH
#13 gonadotropin-releasing hormone
#14 LHRH
#15 luteinizing-hormone releasing hormone
#16 (#11 OR #12 OR #13 OR #14 OR #15)
#17 (#5 AND #10 AND #16)
Appendix 2. MEDLINE OVID search strategy

1 exp Ovarian Failure, Premature/
2 (ovar* and (failure or function or damage)).mp.
Informed decisions.

3 exp Fertility/

4 fertility.mp.
5 1 or 2 or 3 or 4
6 chemotherap*.mp.
7 (gonadal toxicity or gonadotoxic*).mp.
8 exp Antineoplastic Agents/
9 exp Antineoplastic Combined Chemotherapy Protocols/
10 6 or 7 or 8 or 9
11 exp Gonadotropin-Releasing Hormone/
12 GnRH.mp.
13 gonadotropin-releasing hormone.mp.
14 LHRH.mp.
15 luteinizing-hormone releasing hormone.mp.
16 11 or 12 or 13 or 14 or 15
17 5 and 10 and 16
18 "randomized controlled trial".pt.
19 "controlled clinical trial".pt.
20 randomized.ab.
21 placebo.ab.
22 drug therapy.fs.
23 randomly.ab.
24 trial.ab.
25 groups.ab.
26 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25
27 17 and 26
28 Animals/
29 Humans/
30 28 not (28 and 29)
31 27 not 30
Key: mp=title, original title, abstract, name of substance word, subject heading word
ab=abstract
fs=floating subheading
Appendix 3. Embase OVID search strategy

1 exp premature ovarian failure/
2 (ovar* and (failure or function or damage)).mp.
3 exp fertility/
4 fertility.mp.
5 1 or 2 or 3 or 4
6 exp chemotherapy/ or chemotherap*.mp.
7 (gonadal toxicity or gonadotoxic*).mp.
8 exp antineoplastic agent/
9 6 or 7 or 8
10 exp gonadorelin/
11 GnRH.mp.
12 gonadotropin-releasing hormone.mp.
13 LHRH.mp.
14 luteinizing-hormone releasing hormone.mp.
15 10 or 11 or 12 or 13 or 14
16 5 and 9 and 15
17 exp controlled clinical trial/
18 randomized.ab.
19 placebo.ab.
20 dt.fs.
21 randomly.ab.
22 trial.ab.
23 groups.ab.
24 17 or 18 or 19 or 20 or 21 or 22 or 23
25 16 and 24
key:
Informed decisions.

mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name
ab=abstract
fs=floating subheading
Appendix 4. CBM search strategy

#1. 卵巢早衰 ti.
#2. 卵巢早衰 tx.
#3. 卵巢早衰 ab.
#4. 化疗 ti.
#5. 化疗 tx.
#6. 化疗 ab.
#7. 促性腺激素释放激素 ti.
#8. 促性腺激素释放激素 tx.
#9. 促性腺激素释放激素 ab.
#10. OR 1-3
#11 OR 4-5
#12 OR 6-9
#13 10 AND 11 AND 12
Appendix 5. Data extraction form items

• Review ID
• Study ID
• Reference ID
• Person extracting data
• Date of date extraction
• Year of study publication
• Title
• Author
• Type of study design
• Unit of randomisation
• Describe setting
• Funding source
• Inclusion criteria
• Exclusion criteria
• Experimental intervention
• Control/comparison intervention
• Outcomes
• Adequate sequence generation: was the allocation sequence adequately generated?
• Allocation concealment: was allocation concealment adequate?
• Blinding: was knowledge of the allocated intervention adequately prevented during the study?
• Incomplete outcome data addressed: were complete outcome data adequately addressed?
• Free of selective reporting bias: are reports of study free of suggestions of selective reporting bias?
• Free of other bias: was the study apparently free of other problems that could put it at high risk of bias?
• Outcome measures
• Very brief summary of study authors' main findings/conclusions
• Reasons for exclusion
Appendix 6. Risk of bias criteria

Generation of allocation sequence
• Yes - adequate methods applied e.g. random number tables, computer-generated random numbers, coin tossing, or card shuffling
• Unclear - no information was provided
• No - other methods of allocation that are potentially biased
Informed decisions.

Allocation concealment
• Yes - adequate measures such as central randomisation; serially numbered, opaque, sealed envelopes; or another description that
contained convincing elements of concealment
• Unclear - information unavailable
• No - inadequate measures that do not fall into one of the categories under the 'adequate methods' category
Blinding
• Blinding of women (yes, no, or unclear)
• Blinding of caregivers (yes, no, or unclear)
• Blinding of outcome assessment (yes, no, or unclear)
Incomplete outcome data

• Yes - clearly described loss of participants to follow-up at each data collection point and exclusion of participants after randomisation
• Unclear - no information was provided
• No - unreported/missing numbers of losses at follow-up, or no reasons for missing data provided
Free of selective reporting bias

• Yes - all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported
• Unclear - information unavailable
• No - incomplete reporting of study's pre-specified outcomes; one or more reported primary outcomes were not pre-specified; outcomes
of interest were reported incompletely and thus could not be used; study failed to include results of a key outcome that would have
been expected to have been reported
Free of other bias

We described for each included study any important concerns we had about other possible sources of bias, for example, the baseline
balance.
• Yes - no evidence of bias from other sources

• Unclear - insufficient information to permit judgement of adequacy or otherwise of other forms of bias
• No - potential bias present from other sources (e.g. early stopping of trial, fraudulent activity, extreme baseline imbalance, or bias related
to specific study design)
WHAT'S NEW

Date Event Description
12 August 2021 Review declared as stable Conclusions unlikely to change with the addition of new studies.
No update planned.

HISTORY
Protocol first published: Issue 4, 2009
Review first published: Issue 11, 2011

15 April 2019 Amended Amendment made to PLS for clarity.
28 February 2019 New search has been performed New searches run in November 2018. Text of the review updated
as required. Author team revised.
28 February 2019 New citation required but conclusions Eight additional RCTs involving 1212 participants were included.
have not changed Conclusions remain unchanged.
Informed decisions.

1 April 2015 Amended Contact details updated.
27 March 2014 Amended Contact details updated.

CONTRIBUTIONS OF AUTHORS
HC was responsible for developing the protocol, searching for trials, assessing the quality of trials, extracting data, analysing data,
developing the review and amending it.
JL was responsible for searching for trials, assessing the quality of trials and extracting data.
LC and LX were responsible for analysing data and developing the review.
WH was responsible for language revision and amending the review.
DECLARATIONS OF INTEREST
JL: none known
HC: none known
LC: none known
WH: none known
LX: none known
SOURCES OF SUPPORT
Internal sources
• West China Secondary Hospital, Sichuan University, China
External sources
• Cochrane Gynaecological, Neuro-oncology and Orphan Cancers, UK
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
Premature ovarian failure and ovulation were not prescribed as outcomes in the protocol (Chen 2009). Treatment-related premature
ovarian failure is defined as no resumption of menstrual activity with postmenopausal FSH levels at least one year after the end of
chemotherapy. As menstruation recovery or maintenance and FSH levels were two outcomes prespecified in the protocol and premature
ovarian failure reflects severe damage to ovaries by chemotherapy, we included premature ovarian failure as a primary outcome in this
updated review. Ovulation is generally confirmed by serial ovarian ultrasound monitoring or serum levels of progesterone, which were
also two prespecified outcomes in the protocol, and can reflect ovarian function to some extent, and we had included it as a secondary
outcome in the original review (Chen 2011). Thus, we continued to analyse ovulation as an outcome in this updated review. Other clinical
symptoms of premature ovarian failure, such as vasomotor symptoms, hot flushes, and vaginal dryness, were listed as secondary outcomes
in the protocol. As these symptoms are mainly considered as GnRH analogue-related adverse events, we combined them in the adverse
events analyses. We discussed amending the outcome measurements with Clare Jess, Managing Editor of Cochrane Gynaecological, Neuro-
oncology and Orphan Cancers.
In the original review, we discussed the subgroup analysis based on administration routes of GnRH analogues (intramuscular,
subcutaneous, and intranasal administration). In fact, intranasal GnRH analogue is rarely used nowadays and only one included study
(Waxman 1987), used this method. Thus, we deleted this subgroup analysis in this update. As the effects of GnRH analogues on ovarian
protection are closely related to follow-up periods, we added subgroup analyses based on different follow-up periods in the update.
INDEX TERMS
Medical Subject Headings (MeSH)

Administration, Intranasal; Antineoplastic Agents [adverse effects]; Gonadotropin-Releasing Hormone [agonists] [*analogs &
derivatives]; Injections, Intramuscular; Injections, Subcutaneous; Menstruation [*drug effects]; Ovulation [drug effects]; Pregnancy
Rate; *Premenopause; Primary Ovarian Insufficiency [chemically induced] [*prevention & control]; Randomized Controlled Trials as
Topic; Recovery of Function [drug effects]
Informed decisions.

MeSH check words

Adolescent; Adult; Child; Female; Humans; Middle Aged; Pregnancy; Young Adult

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Chen H, Xiao L, Li J, Cui L, Huang W

Chen H, Xiao L, Li J, Cui L, Huang W.

Adjuvant gonadotropin-releasing hormone analogues for the prevention

Hengxi Chen1,2, Li Xiao1, Jinke Li1,2, Ling Cui3, Wei Huang1,2

Contact: Wei Huang, weihuang64@163.com.

Editorial group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group.

Data collection and analysis

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone

Comparison 2: GnRH agonist-antagonist cotreatment plus chemotherapy versus chemotherapy alone

Comparison: chemotherapy alone

Control: chemothera- GnRH agonist plus chemotherapy

Menstruation re- Study population RR 1.60 460 ⊕⊕⊝⊝

496 per 1000 794 per 1000

Menstruation re- Study population RR 1.08 869 ⊕⊕⊝⊝

Cochrane Database of Systematic Reviews

681 per 1000 735 per 1000

Premature ovar- Study population RR 0.44 780 ⊕⊕⊝⊝ We defined prema-

Pregnancy Study population RR 1.59 703 ⊕⊕⊝⊝ Follow-up periods were

95 per 1000 151 per 1000

Ovulation Study population RR 2.47 95 ⊕⊕⊝⊝ Follow-up periods

239 per 1000 590 per 1000

Adverse effects: Study population RR 1.49 731 ⊕⊝⊝⊝ Follow-up periods

Cochrane Database of Systematic Reviews

245 per 1000 365 per 1000

Adverse effects: Study population RR 1.18 488 ⊕⊕⊕⊝ Follow-up periods

88 per 1000 104 per 1000

Cochrane Database of Systematic Reviews

Menstruation recov- Study population RR 1.00 50 ⊕⊝⊝⊝

800 per 1000 800 per 1000

Menstruation recov- Study population RR 0.93 50 ⊕⊝⊝⊝

560 per 1000 521 per 1000

Cochrane Database of Systematic Reviews

0 per 1000 0 per 1000

Adverse events - - Not estimable 0 - No data

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

BACKGROUND Description of the intervention

Searching other resources Dealing with missing data

The review therefore comprises 12 included studies (involving 13

Figure 1. Flow diagram

Blinding (performance bias and detection bias): All outcomes

Selective reporting (reporting bias)

Random sequence generation (selection bias)

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

Leonard 2017 reported a protective effect of GnRH agonist on FSH/LH

Regan 2017 {published data only}

Anderson 2016 {published data only} NCT02483767 {published data only}

Behringer 2007 {published data only} NCT02856048 {published data only}

Bedoschi 2016 Falcone 2005

Blumenfeld 1999 Gerber 2011 [pers comm]

Dayangan Sayan 2018 Higgins 2003

De Koning 2000 Higgins 2017

Peng 2007 chemotherapy-induced ovarian gonadotoxicity. Reproductive

Characteristics of included studies [ordered by study ID]

Methods Study design: single-centre RCT

Study duration: not mentioned

Exclusion criteria: women with macroscopic metastatic spread of the disease

Interventions Treatment group

• Menstruation recovery or maintenance

Notes • Funding source: not mentioned

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Not mentioned

Methods Study design: 2-centre, 4-armed, open-label RCT