Adjuvant gonadotropin‐releasing hormone analogues for the prevention of chemotherapy‐induced premature ovarian failure in premenopausal women

Hengxi Chen; Li Xiao; Jinke Li; Ling Cui; Wei Huang

doi:10.1002/14651858.CD008018.pub3

Analog hormon pelepasan gonadotrofin adjuvan untuk pencegahan kegagalan ovari pramatang akibat kemoterapi dikalangan wanita pra‐menopaus

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.
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:
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

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)

Figure 1

Flow diagram

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Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

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Figure 3

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Analysis 1.1

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 1: Menstruation recovery or maintenance

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Analysis 1.2

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 2: Premature ovarian failure (POF)

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 5: Antral follicle count

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Analysis 1.6

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 6: FSH (mUI/L)

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Analysis 1.7

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 7: FSH < 20 mIU/mL

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Analysis 1.8

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 8: LH (mUI/L)

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Analysis 1.9

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 9: LH < 20 mIU/L

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Analysis 1.10

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 10: AMH (pmol/L)

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Analysis 1.11

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 11: Inhibin B

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Analysis 1.12

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 12: Estradiol

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Analysis 1.13

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 13: Estradiol > 20 pg/mL

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Analysis 1.14

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 14: Adverse effects: hot flush

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Analysis 1.15

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 15: Adverse effect: vaginal dryness

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Analysis 1.16

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 16: Adverse effect: urogenital symptoms

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Analysis 1.17

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 17: Adverse effect: sweating

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Analysis 1.18

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 18: Adverse effect: headache

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Analysis 1.19

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 19: Adverse effect: mood swings

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Analysis 1.20

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 20: Adverse effect: fatigue

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Analysis 1.21

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 21: Adverse effect: joint pain

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Analysis 1.22

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 22: Adverse effect: muscle pain

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Analysis 1.23

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 23: Adverse effect: decrease in lipid

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Analysis 1.24

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 24: Adverse effect: thromboembolism

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Analysis 1.25

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 25: Adverse effect: agitation

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Analysis 1.26

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 26: Adverse effect: anxiety

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Analysis 1.27

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 27: Adverse effect: depression

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Analysis 1.28

Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone, Outcome 28: Adverse effect: insomnia

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Analysis 2.1

Comparison 2: Agonist‐antagonist cotreatment plus chemotherapy versus chemotherapy alone, Outcome 1: Menstruation recovery or maintenance

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Analysis 2.2

Comparison 2: Agonist‐antagonist cotreatment plus chemotherapy versus chemotherapy alone, Outcome 2: Pregnancy

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Summary of findings 1. GnRH agonist plus chemotherapy versus chemotherapy alone for the prevention of chemotherapy‐induced premature ovarian failure in premenopausal women

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
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 Intervention: GnRH agonist plus chemotherapy Comparison: chemotherapy alone
	Assumed risk	Corresponding risk
	Control: chemotherapy alone	GnRH agonist plus chemotherapy
Menstruation recovery or maintenance: Follow‐up ≤ 12 months	Study population		RR 1.60 (1.14 to 2.24)	460 (5 studies)	⊕⊕⊝⊝ Low^1,2
	498 per 1000	796 per 1000 (567 to 1000)
	Moderate
	496 per 1000	794 per 1000 (565 to 1000)
Menstruation recovery or maintenance: Follow‐up > 12 months	Study population		RR 1.08 (0.95 to 1.22)	869 (8 studies)	⊕⊕⊝⊝ Low^3,4
	654 per 1000	706 per 1000 (621 to 798)
	Moderate
	681 per 1000	735 per 1000 (647 to 831)
Premature ovarian failure	Study population		RR 0.44 (0.31 to 0.61)	780 (4 studies)	⊕⊕⊝⊝ Moderate⁵	We defined premature ovarian failure as amenorrhoea after chemotherapy with postmenopausal FSH levels. Follow‐up periods were ≥ 12 months
	253 per 1000	111 per 1000 (79 to 155)
	Moderate
	249 per 1000	110 per 1000 (77 to 152)
Pregnancy	Study population		RR 1.59 (0.93 to 2.70)	703 (7 studies)	⊕⊕⊝⊝ Low^6,7	Follow‐up periods were ≥ 18 months
	63 per 1000	101 per 1000 (59 to 171)
	Moderate
	95 per 1000	151 per 1000 (88 to 257)
Ovulation	Study population		RR 2.47 (1.43 to 4.26)	95 (2 studies)	⊕⊕⊝⊝ Low^8,9	Follow‐up periods ranged from 8 months to > 3 years
	250 per 1000	618 per 1000 (357 to 1000)
	Moderate
	239 per 1000	590 per 1000 (342 to 1000)
Adverse effects: hot flush	Study population		RR 1.49 (0.16 to 13.60)	731 (4 studies)	⊕⊝⊝⊝ Very low^10,11,12	Follow‐up periods ranged from 1 year to > 7 years
	390 per 1000	580 per 1000 (62 to 1000)
	Moderate
	245 per 1000	365 per 1000 (39 to 1000)
Adverse effects: vaginal dryness	Study population		RR 1.18 (0.68 to 2.04)	488 (2 studies)	⊕⊕⊕⊝ Moderate¹³	Follow‐up periods ranged from 5 months to > 7 years
	88 per 1000	104 per 1000 (60 to 180)
	Moderate
	88 per 1000	104 per 1000 (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
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 1. GnRH agonist plus chemotherapy versus chemotherapy alone for the prevention of chemotherapy‐induced premature ovarian failure in premenopausal women

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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

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
GnRH agonist‐antagonist cotreatment 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 Intervention: GnRH agonist‐antagonist cotreatment plus chemotherapy Comparison: chemotherapy alone
	Assumed risk	Corresponding risk
	Control: chemotherapy alone	Agonist‐antagonist cotreatment plus chemotherapy
Menstruation recovery or maintenance: Follow‐up ≤ 12 months	Study population		RR 1.00 (0.76 to 1.32)	50 (1 study)	⊕⊝⊝⊝ Very low^1,2
	800 per 1000	800 per 1000 (608 to 1000)
	Moderate
	800 per 1000	800 per 1000 (608 to 1000)
Menstruation recovery or maintenance: Follow‐up > 12 months	Study population		RR 0.93 (0.56 to 1.55)	50 (1 study)	⊕⊝⊝⊝ Very low^1,2
	560 per 1000	521 per 1000 (314 to 868)
	Moderate
	560 per 1000	521 per 1000 (314 to 868)
Premature ovarian failure	‐	‐	Not estimable	0	‐	No data. We defined premature ovarian failure as amenorrhoea after chemotherapy with postmenopausal FSH levels
Pregnancy	Study population		RR 3.00 (0.13 to 70.30)	50 (1 study)	⊕⊝⊝⊝ Very low^1,2	Follow‐up: 18 months
	0 per 1000	0 per 1000 (0 to 0)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
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).

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

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Table 1. Leonard 2017: amenorrhoea and premature ovarian failure in age subgroups

	Age (years)	Chemotherapy+GnRH agonist group	Chemotherapy group	P value
	Age (years)	Percentage of women with amenorrhoea/POF		P value
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

Table 1. Leonard 2017: amenorrhoea and premature ovarian failure in age subgroups

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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 maintenance/total number of participants		RR	95% CI	P value
Age (years)	Chemotherapy+GnRH agonist group	Chemotherapy group	RR	95% CI	P value
< 35	13/13	3/15	1.5	0.15 to 15.46	0.73
> 35	6/8	4/6	96.43	4.51 to 2059.53	0.003
GnRH: gonadotropin‐releasing hormone; CI: confidence interval; RR: risk ratio

Table 2. Karimi‐Zarchi 2014: menstruation recovery or maintenance at six months after chemotherapy in age subgroups

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Table 3. Song 2013: premature ovarian failure in age subgroups

Age (years)	Number of participants with POF/ total number of participants		RR	95% CI	P value
Age (years)	Chemotherapy+GnRH agonist group	Chemotherapy group	RR	95% CI	P value
≤ 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

Table 3. Song 2013: premature ovarian failure in age subgroups

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Comparison 1. GnRH agonist plus chemotherapy versus chemotherapy alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Menstruation recovery or maintenance Show forest plot	11		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1.1 Follow‐up time ≤ 12 months	5	460	Risk Ratio (M‐H, Random, 95% CI)	1.60 [1.14, 2.24]
1.1.2 Follow‐up time > 12 months	8	869	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.95, 1.22]
1.2 Premature ovarian failure (POF) Show forest plot	4	780	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.31, 0.61]

1.3 Pregnancy Show forest plot	7	703	Risk Ratio (M‐H, Random, 95% CI)	1.59 [0.93, 2.70]

1.4 Ovulation Show forest plot	2	95	Risk Ratio (M‐H, Random, 95% CI)	2.47 [1.43, 4.26]

1.5 Antral follicle count Show forest plot	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected

1.6 FSH (mUI/L) Show forest plot	2	71	Std. Mean Difference (IV, Random, 95% CI)	0.26 [‐0.80, 1.31]

1.7 FSH < 20 mIU/mL Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.8 LH (mUI/L) Show forest plot	2	71	Std. Mean Difference (IV, Random, 95% CI)	‐0.62 [‐1.28, 0.03]

1.9 LH < 20 mIU/L Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.10 AMH (pmol/L) Show forest plot	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected

1.11 Inhibin B Show forest plot	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected

1.12 Estradiol Show forest plot	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected

1.13 Estradiol > 20 pg/mL Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.14 Adverse effects: hot flush Show forest plot	4	731	Risk Ratio (M‐H, Random, 95% CI)	1.49 [0.16, 13.60]

1.15 Adverse effect: vaginal dryness Show forest plot	2	488	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.68, 2.04]

1.16 Adverse effect: urogenital symptoms Show forest plot	2	243	Risk Ratio (M‐H, Random, 95% CI)	2.37 [0.01, 448.16]

1.17 Adverse effect: sweating Show forest plot	2	488	Risk Ratio (M‐H, Random, 95% CI)	1.61 [0.93, 2.80]

1.18 Adverse effect: headache Show forest plot	2	488	Risk Ratio (M‐H, Random, 95% CI)	2.54 [0.54, 11.92]

1.19 Adverse effect: mood swings Show forest plot	3	517	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.98, 1.02]

1.20 Adverse effect: fatigue Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.21 Adverse effect: joint pain Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.22 Adverse effect: muscle pain Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.23 Adverse effect: decrease in lipid Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.24 Adverse effect: thromboembolism Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.25 Adverse effect: agitation Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.26 Adverse effect: anxiety Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.27 Adverse effect: depression Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.28 Adverse effect: insomnia Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 1. GnRH agonist plus chemotherapy versus chemotherapy alone

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Comparison 2. Agonist‐antagonist cotreatment plus chemotherapy versus chemotherapy alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Menstruation recovery or maintenance Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1.1 Follow‐up time ≤ 12 months	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.76, 1.32]
2.1.2 Follow‐up time > 12 months	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.56, 1.55]
2.2 Pregnancy Show forest plot	1	50	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.30]

Comparison 2. Agonist‐antagonist cotreatment plus chemotherapy versus chemotherapy alone

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Analog hormon pelepasan gonadotrofin adjuvan untuk pencegahan kegagalan ovari pramatang akibat kemoterapi dikalangan wanita pra‐menopaus

Appendices

Appendix 1. CENTRAL search strategy

Appendix 2. MEDLINE OVID search strategy

Appendix 3. Embase OVID search strategy

Appendix 4. CBM search strategy

Appendix 5. Data extraction form items

Appendix 6. Risk of bias criteria

Generation of allocation sequence

Allocation concealment

Blinding

Incomplete outcome data

Free of selective reporting bias

Free of other bias

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Appendices

Appendix 1. CENTRAL search strategy

Appendix 2. MEDLINE OVID search strategy

Appendix 3. Embase OVID search strategy

Appendix 4. CBM search strategy

Appendix 5. Data extraction form items

Appendix 6. Risk of bias criteria

Generation of allocation sequence

Allocation concealment

Blinding

Incomplete outcome data

Free of selective reporting bias

Free of other bias

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Idioma de la Revisión Cochrane

Idioma de la web

Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

Otras opciones de acceso