Anti-Müllerian hormone as a marker of ovarian reserve and premature ovarian insufficiency in children and women with cancer: a systematic review.

BACKGROUND: Female patients undergoing anticancer treatment are at elevated risk of adverse ovarian outcomes including infertility and premature ovarian insufficiency (POI), which is associated with short- and long-term health risks. Anti-Müllerian hormone (AMH) is a key biomarker of ovarian reserve, but its role prior to and after cancer treatment is less well understood. OBJECTIVE AND RATIONALE: To conduct a systematic review evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment, which has become a pressing clinical issue in reproductive medicine. There are a large number of observational studies, but differences in patient groups, cancer diagnoses and study design make this a confusing field that will benefit from a thorough and robust review. SEARCH
METHODS: A systematic literature search for AMH in women with cancer was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 April 2021. Bias review was conducted using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol along with qualitative assessment of quality. Exploratory subgroups were established based on age, cancer type and length of follow-up. OUTCOMES: Ninety-two publications (N = 9183 patients) were included in this analysis after quality and bias review. Reduced/undetectable AMH was consistently identified in 69/75 studies (92%) following chemotherapy or radiotherapy, with reductions ranging from 42% to concentrations below the limit of detection, and many reporting mean or median declines of ≥90%. Where longitudinal data were analysed (42 studies), a majority (33/42 (79%)) of studies reported at least partial recovery of AMH at follow-up, however, effect estimates were highly variable, reflecting that AMH levels were strongly impacted by anticancer treatment (i.e. the chemotherapy regimen used and the number of treatment cycles need), with recovery and its degree determined by treatment regimen, age and pre-treatment AMH level. In 16/31 (52%) publications, oligo/amenorrhoea was associated with lower post-treatment AMH consistent with impending POI, although menstruation and/or pregnancy were reported in patients with low or undetectable AMH. Long-term (>5 years) follow-up of paediatric patients following cancer treatment also found significantly lower AMH compared with control groups in 14/20 (70%) of studies, with very variable effect sizes from complete loss of AMH to full recovery depending on treatment exposure, as in adult patients. WIDER IMPLICATIONS: AMH can be used to identify the damaging effect of cancer treatments on ovarian function. This can be applied to individual women, including pre-pubertal and adolescent girls, as well as comparing different treatment regimens, ages and pre-treatment AMH levels in populations of women. While there was evidence for its value in the diagnosis of POI after cancer treatment, further studies across a range of diagnoses/treatment regimens and patient ages are required to clarify this, and to quantify its predictive value. A major limitation for the use of AMH clinically is the very limited data relating post-treatment AMH levels to fertility, duration of reproductive lifespan or time to POI; analysis of these clinically relevant outcomes will be important in further research.

Introduction

Anticancer treatments are known to have substantial impact on ovarian reserve via mechanisms leading to depletion of growing and primordial follicles. This reduction in ovarian reserve may reduce reproductive lifespan and be sufficient in some women to induce premature ovarian insufficiency (POI; Fig. 1; Spears ). This has profound implications for women’s health and is associated with infertility, cardiovascular disease (CVD), neurological disease, osteoporosis and mood disorders, culminating in an increased risk of premature mortality (Webber ; van Dorp ; Panay ). Consequently, knowing a patient’s treatment-related risk of POI aids shared decision-making around the choice of anticancer treatment and the need for additional fertility preservation interventions.

Figure 1.

Putative mechanisms of impact of cancer treatment on ovarian function. (a) In premenopausal individuals, circulating AMH is produced by secondary, preantral and early antral growing follicles, and has been shown in animal models to be one of several molecules which contribute to maintenance of ovarian reserve by inhibiting folliculogenesis; (b) anticancer treatment can reduce the ovarian pool of primordial follicles either by direct or indirect DNA damage, or by overactivation and subsequent depletion of primordial follicles; (c) following treatment, a patient may experience some recovery of the number of AMH-producing growing follicles, depending on the impact of anticancer treatment, or POI. In patients who recover ovarian function, a reduced pool of primordial follicles may still lead to an increased risk of later POI and infertility. AMH, anti-Müllerian hormone; POI, premature ovarian insufficiency; ROS, reactive oxygen species

Measurement of circulating anti-Müllerian hormone (AMH), produced by granulosa cells of growing follicles, is widely used as a surrogate for ovarian reserve and has potential as a diagnostic and predictive biomarker of POI (Anderson and Su 2020). AMH levels are often heavily impacted during anticancer treatment, followed by a highly variable recovery (Anderson and Su 2020). The diagnosis of POI is informed by monitoring a combination of biomarkers, including menstrual function and FSH (Webber ; Panay ). However, confirming POI is more challenging in patients with cancer, as there is potential for recovery of ovarian/menstrual function, which can occur from several months to years after treatment completion (Silva ).

Questions remain about the reliability of AMH for evaluating ovarian reserve in the context of different anticancer treatments, and at what point post-treatment it can provide useful predictive information which may guide later treatment decisions, such as choice of endocrine therapy in women with breast cancer. Our objective was to conduct a systematic review evaluating the value of AMH in assessing ovarian reserve in women with cancer undergoing anticancer treatments, and specifically in the prediction and diagnosis of POI.

Methods

This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42020161717). PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles published up to 1 April 2021 (Supplementary Data) and duplicate articles removed.

Search results were screened in stages by title, abstract and full text based on the following inclusion criteria: female, premenopausal patients who have prospectively or retrospectively undergone treatment for any cancer. Exclusion criteria included pathology other than cancer (with the exception of granulosa cell tumours), AMH/ovarian reserve not measured, cohort size <10, duplicate datasets/cohorts, poor quality (e.g. inconsistent reporting of results), review articles and congress abstracts.

Publications requiring evaluation of full text to determine inclusion underwent bias review via the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol (Sterne ). Bias conclusions were verified by a second author, with any disagreements mediated by a third author. All authors approved the final selection.

Data were extracted using the Synthesis Without Meta-analysis (SWiM) in systematic reviews reporting guideline (Campbell ). The main metrics assessed were differences in AMH following anticancer treatment (change versus pre-treatment or control groups), recovery of AMH (in longitudinal cohorts) and correlation of AMH with menstrual function (regular cycles, oligomenorrhoea or amenorrhoea as reported by patient at follow-up). Certainty of evidence was based on vote counting.

Extracted data also included description of study types (prospective/retrospective, cross-sectional, longitudinal), year of publication, cancer type, treatment, cohort mean/median age, timing of AMH measurement and assay type. Exploratory subgroups were established according to age (paediatric, adult,

The data underlying this article are available in the article and in its online supplementary material, or as referenced publications.

Results

Study characteristics

Figure 2 shows the number of citations retrieved, the number after screening and the final number included in the analysis. The searches initially identified over 3700 citations. After removal of duplicates and assessment for quality and relevance to the study question at the title, abstract and full-text level, 110 were included for bias review. Of these, a further 20 were assessed to be at severe or critical risk of bias and excluded (Supplementary Table SI), leaving 90 publications including 8916 patients (N) for systematic review, published between 2003 and 2021. During the publication review process, a further two relevant articles that were published after 1 April 2021 were identified (total 112 for bias review), resulting in a total of 92 publications and 9183 patients. An overview of publications included in this review is summarized in Table I, and details of the individual publications are summarized in Supplementary Table SII.

Figure 2.

Database search results and exclusion flow of publications. AMH, anti-Müllerian hormone.

Table I

Summary of publications included in review.

Subgroups	Number of publications	Number of patients	AMH reduction reported during/after anticancer treatment	AMH correlated with menstrual function*
All publications	92	9183	69/75 (92%)	15/30 (50%)
Longitudinal (pre-/post-treatment)	56	4825	46/49 (94%)	11/18 (61%)
Cross-sectional (post-treatment data only)	36	4358	23/26 (88%)	4/12 (33%)
Cancer type†
Breast	38	3600	31/31 (100%)	11/18 (61%)
Lymphoma	11	1199	9/9 (100%)	3/43 (75%)
Multiple	33	3877	21/25 (84%)	2/8 (25%)
Other‡	11	573	9/11 (82%)	0/1 (0%)
Follow-up period (mean/median)
<1 year	11	796	9/9 (100%)	4/6 (67%)
1–2 years	36	2943	33/33 (100%)	7/15 (47%)
>2–5.5 years	19	2010	15/15 (100%)	3/6 (50%)
>5.5 years	26	3434	12/18 (67%)	1/4 (25%)
Cohort age
Paediatric	24	2392	14/19 (74%)	1/6 (17%)
Adult	61	5991	48/49 (98%)	13/22 (59%)
Mixed	7	800	7/7 (100%)	1/3 (33%)
<35 years old at follow-up§	57	5917	43/47 (91%)	6/16 (38%)
≥35 years old at follow-up§	33	2999	24/26 (92%)	8/13 (62%)

*Regular menstruation, oligomenorrhoea or amenorrhoea at follow-up.

N = 91 as Palinska-Rudzka included separate analysis for breast cancer and lymphoma.

Acute lymphoblastic leukaemia, differentiated thyroid cancer and gestational trophoblastic neoplasia.

Mean or median as reported.

AMH, anti-Müllerian hormone.

Changes in AMH as a result of anticancer treatments

Papers reporting AMH before and after treatment (N = 46; N = 4117), and a clear majority of cross-sectional papers comparing post-treatment survivors with control groups (23/26, 88%; n/N = 2283/3088) reported a large reduction in AMH following treatment (Table I;Supplementary Table SII). Effect sizes were variable depending on the treatment and diagnosis, but in the 26 papers that reported AMH values at both baseline and ≤3 months from end of treatment (Lutchman Singh ; Decanter , 2018, 2021; Rosendahl ; Yu ; Brougham ; Henry ; Ben-Aharon ; Gharwan ; Gupta ; Anderson , 2018; Bi ; D'Avila ; Leonard ; Trapp ; Cameron ; Evranos ; Yaish ; Passildas ; Silva ; Loubersac ; Berjeb ; Demeestere ; Martin ), reductions ranged from 42% to below the limit of detection (LOD) and 18 reported mean or median declines of ≥90% (Rosendahl ; Brougham ; Dillon , b; Henry ; Gharwan ; Ben-Aharon ; D'Avila ; Dezellus ; Trapp ; Cameron ; Decanter ; Lambertini ; Palinska-Rudzka ; Passildas ; Silva ; Oktay ; Ruddy ; Yu ). The six papers that did not detect a significant difference in AMH versus controls after treatment were all in paediatric populations (i.e. under 18 years of age at cancer diagnosis) and represented long-term follow-up periods of 10–30 years in heterogeneous populations of childhood cancer survivors (Lie Fong ; Nielsen ; van den Berg ; Nystrom ; Nies ; Elitzur ). A shorter-term longitudinal study (follow-up of up to 43 months) in this population did, however, show clear reductions in AMH following treatment (Brougham ), with large differences in the degree of recovery of AMH by treatment gonadotoxicity: thus in those exposed to high-risk treatment, AMH remained undetectable, while recovering to levels similar to pre-treatment in those exposed to lower risk treatment.

Recovery of AMH in longitudinal studies

In publications examining longitudinal data, post-treatment recovery of AMH was described in 33/42 (79%). With several notable exceptions described below, recovery was typically partial (i.e. to lower than pre-treatment level) or only occurred in a subset of patients. Twelve publications specifically evaluated the association of pre- and post-treatment AMH levels, with all reporting a significant association (Rosendahl ; Dillon ; D’Avila ; Dezellus ; Anderson ; Lee , 2020; Palinska-Rudzka ; Silva ; Celebi ; Loubersac ; Decanter ).

Overall relationship of AMH with measures of POI and menstrual function after anticancer treatment

Ten publications specifically evaluated either the value of post-treatment AMH in the diagnosis of POI, or pre-treatment AMH in predicting the likelihood of POI. These studies were either in breast cancer or across multiple diagnoses, representing 762 patients (Nielsen ; Lunsford ; Elchuri ; Anderson ; Nystrom ; Passildas ; Silva ; Zhong ; Demeestere ; Parissone ). Six studies (two of which were in paedia3tric cohorts) reported post-treatment AMH levels <1.0 ng/ml or undetectable in patients with POI (Nielsen ; Lunsford ; Anderson ; Silva ; Zhong ; Parissone ) but the diagnostic accuracy of AMH for post-treatment POI has only been reported in one study (Anderson ). Two papers found that lower pre-treatment AMH levels were associated with higher risk of POI (as assessed) post-treatment (Passildas ; Zhong ), but no studies have assessed post-treatment AMH as a predictor of time to POI.

Of 37 papers that specifically investigated menstrual function after treatment, all used prospective evaluation, and 14 (38%) found that reduced post-treatment AMH was associated with oligomenorrhoea or amenorrhoea (Rosendahl ; Su ; Lunsford ; Ruddy ; D'Avila ; Gharwan ; Palinska-Morarji ; Wenners ; Decanter , 2021; Kim ; Palinska-Rudzka ; Silva ; Li ). In some of these studies, the observations were nuanced, for example Su found that post-treatment AMH was associated with amenorrhoea but was not associated with recovery of menses (at 5.2 years post-treatment follow-up). Palinska-Rudzka found that AMH was lower in patients with amenorrhoea, but that some (7/17) patients with AMH

Post-treatment AMH and pregnancy

A small number of studies have reported pregnancies in some patients despite low or undetectable AMH levels after cancer treatment (Hamy ; Dezellus ; Anderson ; Loubersac ; Demeestere ). A recent analysis of AMH in women treated for advanced Hodgkin lymphoma in a randomized controlled trial showed similar pregnancy rates in the two treatment arms after 5 years of follow-up, despite much lower AMH levels and a higher POI rate in the arm receiving higher doses of alkylating agents (Demeestere ). This is consistent with the lack of predictive value of AMH for pregnancy in healthy women (Steiner ), but these limited data on a clinically highly relevant topic highlight the need for further prospective studies to inform on this subject.

Age at treatment, ovarian reserve and extent of recovery

Of 39 publications that evaluated whether patient age at treatment was associated with post-treatment AMH levels, 30 (77%) found higher post-treatment AMH in younger individuals (Lutchman Singh ; Lie Fong ; Charpentier ; Henry ; Ben-Aharon ; D'Avila ; Acibucu ; Elchuri ; Anderson , 2018; Dezellus ; Morarji ; Shandley ; Wenners ; Al-Janabi ; Evranos ; Lee ; Malisic ; Yaish ; Cameron ; Silva ; Celebi ; Li ; Loubersac ; Su ; van Velsen ; Berjeb ; Decanter ; Elitzur ; Martin 2021). Thirteen of these studies also stratified patient groups by <35 versus ≥35 years old, with 10 (83%) reporting lower AMH and poorer recovery in the older age group (Yu ; Ben-Aharon ; Acibucu ; Dezellus ; Trapp ; Al-Janabi ; Anderson ; van den Berg ; Yaish ; Li ; Mittica ; van Velsen ; Decanter ). However, only five publications both stratified these two age groups and evaluated menstrual function, with three also showing a reduced chance of recovery of menstruation in older women (Yu ; Dezellus ; Decanter ).

Studies investigating gonadotoxicity of anticancer treatments

Fifty-two papers specifically investigated gonadotoxicity of treatments either by comparison of groups receiving specific regimens or by cumulative toxicity scores (e.g. cyclophosphamide equivalent dose [CED]; summarized in Supplementary Table SIII). In order to specifically evaluate treatment effect, papers that evaluated patient risk of gonadotoxicity based on other factors, such as diagnosis and disease stage, were not counted. Forty papers (77%) reported a treatment effect on AMH, with higher gonadotoxicity correlating with lower post-treatment AMH. In general, chemotherapy regimens containing alkylating agents, such as cyclophosphamide (e.g. ACVBP, BEACOPP, CHOP, FEC), resulted in lower levels of AMH and poorer recovery of AMH after treatment than non-alkylating treatment regimens (Rosendahl ; Gracia ; Thomas-Teinturier ; Morarji ; Anderson ; Leiper ; Decanter ).

Twenty-one publications reported gonadotoxicity scores or ranked treatments as higher/lower toxicity or higher/lower risk, based on treatment type and/or cumulative chemotherapy. In every study where higher versus lower toxicity was assessed, higher toxicity therapies and more treatment cycles resulted in lower post-treatment AMH compared with lower overall toxicity exposure (Rosendahl ; Brougham ; Gracia ; Hamre ; Di Paola ; Nielsen ; Krawczuk-Rybak , 2013b, 2019; Charpentier ; Lunsford ; Thomas-Teinturier ; Elchuri ; van der Kooi , 2019; van den Berg ; Cameron ; George ; Su ; van Velsen ; Parissone ).

The evidence regarding radiotherapy was less conclusive as its use was only cited in 10 publications (van Beek ; Lie Fong ; Brougham ; Gracia ; Dillon ; Miyoshi ; Elchuri ; van den Berg ; George ; Nies ). However, in studies where radiotherapy did result in significantly lower AMH, this was typically when targeted to pelvic/abdominal regions or total body irradiation (Lie Fong ; Gracia ; Miyoshi ; Elchuri ; van den Berg ; George ).

AMH in patients with breast cancer

Thirty-eight papers evaluated AMH levels in women following treatment for breast cancer, representing a total of 3600 patients (Table II). All reported a negative treatment effect on AMH, and in 12 papers with data available, reductions in AMH from pre-treatment to <3 months post-treatment ranged from ∼80% to 99% (Lutchman Singh ; Yu ; Henry ; Ben-Aharon ; Anderson ; D'Avila ; Leonard ; Trapp ; Decanter ; Passildas ; Silva ; Loubersac ). Of those publications with available data, 13/16 found that post-treatment AMH levels were associated with age at baseline (Lutchman Singh ; Henry ; Ben-Aharon ; D'Avila et al., 2015; Anderson ; Dezellus ; Wenners ; Al-Janabi ; Lee ; Silva ; Celebi ; Li ; Loubersac ). Some degree of recovery in average AMH levels during follow-up was reported in 14/20 publications; however, the extent of this recovery was marginal (<15% average recovery from nadir levels as a percentage of baseline values) in 12 publications, and only partial in the remainder (range of follow-up 0–5 years), with none demonstrating a return of AMH to pre-treatment levels (Yu ; Henry ; Ben-Aharon ; Anderson ; Dezellus ; Leonard ; Decanter ; Lambertini ; Palinska-Rudzka ; Silva ; Zhong ; Loubersac ; Oktay ; Goldfarb ). In all studies reporting no recovery of AMH levels, patients received treatment with alkylating agents, such as cyclophosphamide-based chemotherapy regimens; however, higher pre-treatment AMH and lower age were identified as factors associated with greater recovery after these regimens (Yu ; Anderson and Cameron 2011; Anderson ; Elgindy ; D'Avila ; Wenners ; Palinska-Rudzka ; Zhong ).

Table II

Characteristics of studies in breast cancer cohorts included in the systematic review (N = 38).

Publication	Study design	Adult/ paediatric	Cohort size	Timing of AMH assessment	AMH assay	LOD (ng/ml)	Reduced/low AMH following anticancer treatment*	Correlation of post-treatment AMH with menstrual function †	Correlation of post-treatment AMH recovery with age
Al-Janabi et al. (2018)	Prospective longitudinal	Adult	60	BL, after first menses after 1st dose, after 4th dose	Gen II ELISA (Beckman Coulter)	Not reported	Yes	N/A	Yes
Anderson et al. (2011)	Prospective longitudinal	Adult	42	BL, PTFU 2, 3, 4, 5 years	ELISA (Beckman Coulter)	0.05	Yes	Yes	N/A
Anderson et al. (2013)	Prospective longitudinal	Adult	55	BL, after 1st and 2nd cycle, PTFU 1 year	Gen II ELISA (Beckman Coulter)	0.16	Yes	Yes	N/A
Anderson et al. (2017)	Prospective longitudinal	Adult	101	BL, PTFU 0, 12, 24 months	Elecsys® AMH (Roche Diagnostics)	0.01	Yes	N/A	Yes
Ben-Aharon et al. (2015)	Prospective longitudinal	Adult	20	BL, PTFU 3–4 days, 6, 12 months	ELISA (Beckman Coulter)	0.01	Yes	N/A	Yes
Çelebi et al. (2020)	Prospective cross-sectional	Adult	31	BL, during/after treatment every 3 months up to 12 months	ELISA	Not reported	Yes	N/A	Yes
D'Avila et al. (2015)	Prospective longitudinal	Adult	52	BL, PTFU 6 months	ELISA (Beckman Coulter)	Not reported	Yes	Yes	Yes
D'Avila et al. (2017)	Prospective longitudinal	Adult	52	BL, PTFU 2, 6 months	ELISA (Beckman Coulter—Immunotech)	Not reported	Yes	Yes	N/A
Decanter et al. (2018)	Prospective longitudinal	Adult	32	BL, 15 days before last cycle, PTFU 3, 6, 9 and 12 months	picoAMH ELISA (Ansh)	0.0224 (0.16 pmol/l)	Yes	Yes	N/A
Dezellus et al. (2017)	Prospective cross-sectional	Adult	249	BL, before each of 6 cycles, PTFU 6, 12 and 24 months	ELISA (Beckman Coulter—Immunotech)	0.14	Yes	No	Yes
Elgindy et al. (2013)	Prospective cross-sectional	Adult	100	BL, PTFU 12 months	Not reported	Not reported	Yes	N/A	N/A
Goldfarb et al. (2020)	Prospective cross-sectional	Adult	142	BL, PTFU 12, 18 and 24 months	picoAMH ELISA (Ansh Labs)	Not reported	Yes	N/A	N/A
Hamy et al. (2016)	Prospective cross-sectional	Adult	134	BL, during treatment, PTFU 4–66 months	ELISA (Beckman Coulter—Immunotech)	0.14	N/A	N/A	N/A
Henry et al. (2014)	Prospective cross-sectional	Adult	27	BL, mean PTFU 4.9 weeks, 13.6 months	Gen II ELISA (Beckman Coulter)	0.16	Yes	No	Yes
Kim et al. (2018)	Prospective cross-sectional	Adult	82	PTFU <2 months	ELISA (USCN Life Science)	0.003	N/A	Yes	N/A
Lambertini et al. (2019)	Prospective longitudinal	Adult	148	BL, PTFU 1, 3 years	Elecsys AMH (Roche Diagnostics)	0.01	Yes	N/A	N/A
Lee et al. (2018)	Prospective cross-sectional	Adult	105	PTFU 508 days	Gen II ELISA (Beckman Coulter)	0.16	N/A	No	Yes
Lee et al. (2020)	Prospective cross-sectional	Adult	67	BL, PTFU 1 year	Gen II ELISA (Beckman Coulter)	0.16	Yes	No	No
Leonard et al. (2017)	Prospective cross-sectional	Adult	202	BL, during treatment (C3), PTFU 0, 9, 12, 24 months	Elecsys AMH (Roche Diagnostics)	Not reported	Yes	N/A	N/A
Li et al. (2020)	Prospective cross-sectional	Adult	144	BL, PTFU 6 months	Human AMH ELISA (Cusabio Biotech)	Not reported	Yes	Yes	Yes
Lutchman Singh et al. (2007)	Prospective cross-sectional	Adult	35	BL, PTFU after resumption of menses	ELISA (Beckman Coulter—Immunotech)	Not reported	Yes	N/A	Yes
Malisic et al. (2018)	Prospective cross-sectional	Adult	40	PTFU 1–66 months	ELISA (Ansh Labs)	0.023	N/A	N/A	Yes
Morarji et al. (2017)	Prospective longitudinal	Adult	100	PTFU 2 years	Gen II ELISA (Beckman Coulter)	0.08	Yes	Yes	Yes
Oktay et al. (2020)	Prospective cross-sectional	Adult	108	BL, PTFU <24 months	picoAMH ELISA (Ansh Labs)	0.003	Yes	N/A	N/A
Palinska-Rudzka et al. (2019)	Prospective longitudinal	Adult	54	BL, PTFU 1, 5 years	Gen II ELISA (Beckman Coulter)	0.02	Yes	Yes	N/A
Partridge et al. (2010)	Prospective cross-sectional	Adult	20	PTFU 5 years	ELISA (Diagnostic Systems Laboratories)	0.03	Yes	N/A	N/A
Passildas et al. (2019)	Prospective longitudinal	Adult	58	BL, PTFU 1 month	Elecsys AMH (Roche Diagnostics)	0.03	Yes	No	N/A
Ruddy et al. (2014)	Retrospective cross-sectional	Adult	124	BL, PTFU 12, 18 months	ELISA (Diagnostic Systems Laboratories)	Not reported	N/A	Yes	N/A
Ruddy et al. (2021)	Prospective longitudinal	Adult	277	BL, PTFU 1 year	Ultrasensitive ELISA (Ansh Labs)	Not reported	Yes	N/A	N/A
Shandley et al. (2017)	Prospective longitudinal	Adult	108	PTFU 7 years	Ultrasensitive ELISA and pico AMH ELISA (Ansh Labs)	0.006	N/A	N/A	Yes
Silva et al. (2019)	Prospective longitudinal	Adult	38	BL, during treatment, PTFU 1, 6 and >9 months up to 18 months	Ultrasensitive ELISA (Ansh Labs)	0.06	Yes	Yes	Yes
Su et al. (2014)	Prospective longitudinal	Adult	109	BL, PTFU 1–1009 days	Gen II ELISA (Beckman Coulter)	0.17	N/A	N/A	N/A
Su et al. (2010)	Prospective longitudinal	Adult	127	PTFU 1–4 years	ELISA (Diagnostic Systems Laboratories)	0.025	Yes	Yes	N/A
Trapp et al. (2017)	Prospective cross-sectional	Adult	170	BL, PTFU 2 years	ELISA (Beckman Coulter)	0.08	Yes	No	No
Wenners et al. (2017)	Prospective longitudinal	Adult	51	BL, during treatment, PTFU 6, 12, 24 months	Elecsys AMH (Roche Diagnostics)	Not reported	Yes	Yes	Yes
Yu et al. (2010)	Prospective longitudinal	Adult	26	BL, PTFU 6, 12, 24, 36, 52 weeks	ELISA (Diagnostic Systems Laboratories)	Not reported	Yes	No	No
Zhong et al. (2019)	Prospective cross-sectional	Adult	96	BL, PTFU 6, 12 months	Immunoassay (Beckman Coulter Unicel DX1800)	Not reported	Yes	N/A	N/A

*Between baseline and follow-up in longitudinal studies, and versus controls in cross-sectional studies.

Presence of regular cycles, oligomenorrhoea or amenorrhoea.

AMH: anti-Müllerian hormone; BL, baseline; LOD, limit of detection; N/A, not applicable; PTFU, post-treatment follow-up.

In patients with breast cancer, post-treatment AMH was also linked to menstrual function at follow-up in 11/18 publications (Su ; Ruddy ; D'Avila , 2017; Morarji ; Wenners ; Decanter ; Kim ; Palinska-Rudzka ; Silva ; Li ). Patients with undetectable AMH generally had a higher risk of amenorrhoea, although several studies reported patients with low or undetectable AMH who did recover menstrual function.

The impact of BRCA status was investigated in two studies (Lambertini ; Oktay ), with one identifying increased loss of ovarian reserve and greater reduction in AMH post-treatment recovery in BRCA+ individuals (Oktay ).

AMH in patients with lymphoma

Of 11 studies in lymphoma (Table III), all nine publications evaluating treatment effect on AMH in patients with lymphoma (including Hodgkin lymphoma), representing a total of 521 patients, found a significant impact (van Beek ; Decanter , 2021; Nitzschke ; Demeestere , 2021; Gharwan ; Anderson ; Palinska-Rudzka ). Eight papers reported significant decline in AMH values from pre-treatment to ≤3 months’ post-treatment (Decanter , 2021; Demeestere , 2021; Gharwan ; Anderson ; Palinska-Rudzka ). An additional study also reported significant decline in post-treatment AMH compared with controls (Nitzschke ). All eight papers evaluating gonadotoxicity found a regimen- or dose-dependent effect on AMH following treatment and during recovery (van Beek ; Decanter , 2021; Hamre ; Behringer ; Anderson ; Palinska-Rudzka ; Demeestere ). Five of these studies identified that patients receiving doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD)-based regimens had at least partial post-treatment recovery of AMH at follow-up compared with those receiving cyclophosphamide-containing regimens (Decanter , 2021; Anderson ; Palinska-Rudzka ; Demeestere ). One paper described limited recovery of AMH in older ABVD-treated patients (Anderson ) whereas another found that the impact of age on recovery was only found in women treated with alkylating agents (Decanter ).

Table III

Characteristics of studies in lymphoma cohorts included in the systematic review (N = 11).

Publication	Study design	Adult/ paediatric	Cohort size	Timing of AMH assessment	AMH assay	LOD (ng/ml)	Reduced/low AMH following anticancer treatment*	Correlation of post-treatment AMH with menstrual function †	Correlation of post-treatment AMH recovery with age
Anderson et al. (2018)	Prospective longitudinal	Adult	67	BL, after 2nd cycle, PTFU 0, 1, 2, 3 years	Elecsys AMH (Roche Diagnostics)	0.01	Yes	N/A	Yes
Behringer et al. (2013)	Prospective cross-sectional	Adult	562	PTFU 46 months	Gen II ELISA (Beckman Coulter)	Not reported	N/A	N/A	Yes
Decanter et al. (2010)	Prospective longitudinal	Adult	30	BL, 15 days after 1st cycle, 15 days before last cycle, PTFU 0, 3, 6, 9, 12 months	Gen II ELISA (Beckman Coulter)	0.098 (0.7 pmol/L)	Yes	N/A	N/A
Decanter et al. (2021)	Prospective longitudinal	Adolescent, Young adult, Adult	122	BL, 15 days after 1st cycle, 15 days before last cycle, PTFU 3, 6, 9, 12 months	Gen II ELISA (Beckman Coulter)	Not reported	Yes	Yes	Yes
Demeestere et al. (2016)	Prospective longitudinal	Adult	67	BL, PTFU 2, 3, 4, 5–7 years	Elecsys AMH (Roche Diagnostics)	Not reported	Yes	N/A	N/A
Demeestere et al. (2021)	Prospective longitudinal	Adult	145	BL, PTFU 0, 1, 2, 3, 4, 5 years	Elecsys AMH (Roche Diagnostics)	0.01 ng/ml	Yes	N/A	Yes
Gharwan et al. (2016)	Prospective longitudinal	Adult	28	BL, PTFU 4–18 months	Gen II ELISA (Beckman Coulter)	Not reported	Yes	Yes (in 21- to 25-year-old group)	N/A
Hamre et al. (2012)	Prospective cross-sectional	Paediatric	62	PTFU 18.1 years	ELISA (Beckman Coulter)	0.15	N/A	No	N/A
Nitzschke et al. (2010)	Prospective longitudinal	Adult	20	PTFU 30.6–32.2  months	ELISA (Diagnostic Systems Laboratories)	0.025	Yes	N/A	N/A
Palinska-Rudzka et al. (2019)	Prospective longitudinal	Adult	12	BL, PTFU 1, 5 years	Gen II ELISA (Beckman Coulter)	0.02	Yes	Yes	N/A
van Beek et al. (2007)	Prospective longitudinal	Paediatric	30	PTFU 11.6 years	ELISA (Diagnostic Systems Laboratories)	Not reported	Yes (in patients receiving MOPP)	N/A	No

*Between baseline and follow-up in longitudinal studies, and vs controls in cross-sectional studies.

Presence of regular cycles, oligomenorrhoea or amenorrhoea.

AMH: anti-Müllerian hormone; BL, baseline; LOD, limit of detection; N/A, not applicable; PTFU, post-treatment follow-up.

Paediatric patients

The majority (20/29; 69%) of papers including paediatric cancer patients were cross-sectional studies reporting on adult childhood cancer survivors (Bath ; van Beek ; Lie Fong ; Gracia ; Hamre ; El-Shalakany ; Miyoshi ; Nielsen ; Krawczuk-Rybak , 2019; Charpentier ; Lunsford ; Thomas-Teinturier ; Elchuri ; van der Kooi ; van den Berg ; Cameron ; George ; Nystrom ; Nies ), of which 19 had follow-up periods of >5 years. Reductions in AMH compared with pre-treatment levels or versus controls were reported by 14/20 (70%) publications (Bath ; van Beek ; Brougham ; El-Shalakany ; Krawczuk-Rybak , 2013b, 2019; Elchuri ; Gupta ; Morse ; van der Kooi , 2019; Cameron ; George ). As with adult cancer patients, the degree of reduction varied with treatment received, with complete loss of AMH in some patients. Low AMH levels were found in some cancer survivors despite normal FSH levels (e.g. in 20% of survivors (George )), indicating the added value of AMH in detecting partial ovarian damage. Additional studies reported trends to lower AMH, or low AMH levels in patients following childhood cancer that were not compared with a control group or baseline data (Hamre ; Miyoshi ; Nielsen ; Charpentier ; Lunsford ; van den Berg ; George ). While these studies support that long-term AMH levels can be reduced in survivors of childhood cancer, important outcomes such as relationships with fertility and age at menopause have not been evaluated.

Most studies (10/12 (90.9%)) (van Beek ; Lie Fong ; Brougham ; Hamre ; Miyoshi ; Krawczuk-Rybak , 2019; Charpentier ; Thomas-Teinturier ; van der Kooi ) which had data for both pre- and post-menarchal patients did not detect significant differences in post-treatment AMH by this parameter, and one reported better AMH recovery in pre-menarchal patients (van der Kooi ). Two publications also reported delayed puberty in patients with low post-treatment AMH (El-Shalakany ; Lunsford ).

Impact of duration of follow-up

To assess the impact of cancer treatment on AMH levels during long-term follow-up, studies with <1 year of follow-up were excluded owing to the potential for a residual effect of cancer treatment and incomplete recovery. Based on median reported follow-up post-treatment periods, there were 35 studies with 1- to 2-year follow-up (Bath ; Rosendahl ; Yu ; Brougham ; Anderson , 2017; Elgindy ; Iwase ; Dillon ; Henry ; Ruddy , 2021; Ben-Aharon ; Gharwan ; Gupta ; Dezellus ; Leonard ; Morarji ; Trapp ; Wenners ; Decanter , 2018; Evranos ; Lee , 2020; Yaish ; Silva ; van der Kooi ; Zhong ; Celebi ; Loubersac ; Oktay ; Berjeb ; Goldfarb ; Martin, 2021). Most (33/35; 96%) found that AMH was reduced after treatment, 19/25 (76%) later then identified some degree of increase in AMH at follow-up. Although only a few studies found a (very modest) increase in AMH after 12 months, several studies with a maximum post-treatment follow-up period of 12 months showed the highest post-treatment AMH value at 12 months, raising the possibility that further recovery could have been observed (Brougham ; Ben-Aharon ; Gupta ; Decanter ; Yaish ). It therefore appears that 12 months after completion of treatment is a minimum period to allow complete or near-complete recovery of ovarian function: little recovery is seen thereafter and becomes confounded with the normal decline in AMH with increasing age.

Of 18 studies with a median >2–5.5 years of follow-up, 15/15 with available data (100%) identified AMH reductions in cancer survivors (Nitzschke ; Partridge ; Su ; Anderson and Cameron 2011; El-Shalakany ; Acibucu ; Demeestere , 2021; Morse ; Anderson ; Cameron ; Lambertini ; Palinska-Rudzka ; Chemerinski ; van Velsen ), 8/10 (80%) identified at least partial recovery at follow-up in ≥1 patient group (Demeestere , 2021; Morse ; Anderson ; Malisic ; Cameron ; Lambertini ; Palinska-Rudzka ) and 3/5 (60%) reported correlation of post-treatment AMH with menstrual function in some patients (Rosendahl ; Su ; Palinska-Rudzka). Of 24 cross-sectional studies with follow-up >5.5 years, 11/17 (65%) found AMH reductions with treatment when compared with controls (van Beek ; Gracia ; Di Paola ; Krawczuk-Rybak , 2013b, 2019; Thomas-Teinturier ; Elchuri ; Leiper ; Mittica ; Roshandel ) and 1/4 (25%) linked AMH to menstrual function in some patients (Lunsford ). There are very limited data regarding continuing changes in AMH after cancer treatment and whether cancer survivors show an accelerated decline in AMH in the later reproductive years. In a mixed longitudinal/cross-sectional analysis, AMH levels were shown to be reduced according to gonadotoxicity but maintained a plateau for a prolonged period after treatment (Su ). Supporting that, cancer survivors showed no evidence of an increased rate of decline in AMH compared to age-matched controls (Cameron ).

Discussion

Anticancer treatment has a clear negative impact on women’s ovarian reserve, with reduced AMH levels observed across studies and diagnoses, and reductions of ≥90% commonly identified. Some degree of post-treatment recovery in AMH levels was described in many patient groups, although full- or near-complete restoration to pre-treatment levels was rare and typically occurred in patients receiving milder treatment. Figure 3 gives a representation of the key findings of this review. It is notable that there are relatively few prospective studies, and among those with longitudinal data, several had a maximum 1 year of follow-up. While AMH levels measured 1–2 years after treatment are likely to be reliable at indicating longer-term menstrual outcomes, further research is required to confirm this, especially in older women where recovery is slower and more limited (van Beek ; Decanter ; Behringer ; Anderson ; Palinska-Rudzka ).

Figure 3.

Summary of findings of systematic review represented graphically. The three lines represent women with high (green), average (blue) and low (red) AMH levels before treatment, with treatment represented by the shaded area and a threshold indicating POI is also represented. (1) AMH concentrations are reduced by cancer treatments. (2) Recovery is variable, depending on patient age, treatment regimen and pre-treatment AMH levels. Recovery can be near complete or absent, with the latter resulting in permanent POI. The relationship of post-treatment AMH to POI needs to be explored further. (3) Prediction of permanent POI at the time of end of treatment may be possible in some situations, but further studies are required to determine the patient groups for which this may and may not be possible. (4) There are insufficient data to be able to predict the duration of post-recovery ovarian function using AMH levels before or after treatment, which will interact with the physiological decline in AMH with increasing age. Reproduced from Jayasinghe with permission.

Treatments known to be more gonadotoxic, whether this be drug or cumulative exposure related, generally caused a greater reduction in AMH. The clearest evidence comes from lymphoma, where patients receiving ABVD-based regimens showed more complete AMH recovery and resumption of menstruation compared to more severe treatment strategies (van Beek ; Decanter , 2021; Behringer ; Anderson ; Palinska-Rudzka ). Studies in breast cancer also identified taxanes as contributing to lower AMH (Hamy ; Lambertini ; Silva ). However, studies evaluating cumulative dose of chemotherapy, regardless of regimen, show this to be a key factor in ovarian outcomes (Charpentier ; Elchuri ; van den Berg ; Cameron ; George ).

Pre-treatment AMH values were associated with post-treatment AMH in all 11 studies that evaluated this, supporting the predictive value of AMH at baseline. All of these studies were in post-menarchal patients. Several studies also identified low pre-treatment AMH in some patients (Lutchman Singh ; Cameron ; Palinska-Rudzka ; van der Kooi ), which was not limited to a particular diagnosis.

An important question is whether the lower AMH levels after cancer treatment then decline at a different rate compared to other women. Three studies found no significant difference in rates between patients and age-matched controls (van der Kooi ; Cameron ; Elitzur ). However, there is a higher rate of decline in older women, both cancer survivors and controls (Dezellus ; Cameron ). These studies highlight the need for research investigating the relationships between post-treatment AMH, age and age of POI/menopause, which would be of substantial clinical value.

While the picture regarding treatment impact on AMH is clear, there was no clear relationship between AMH and menstrual status at follow-up, with menstruation reported in patients with undetectable AMH across different diagnoses and treatments (Decanter ; Rosendahl ; Ben-Aharon ). The reliability of AMH in predicting menstrual function may be better in older patients, consistent with AMH becoming undetectable in advance of natural menopause in healthy women. In contrast, in younger women, menstrual cycles may continue despite a very limited ovarian reserve and undetectable AMH. Although several studies have reported a clear relationship between low/undetectable AMH and diagnosis of POI, the diagnostic validity of AMH for post-cancer treatment POI has not been sufficiently evaluated, either alone or in combination with established criteria.

Interpretation of AMH in paediatric cohorts is potentially complicated by the natural arc of AMH, which increases during childhood and through the early adult years before a decline to the menopause (Kelsey ). With the exception of one publication (van der Kooi ), there were no differences in the effect of treatment on post-treatment AMH levels between pre- and post-menarchal patients, suggesting the reliability of AMH as a biomarker in younger populations. It should also be noted that all six studies that did not find a treatment influence on AMH were in adult survivors of childhood cancer (Lie Fong ; Nielsen ; van den Berg ; Nystrom ; Nies ; Elitzur ), whereas other studies did find an effect. Further longitudinal studies, from diagnosis through to adulthood, are required to further explore the value of AMH for predicting late ovarian function shortly after completion of therapy in paediatric and adolescent patients with cancer.

Across the different publications, spanning nearly two decades, multiple AMH assay types, most commonly ELISAs or electrochemiluminescence immunoassays (ECLIAs), from a variety of manufacturers have been used. There is currently no internationally agreed calibration standardization for AMH, and the improvements in sensitivity afforded by automated assays in comparison with historical methods, as well as inherent variation and non-linear conversion between assays, can complicate interpretation of the data (Li ). Whether variations in assay calibration and performance influence the clinical value of AMH assessment was not formally assessed, but the overall consistency of the main findings indicates that this is not a major issue. It is possible though that the use of assays with greater sensitivity (Chai ; Decanter ) will impact on analysis of AMH as a diagnostic test for POI.

A variety of additional independent factors can influence levels of AMH (Dafopoulos ; Dólleman ). Although publications featuring potentially AMH-modifying conditions, such as systemic illness, endometriosis, polycystic ovary syndrome and granulosa cell tumours, were excluded, studies with patients who use cigarettes or oral contraceptives (Elitzur ), as well as BRCA mutation carriers (Lambertini ; Oktay ), were included. The studies described here represent highly heterogeneous patient populations, incorporating a wide range of ages, diagnoses and treatment types. While this may limit the ability of this review to make specific recommendations, it reinforces the wider applicability of our observations.

This review confirms AMH as a marker of ovarian reserve but does not specifically address assessment of time to menopause, which may be clinically useful. This has previously been addressed in relation to natural menopause via probability (Finkelstein ) and estimated rate of decline-based models (de Kat ; Ramezani Tehrani ). As AMH has been shown to correlate with patient age and treatment gonadotoxicity and declines at a similar rate to healthy individuals following any post-treatment recovery, it should be possible to develop a model for menopause risk over time based on pre- and post-treatment AMH measurements. Additional longitudinal studies would support such a model and help to further establish the time course of any AMH recovery, and in which patient groups it occurs, especially whether a time point <2 years’ post-treatment can reliably provide a long-term predictive marker.

Conclusion

In this systematic review, we confirm that anticancer treatment substantially impacts AMH, with large reductions during treatment followed by a period of partial recovery in some women, peaking within 1–2 years (Fig. 3). Low post-treatment AMH was predicted by lower pre-treatment AMH, as well as by older age and gonadotoxicity of treatment. Consequently, discussions around treatment and ovarian outcomes should consider the risk of POI and need for family planning and fertility preservation, informed by AMH. While low post-treatment AMH correlated with increased likelihood of POI, the evidence with respect to oligo- or amenorrhoea was less clear and there were very little data relating AMH to fertility or time to/age at POI or menopause. AMH is therefore a clinically useful biomarker of ovarian reserve before and after cancer treatment and it is likely to be of value in the diagnosis of POI after cancer treatment but relationships with post-treatment fertility and reproductive lifespan require further investigation.

Supplementary data

Supplementary data are available at Human Reproduction Update online.

Data availability

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