Role of anti-Müllerian hormone in predicting premature ovarian insufficiency after pelvic radiotherapy

Abstract

Background and purpose

Premature ovarian insufficiency (POI) frequently occurs in premenopausal women undergoing pelvic radiotherapy. Anti-Müllerian hormone (AMH) has emerged as a promising biomarker of ovarian reserve, but its role in evaluating post-radiotherapy ovarian function remains uncertain.

Materials and methods

We retrospectively analyzed 23 premenopausal women (≤ 45 years) who received pelvic radiotherapy. POI was defined using two criteria: (1) persistently undetectable AMH (<0.0714 pmol/L) beyond 6 months post-radiotherapy or at last follow-up; and (2) sustained elevation of FSH (>30 mIU/mL) at the same timepoints. Logistic regression was used to identify clinical and dosimetric predictors for POI.

Results

Based on AMH and FSH criteria, POI occurred in nine (39.1%) and eight (34.8%) patients, respectively, with 19 patients showing concordant classifications. AMH declined sharply after radiotherapy, and in some patients, recovered between 6 and 10 months, typically preceding FSH normalization. In AMH-based analysis, sequential brachytherapy following external beam radiotherapy was associated with a higher risk of POI (odds ratio [OR] 55.695, 95% confidence interval [CI] 1.456–2129.833, p = 0.031), and higher minimum radiation dose (Dmin) to the ovary was significantly associated with an increased risk of POI (OR 1.026, 95% CI 1.002–1.051, p = 0.037). For FSH-defined POI, higher ovarian Dmin was also an independent predictor (OR 1.046, 95% CI 1.008–1.086, p = 0.019), indicating a 4.6% increase in the odds of POI per 1 cGy increase in Dmin.

Conclusion

In premenopausal women undergoing pelvic radiotherapy, AMH levels declined earlier than FSH and may provide additional information for assessing ovarian reserve. Minimizing ovarian Dmin is important for preserving ovarian function.

Highlights

• •AMH may reflect earlier changes in ovarian reserve after pelvic radiotherapy.
• •Higher ovarian Dmin was significantly associated with increased risk of ovarian dysfunction.
• •Serial AMH monitoring may provide additional information for ovarian-sparing strategies and post-RT hormone management.

1. Introduction

Premature ovarian insufficiency (POI) is a frequent complication in premenopausal women undergoing pelvic radiotherapy (RT) (Wallace et al., 1989), as the ovaries are very radiosensitive (Wallace et al., 2003), with an estimated radiation dose at which half of the follicles are lost (LD₅₀) less than 2 Gy. POI remains a major concern despite ovarian preservation strategies such as ovarian transposition (OT) and ovary-sparing RT techniques. A major challenge in evaluating ovarian function preservation is the lack of standardized diagnostic criteria and reliable biomarkers for POI.

The European Society of Human Reproduction and Embryology (ESHRE) Guideline defined POI as oligo/amenorrhea lasting at least 4 months, accompanied by follicle-stimulating hormone (FSH) level > 25 IU/L on two separate occasions more than four weeks apart before the age of 40 (Eshre Guideline Group on POI et al., 2016). However, in women who have undergone hysterectomy due to malignancy, menstrual status cannot be assessed. Additionally, FSH levels are subject to fluctuation and may lack reliability and consistency needed for accurate POI diagnosis (Burger et al., 2008). Because FSH secretion is regulated through hypothalamic–pituitary–ovarian feedback mechanisms, levels may vary over time depending on residual follicular activity and endocrine status. As a result, repeated measurements are often required to confirm the diagnosis of POI. In addition, treatments such as luteinizing hormone-releasing hormone (LHRH) agonists may influence FSH levels during follow-up. Therefore, biomarkers that directly reflect ovarian reserve may provide complementary information for evaluating ovarian function after pelvic RT.

Anti-Müllerian hormone (AMH), secreted by granulosa cells of preantral and small antral follicles, has emerged as a promising biomarker of ovarian reserve and function (Toner and Seifer, 2013). Although AMH levels decline naturally with age (Shebl et al., 2011), they have been shown to independently predict amenorrhea following chemotherapy (D'Avila et al., 2015). Several studies have proposed AMH threshold levels for predicting chemotherapy-induced amenorrhea (Kim et al., 2021); however, longitudinal data on AMH changes following pelvic RT are scarce, and its clinical utility in this setting remains unclear.

This study aims to investigate serial changes in AMH levels among premenopausal women receiving pelvic RT and to explore the potential role of AMH as an indicator of post-RT ovarian function in comparison with conventional FSH-based criteria. Furthermore, we seek to identify clinical and treatment-related factors associated with the development of POI following RT.

2. Materials and methods

This retrospective study included consecutive premenopausal women who underwent pelvic RT at our medical center between January 2022 and April 2024. Eligible patients met the following criteria: (1) premenopausal women aged > 20 and ≤ 45 years at the time of RT; (2) no radiologic or pathologic evidence of ovarian metastasis at the time of initial staging; (3) treatment with pelvic RT; (4) availability of baseline and at least one follow-up serum AMH measurement after RT; and (5) mean radiation dose (Dmean) to at least one ovary ≤ 10 Gy, as determined by treatment planning dosimetry. This study was approved by the Institutional Review Board of our medical center (approval number: 2025-0417) and conducted in accordance with the principles of the Declaration of Helsinki.

Collected clinical data included age, body mass index (BMI), cancer type and stage, surgical history including OT, use of LHRH agonists, RT parameters, and hormonal profiles (AMH, FSH, estradiol). Dosimetric parameters were assessed for each ovary, including maximum dose (Dmax), minimum dose (Dmin), Dmean, and the minimum distance from the ovary to the planning target volume (PTV), defined as the shortest three-dimensional distance between their outer contours on simulation computed tomography (CT) images.

All patients received external beam RT (EBRT) using either intensity modulated RT or volumetric modulated arc therapy. CT simulation was performed in the supine position with appropriate immobilization, and planning CT images with a slice thickness of 2.5 mm were acquired. Target volumes and organs at risk, including both ovaries, were delineated according to institutional protocols. The ovary contours were defined based on simulation CT images, supplemented by surgical records and diagnostic imaging when available. In selected patients, brachytherapy was delivered with a total dose of 10–20 Gy in 2–4 fractions.

Serum AMH, FSH, and estradiol levels were measured before RT and every 3–6 months after treatment as part of routine surveillance. POI was defined as either (1) persistently undetectable AMH (< 0.0714 pmol/L, corresponding to the lower limit of detection of the assay) beyond 6 months after RT or at last follow-up, or (2) sustained elevation of FSH > 30 mIU/mL at the same timepoints, regardless of estradiol levels, consistent with thresholds used in prior studies of POI (Valduga et al., 2024; Shogan et al., 2024). Serum AMH levels were measured using an Elecsys AMH assay (Roche Diagnostics, Germany).

The primary endpoint of this study was to characterize longitudinal changes in AMH and FSH following pelvic RT and to compare patterns of ovarian function assessment based on serial AMH and conventional FSH-based criteria. The secondary endpoint was to perform exploratory analyses of clinical and dosimetric factors associated with ovarian function outcomes after RT. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 29.0 (IBM Corp., Armonk, NY, USA). Continuous variables were compared using the Mann–Whitney U test, and categorical variables were analyzed using the chi-square test or Fisher's exact test, as appropriate. Logistic regression analysis was used to identify significant predictors of POI. Variables with p < 0.1 in univariate analysis were included in the multivariable model.

3. Results

3.1. Patient and treatment characteristics

A total of 23 premenopausal women who received pelvic RT between January 2022 and April 2024 were included. Median follow-up time was 20.3 months (median, 9.3–32.2). Baseline clinical and treatment characteristics are presented in Table 1. The median age was 35 years (range, 25–41), and the median BMI was 21.6 kg/m² (range, 18.9–32.7). The majority of patients (87.0%) were diagnosed with cervical cancer, and 91.3% had undergone hysterectomy. Concurrent chemoradiotherapy with weekly cisplatin (40 mg/m²) was administered in 78.3% of patients, and LHRH agonists were used in 60.9%.

Table 1.

Clinical characteristics for all patients.

Characteristic	Data
Age (yr), median (range)	35 (25–41)
BMI (kg/m2), median (range)	21.6 (18.9–32.7)
Cancer type, N (%)
Cervix cancer	20 (87.0)
Others	3 (13.0)
Hysterectomy, N (%)
Yes	21 (91.3)
No	2 (8.7)
Preoperative chemotherapy, N (%)
Yes	1 (4.3)
No	22 (95.7)
OT, N (%)
Bilateral OT	14 (60.9)
Ipsilateral OT	7 (30.4)
None	2 (8.7)
OT location, N (%)
Superior to the iliac crest	13 (56.5)
Inferior to the iliac crest	8 (34.8)
None	2 (8.7)
Pre-RT AMH (pmol/L), median (range)	8.57 (0.86–38.06)
Pre-RT FSH (mIU/mL), median (range)	3.45 (0.74–11.80)
Pre-RT estradiol (pg/mL), median (range)	12.40 (4.00–171.00)
CCRT, N (%)
Yes	18 (78.3)
No	5 (21.7)
Use of LHRH agonist, N (%)
Yes	14 (60.9)
No	9 (39.1)
EBRT dose, median (range)	46 (46–70)
EBRT fx, median (range)	23 (23–35)
RT field, N (%)
WPRT	17 (73.9)
EFRT/others	6 (26.1)
Sequential BT after EBRT, N (%)
Yes	6 (26.1)
No	17 (73.9)
Ovary dose (cGy), median (range)
Dmax	371.2 (123.6–5224.5)
Dmin	179.0 (56.6–322.9)
Dmean	258.4 (83.6–445.9)
Distance from ovary to PTV (mm), median (range)	34.8 (0.0–67.7)

BMI, body mass index; OT, ovarian transposition; RT, radiotherapy; AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; CCRT, concurrent chemoradiotherapy; LHRH, lutenizing hormone-releasing hormone; EBRT, external beam radiotherapy; fx, fraction; WPRT, whole pelvic radiotherapy; EFRT, extended-field radiotherapy; BT, brachytherapy; Dmax, maximum dose; Dmin, minimum dose; Dmean, mean dose; PTV, planning target volume.

The median EBRT dose was 46 Gy (range, 46–70 Gy), delivered in a median of 23 fractions (range, 23–35). Six patients (26.1%) received additional high-dose-rate brachytherapy with a fractional dose of 5–6 Gy administered in two to four fractions twice weekly. OT was performed in 91.3% of patients, with 56.5% of transposed ovaries positioned superior to the iliac crest. The median ovarian radiation dose was 371.2 cGy for Dmax, 179.0 cGy for Dmin, and 258.4 cGy for Dmean. The median distance from the ovary to the PTV was 34.8 mm (range, 0.0–67.7 mm).

3.2. Hormonal changes after radiotherapy

Serial measurements of serum FSH, AMH, and estradiol are shown in Fig. 1. Regardless of the initial AMH levels, AMH uniformly declined sharply after RT, reaching < 1.5 pmol/L by 3 months, with partial recovery observed in some patients between 6 and 10 months (Fig. 1A). FSH levels exhibited a transient post-treatment surge with wide inter-patient variation, followed by a gradual decline (Fig. 1B). At the first follow-up of median 3.1 months, 16 patients demonstrated undetectable AMH while only eight of them showed an FSH increase above 30 mIU/mL, and similar patterns were observed at consequent timepoints. Estradiol levels generally decreased after RT, although a subset of patients showed paradoxical increases, contributing to considerable inter-patient variability (Fig. 1C).

Fig. 1.

Changes in AMH (A), FSH (B) and estradiol (C) levels before and after radiotherapy.

By study-defined criteria, POI occurred in nine patients (39.1%) based on AMH and in eight (34.8%) based on FSH. Eighteen patients (78.3%) showed concordant classification between the two criteria, including six patients classified as POI and twelve as non-POI by both. Five patients (21.7%) showed discordant results, with three patients classified as POI based on AMH but not FSH, and two patients classified as POI based on FSH but not AMH. Fig. 2 illustrates representative cases of concordance between AMH and FSH levels. As for case #10, the decline in AMH at 3 months (0.000 pmol/L) corresponded with a rise in FSH (65.80 mIU/mL) and this trend persisted at subsequent follow-ups, indicating POI according to both definitions. Likewise, in case #13, AMH remained at 0.571 pmol/L at 3 months while FSH was below 30 mIU/mL, indicating non-POI by both definitions. In contrast, Fig. 3 illustrates two representative discordant cases in which AMH levels remained persistently undetectable, whereas FSH levels stayed below the menopausal threshold of 30 mIU/mL.

Fig. 2.

Representative cases of concordance between AMH and FSH changes following pelvic radiotherapy. Solid blue lines, AMH (left y-axis); dashed orange lines, FSH (right y-axis). Dotted horizontal lines indicate AMH POI threshold (0.0714 pmol/L) and FSH POI threshold (30 mIU/mL). POI classification is indicated in the upper right corner of each panel.

Fig. 3.

Representative cases of discordance between AMH and FSH changes following pelvic radiotherapy. Line styles and threshold markings are as described in Fig. 2.

3.3. Predictors of ovarian function recovery – AMH-based criteria

Univariate logistic regression analysis (Table 2) showed that older age was significantly associated with POI, with the odds of POI increasing by approximately 37% per year of age (odds ratio [OR] 1.369, 95% confidence interval [CI], 1.012–1.854, p = 0.042). Brachytherapy after EBRT was associated with a markedly higher risk (OR 16.250, 95% CI 1.442–183.093, p = 0.024), and higher Dmin showed a borderline association (OR 1.020, 95% CI 1.000–1.040, p = 0.053). In multivariable analysis, brachytherapy and higher Dmin remained significant predictors. Patients receiving brachytherapy had a 56-fold increased risk of POI (OR 55.695, 95% CI 1.456–2129.833, p = 0.031), and among the six patients who received brachytherapy, five were classified as having POI according to the AMH-based criteria. Each 1 cGy increase in Dmin was associated with a 2.6% higher odds of POI (OR 1.026, 95% CI 1.002–1.051, p = 0.037). In descriptive comparisons, patients with POI had higher ovarian radiation exposure (median Dmin, 223.1 cGy vs. 162.5 cGy) and were older (median age, 38 vs. 34).

Table 2.

Univariate and multivariable analyses of premature ovarian insufficiency defined by AMH criteria (persistently undetectable < 0.0714 pmol/L).

	Univariate		Multivariable
Variable	OR (95% CI)	p-value	OR (95% CI)	p-value
Age (median, range)	1.369 (1.012–1.854)	0.042	1.268 (0.860–1.872)	0.231
BMI (median, range)	0.956 (0.739–1.237)	0.731
OT location
Superior to the iliac crest	1	0.353
Inferior to the iliac crest/None	2.250 (0.407–12.439)
OT
Ipsilateral OT/None	1	0.203
Bilateral OT	0.320 (0.055–1.847)
Pre-RT AMH (pmol/L) (median, range)	0.889 (0.773–1.024)	0.103
Pre-RT FSH (mIU/mL) (median, range)	1.027 (0.779–1.353)	0.853
Pre-RT estradiol (pg/mL) (median, range)	1.015 (0.990–1.041)	0.239
CCRT
Yes	3.222 (0.296–34.588)	0.338
No	1
Use of LHRH agonist
Yes	0.694 (0.126–3.839)	0.676
No	1
RT field
WPRT	1	0.736
EFRT/others	0.714 (0.101–5.035)
Sequential BT after EBRT
Yes	16.250 (1.442–183.093)	0.024	55.695 (1.456–2129.833)	0.031
No	1
Ovary dose (cGy), (median, range)
Dmax	1.000 (0.998–1.001)	0.569
Dmin	1.020 (1.000–1.040)	0.053	1.026 (1.002–1.051)	0.037
Dmean	1.007 (0.995–1.019)	0.238
Distance from ovary to PTV (mm) (median, range)	0.997 (0.942–1.055)	0.915

OR, odds ratio; CI, confidence interval; BMI, body mass index; OT, ovarian transposition, RT, radiotherapy; AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; CCRT, concurrent chemoradiotherapy; LHRH, luteinizing hormone-releasing hormone; WPRT, whole pelvic radiotherapy; EFRT, extended-field radiotherapy; BT, brachytherapy; Dmax, maximum dose; Dmin, minimum dose; Dmean, mean dose; PTV, planning target volume.

3.4. Predictors of ovarian function recovery – FSH-based criteria

In the univariate analysis (Table 3), older age showed a borderline association with POI (OR 1.286, 95% CI 0.975–1.697, p = 0.075), although it did not remain significant in the multivariable model. A higher pre-RT AMH level suggested a protective effect against POI (OR 0.877, 95% CI 0.751–1.023, p = 0.096). Among dosimetric parameters, higher Dmin was significantly associated with POI (OR 1.046, 95% CI 1.008–1.086, p = 0.019), and higher Dmean also showed a trend toward increased risk (OR 1.016, 95% CI 0.999–1.032, p = 0.069). In multivariable analysis, only higher Dmin remained significant (OR 1.046, 95% CI 1.008–1.086), p = 0.019), indicating a 4.6% increase in POI risk for every 1 cGy increase in Dmin. In descriptive comparisons, patients with POI had higher ovarian radiation exposure (median Dmin 234.2 cGy vs. 155.1 cGy) and were older (median age, 38 vs. 34).

Table 3.

Univariate and multivariable analyses of premature ovarian insufficiency defined by FSH criteria (sustained elevation >30 mIU/mL).

	Univariate		Multivariable
Variable	OR (95% CI)	p-value	OR (95% CI)	p-value
Age (median, range)	1.286 (0.975–1.697)	0.075	1.105 (0.763–1.601)	0.595
BMI (median, range)	0.975 (0.754–1.268)	0.866
OT location
Superior to the iliac crest	1	0.646
Inferior to the iliac crest/None	1.500 (0.266–8.449)
OT
Ipsilateral OT/None	1	0.907
Bilateral OT	1.111 (0.190–6.492)
Pre-RT AMH (pmol/L) (median, range)	0.877 (0.751–1.023)	0.096	0.879 (0.675–1.144)	0.337
Pre-RT FSH (mIU/mL) (median, range)	0.916 (0.671–1.252)	0.583
Pre-RT estradiol (pg/mL) (median, range)	1.006 (0.984–1.028)	0.595
CCRT
Yes	0.750 (0.098–5.768)	0.782
No	1
Use of LHRH agonist
Yes	0.218 (0.035–1.364)	0.103
No	1
RT field
WPRT	1	0.931
EFRT/others	0.917 (0.128–6.556)
Sequential BT after EBRT
Yes	2.400 (0.355–16.213)	0.369
No	1
Ovary dose (cGy) (median, range)
Dmax	1.000 (0.998–1.001)	0.642
Dmin	1.046 (1.008–1.086)	0.019	1.046 (1.008–1.086)	0.019
Dmean	1.016 (0.999–1.032)	0.069	1.014 (0.980–1.049)	0.427
Distance from ovary to PTV (mm) (median, range)	0.990 (0.933–1.049)	0.728

OR, odds ratio; CI, confidence interval; BMI, body mass index; OT, ovarian transposition; AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; CCRT, concurrent chemoradiotherapy; LHRH, luteinizing hormone-releasing hormone; RT, radiotherapy; WPRT, whole pelvic radiotherapy; EFRT, extended-field radiotherapy; BT, brachytherapy; Dmax, maximum dose; Dmin, minimum dose; Dmean, mean dose; PTV, planning target volume.

4. Discussion

In this retrospective study of premenopausal women treated with pelvic RT, our findings suggest that AMH reflects early changes in ovarian reserve following pelvic RT and may provide complementary information to conventional FSH-based assessment. Our data highlight the temporal dynamics of ovarian hormone suppression and recovery, as well as clinical and dosimetric predictors of POI.

The definition of POI remains controversial. Traditionally, FSH elevation has been used as the main surrogate marker; however, its inherent variability and delayed rise after ovarian damage limit its reliability (Racoubian et al., 2020). Prior studies on POI after pelvic RT have adopted heterogenous criteria, including FSH thresholds ranging from 20 to 40 IU/mL and/or estradiol levels below 30–100 pmol/L (Hoekman et al., 2018; Gay et al., 2022; Hilal et al., 2022). Using FSH-based definitions, one report showed that patients who developed POI were significantly older (median 44 vs. 34 years, p < 0.001), and no patient with an ovarian Dmean <1.36 Gy developed POI (Hilal et al., 2022). Yin et al. reported that ovarian Dmax < 9.985 Gy, Dmean < 5.32 Gy, and V_5.5 (the percentage of an ovary volume receiving ≥ 5.5 Gy) < 29.65% predicted preserved ovarian function (Yin et al., 2019). In contrast, Gay et al. reported significant association between median ovarian Dmean, Dmax, and cranio-caudal distance to the sacral promontory or iliac crest and POI (all p > 0.35) (Gay et al., 2022).

Previous studies have also reported that AMH is a more sensitive predictor of ovarian aging than FSH, as AMH levels decline earlier than FSH (Racoubian et al., 2020; Depmann et al., 2016). In line with this, we hypothesized that AMH may better reflect ovarian function after pelvic RT. In our cohort, AMH uniformly declined shortly after RT, typically preceding FSH elevation, and in some patients, AMH recovery was observed despite persistently elevated FSH. At the first post-RT follow-up, half of the patients with undetectable AMH had not yet reached the FSH threshold of 30 mIU/mL, further highlighting that AMH may capture earlier changes in ovarian reserve compared with FSH, consistent with prior chemotherapy-related studies (D'Avila et al., 2015; Kim et al., 2021). AMH reflects the number and growth status of ovarian follicles, whereas FSH is subject to gonadotropin feedback and may normalize despite follicular depletion.

Importantly, AMH is unaffected by exogenous hormone replacement therapy (HRT), further supporting its clinical utility. Given that transient ovarian suppression is common after pelvic RT, serial AMH monitoring may help guide the timely initiation and discontinuation of HRT in premenopausal patients, preventing both undertreatment and unnecessary prolonged hormone exposure. Early recognition and timely intervention remain essential to mitigate the consequences of POI beyond infertility, including vasomotor symptoms, bone loss, cardiovascular disease, metabolic disturbances, and psychological distress.

In the present study, higher ovarian Dmin was a meaningful predictor of POI using both AMH- and FSH-based definitions. Sequential brachytherapy also emerged as a risk factor, likely due to its contribution to increased Dmin. Although no universally accepted dose constraints to prevent POI exist, the overall trend is clear: minimizing ovarian radiation dose as much as possible improve the likelihood of function preservation. Our results suggest that residual ovarian regions exposed to lower radiation doses may retain recovery potential. Function recovery was more apparent around 10 months after RT, whereas patients without recovery by 10–12 months typically remained in POI thereafter.

This study has several limitations. The small sample size and retrospective design limit statistical power and introduce potential bias. The relatively short follow-up period of less than two years may underestimate the true incidence of POI, and non-uniform follow-up intervals with occasional missing data could obscure transient hormonal fluctuations. In addition, the predominance of cervical cancer patients who underwent hysterectomy with OT may restrict the generalizability of our findings to other pelvic malignancies. Furthermore, because no universally accepted AMH-based definition of POI currently exists, analyses based on AMH-defined ovarian function outcomes, including recovery analyses, should be interpreted cautiously and considered exploratory. Finally, although we empirically observed some patients reporting menopausal symptoms as early as 3 months after RT, these reports were not systematically captured; future studies should incorporate structured questionnaires to obtain more objective data on patient-reported menopausal symptoms.

Despite these limitations, our study provides one of the few longitudinal datasets on serial AMH changes after pelvic RT, demonstrating the potential of AMH as an earlier biomarker that may provide complementary information to FSH. Furthermore, by identifying dosimetric factors associated with POI, our results offer practical insights into strategies for ovarian function preservation in women receiving pelvic RT. These findings warrant validation in larger, prospective cohorts.

In conclusion, AMH showed earlier changes in ovarian reserve compared with FSH in premenopausal women treated with pelvic RT. Higher ovarian Dmin was significantly associated with an increased risk of POI, and sequential brachytherapy was also associated with an increased risk of ovarian dysfunction. Because hormonal recovery was largely observed within the first year, timely recognition of ovarian insufficiency through serial AMH monitoring may provide helpful information for clinical decision-making in personalized survivorship care.

CRediT authorship contribution statement

Youngju Song: Writing – review & editing, Validation, Investigation, Data curation. Yoon Young Jo: Writing – original draft, Visualization, Investigation, Formal analysis. Yeon Joo Kim: Writing – review & editing, Writing – original draft, Resources, Project administration, Methodology, Conceptualization.

Funding resources

This study was supported by a grant (grant number 2023IL0008–1) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

Declaration of competing interest

No potential conflict of interest relevant to this article was reported.

Data availability

Research data are stored in an institutional repository and will be shared upon request to the corresponding author.