Sex specific ocular parameter trajectories during low intensity red light exposure in myopic adolescents in Liaoning China

Abstract

To describe, in the absence of a control group, sex-specific trajectories of ocular parameters during low-intensity red light exposure in myopic adolescents in Liaoning, China. Given the uncontrolled design, this study was exploratory and hypothesis generating. This prospective, non-randomized, uncontrolled cohort enrolled 180 myopic adolescents (90 males, 90 females). All participants used a 650 nm low-intensity red light device twice daily. Ophthalmic examinations were conducted at baseline and at 1, 3, 6, and 12 months. Repeated-measures analysis of variance assessed time effects, sex effects, and time × sex interactions. At baseline, males had longer axial length (24.35 ± 0.94 vs. 24.02 ± 0.79 mm; P = 0.014) and more myopic spherical equivalent (− 2.25 ± 1.46 vs. −1.70 ± 1.43 D; P = 0.011) than females, while baseline UDVA and intraocular pressure did not differ significantly (both P > 0.05). Over 12 months, axial length increased in both sexes (time effect P < 0.001) and spherical equivalent became less negative (time effect P < 0.001), but time × sex interactions were not significant for axial length or spherical equivalent (both P > 0.05). The between-sex difference in annual axial elongation was 0.01 mm (95% CI − 0.023 to 0.066). UDVA (decimal) increased over time (P < 0.01) with a small time × sex interaction (P < 0.05): females showed earlier increases (significant at 1 month), whereas males showed later increases (significant at 3 months). This uncontrolled, nonrandomized exploratory cohort describes 12-month trajectories of ocular parameters observed in adolescents undergoing low-intensity red light exposure. Without a comparator group, these observations cannot be attributed to the exposure and should be interpreted as descriptive and hypothesis generating.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-39824-6.

Introduction

The global incidence of myopia among adolescents continues to rise, constituting a significant public health challenge. According to the World Health Organization (WHO), approximately 2.6 billion people worldwide are affected by myopia, a number projected to reach nearly 5 billion by 2050¹. This trend is particularly pronounced in East Asia. In China, recent data indicate over 710 million individuals with myopia and an adolescent myopia rate exceeding 80%, among the highest globally². National statistics further reveal a high prevalence across all school stages, reflecting a trend towards earlier onset and greater severity³. Effectively controlling myopia progression is therefore an urgent priority.

Photobiomodulation (PBM), a non-invasive therapy utilizing low-intensity light to modulate biological pathways, has shown expanding application in ophthalmology. In myopia research, repeated low-level red light (RLRL) therapy (typically ~ 650 nm) has been investigated^4,5; randomized trials and observational studies in several populations have reported slower axial elongation under RLRL exposure compared with controls^6–9, although the underlying mechanisms remain incompletely understood¹⁰. Emerging work also suggests potential applicability beyond Asian cohorts; for example, a randomized controlled study in Spanish children reported that combining RLRL with orthokeratology was associated with less axial elongation than orthokeratology alone^11,12.

However, whether ocular trajectories observed during RLRL exposure differ by sex has not been systematically examined. Sex, as a biological variable, may be associated with differences in baseline ocular anatomy (e.g., axial length, corneal curvature) and behavioral or developmental factors, which could contribute to observed patterns over time. Evidence addressing sex-specific patterns in the context of RLRL remains limited.

Therefore, this prospective, non-randomized, uncontrolled cohort aimed to describe sex-specific trajectories of axial length (AL), spherical equivalent (SE), and uncorrected distance visual acuity (UDVA) over 12 months in myopic adolescents in Liaoning Province, China under standardized low-intensity red light exposure. The findings are intended to be descriptive and hypothesis generating, to inform the design of future controlled comparative studies.

Materials and methods

General information

This was a prospective, non-randomized, uncontrolled, exploratory cohort study. The absence of a parallel control group is a fundamental limitation that precludes causal inference regarding exposure effects or sex-specific effects. 180 children (180 eyes) aged 7–16 years with myopia, who were recruited from the Ophthalmology Clinic of Dalian University Affiliated Xinhua Hospital between July 2023 and July 2024. Participants were included based on their guardians’ preference for RLRL exposure; no randomization was performed. To ensure sex balance and enhance baseline comparability, participants were grouped according to sex into a male exposure group and a female exposure group, each comprising 90 participants (90 eyes), resulting in balanced sex groups.

The study protocol was approved by the Ethics Committee of Dalian University Affiliated Xinhua Hospital (Approval No.: 2024-82-02) and conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants and their legal guardians prior to enrollment.

Study subjects

Inclusion criteria: (1) Age 7–16 years; (2) Each eye diagnosed with myopic refractive error after cycloplegic refraction, with best-corrected visual acuity > 0.0 and corneal curvature between 40.0 D and 46.0 D; (3) Willingness to participate in red light therapy; (4) Normal cognitive and language communication abilities with good compliance.

Exclusion criteria: (1)Ocular diseases such as glaucoma, glaucomatocyclitic crisis, uveitis, ocular hypertension, macular lesions, or damage; (2) Systemic diseases such as albinism, psoriasis, nephrotic syndrome, or systemic lupus erythematosus; (3) Previous treatment with orthokeratology or 0.01% atropine; (4) Contraindications to light therapy; (5) Other reasons deemed unsuitable for inclusion by the study physician; (6) Occurrence of ocular abnormalities or withdrawal during the 650 nm low-intensity monochromatic red light exposure regimen.

Device and exposure protocol

All participants received standardized optical correction (single-vision spectacles) based on a comprehensive cycloplegic refraction performed by a licensed optometrist. In addition, they used a low-intensity red light irradiation device (Eyesight Myopia and Amblyopia Therapeutic Apparatus, model RS-200–2 A, Suzhou Xuanjia Photoelectric Technology Co., Ltd.). The device emits light at a wavelength of 650 ± 10 nm. Device calibration was performed according to the manufacturer’s guidelines prior to the study and periodically checked to ensure consistent output.

The exposure protocol required twice-daily sessions, each lasting 3 min, with both eyes exposed simultaneously. An interval of at least 4 h was required between sessions. Exposure frequency was set at a minimum of 12 sessions per week. Participants and guardians were instructed to use the device in a consistent indoor environment with ambient room lighting and to avoid direct sunlight exposure during sessions. The planned exposure period was one year.

Participant flow and exposure adherence

Follow-up examinations were scheduled at 1, 3, 6, and 12 months after baseline. Adherence was monitored using participant-held session logs reviewed at each follow-up visit. Participants were considered adherent if they completed > 90% of the prescribed sessions; adherence assessment was based on self-reported logs and may be subject to reporting bias. Participants who discontinued sessions or missed follow-up visits were to be recorded as withdrawals. In this cohort, all 180 enrolled participants completed the 12 month visit and met the prespecified adherence criterion; therefore the analytic dataset was complete at all time points (90 males and 90 females at each visit) for this per-protocol descriptive analysis.

Outcome measures and examination procedures

All outcomes were exploratory; axial length (AL) and spherical equivalent (SE) were considered key structural measures of ocular growth, while other measures (including UDVA) provided supplementary descriptive context. Ocular parameters were measured at baseline and at each follow-up visit. Uncorrected distance visual acuity (UDVA) was assessed at 5 m using a standard decimal visual acuity chart. Acuity was recorded in decimal notation (e.g., 1.0, 0.8, 0.5), where a higher value indicates better vision, and these values were analyzed directly. Axial length (AL) and central corneal thickness (CCT) were measured using the IOLMaster 500 optical biometer (Carl Zeiss Meditec, Germany), with the average of five consecutive readings recorded. Intraocular pressure (IOP) was measured with a rebound tonometer (iCare TA01i, Finland). Spherical equivalent (SE) was determined using a Topcon auto-refractometer (KR-8900, Japan) after cycloplegia. Cycloplegia was induced using 1% cyclopentolate eye drops (one drop every 5 min, total of three doses), with refraction performed at least 30 min after the last instillation. Corneal curvature (CC) and anterior chamber depth (AD) were obtained using the Pentacam rotating Scheimpflug camera (Oculus, Germany). Lens thickness (LT) and vitreous thickness (VT) were measured using ocular ultrasonography (VuMax, Sonomed Escalon, USA). VT was defined as the axial distance from the posterior lens capsule to the retinal surface (vitreous chamber depth) measured along the optical axis. All examinations were performed by trained ophthalmologists following standardized operating procedures. For participants with bilateral data, only measurements from the right eye were included in the statistical analysis to maintain data independence.

Statistical analysis

Statistical analyses were performed using SPSS version 27.0 (IBM Corp., USA). Continuous variables are presented as mean ± standard deviation (SD). The normality of data distribution was assessed using the Kolmogorov-Smirnov test. Repeated-measures analysis of variance (ANOVA) was employed to evaluate the main effects of time and gender group, as well as their interaction. When the assumption of sphericity was violated (Mauchly’s test, P < 0.05), the Greenhouse-Geisser correction was applied. Post-hoc comparisons between groups were conducted using the least significant difference (LSD) test, and pairwise comparisons across time points were adjusted using the Bonferroni method. For significant interaction effects, simple effect analyses were performed. To control for type I error across multiple comparisons, all post-hoc P-values were Bonferroni-adjusted. Statistical significance was set at α = 0.05 (two-tailed).

Results

Participant flow and exposure adherence: A total of 180 myopic adolescents were enrolled (90 males and 90 females). All participants completed baseline and all scheduled follow-up visits (1, 3, 6, and 12 months) and met the prespecified adherence criterion (> 90% of scheduled sessions by self-reported session logs). Therefore, sample size remained 90 per sex group at each time point with no missing outcome data in the analytic cohort.

Changes in uncorrected distance visual acuity (UDVA) over follow-up

A significant time effect was observed for UDVA (decimal) (P < 0.001), indicating that UDVA changed over follow-up. A significant time × sex interaction was also observed (P = 0.018), indicating different temporal patterns between sexes (Table 7). Between-sex differences were not significant at baseline (P = 0.180), but females had higher UDVA than males at 1, 3, 6, and 12 months (all P < 0.05; Table 1). Relative to baseline, UDVA values increased in males at 3, 6, and 12 months and in females at 1, 3, 6, and 12 months (all Bonferroni-adjusted P < 0.05).

Table 2.

Comparison of axial length between groups over Time .

Group	n	Baseline	1 Month	3 Months	6 Months	12 Months
Male	90	24.35 ± 0.94	24.37 ± 0.92	24.41 ± 0.89	24.42 ± 0.88	24.46 ± 0.90
Female	90	24.02 ± 0.79	24.00 ± 0.79	24.01 ± 0.79	24.07 ± 0.81	24.12 ± 0.81
F-value		6.225	8.322	9.634	8.020	7.312
P-value		0.014	0.004	0.002	0.005	0.008

Table 1.

Comparison of uncorrected distance visual acuity (Decimal) between groups over time .

Group	n	Baseline	1 Month	3 Months	6 Months	12 Months
Male	90	0.45 ± 0.26	0.48 ± 0.26	0.53 ± 0.29	0.54 ± 0.31	0.56 ± 0.33
Female	90	0.51 ± 0.25	0.59 ± 0.29	0.64 ± 0.32	0.67 ± 0.32	0.68 ± 0.30
F-value		1.814	6.720	5.890	7.026	6.842
P-value		0.180	0.010	0.016	0.009	0.010

Changes in axial length (AL) over follow-up

A significant main effect of time was observed for axial length (P < 0.001), indicating that AL changed over follow-up. The time × sex interaction was borderline (P = 0.050), suggesting no strong evidence for materially different AL trajectories between sexes (Table 7).

Male participants had longer AL than females at baseline, with a mean difference of 0.34 mm (95% CI: 0.107 to 0.606 mm; P < 0.01). Compared with baseline, AL in the male group differed at the 3-, 6-, and 12 month visits (all Bonferroni-adjusted P < 0.01). In the female group, a difference versus baseline was observed at the 12 month visit (Bonferroni-adjusted P < 0.001). The between-sex difference in annual AL elongation was 0.01 mm (95% CI: -0.023 to 0.066 mm) and is likely clinically negligible (Table 2).

Table 3.

Comparison of intraocular pressure between groups over Time .

Group	n	Baseline	1 Month	3 Months	6 Months	12 Months
Male	90	16.55 ± 2.33	16.49 ± 2.29	16.13 ± 2.39	16.00 ± 2.53	16.06 ± 2.49
Female	90	17.07 ± 2.42	17.12 ± 2.24	17.09 ± 2.21	16.93 ± 2.38	17.14 ± 2.20
F-value		2.118	3.477	7.804	6.468	9.510
P-value		0.147	0.064	0.006	0.012	0.002

Changes in intraocular pressure (IOP) over follow-up

No significant time effect or time × sex interaction was observed for IOP (both P > 0.05, Table 7). Although between-sex differences were not significant at baseline (P = 0.147), females showed higher IOP than males at 3, 6, and 12 months (all P < 0.05; Table 3). No within-sex differences versus baseline were detected at any follow-up time point (all P > 0.05).

Table 4.

Comparison of spherical equivalent between groups over Time negative values denote myopia.

Group	n	Baseline	1 Month	3 Months	6 Months	12 Months
Male	90	− (2.25 ± 1.46)	− (2.07 ± 1.41)	− (2.04 ± 1.50)	− (2.01 ± 1.45)	− (1.97 ± 1.44)
Female	90	− (1.70 ± 1.43)	− (1.51 ± 1.37)	− (1.47 ± 1.44)	− (1.44 ± 1.39)	− (1.47 ± 1.45)
F-value		6.524	7.462	6.854	7.140	5.346
P-value		0.011	0.007	0.010	0.008	0.022

Changes in spherical equivalent (SE) over follow-up

A significant time effect was observed for SE (P < 0.001), indicating that SE changed over follow-up. The time × sex interaction was not significant (P = 0.630, Table 7). Across follow-up visits, males had more myopic SE than females (P < 0.01). Relative to baseline, SE values became less negative (less myopic) in both sexes at 1, 3, 6, and 12 months (all Bonferroni-adjusted P < 0.001; Table 4).

Table 5.

Comparison of ocular biometric parameters between groups over Time .

Group	Parameter	Baseline	1 Month	3 Months	6 Months	12 Months
Male	CCT	540.38 ± 37.55	541.66 ± 37.20	545.00 ± 36.93	544.17 ± 37.70	546.31 ± 41.31
	AD	3.19 ± 0.29	3.16 ± 0.26	3.29 ± 0.41	3.17 ± 0.25	3.19 ± 0.25
	CC	43.37 ± 1.37	43.37 ± 1.55	43.33 ± 1.41	43.39 ± 1.38	43.31 ± 1.37
	VT	17.11 ± 0.99	17.11 ± 0.96	17.18 ± 0.97	17.22 ± 1.00	17.24 ± 1.00
Female	CCT	533.11 ± 38.28	532.57 ± 38.25	532.88 ± 38.81	532.36 ± 39.85	533.79 ± 39.07
	AD	3.15 ± 0.34	3.20 ± 0.28	3.21 ± 0.27	3.20 ± 0.29	3.15 ± 0.24
	CC	43.58 ± 1.71	43.65 ± 1.80	43.57 ± 1.80	43.53 ± 1.77	43.58 ± 1.79
	VT	16.88 ± 0.76	16.95 ± 0.77	16.94 ± 0.76	16.98 ± 0.80	17.03 ± 0.80

Changes in central corneal thickness (CCT) over follow-up

No significant time effect was found for CCT (P = 0.233), and the time × sex interaction was not significant (P = 0.406; Table 7). Although CCT was slightly higher in males at all time points, the between-sex difference was borderline (P = 0.051). No within-sex differences versus baseline were detected at any follow-up time point (all Bonferroni-adjusted P > 0.05; Table 5).

Table 6.

Comparison of lens thickness between groups over Time .

Group	n	Baseline	1 Month	3 Months	6 Months	12 Months
Male	90	3.43 ± 0.19	3.48 ± 0.21	3.46 ± 0.17	3.45 ± 0.18	3.44 ± 0.17
Female	90	3.46 ± 0.28	3.42 ± 0.19	3.42 ± 0.19	3.46 ± 0.26	3.41 ± 0.20
F-value		0.728	3.681	2.767	0.012	1.516
P-value		0.395	0.057	0.098	0.913	0.220

Changes in anterior chamber depth (AD) and corneal curvature (CC) over follow-up

At baseline, there was no statistically significant difference in corneal curvature between males and females (43.37 ± 1.37 D vs. 43.58 ± 1.71 D, P = 0.161). No significant time effects or time × sex interactions were observed for AD or CC (all P > 0.05; Table 7). There were no significant between-sex differences in AD or CC at any time point (all P > 0.05), and no within-sex changes versus baseline were detected (all Bonferroni-adjusted P > 0.05; Table 5).

Changes in vitreous thickness (VT) over follow-up

A significant time effect was observed for vitreous thickness (VT) (P < 0.001), indicating that VT changed over follow-up. The time × sex interaction was not significant (P > 0.05, Table 7), and no between-sex difference was detected (P > 0.05). Relative to baseline, VT increased in males at 6 and 12 months (both P < 0.05) and in females at 12 months (P < 0.05; Table 5).

Changes in lens thickness (LT) over follow-up

No significant main effect of time was observed for lens thickness (LT) (P = 0.460; Table 7). However, a modest time × sex interaction was observed (P = 0.031), suggesting small differences in temporal fluctuation patterns between sexes. Consistent with this, no between-sex difference was detected at any single time point (all P > 0.05), and no within-sex changes versus baseline were detected at any follow-up visit (all Bonferroni-adjusted P > 0.05; Table 6). Overall, LT did not show a consistent monotonic trend over time in either sex.

Table 7.

Repeated-measures ANOVA results for outcome Measures.

Outcome Measure	Effect	F-value	df(num, den)	P-value	η²
Axial Length	Time	30.304	4.000	< 0.001	0.146
	Time × Sex	2.383	4.000	0.050	0.013
Anterior Chamber Depth	Time	1.988	4.000	0.095	0.011
	Time × Sex	2.055	4.000	0.085	0.011
Intraocular Pressure	Time	1.627	4.000	0.166	0.009
	Time × Sex	1.099	4.000	0.356	0.006
Spherical Equivalent	Time	30.207	4.000	< 0.001	0.145
	Time × Sex	0.646	4.000	0.630	0.004
Uncorrected Visual Acuity	Time	41.854	4.000	< 0.001	0.190
	Time × Sex	3.015	4.000	0.018	0.017
Corneal Thickness	Time	1.397	4.000	0.233	0.008
	Time × Sex	1.002	4.000	0.406	0.006
Corneal Curvature	Time	1.644	4.000	0.161	0.009
	Time × Sex	1.697	4.000	0.149	0.009
Vitreous Thickness	Time	16.961	4.000	< 0.001	0.087
	Time × Sex	1.553	4.000	0.185	0.009
Lens Thickness	Time	0.906	4.000	0.460	0.005
	Time × Sex	2.681	4.000	0.031	0.015

Adverse events

Among participants who completed the 12-month follow-up, no serious adverse events (e.g., rapid decline in visual acuity or central scotoma) were reported during follow-up. These descriptive safety observations are limited by the uncontrolled design, the sample size, and the follow-up duration (Table 7).

Discussion

This exploratory, non-randomized, uncontrolled cohort describes 12-month trajectories of multiple ocular parameters in male and female myopic adolescents undergoing a standardized low-intensity red light exposure regimen. Over follow-up, axial length increased and spherical equivalent became less negative in both sexes, with no significant time × sex interactions for axial length or spherical equivalent. In contrast, small time × sex interactions were observed for UDVA and lens thickness, suggesting different temporal patterns between sexes; however, the magnitudes of these changes were modest.

Because all participants received the same exposure regimen and no internal or external comparator was included, the study design does not allow inference about exposure effects. Observed changes may reflect natural myopia progression, measurement variability (including learning effects for visual acuity testing)¹³, regression to the mean, changes in refractive correction, or unmeasured confounding. Accordingly, we interpret the findings as descriptive and hypothesis generating rather than evidence of efficacy.

Possible explanations for sex-related patterns (speculative)

Although we observed different temporal patterns in UDVA between sexes, these differences do not establish structural or refractive control. UDVA is a functional measure influenced by test–retest variability, learning effects, and spectacle updating, and it is not a robust surrogate for myopia progression in adolescents. Therefore, we consider AL and SE as the more informative outcomes for ocular growth, and we report UDVA primarily for descriptive functional context^13–15.

Potential contributors to observed sex-related patterns may include differences in baseline ocular anatomy, growth and pubertal timing, behavior (e.g., near work and outdoor time)^13,16, and optical correction practices; however, the present data do not support mechanistic conclusions. Future studies that incorporate additional physiological measures (e.g., choroidal thickness) and controlled comparative designs are needed to test specific hypotheses.

Clinical relevance and effect sizes

Several statistically significant findings were small in magnitude. For example, the between-sex difference in annual axial elongation was 0.01 mm, a difference that is likely clinically negligible. Throughout the manuscript we therefore emphasize effect sizes and interpret statistically significant results in the context of potential clinical relevance.

Future research priorities

Future work should include controlled, randomized, or well-matched comparative cohorts to distinguish exposure-associated changes from natural progression and other confounding influences. Incorporating choroidal thickness measurements and standardized spectacle updating protocols would help clarify whether and how sex might be associated with different ocular trajectories under exposure.

We also observed higher IOP values in females than males at later follow-up visits, although within-sex changes relative to baseline were not statistically significant. The clinical implications are uncertain, and this finding may reflect physiological variation or measurement variability^17–19. Further research is needed to clarify whether such differences persist and whether they have clinical relevance in the context of myopia management.

Limitations

(1) Lack of a control group: As a single-arm, non-randomized cohort, the study cannot attribute observed changes to the exposure regimen. (2) Outcome limitations: UDVA is influenced by test conditions and optical correction and should not be interpreted as evidence of structural or refractive control. (3) Missing choroidal thickness: Choroidal thickness was not measured, limiting assessment of potential physiological changes. (4) Selection and adherence: Analyses were restricted to adherent completers, which may introduce selection bias. (5) Generalizability: Participants were recruited from a single region in Liaoning Province, potentially limiting external validity.

Despite these limitations, the study provides a detailed descriptive dataset on sex-specific ocular trajectories under low-intensity red light exposure that may help generate hypotheses for future controlled studies.

Comparison with prior studies on gender effects

Evidence on sex-related differences in outcomes during low-intensity red light exposure remains limited and mixed. While some reports have suggested possible sex differences, others have not observed consistent between-sex contrasts⁹. Our findings should therefore be interpreted as descriptive and hypothesis generating, and any apparent sex-related patterns require confirmation in controlled comparative studies with standardized outcome assessment.

Conclusion

In conclusion, this exploratory, non-randomized, uncontrolled cohort described 12-month trajectories of ocular parameters in male and female myopic adolescents undergoing standardized low-intensity red light exposure. We observed sex-specific temporal patterns for UDVA and lens thickness, whereas time × sex interactions for axial length and spherical equivalent were not significant and the between-sex difference in annual axial elongation was small. These observations are descriptive and hypothesis generating; without a comparator group, they should not be interpreted as evidence of efficacy or used to guide clinical management. Future controlled comparative studies, ideally with standardized outcome assessment (including choroidal thickness), are needed to clarify whether sex is associated with different trajectories under exposure.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Wang Junying conceived the study and acquired funding.Xiaofeng Li and Kexuan Ren designed the study and revised the manuscript.Kexuan Ren performed the statistical analyses.Yang Liu assisted with device implementation, participant data organization, and supervision of treatment procedures.All authors reviewed and approved the final manuscript.

Funding

This study was supported by China Medicine Education Association Project (CMEA, No. 2024KTM031).

Data availability

Data will be made available on request.The de-identified datasets generated and analyzed during this study are available from the corresponding author (Wang Junying) upon reasonable request. Data include anonymized participant baseline characteristics, ocular biometric measurements, and follow-up outcomes. Requests will be reviewed for compliance with ethical and privacy regulations.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval

This study was prospectively registered and approved in the National Medical Research Registration and Filing Information System of China (Registration-Filing No.: MR-21-26-010860). The registration record has been synchronized to the Chinese Clinical Trial Registry (ChiCTR) and is currently under review by the ChiCTR. The study protocol adhered to the ethical principles of the Declaration of Helsinki.