HIGHLIGHTS
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MHT usage in the menopausal period may be linked to strabismus diagnosis and surgery.
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Sex hormones may influence extraocular muscle alignment.
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Delayed initiation of MHT is associated with strabismus diagnosis.
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Estrogen receptor alpha is expressed in human extraocular muscle.
Purpose
To evaluate the association between menopausal hormone therapy (MHT) and strabismus outcomes in menopausal women.
Design
Retrospective clinical cohort study.
Participants
Female patients in Epic Cosmos with a first menopause diagnosis between ages 44 and 60 years from January 1, 2010, to October 31, 2025 were included. MHT exposure was defined as estrogen or combined estrogen-progestin use for ≥90 days after menopause diagnosis; patients with prior MHT use were excluded.
Methods
Demographic, clinical, and MHT data were extracted. Associations between MHT and strabismus diagnosis, surgery, and reoperation were assessed using time-varying Cox proportional hazards models adjusted for age and year of menopause diagnosis, race, and ethnicity.
Main Outcome Measures
Strabismus diagnosis, strabismus surgery, and reoperation, excluding congenital, mechanical, neurological, paralytic, and traumatic causes.
Results
Among 2,154,255 menopausal patients, 197,576 (9.2%) received MHT and 1,956,679 (90.8%) did not. Mean age at menopause diagnosis was 54.9 (4.1) years, and 67.3% identified as White. MHT use was associated with higher hazards of strabismus diagnosis (HR 1.11, 95% CI 1.02-1.22; P = 0.015) and strabismus surgery (HR 1.76, 95% CI 1.38-2.25; P < 0.001), but not reoperation.
Conclusion
MHT was associated with increased risk of strabismus diagnosis and surgery in menopausal women, suggesting a potential relationship between MHT and ocular alignment outcomes.
INTRODUCTION
Strabismus is an eye misalignment that affects approximately 2.75% of individuals in the United States. Adult onset strabismus may be idiopathic or caused by trauma, neurologic disease, eye surgery, age related changes, or other eye pathology. , Prior studies have shown that the incidence of adult-onset strabismus increases with age from the second decade to the eighth decade of life. Additionally, diplopic individuals with sagging eye syndrome, a known cause of acquired adult strabismus, were found to be older and predominately female, suggesting that older adult women may be at a greater risk for developing strabismus.
One potential reason for the increased risk of strabismus in older women may be due to hormonal changes associated with menopause. During menopause, the secretion of estrogen and progesterone is reduced, leading to widespread physiological changes across multiple body systems. , While there is limited data on menopause and strabismus outcomes, individuals in other hypoestrogenic states, such as Turner syndrome, have been found to have a greater prevalence of strabismus compared to the general population.
Menopausal hormone therapy (MHT) is the primary treatment option for patients experiencing symptoms related to fluctuating hormonal levels during perimenopause and the eventual decline in hormones during menopause. Formulations for MHT include estrogen-progestin therapy for patient with a uterus and estrogen only therapy for patients without a uterus. Different routes of MHT administration are thought to lead to differential effects on lean mass, with transdermal estrogen exerting a more profound impact on muscle mass. ,
Prior studies have examined the role of MHT on ocular function. These studies have found that MHT may lead to reductions in foreign body sensation, sensitivity to light, and IOP. , Other studies have found mixed effects of MHT on dry eye syndrome in menopausal women. However, little is known about the relationship between MHT and strabismus outcomes.
Sex hormone receptors have been localized to multiple parts of the eye, including the lacrimal glands, meibomian glands, bulbar and eyelid conjunctiva, cornea, iris, ciliary body, lens, retina, and choroid. However, to our knowledge, sex hormone receptors have not been identified in human extraocular muscles and their role in extraocular muscles has not been well characterized. Extraocular muscles are a specialized type of skeletal muscle with a greater mitochondrial content, increased metabolic rate, and higher fatigue resistance than other skeletal muscles. , Another unique feature of these muscles are that muscle stem cells are mainly quiescent in postnatal homeostatic muscles while they proliferate continuously in extraocular muscles.
Prior studies have shown that sex hormones play a crucial role in the maintenance of skeletal muscle and the supporting tendons elsewhere in the body. ,,,, Estrogen has been shown to play a vital role in the regulation of muscle regeneration with additional effects on skeletal muscle homeostasis, maintenance of mitochondrial function, and reduction of connective tissue stiffness. ,,, Studies have demonstrated that altering estrogen or estrogen receptor levels influence myofiber proliferation and differentiation. ,,, A previous study showed that ovariectomy, which reduces systemic estrogen and testosterone levels, resulted in muscle atrophy with decreased muscle function and impaired muscle stem cell proliferation and differentiation, with a shift in myofiber expression profile in the tibialis anterior muscle. Additionally, pharmacological inhibition of estrogen receptor alpha (ER⍺), an estrogen receptor isoform, has been shown to block myogenesis in skeletal muscles. ,, Based on estrogen’s effects on muscle mass and the unique structural properties of extraocular muscles, these muscles may be particularly susceptible to estrogen’s influence.
As extraocular muscles are a specialized form of skeletal muscle, changes in sex hormones during menopause or exposure to MHT may similarly affect extraocular muscle function, ocular alignment, and the development of strabismus in women. Based on this rationale, we hypothesize that menopausal women receiving menopausal hormone replacement therapy will demonstrate lower rates of strabismus compared to menopausal women not on MHT. Additionally, we hypothesize MHT use will be associated with decreased frequency of strabismus surgery and lower reoperation rates. We will also assess whether extraocular muscles express estrogen receptors, supporting a direct mechanistic role for estrogen signaling in the extraocular muscles.
The purpose of this study was two-fold: (1) to explore the association between menopausal hormone therapy and the development of strabismus, frequency of strabismus surgery, and the rate of reoperation in menopausal women and (2) to establish whether estrogen receptors are expressed in human extraocular muscles.
METHODS
MHT AND STRABISMUS OUTCOMES
This retrospective clinical cohort study was conducted using data from the Epic Cosmos platform. This database is an electronic health record (EHR) aggregation tool that integrates demographic, clinical, and procedural data from approximately 1,800 hospitals and over 300 million patients from United States, Canada, Lebanon, and Saudi Arabia, providing a diverse, representative sample. , By combining inpatient and outpatient data, the Cosmos database provides comprehensive longitudinal health information for patients. As this study did not involve identifiable private information or biospecimens, this study was deemed exempt from the University of California San Diego Institutional Review Board and adhered to the ethical principles of the Declaration of Helsinki.
This study included patients between January 1, 2010 and October 31, 2025 in Epic Cosmos. Female patients whose first menopausal diagnosis occurred between ages 44 and 60 years old were included. This age range was selected to capture the interval during which the majority of women experience menopause. , Menopause was identified using a curated set of menopausal diagnoses recorded in the EHR (Supplemental Table 1), which were linked to diagnosis events and mapped to ICD-9 and ICD-10 terminology. The exposure group (“MHT cohort”) included menopausal women who were prescribed MHT after the first recorded menopause diagnosis. The comparison group (“non-MHT cohort”) included menopausal women with no record of MHT prescriptions. Individuals who used MHT prior to a recorded menopause diagnosis were excluded. MHT exposure was defined as at least 1 course of MHT lasting ≥90 days after the diagnosis of menopause. This threshold was chosen to capture sustained hormone exposure and to reduce misclassification related to short-term or peri‑diagnostic prescriptions. In time-varying analyses, patients were considered unexposed prior to MHT initiation and exposed thereafter.
Demographic and clinical data were collected for all participants, including age at menopause diagnosis, age at strabismus diagnosis, age at first strabismus surgery, calendar year of menopause diagnosis, race, and ethnicity. Menopause-related diagnoses were categorized as delayed menopause (entering menopause after age 55), normal/typical menopause, posthysterectomy menopause, postsurgical menopause, and early menopause (entering menopause between ages of 40-44). The posthysterectomy menopause group was included because hysterectomy may influence hormonal status, however specific information regarding ovarian conservation or oophorectomy was not available in this group. The posthysterectomy menopause group was a strict proxy for absence of uterus. Postsurgical menopause was not classified as absence of uterus because it indicates ovarian removal but does not necessarily imply uterine removal.
Among MHT users, we extracted the recorded MHT category, route of administration, duration of use, and interval from menopause diagnosis to MHT initiation. MHT category was classified as estrogen or estrogen-progestin based on recorded medication histories. For patients with more than 1 recorded MHT exposure pattern over time, the assigned category reflected the qualifying MHT medication category with the greatest number of recorded medication orders, with ties resolved by the earlier recorded start date. Accordingly, these categories should be interpreted as recorded MHT groupings rather than strictly mutually exclusive lifetime exposure groups. The route of MHT was categorized as intramuscular, patch, pill, or other. For the duration of MHT usage both continuous and categorical data (<6 months, 6- <12 months, 1 < 3 years, ≥3 years) were collected. Data on the interval between menopause onset and MHT initiation included continuous and categorical outcomes (0- <3 years, 3- <10 years, ≥10 years).
The outcomes included strabismus diagnosis, strabismus surgery, and strabismus reoperation. For all analyses, incident strabismus was defined as the first recorded diagnosis occurring after the menopause diagnosis during follow-up. Strabismus attributable to congenital, genetic, mechanical, neurological, paralytic, traumatic causes were excluded. Supplemental Table 2 provides the full list of strabismus diagnoses that were included. Strabismus surgery was classified using procedural terminology (CPT) codes (Supplemental Table 3) . Patients who had strabismus surgery prior to the diagnosis of menopause were included in our analysis to reflect the real-world clinical population. Reoperation was defined as a subsequent strabismus surgery following an initial strabismus surgical procedure. For reoperation analyses, the cohort was restricted to patients who underwent an initial strabismus surgery, with another procedure after the date of the first surgery.
STATISTICAL ANALYSIS
Data was extracted from Epic Cosmos using SQL Server Management Studio (Microsoft) and statistical analyses were conducted in R version 4.1.2 (R Foundation for Statistical Computing). All analyses were conducted at the patient level. Baseline characteristics were summarized as means with standard deviations (SDs) for continuous variables and counts with percentages for categorical variables. Group differences between MHT users and non-MHT users were evaluated using linear regression for continuous variables (reporting mean differences and SEs) and binomial regression or χ² tests for categorical variables (reporting risk differences and P -values). The primary analyses used time-varying Cox proportional hazards models to evaluate the association between MHT use and each strabismus outcome, with MHT modeled as a time-varying exposure. Time zero was defined as the date of menopause diagnosis for strabismus diagnosis and surgery outcomes, and as the date of first strabismus surgery for reoperation analyses.
Covariates included age at menopause diagnosis, calendar year of menopause diagnosis, race, and ethnicity. Calendar year of menopause was included as a covariate to account for potential variations in MHT prescription patterns, diagnostic practices, referral patterns, and surgery use. All Cox models were adjusted for the specified covariates. We additionally performed sensitivity analyses that adjusted for menopausal group and an exploratory route-specific analysis comparing strabismus outcomes in patients receiving transdermal MHT with menopausal patients who have no MHT exposure. Secondary analyses included unadjusted and adjusted logistic regression models treating MHT as a fixed ever-use exposure for comparison. To complement regression adjustment, inverse probability of treatment weighting (IPTW) based on the propensity for receiving MHT, estimated from a logistic regression model including covariates. Stabilized IPTW were truncated at the first and 99th percentiles of the weight distribution to limit the influence of extreme weights, then applied in weighted logistic regression models. Odds ratios (OR) and 95% CIs (95% CI) were calculated. All statistical tests were 2-sided, and statistical significance was defined as P <.05.
TISSUE PREPARATION
The medial rectus of a de-identified 74-year-old female donor cadaver was obtained by the San Diego Eye Bank. The sample had a death to preservation time of under 24 hours and fixed in formalin. The collected tissue was embedded in optimal cutting temperature (OCT) compound, flash frozen in liquid nitrogen cooled isopentane, and stored at −80 degrees Celsius prior to sectioning. The muscle was cryosectioned on a Leica cryostat at 14 µm thickness and mounted on glass microslides and stored at −80 degrees Celsius.
IMMUNOSTAINING
For estrogen receptor alpha immunostaining, slides were rinsed in phosphate buffered saline (PBS) before blocking in blocking buffer (20% goat serum and 0.3% Triton X-100 in PBS) for 30 minutes at room temperature. Slides were then incubated at room temperature overnight in a humidity chamber with estrogen receptor alpha (ER⍺) (PCRP-ESRRA-1B10, 1:5; Developmental Studies Hybridoma Bank) and laminin (L9393, 1:200; Millipore Sigma) primary antibodies. ER⍺ was chosen because it is the ER known to have the highest expression in skeletal muscles. Then, slides were washed again with PBS and incubated with goat-anti-mouse PLUS Alexa Fluor 488 secondary antibody (A32723, 1:500; Invitrogen), goat-anti-rabbit Alexa Fluor 546 secondary antibody (A11035, 1:500; Invitrogen), and Wheat Germ Agglutinin fluorescent conjugate (W32466, 1:125; Invitrogen). After rinsing in PBS a final time, slides were mounted with VECTASHIELD PLUS Antifade Mounting Medium with DAPI (H-1200; Vector Laboratories Inc.), coverslipped, and sealed. Slides were imaged on a BZ-X810 Keyence fluorescence microscope at 20x magnification.
RESULTS
STUDY POPULATION
This study included individuals in the Epic Cosmos database from January 1, 2010 to October 31, 2025 who identified as females and were between the age 44 and 60 years old at their first menopause diagnosis. After applying all inclusion and exclusion criteria, including exclusion of MHT use prior to menopause diagnosis and the requirement for sustained MHT exposure, a total of 2,154,255 menopausal patients were included in the final analytic cohort. Of these, 197,576 (9.2%) were classified into the MHT cohort and 1956,679 (90.8%) into the non-MHT cohort ( Figure 1 ).
Flow diagram of patient selection. The figure illustrates the inclusion criteria and final analytic cohort for the study. MHT = menopause hormone therapy.
PATIENT CHARACTERISTICS
Overall, the average (SD) age at menopause was 54.9 (4.1) years and 67.3% of women identified as White. The demographic characteristics of the MHT and non-MHT cohort are shown in Table 1 . There were significant differences in age at menopause diagnosis, age at strabismus diagnosis, race, and ethnicity between the 2 cohorts ( P <.02 for all). The age (SD) at menopause diagnosis was 52.9 (4.1) years in the MHT cohort and 55.1 (4.1) years in the non-MHT cohort. The average (SD) age at strabismus diagnosis was 54.3 (7.0) in the MHT cohort and 54.7 (6.6) in the non-MHT cohort. The percentage of patients that identified as Hispanic or Latino was lower in the MHT cohort (5.9%) compared to the non-MHT cohort (8.3%, P <.001). In terms of race, the MHT cohort has a higher percentage of White patients (73.4%) compared to the non-MHT cohort (66.7%, P <.001). In contrast, there were lower percentages of Asian (2.1%) and Black or African American (7.9%) patients in the MHT cohort compared to the non-MHT cohort (4.1% and 10.8% respectively, P <.001). The distribution of patients by menopausal group and presence/absence of uterus are seen in Supplemental Table 4 and 5 respectively.
TABLE 1
Demographic Characteristics of MHT and Non-MHT Cohort
| Characteristic | Total (n = 2,154,255) N (%) | MHT Cohort (n = 197,576) N (%) | Non-MHT Cohort (n = 1,956,679) N (%) | Difference (SE) | P Value |
|---|---|---|---|---|---|
| Race | |||||
| American Indian or Alaskan Native | 19,617 (0.9%) | 1606 (0.8%) | 18,011 (0.9%) | −0.1 (0.0) | <.001 |
| Asian | 84,540 (3.9%) | 4152 (2.1%) | 80,388 (4.1%) | −2.0 (0.0) | <.001 |
| Black or African American | 227,853 (10.6%) | 15,638 (7.9%) | 212,215 (10.8%) | −2.9 (0.1) | <.001 |
| Native Hawaiian or Other Pacific Islander | 6727 (0.3%) | 382 (0.2%) | 6345 (0.3%) | −0.1 (0.0) | <.001 |
| White | 1,449,732 (67.3%) | 145,008 (73.4%) | 1,304,724 (66.7%) | 6.7 (0.1) | <.001 |
| Other | 61,743 (2.9%) | 3804 (1.9%) | 57,939 (3.0%) | −1.0 (0.0) | <.001 |
| Unknown/Missing | 304,043 (14.1%) | 26,986 (13.7%) | 277,057 (14.2%) | −0.5 (0.1) | <.001 |
| Ethnicity | |||||
| Hispanic or Latino | 174,136 (8.1%) | 11,638 (5.9%) | 162,498 (8.3%) | −2.4 (0.1) | <.001 |
| Not Hispanic or Latino | 1,610,685 (74.8%) | 152,946 (77.4%) | 1,457,739 (74.5%) | 2.9 (0.1) | <.001 |
| Unknown | 369,434 (17.1%) | 32,992 (16.7%) | 336,442 (17.2%) | −0.5 (0.1) | <.001 |
| Average age at menopause diagnosis (y) | 54.9 (4.1) | 52.9 (4.1) | 55.1 (4.1) | −2.2 (0.0) | <.001 |
| Average age of strabismus diagnosis (y) | 54.7 (6.7) | 54.3 (7.0) | 54.7 (6.6) | −0.5 (0.2) | .022 |
| Average age at first strabismus surgery (y) | 56.3 (6.0) | 56.1 (6.4) | 56.3 (5.9) | −0.2 (0.5) | .734 |
MHT = menopausal hormone therapy, SE = standard error.
STRABISMUS DIAGNOSIS
During follow-up, 12,517 individuals developed incident strabismus. The cumulative incidence of strabismus diagnosis was 0.62% in the MHT cohort and 0.58% in the non-MHT cohort ( Table 2 ). In time-varying Cox proportional hazards models, MHT use was associated with a higher hazard of incident strabismus diagnosis (hazard ratio [HR] 1.11, 95% CI 1.02-1.22, P =.015) ( Table 3 ). In secondary analyses using adjusted logistic regression and IPTW-weighted models, the association between MHT use and strabismus diagnosis was attenuated and no longer statistically significant (Supplemental Table 6).
TABLE 2
Strabismus Outcomes of MHT and Non-MHT Cohort
| Outcome | MHT Cohort (n = 197,576) N (%) | Non-MHT Cohort (n = 1,956,679) N (%) | Risk Difference (SE) | P Value |
|---|---|---|---|---|
| Strabismus diagnosis | 1233 (0.62%) | 11,284 (0.58%) | 0.05 (0.02) | .011 |
| Strabismus surgery | 164 (0.08%) | 1000 (0.05%) | 0.03 (0.01) | <.001 |
| Reoperation | 20 (0.01%) | 131 (0.007%) | 0.00 (0.00) | .143 |
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