More than 2 million women in the United States and 50 million women worldwide enter menopause each year, and approximately 62% of these women experience joint and muscle pain.1, 2, 3 Despite the increasing number of women entering menopause each year, rates of menopausal hormone therapy (MHT) usage have declined from 26.9% in 1999 to 4.7% in 2020.4 This may be, in part, because of concern about complications including blood clots, stroke, or endometrial/breast cancer. Menopause is characterized by a decline in ovarian function and the production of female sex hormones. Estrogen is a key contributor to maintaining bone density in female patients, with the prevalence of osteoporosis increasing drastically during menopause.
Estrogen deficiency has been shown to increase the sensitivity of musculoskeletal tissues to mechanical and metabolic stressors. Furthermore, postmenopausal women have been shown to experience reductions in muscle mass, muscle quality, and muscle strength and display increased markers of muscle proteolysis and neuromuscular degradation.1, 5, 6, 7, 8, 9
Women are 1.5 times more likely to have calcific deposits in the shoulder, twice as likely to have adhesive capsulitis (AC), and twice as likely to experience rotator cuff disease compared with men.10, 11, 12, 13, 14 Studies have also shown that female patients are more likely to suffer from shoulder impingement syndrome (SIS) and bicipital tendinitis (BT).15, 16, 17 Notably, the incidence of musculoskeletal pathology in women increases between the ages of 40 and 60, which coincides with the onset of menopause.12, 18 Of patients presenting with AC, 70% of them are women with the incidence peaking in the mid‐50s to 60s.1, 19
Given the detrimental effects of sex hormone loss, MHT has been highlighted as a method for addressing symptoms of menopause, including the associated musculoskeletal manifestations.1 MHT has robust efficacy in female patients who are recently menopausal and under the age of 60 to prevent fractures.20, 21 Some evidence has suggested that MHT may help maintain and increase muscle mass and strength, which can reduce fragility in postmenopausal women.22, 23 Previous research suggests that both oral and transdermal MHT have positive effects on bone mineral density.24 Thus, we postulate that MHT, given its role in stabilizing estrogen and progesterone levels, may be able to modulate musculoskeletal degradation, specifically in the soft tissue.
Despite the widespread prevalence of musculoskeletal complaints in perimenopausal women, there is limited research on the impact of MHT on soft‐tissue disorders of the shoulder. The purposes of this study were to determine whether perimenopausal women receiving MHT have decreased odds of developing soft‐tissue shoulder disorders compared with women without an active MHT prescription, specifically AC, bursitis, BT, calcific tendinitis (CT), atraumatic rotator cuff tear/rupture (RCTR), and SIS, and to quantify the impact of differing formulations and administration route. We hypothesize that MHT will be protective against developing soft‐tissue disorders of the shoulder due of the stabilizing effects of estrogen on menopausal symptoms and that the formulation and route of administration will significantly influence the MHT performance in this regard.
METHODS
Data Source
The TriNetX US Collaborative Research Network, a federated platform using electronic health record data from over 170 health care organizations with over 180 million patients, was used to identify subjects. This database contains deidentified electronic health records that are updated in real time, including patient demographics, diagnoses, medications, laboratory values, genomic information, and procedures. Institutional Review Board approval was not needed in this study because all data was deidentified per the standard defined in Section §164.514(a) of the Health Insurance Portability and Accountability Act Privacy Rule and was attested to by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule.
Patient Selection
The database was queried on June 11, 2026. A preliminary analysis was conducted to establish menopause as a risk factor for shoulder soft‐tissue disorders. Patients were included in the menopause cohort if they were biological women between the ages of 40 and 60 years old with a diagnosis of menopausal and perimenopausal disorders (ICD‐10 N95.1) or primary ovarian insufficiency (ICD‐10 E28.3).
Patients were included in the nonmenopause cohort if there was no diagnosis of menopause or primary ovarian insufficiency. Patients were excluded from all cohorts if they had a prior history of rotator cuff repair or antecedent shoulder trauma to minimize confounding by pre‐existing structural shoulder pathology (Supporting Information).
Systemic MHT was identified using standardized medication classes including estradiol, conjugated estrogens, and combined estrogen‐progestogen preparations (Supporting Information). Oral and topical formulations (for example transdermal patch) were included, whereas vaginal, injectable, and unknown preparations were excluded as a proxy for the inclusion of only systemic MHTs.
Within the base menopause population, five separate exposure versus comparator groups were established: any MHT, oral estrogen only, topical estrogen only, oral combined formulations, and topical combined formulations (Supporting Information). Only patients whose exposure instances were within a 5‐year window or after the recorded menopause diagnosis were included.
To establish the relation between a menopausal state and soft‐tissue disorders independent of MHT, a separate propensity score‐matched analysis was conducted. Patients were one‐to‐one propensity‐matched using the nearest matching neighbor algorithm on age, race, ethnicity, and medical risk factors including type 2 diabetes mellitus, hypothyroidism, hyperlipidemia, obesity, tobacco use, and chronic kidney disease because these have been previously independently associated with increased risk and represent a spectrum of metabolic comorbidities.25, 26, 27 Outcome ascertainment windows began 1 year after the index date, allowing for at least 1 year between initiation of MHT and any outcome inclusion.
Sensitivity analysis was also conducted as a check on cohort logic. The “Any MHT” cohort was analyzed against the control cohort without the 5 years prior or any time after temporal rule. Thus, the concurrent presence of the qualifying menopause diagnosis and MHT use was required.
Outcomes
The primary outcomes were incidence of shoulder soft‐tissue disorders, which were assessed using their respective International Classification of Diseases‐10 codes. Soft‐tissue disorders included AC, BT, bursitis, CT, atraumatic RCTR, and SIS (Supporting Information).
Statistical Analysis
All statistical analyses were performed on the TriNetX platform. One‐to‐one propensity score matching used a greedy nearest‐neighbor matching algorithm without replacement. The caliper distance was 0.10 standard deviations, and cohorts were randomly shuffled before matching.
Patients were matched on age, race, ethnicity, type 2 diabetes mellitus, hypothyroidism, hyperlipidemia, obesity, tobacco use, and chronic kidney disease. Patients were considered well‐matched if the standardized mean difference was less than 0.1. The TriNetX platform was used to assess the dichotomous postmatch outcomes using an odds ratio (OR) with a 95% confidence interval (CI) to compare the number of patients who develop soft‐tissue pathology of the shoulder in patients prescribed MHTs compared with control cohorts.
RESULTS
Patient Selection
At the time of our search, there were 181,491,543 patients in the TriNetX US Collaborative Research Network (Figure 1). After applying the exclusion criteria, 7,031,432 patients remained. There were 602,624 patients in the menopause cohort and 6,428,808 patients in the nonmenopause cohort prior to matching.
After matching, there were 583,003 patients in each cohort. Prior to propensity matching, there were 149,428 patients in the MHT cohort and 453,196 in the control cohort. After propensity score matching, there were 147,564 patients remaining.
In the subgroup analyses before matching, there were 46,816 patients in the oral estrogen cohort, 62,824 patients in the topical estrogen cohort, 7164 patients in the oral combined cohort, and 902 patients in the topical combined cohort. In the subgroup analysis after matching, there were 46,789 patients in the oral estrogen cohort, 62,817 patients in the topical estrogen cohort, 7161 patients in the oral combined cohort, and 902 patients in the topical combined cohort.
Patient Characteristics
After matching, there were no statistically significant differences between the patients in the MHT and non‐MHT cohorts (standardized mean difference < 0.1) (Table 1). The average age of the MHT cohort was 49.1 ± 5.4, and the non‐MHT cohort was 49.1 ± 5.3. The MHT cohort was 74.5% White, 9% African American, and 4.1% Asian, whereas the non‐MHT cohort was 74.6% White, 9% African American, and 4.1% Asian.
There were no significant differences in any medical comorbidities after matching. Among all subgroup and sensitivity analyses, there were no significant differences after matching (Tables 2, 3, 4, 5, 6, 7).
Outcomes
Menopausal status was associated with significantly increased odds of all 6 shoulder pathologies compared with age‐matched controls: AC (OR 1.367, 95% CI 1.296‐1.442; P < .001), bursitis of the shoulder (OR 1.298, 95% CI 1.225‐1.376; P < .001), BT (OR 1.258, 95% CI 1.170‐1.354; P < .001), CT (OR 1.149, 95% CI 1.062‐1.243; P = .001), SIS (OR 1.260, 95% CI 1.200‐1.324; P < .001), and RCTR (OR 1.109, 95% CI 1.055‐1.165; P < .001) (Table 8). In the primary analysis, women prescribed any form of systemic MHT showed significantly lower odds of developing AC (OR 0.875, 95% CI 0.786‐0.973; P = .014), BT (OR 0.775, 95% CI 0.669‐0.898; P = .001), CT (OR 0.829, 95% CI 0.706‐0.974; P = .023), SIS (OR 0.873, 95% CI 0.792‐0.962; P = .006), and RCTR (OR 0.892, 95% CI 0.804‐0.991; P = .032) (Table 9). In the sensitivity analysis relaxing the temporal window requirement, findings were directionally identical to the primary analysis, with significant reductions in odds of AC (OR 0.853, 95% CI 0.769‐0.947; P = .003), BT (OR 0.779, 95% CI 0.675‐0.899; P = .001), CT (OR 0.823, 95% CI 0.703‐0.965; P = .016), SIS (OR 0.865, 95% CI 0.786‐0.951; P = .003), and RCTR (OR 0.887, 95% CI 0.801‐0.982; P = .021) (Table 10).
The consistency between the sensitivity analysis and primary analysis confirms that the primary findings are not an artifact of the temporal window and that the reduction in odds holds regardless of how the timing relation is operationalized.
In the oral estrogen comparison, women prescribed oral estrogen had significantly increased odds of developing bursitis (OR 1.729, 95% CI 1.417‐2.109; P < .001), SIS (OR 1.377, 95% CI 1.158‐1.637; P < .001), and RCTR (OR 1.325, 95% CI 1.117‐1.570; P < .001) (Table 11). In the topical estrogen comparison, women prescribed topical estrogen had a significantly decreased risk of developing AC (OR 0.717, 95% CI 0.600‐0.856; P < .001), bursitis of the shoulder (OR 0.717, 95% CI 0.586‐0.876; P = .001), BT (OR 0.715, 95% CI 0.566‐0.904; P = .005), SIS (OR 0.729, 95% CI 0.617‐0.861; P < .001), and RCTR (OR 0.738, 95% CI 0.623‐0.874; P < .001) (Table 12). In the oral combined comparison, women prescribed combined oral MHT formulations had no significant differences in the odds of developing any soft‐tissue pathologies of the shoulder (Table 13).
No results were available for the topical combined MHT formulations because the corresponding patient count was fewer than 10, leading to censoring by TriNetX to preserve patient confidentiality.
DISCUSSION
The most important finding of this study was that female patients in menopause had a significantly higher incidence of shoudler soft tissue diagnosis than age‐matched controls. Within the menopausal cohort, women who were prescribed MHT had a decreased likelihood of developing soft‐tissue disorders of the shoulder, specifically AC, BT, CT, RCTR, and SIS, compared with a similar cohort of women who were not prescribed MHT. This suggests that exogenous sex hormone replacement in menopause or during the menopausal transition may confer a protective effect on periarticular connective tissues in the shoulder, consistent with the growing body of literature.
Menopause as an Independent Risk Factor for Shoulder Soft‐Tissue Pathologies
In this study, menopause was associated with a significantly increased odds of AC, bursitis, BT, CT, SIS, and RCTR. Estrogen receptors are expressed in tenocytes, synovial membranes, articular cartilage, and vascular cells of the shoulder, and their activation regulates collagen synthesis, extracellular matrix turnover, and local inflammation.11, 28, 29, 30, 31, 32 The estrogen‐deficient state of menopause is associated with reduced collagen turnover, elevated proinflammatory cytokines, and decreased muscle mass.33, 34, 35 This collectively creates a biological basis for heightened susceptibility to soft‐tissue pathologies such as AC, CT, SIS, and RCTR which have been previously associated with menopause and estrogen deficiency in women.36, 37, 38, 39 This study confirms these associations and finds additional associations with BT and bursitis.
Impact of MHT on Shoulder Soft‐Tissue Disorders
MHT was associated with significantly decreased odds of AC, BT, CT, SIS, and RCTR in menopausal women. Prior biologic and clinical studies have shown similar associations. MHT has been shown to improve the repair of muscle damage and remodeling of connective tissue within the skeletal muscle after exercise in postmenopausal women by upregulating connective tissue protein synthesis which occurs in response to mechanical loading.28 Cook et al. measured differences in Achilles tendon structure and diameter between active and inactive women who were currently using MHT or had stopped 12 months prior to the study.
They found that MHT mitigates Achilles tendon thickening and structural abnormalities in the active women group. This suggests a normalizing effect of MHT on tendon health in active women.40 Cowan et al., in a 2 × 2 randomized control trial of transdermal MHT or placebo and tendon‐specific exercises or sham exercises on greater trochanteric pain syndrome, found that MHT combined with any form of exercise and patient education was effective in reducing pain and improving function.41
Estradiol administration in postmenopausal women has been associated with a higher tendon collagen fractional synthesis rate and reduced tendon stiffness. Estradiol and activation of the estrogen‐related receptor G‐protein coupled estrogen receptor have been shown to exert antifibrotic effects in animal models and in vitro models; importantly, inhibition of these pathways reverses the protective antifibrotic effects which shows a direct mechanistic link between estrogen signaling and fibrosis in AC.11 In vitro human cell‐based studies found that estradiol induces a significant increase in type I collagen in human dermal fibroblasts, which comprises 95% of rotator cuff tendon tissue. This may indicate a direct stimulatory effect on extracellular matrix protein production, enhancing the structural integrity and mechanical properties of skeletal muscle and connective tissue.29
Animal studies have found that estradiol‐17β stimulation increases fibroblast proliferation in tendon‐derived rat cells which promotes type I collagen deposition during tendon healing, both of which are critical for optimal functional recovery and biomechanical strength.30, 31 Reinke et al., in a single‐center retrospective cohort study, found that female patients between 40 and 60 years using hormone therapy had lower odds of AC, although this did not reach statistical significance because of a small sample size.42 Our study confirms this association at scale. Lin et al., in a large database study, found that after controlling for hormone use, menopause was still independently associated with CT, suggesting that hormone use did not fully eliminate the risk.39 This study defined hormone use broadly, including those using Western hormonal medications, traditional Chinese medicine, or female nutritional supplements, which may explain the discrepancy between our findings.
Route of Administration and Formulation‐Specific Analyses
Interestingly, this study found topical estrogen to be superior to oral estrogen and oral combined MHT formulations in modulating soft‐tissue disorders of the shoulder. Topical estrogen was associated with reduced odds of AC, bursitis, BT, SIS, and RCTR. In contrast, oral estrogen was associated with increased odds of bursitis, SIS, and RCTR.
Oral estrogen undergoes first‐pass hepatic metabolism which increases C‐reactive protein, sex hormone binding globulin, and coagulation factors and decreases IGF‐1, whereas topical/transdermal formulations do not.43, 44 Women prescribed topical estrogens may also differ systematically from oral estrogen users with respect to health care use, socioeconomic status, treatment adherence, and clinical prescribing practices.
The combination of increased systemic inflammation and reduced bioavailability of anabolic hormones may explain the paradoxical increase in inflammatory shoulder pathologies like bursitis and SIS seen with oral estrogen. The combined oral estrogen‐progestin cohort showed no significant change for any of the shoulder outcomes. The absence of a protective signal likely reflects contributions from first‐pass metabolism and the contribution of progestins.
This cohort was also substantially smaller with wider CIs, suggesting that this analysis may have been underpowered to detect significant differences. The mechanism underscoring these findings cannot be determined from the present data and warrants further investigation.
Further research is recommended to assess the mechanistic impact of estrogen on the soft tissue within the shoulder and to understand estrogen's role in the cause of shoulder pathologies. Furthermore, the longitudinal impact of MHT on disease progression or reversal should be investigated to understand if there is an opportunity for MHT's therapeutic role to be expanded.
Limitations
This study has various limitations. This study relied on data from a large database of electronic health records which means there may be inconsistencies in coding practices, data filtering, and mapping processes. Furthermore, the platform is reliant on diagnostic codes and structured data, which can contribute to the under‐representation of noncoded conditions or symptoms.
Additionally, it was not possible to account for anatomical factors, dysfunctional rotator cuff or scapular musculature, postural abnormalities, and compliance with or length of MHT usage. The incidence of shoulder soft‐tissue pathologies in our study was lower than that of the general population, which may be because of undercounting via TriNetX or the strict exclusion criterion used in this study. Lastly, this study could not assess the longitudinal impact of MHT to assess the progression to disease state over time and the impact of targeted MHT interventions in at‐risk populations.
CONCLUSIONS
In peri‐ and postmenopausal women, MHT use was associated with decreased odds of soft‐tissue shoulder disorders compared with individuals not using MHT. Topical estrogen was more closely associated with reduced odds of soft‐tissue shoulder disorders compared with oral estrogen and oral combined formulations.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section.
DISCLOSURES
The authors (I.K.S., A.K.S., R.J.B., C.A.D., N.N.D., J.G.C., A.L.C.) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
Supporting information