A Phase II, Multicenter, Randomized, Placebo-Controlled, Double-Masked Trial of a Topical Estradiol Ophthalmic Formulation in Postmenopausal Women with Moderate-to-Severe Dry Eye Disease

Schmidl, Doreen; Szalai, László; Kiss, Orsolya G; Schmetterer, Leopold; Garhöfer, Gerhard

doi:10.1007/s12325-021-01680-3

Cited by 10 publications

(7 citation statements)

References 19 publications

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“…Of note, the androgen receptor protein exists in the human cornea [ 52 ]. This supports the notion that androgen deficiency could be a major contributor to dry eye disease [ 42 , 44 , 48 ]. Along these lines and as alluded to above, the topical use of 17-β-estradiol-3-phosphate drops did not significantly change Schirmer’s test scores in postmenopausal women [ 48 ].…”

Section: Methodssupporting

confidence: 86%

“…While future studies are needed to investigate the impact of systemic HRT on postmenopausal DED, others have begun exploring the clinical potential of local HRT in the form of topical estradiol ophthalmic formulations. However, one randomized, placebo-controlled trial failed to detect significant differences in Schirmer’s test scores using topical 17-β-estradiol-3-phosphate drops [ 48 ].…”

Section: Methodsmentioning

confidence: 99%

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The effects of female sex hormones on the human cornea across a woman’s life cycle

et al. 2023

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The cornea is a hormone-responsive tissue that responds to changing levels of female sex hormones. This review focuses on the structural and functional changes in the human cornea associated with the hormonal milestones of menarche, pregnancy, and menopause, as well as consequences stemming from the use of exogenous sex hormones for fertility control and replacement. Articles were identified by searching PubMed without language or region restrictions. The primary outcomes evaluated were changes in central corneal thickness (CCT), intraocular pressure (IOP), and quality of the ocular tear film. The potential impact of hormone-associated changes on the diagnosis and surgical management of common eye diseases, as well as the potential use of sex hormones as therapeutic agents is also considered. Understanding the physiological effects of female sex hormones on the cornea is important because that knowledge can shape the management decisions physicians and women face about ocular health across their life stages.

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Section: Methodssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

The effects of female sex hormones on the human cornea across a woman’s life cycle

et al. 2023

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“…Although current studies do not clarify the specific mechanism of estrogen action in DED, epidemiological studies suggest that increased tear osmolarity, reduced tear film stability, and lid gland dysfunction are associated with lower endogenous serum estrogen levels [59,60]. Topical estradiol eye drops may reduce symptoms in postmenopausal women with moderate to severe DED [61]. In a clinical study, QJDHP increased both serum and tear levels of estrogen in patients with DED and relieved dry eye symptoms [62].…”

Section: Discussionmentioning

confidence: 99%

Using Network Pharmacology and Molecular Docking to Explore the Mechanism of Qiju Dihuang Pill against Dry Eye Disease

Zhao

et al. 2022

Computational and Mathematical Methods in Medicine

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Background. Dry eye disease (DED) is a multifactorial disease of the ocular surface, which affects the quality of life and work efficiency of affected patients. The traditional Chinese medicine formula Qiju Dihuang Pill (QJDHP) has a good therapeutic effect on DED. However, the pharmacological mechanism is not clear. Objective. To explore the mechanism of QJDHP in the treatment of DED based on network pharmacology. Method. The active components in QJDHP were screened in Traditional Chinese Medicine Systems Pharmacology (TCMSP), and putative molecular targets of QJDHP were identified using the SwissTargetPrediction database. DED-related targets were screened by GeneCards and OMIM. We established protein-protein interaction (PPI) and core targets and corresponding active compound network by Cytoscape to identify the core targets and main compounds of QJDHP against DED. DAVID database was utilized for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking was used to evaluate the binding activity between key active compounds and core targets. Results. The results of network pharmacology showed that 253 targets of QJDHP were related to DED. PPI network analysis showed the 18 core targets. The binding affinity of docking results ranged from -5.7 to -9.3 kcal/mol, indicating a good docking effect. The results of GO enrichment analysis showed that the mechanism of QJDHP in the treatment of DED mainly involved biological processes such as apoptosis, oxidative stress, response to estrogen, angiogenesis, and the regulation of transcription factors. KEGG analysis showed that QJDHP may be regulated by the TNF signaling pathway, Toll-like receptor signaling pathway, MAPK signaling pathway, and estrogen signaling pathway in the treatment of DED. Conclusion. In this study, we demonstrated the multicomponent, multitarget, and multichannel action mechanism of QJDHP in the treatment of DED and provided a foundation for further drug development research.

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“…It has been postulated that an estrogen imbalance contributes to the dry eye disease etiology, and histological evidence supports that estrogen receptors are observed within glandular tissues of human lacrimal and meibomian glands, as well as the cornea and the conjunctiva [ 40 – 42 ]. However, recent phase 2 evidence with a topical estradiol ophthalmic formulation in postmenopausal women with moderate-to-severe dry eye disease did not meet its primary endpoint of improving Schirmer’s II test score (with anesthesia) at day 90 compared to placebo [ 43 ]. Additionally, a recent systematic review of HRT use in postmenopausal women with dry eye disease did not demonstrate significance in tear breakup time outcomes at 3 and 6 months [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Does Menopausal Status Affect Dry Eye Disease Treatment Outcomes with OC-01 (Varenicline Solution) Nasal Spray? A Post Hoc Analysis of ONSET-1 and ONSET-2 Clinical Trials

Nijm

Zhu

Hemphill³

et al. 2022

Ophthalmol Ther

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Introduction This study sought to compare the efficacy of OC-01 (varenicline solution) nasal spray for treatment of dry eye disease (DED) in postmenopausal women (PM+) versus women who were not postmenopausal (PM−). Methods This was a post hoc subgroup analysis of data integrated from two prior randomized controlled clinical trials, ONSET-1 and ONSET-2. Women randomized to treatment with OC-01 (varenicline solution) nasal spray 0.03 mg or vehicle control (VC) whose self-reported menopausal status (PM+ versus PM−) was known were included. Outcomes included the treatment difference (the OC-01 [varenicline solution] nasal spray change from baseline [CFB] minus VC CFB) in Schirmer test score (STS, mm) with anesthesia and the eye dryness score (EDS) measured on a 100-mm visual analog scale (0 = no discomfort, 100 = maximal discomfort). Least-squares mean treatment differences were derived from analysis of covariance (ANCOVA) models. Results Overall, 449 female participants in the ONSET-1 and ONSET-2 trials randomized to the OC-01 (varenicline solution) nasal spray 0.03 mg or VC groups were included in this analysis. The treatment–menopausal status interaction terms in the STS and EDS ANCOVA and logistic regression models were not statistically significant ( p > 0.05), indicating consistency of treatment effect between the PM− and PM+ groups. The treatment difference in STS was similar in the PM− and PM+ groups (6.7 and 5.5 mm, respectively). The treatment difference in EDS was similar in the PM− and PM+ groups (− 5.5 and − 4.1, respectively). Conclusions OC-01 (varenicline solution) nasal spray demonstrated similar efficacy in promoting natural tear production and improving symptoms in both PM− and PM+ groups. As menopausal-related hormonal changes may be associated with more severe DED, these results may support OC-01 (varenicline solution) nasal spray as an effective treatment for DED in women regardless of presenting menopausal status. Trial Registration Post hoc subgroup analysis of data integrated from ONSET-1 (ClinicalTrials.gov identifier NCT03636061) and ONSET-2 (ClinicalTrials.gov identifier NCT04036292).

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A Phase II, Multicenter, Randomized, Placebo-Controlled, Double-Masked Trial of a Topical Estradiol Ophthalmic Formulation in Postmenopausal Women with Moderate-to-Severe Dry Eye Disease

Cited by 10 publications

References 19 publications

The effects of female sex hormones on the human cornea across a woman’s life cycle

The effects of female sex hormones on the human cornea across a woman’s life cycle

Using Network Pharmacology and Molecular Docking to Explore the Mechanism of Qiju Dihuang Pill against Dry Eye Disease

Does Menopausal Status Affect Dry Eye Disease Treatment Outcomes with OC-01 (Varenicline Solution) Nasal Spray? A Post Hoc Analysis of ONSET-1 and ONSET-2 Clinical Trials

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