Sex Differences in the Lacrimal Gland: Implications for Dry Eye Disease

Abstract

Sexual dimorphism significantly impacts the lacrimal gland's structure, function, and ageing processes, playing an important role in dry eye disease (DED) pathophysiology. This multifactorial disorder, characterised by tear film instability, inflammation, and visual impairment, disproportionately affects women, especially after menopause. It highlights the interplay between sex steroid hormones, lacrimal gland function, and environmental factors. Systemic and local androgens are vital for maintaining lacrimal gland health and tear production, while the role of oestrogens remains less clear. Evidence suggests dose and context-dependent effects on inflammation and glandular function. Histopathological and molecular studies reveal significant sex differences in the lacrimal gland, with women exhibiting more pronounced age-related degenerative changes, including fibrosis and acinar atrophy, contributing to their increased susceptibility to DED. Despite these findings, the underlying mechanisms connecting sex steroid hormones, receptor expression, and local tissue regulation to these disparities remain poorly understood, highlighting the need for further research. This review synthesises the current knowledge of sex-specific differences in the lacrimal gland, emphasising the importance of integrating systemic and local biomarkers, histological data, and molecular insights into personalised therapeutic strategies. By tailoring treatments to patients' unique hormonal and molecular profiles, personalised medicine has the potential to transform DED management, addressing unmet clinical needs and improving outcomes.

Keywords: androgens; dry eye disease; lacrimal gland; oestrogens; personalised treatment; sex steroid hormones; sexual dimorphism; tear film.

Figure 1

Sex- and age-related histopathological differences of the human lacrimal gland.

Figure 2

Schematic presentation of dry eye disease subtypes and etiological factors contributing to its development. DED: dry eye disease; ADDE: aqueous tear-deficient dry eye; EDE: evaporative dry eye.

Figure 3

Schematic overview of steroidogenesis: Steroidogenesis begins with cholesterol, converted into pregnenolone, the precursor for all mineralocorticoids, glucocorticoids, and sex steroids. Pregnenolone can be metabolised into either progesterone or 17-hydroxypregnenolone. Progesterone serves as the primary precursor for mineralocorticoids. 17-hydroxypregnenolone acts as the precursor for all androgens, oestrogens, and glucocorticoids. Androgens can undergo aromatisation to form oestrogens, while testosterone can be converted into dihydrotestosterone through 5α-reductase action.

Figure 4

Factors influencing the development of sex differences: (A) Sex chromosomes determine chromosomal sex, with the Y chromosome facilitating male gonadal differentiation through the sex-determining region Y gene. (B) Different extents of X chromosome inactivation contribute to sex differences. (C) Mosaicism occurs in various tissues in females. (D) Environmental and behavioural factors directly impact sex steroid hormone receptors as endocrine disruptors and induce epigenetic changes. (E) Epigenetic influences are primarily mediated through DNA methylation. (F) Levels of SSHs at various life stages play a crucial role in shaping and enhancing sex differences.