The Role of Estriol and Estrone in Keratoconic Stromal Sex Hormone Receptors

Abstract

Keratoconus (KC) is a progressive corneal thinning disease that manifests in puberty and worsens during pregnancy. KC onset and progression are attributed to diverse factors that include: environmental, genetics, and hormonal imbalances; however, the pathobiology remains elusive. This study aims to determine the role of corneal stroma sex hormone receptors in KC and their interplay with estrone (E1) and estriol (E3) using our established 3D in vitro model. Healthy cornea stromal cells (HCFs) and KC cornea stromal cells (HKCs), both male and female, were stimulated with various concentrations of E1 and E3. Significant changes were observed between cell types, as well as between males and females in the sex hormone receptors tested; androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) using Western blot analysis. E1 and E3 stimulations in HCF females showed AR, PR, and ERβ were significantly upregulated compared to HCF males. In contrast, ERα and ERβ had significantly higher expression in HKC’s females than HKC’s males. Our data suggest that the human cornea is a sex-dependent, hormone-responsive tissue that is significantly influenced by E1 and E3. Therefore, it is plausible that E1, E3, and sex hormone receptors are involved in the KC pathobiology, warranting further investigation.

Prospective Observational Study Evaluating Systemic Hormones and Corneal Crosslinking Effects in Keratoconus

“… 15 , 45 Human corneal fibroblasts derived from patients with KC have also been found to express differential levels of androgen, estrogen, and progesterone receptors; these differences are accompanied by altered responsiveness to hormone stimulation compared with controls. 46 , 47 These findings suggest that systemic hormones, particularly estriol and estradiol, may influence corneal structure during KC.…”

Corneal Fourier and Belin–Ambrósio Enhanced Ectasia Analysis in Healthy 4-Year-Old White Children

“…[15][16][17] It has been demonstrated that the human cornea is a sex-dependent, hormone-responsive tissue that is significantly influenced by estrogen. 18 Significant differences in steepening of the corneal curvature and thickness during normal menstrual cycle 19,20 and pregnancy 21,22 have been reported.…”

Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms

“…To create the 3D constructs, we utilized our previously described self-assembled ECM model [ 30 , 31 ]. Briefly, HCFs and HKCs were seeded on transwell 6-well plates with polycarbonate membrane inserts with 0.4-μm pores (Transwell; Corning Costar; Charlotte, NC, USA) at a density of 1 × 10 6 cells/well and cultured in 1.5 mL of 10% FBS EMEM medium and 1% antibiotic stimulated with 0.5 mM 2-O-α-D-glucopyranosyl-L-ascorbic acid (Vitamin C, American Custom Chemicals Corporation, San Diego, CA, USA) in both top and bottom wells.…”