Study reveals sex steroid inhibits inflammatory response

It is now well established that dry eye disease (DED) is an inflammatory process comprised of ocular surface hyperosmolarity, inflammatory cytokines, and cell damage, as discussed in the International Dry Eye Workshop (DEWS II) definition.¹ While the current commercially available treatments, cyclosporine (Restasis, Allergan, Cequa, Sun Pharma) and lifitegrast (Xiidra, Novartis), are excellent at improving DED signs and symptoms, some patients also benefit from additional interventions. One such intervention is androgen therapy.

Here, I discuss the study “Androgen Suppresses Hyperosmolarity-Induced Inflammatory Mediators in Human Corneal Epithelial Cells,” which adds credence to androgen therapy for DED.”²

Overview

In this study, Zibandeh N, et al. investigated the effects of sex steroids, specifically androgens, on hyperosmolar stress-induced proinflammatory cytokine expression and on the mitogen-activated protein kinase pathway in immortalized human corneal epithelial cells.

Cultured corneal epithelial cells were treated with dihidrotestosterone (DHT) or 17 ß-estradiol and then exposed to a hyperosmolar environment. The results show that DHT treatment and 17 ß-estradiol inhibited the hyperosmolar-induced expression of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-8 and IL-6. These same proinflammatory cytokines, as well as others, are found on the ocular surface and in tears of DED patients^3,4 and help propagate the inflammatory response. Additionally, in a hyperosmolar environment, the corneal epithelial cell viability was increased with DHT.

The study’s researchers concluded that in hyperosmolar conditions, DHT strongly inhibits the expression of proinflammatory cytokines through the protein kinase signaling pathways and that “these findings may contribute to the understanding of the roles and therapeutic implications of androgens” in DED.²

Value

Sex steroids have important effects on several aspects of the tear film and ocular surface, including the production of aqueous and meibum, the expression of mucus, and on immune activity.^2,5 Androgens often decrease with age, especially post menopause,^2,6 and DED is 2 to 4 times more common in men and postmenopausal women who have androgen deficiency.^2,7 Topical hormonal treatments, such as topical androgens, have been used anecdotally as compounded drops to treat DED.⁸

In my own clinical practice, I use compounded hormone drops to treat recalcitrant DED, including medroxyprogesterone acetate 1%, dihydroepiandrosterone 0.5 or 1.0% and a progesterone 0.5%/testosterone 0.5% combination drop 2 to 6 times daily. The use of topical compounded hormones is off label and, thus, left to the judgment of each clinician. CP

References

1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. The Ocular Surface. 2017;15:278-283.
2. Zibandeh N, Yildiz E, Ozer B, et al., Androgen suppresses hyperosmolarity-induced inflammatory mediators in human corneal epithelial cells. Cornea. 2020, Mar 2.
3. Bron AJ, Paiva CS, Chauhan SK, et al., TFOS DEWS II: pathophysiology report, The Ocular Surface 2017);15: 438-510.
4. Boehm N, Riechardt AI, Wiegand M, et al. Proinflammatory cytokine profiling of tears from dry eye patients by means of antibody microarrays, Invest Ophthalmol Vis Sci. 2011;52(10):7725-7730.
5. Knop E, Knop N, Millar T, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011;52:1938–1978.
6. Davison SL, Bell R, Donath S, et al. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. 2005;90(7):3847–3853.
7. Schaumberg DA, Sullivan DA, Buring JE, et al. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136(2):318–326.
8. Milner MS, Beckman KA, Luchs JI, et al., Dysfunctional tear syndrome: dry eye disease and associated tear film disorders-new strategies for diagnosis and treatment, Curr Opin Ophthal. 2017;27 Suppl 1:3-47.

DR. MILNER is partner and director of Cornea at Goldman Eye in Palm Beach Gardens, FL. and a founding member of the CEDARS/ASPENS (Cornea, External Diseases and Refractive Surgery/American Society of Progressive Enterprising Surgeons) Society. Disclosures: Dr. Milner reports relationships with Aldeyra Therapeutics, Allergan, Avedro, Bausch + Lomb, BioTherapeutics, Bio-Tissue, Dompé, EyeGate Pharma, Eyevance Pharmaceuticals, Icare, Johnson & Johnson Vision, Kala Pharmaceuticals, Ocular Science, Omeros, Percept Technologies, Quidel, Shire, Sun Ophthalmics and Valeant.