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The Dry Eye Ménage-a-Trois: Sex, Hormones, and Cosmetics
Understanding the link between menopause and dry eye disease
Rachna Murthy, Amy Gallant Sullivan, David A. Sullivan | | 6 min read | Review
Though menopause is a natural part of the female aging process, it comes with many unwelcome symptoms – hot flushes, weight gain, joint pain, hair loss, sleep deprivation, and depression, to name a few (1). Lifestyle choices can expedite this process; for example, exposing oneself often to polychlorinated biphenyls (PCBs), phthalates (2), and a myriad of other widely used ingredients in product formulations. It is not well known that various forms of these chemicals are used in personal care products (for example, PCBs can be found in soap and hydrating beauty bars) (3) and cosmetics (for example, phthalates in makeup remover) (4).
The link between menopause and dry eye disease (DED) is even less well-known. Symptoms include ocular irritation, a gritty sensation, redness, secondary epiphora, and visual disturbance. With the cumulative use of eye makeup and skincare that contain one of the following ingredients: parabens (for example, ethylparaben and methylparaben) or essential oils such as tea tree oil (for example, terpinen-4-ol), the process of peri-menopausal DED can be expedited. Parabens abound in many around-eye creams, eyeliners, eyeshadows, glitter, mascaras, moisturizers, and serums, and tea tree oil is a featured ingredient in certain eye makeup removers, eyelash cleansers, moisturizers and toners (4).
How do PCBs, phthalates, parabens, and tea tree oil induce these effects? The answer is that they are all endocrine disruptors (4,5). Endocrine disruptors are natural or human-made chemicals that may mimic, prevent, or interfere with the body’s hormones. Most often these disruptors act as estrogens or anti-androgens and may elicit significant adverse effects (6). Parabens have estrogen potency, tea tree oil and phthalates possess estrogen and antiandrogen activities, and PCBs, depending on their structure, may block or imitate sex steroid actions (4,5).
But, given that menopause and postmenopause are characterized by a loss of estrogen, and androgens are male hormones, why would compounds with estrogen or anti-androgen actions engender a disease like DED in women? One might expect the application of estrogen-like chemicals to help with the restoration of tear film stability and prevent DED, but this is not the case.
Estrogens, and chemicals that act as estrogens, may actually promote the development of DED (7,8), while androgens may prevent DED (7,8).
The major cause of DED is meibomian gland dysfunction (MGD). Meibomian glands (MGs), which are large sebaceous glands situated in the eyelids, secrete an oil (i.e., lipid) and protein mixture that stabilizes and prevents the evaporation of the tear film, and play an essential role in the health and well-being of the ocular surface. Conversely, MGD destabilizes the tear film, increases its evaporation, and is a key trigger for the induction of DED (7,9) (Figure 1).
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Figure 1. Schematic diagram to show the mechanism of meibomian gland dysfunction (MGD). Adapted from TFOS DEWS II Sex, Gender and Hormones Report.
Estrogens cause a significant decrease in the size, activity, and lipid production of sebaceous glands (7). Indeed, estrogen was once called the prototype agent for the suppression of sebaceous gland activity, and estrogen treatment has been used to decrease sebaceous gland function and secretion in humans (7). Aside from prematurely destroying sebaceous gland cells, mechanisms for this negative estrogen effect include reduced androgen uptake, interference with local androgen synthesis, and antagonism of androgen action (7).
In the MGs estrogen suppresses the transcription of genes involved with lipid generation, mobilization and processing, and significantly reduces the activity of a critical signaling pathway in human MG epithelial cells (7,8). Given these antagonistic effects, as well as the impact of estrogens on sebaceous glands in general, it is most likely that estrogen exposure decreases MG function and promotes both MGD and evaporative DED. Such estrogen action would help answer three conundrums: i) why an epidemiological evaluation of over 25,000 postmenopausal women demonstrated that estrogen replacement therapy significantly increases the signs and symptoms of DED; ii) why an assessment of more than 44,000 women with DED showed that one of the highest prevalences of comorbid conditions was the use of estrogen replacement therapy; and iii) why estrogen treatment of women in several studies led to diminished tear film breakup time (the time taken for the tear film to destabilize), foreign body sensation, contact lens intolerance and ocular surface dryness (7). In effect, chemicals that act like estrogens do not appear ideal for eyelid MGs or for the tear film.
In contrast, androgens stimulate MG function, improve the quality and/or quantity of lipids produced by this tissue and enhance the formation of the tear film’s lipid layer. Androgen deficiency, in turn, will lead to MGD, tear film instability and evaporative DED (7,8). Consequently, endocrine disrupting ingredients in eye makeup, which have anti-androgen activities, will promote the development of DED.
Why are anti-androgens a problem for women? Androgens are very important hormones for women and are critical for reproductive ability, cardiac health, bone metabolism, muscle structure, and brain function (10). Human females produce an amount of androgens equivalent to over two-thirds of the androgens made by men (7,8). A woman's androgen production decreases progressively from the age of 30 years, leading to an androgen deficiency by post-menopause. This androgen loss may well be a significant reason for why the prevalence of DED is so high in post-menopausal women (7,8). Women have twice the risk of developing DED compared to men and the combination of lower androgen levels and endocrine disrupting makeup ingredients are likely to be a significant contributor (8).
Phthalates, parabens, and tea tree oil are not the only endocrine disrupting culprits in eye makeup. Soy ingredients, such as isoflavones, are phytestrogens and also act as endocrine disruptors (11). Additional endocrine disruptors in eye makeup include benzophenone, butylated hydroxyanisole, butylated hydroxytoluene, cyclopentasiloxane (cyclomethicone), per- and poly-fluoroalkyl substances, siloxane D4, thimerosal and triclosan (4) (Figure 2:)
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Figure 2. Schematic diagram to show the etiology of MGD, which results in low delivery of meibomian oil.
Overall, endocrine disruptors can be harmful to our health. They are linked not only to DED but also to reproductive disorders, obesity, diabetes, cancers, neurological problems, immune and thyroid disorders and osteoporosis (12).
The eye care professional can significantly influence the onset and prevention of DED in their female patients. Encourage ingredient checking with apps and websites such as www.incidecoder.com, discourage the use of recognized endocrine disruptors, and counsel their menopausal patients who are on estrogen replacement therapy.
- P Monteleone et al., “Symptoms of menopause – global prevalence, physiology and implications,” Nat Rev Endocrinol., 14, 199-215 (2018). Epub 2018 Feb 2. PMID: 29393299.
- apps.ecology.wa.gov/publications/documents/1604014.pdf
- NM Grindler et al., “Persistent organic pollutants and early menopause in U.S. women,” PLoS One, 10 (2015). PMID: 25629726.
- DA Sullivan et al., “TFOS Lifestyle: Impact of cosmetics on the ocular surface,” Ocul Surf., 29m, 77 (2023). PMID: 37061220.
- LK Akinola et al., “A computational insight into endocrine disruption by polychlorinated biphenyls via non-covalent interactions with human nuclear receptors,” Ecotoxicol Environ Saf., 214, 112086 (2021). PMID: 33640727.
- ET Chow, S Mahalingaiah, “Cosmetics use and age at menopause: is there a connection?” Fertil Steril., 106, 978 (2016). PMID: 27545020.
- E Knop 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., 52, 1938 (2011). PMID: 21450915.
- DA Sullivan et al., “TFOS DEWS II Sex, Gender, and Hormones Report.,” Ocul Surf., 15, 284 (2017). PMID: 28736336.
- AJ Bron et al., “TFOS DEWS II Pathophysiology Report,” Ocul Surf., 15, 438 (2017). PMID: 28736340.
- VE Bianchi et al., “The role of androgens in women's health and wellbeing,” Pharmacol Res., 171, 105758 (2021). PMID: 34242799.
- HB Patisaul, “Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviors,” Proc Nutr Soc., 76, 130 (2017). PMID: 27389644; PMCID: PMC5646220.
- www.endocrine.org/topics/edc/why-you-should-care
An award-winning Consultant Ophthalmologist & Oculoplastic Surgeon, previously at Ipswich Hospital NHS Trust (UK) since 2008 and Cambridge University Hospital between 2012 to 2020, providing a globally recognized tertiary referral thyroid eye disease service. She is now in full time private practice at FaceRestoration (London & Cambridge, UK) providing a holistic oculoplastics, dry eye disease, and medical aesthetic service. She is a full member of the American , European and British Oculoplastic Surgery Societies and regularly sits on the faculty at Optometry and Ophthalmic conferences. She is also the lead of the complications faculty for Allergan/Abbvie and is a co-author of the TFOS report, Ocular Surface Disease – A Lifestyle Epidemic Cosmetics.
The Executive Director and Co-Founder of the Tear Film & Ocular Surface Society (TFOS) – a non-profit organization, which was created to advance the research, literacy, and educational aspects of the scientific field of the tear film and ocular surface throughout the world – as well as the Founder & CEO of ESSIRI Labs and Creator of Eyes Are The Story. For two decades Amy has passionately championed eye health and wellness education worldwide. In addition to her work with TFOS, she is leading a global initiative to raise awareness about the impact of cosmetics on the ocular surface.
Until recently, David A. Sullivan, MS, PhD, FARVO, was an Associate Professor in the Department of Ophthalmology at Harvard Medical School and a Senior Scientist at the Schepens Eye Research Institute (Boston, MA, USA). During his 38 years at those institutions, his research focused on the interrelationships between sex, sex steroids and dry eye disease, as well as on the role of lubricin on the ocular surface. He is also a Founder, recent President, and current Chairman of the Board of Directors of TFOS.