Ménage à Trois: Sex, Sex Steroids, and Dry Eye Disease

“Ménage à Trois: Sex, Sex Steroids, and Dry Eye Disease”; the audience could be forgiven for speculating that a wild departure away from those topics normally covered in corneal disease was about to take place. This suggestive title was on the program at the Ocular Surface Disease Symposium at the annual Irish College of Ophthalmologists conference.

Alas, the “sex” referred to in the title was the demographic variable. Nevertheless, David A Sullivan PhD, a former Associate Professor at Harvard Medical School, delivered an insightful discussion of the associations between sex (male or female), sex hormones, and dry eye disease.

“The influence of sex on the eye has been known since the time of Hippocrates. Indeed, in the late 1800s, there was widespread belief among European physicians that ocular health was dramatically influenced by sex, and that males were by no means as prone to diseases of the eye from sexual causes as females,” Dr Sullivan said.

Dry eye disease burden is a major problem. In the United States, because of diminished productivity, the annual cost exceeds 55 billion dollars, he noted.

Female sex is known to be a significant risk factor for dry eye disease, with women comprising about two-thirds of those with the disease. Some of this association has been attributed to sex steroids.

Sex steroids act on the meibomian gland, lacrimal gland, conjunctiva, and cornea. These hormone actions occur most likely after local intracrine synthesis and appear to be mediated primarily through nuclear – and possibly membrane – receptors. Sex steroids impact multiple structural and functional aspects of the ocular surface and adnexa.

The actions of sex steroids on the lacrimal system and ocular surface are widespread, including tissue architecture, gene expression, and protein synthesis. Androgens also inhibit keratinisation pathways and suppress the immune response, he explained.

SEX AND SJÖGREN’S

In Sjögren’s disease, an even stronger sex association is seen, with more than 90% of cases seen in women. The autoimmune disease features lymphocytic infiltration of the lacrimal gland, with loss of tear secretion and secondary dry eye.

“In Sjögren’s syndrome, we have shown a significant decrease in the androgen pool in women. In autoimmune diseases, sex hormones can modulate the immune response. Androgens are known typically to suppress that immune response and the development of autoimmune disease,” he said.

Given the widespread action of sex steroids, they can contribute to the pathogenesis of both aqueous deficient and evaporative dry eye disease. Indeed, as well as females having more dry eye than males, studies found males with androgen deficiency to develop more dry eye. Sullivan described epidemiologic study findings in which men who have their androgen activity pharmacologically inhibited – for example, during treatment with anti-androgens for prostatic hypertrophy management – go on to develop dry eye.

“When men get over the age of 55, 60, their androgens start to drop, and that’s when they start to develop dry eye disease,” Dr Sullivan said. Given this, and the predominantly female population with dry eye, the question becomes, “Should we consider investigating a male patient who has dry eye disease in case they have androgen deficiency that could benefit from treatment?”

“No,” Dr Sullivan said. “The measurement of testosterone in the blood for a woman or a man really doesn’t mean anything. Blood levels of androgens grossly underestimate the total body levels, especially in women, as the androgens are synthesized in peripheral tissues.”

HARMFUL COSMETICS?

One area Sullivan did not get to cover in his presentation, but that he spoke to EuroTimes about it in discussion afterwards, was the probable negative effect of oestrogen on the meibomian glands, which may occur with the use of some cosmetics.

“There are a number of eye makeup ingredients – such as parabens, tea tree oil, and soy products – that contain oestrogen activity. Oestrogens, in turn, may promote meibomian gland dysfunction. A reason is that meibomian glands are large sebaceous glands, and oestrogens are known to suppress sebaceous gland function. This negative oestrogen action on meibomian glands may help to explain why oestrogen replacement therapy in postmenopausal women is a significant risk factor for the development of dry eye disease.”

The sex association with dry eye is not a simple topic. In addition to being mediated through sex steroids, the association may also be due to autosomal genetic and epigenetic factors. Complicating the analysis of the sex association, women report pain differently and exhibit different care-seeking behaviour compared to men. This may further influence the sex association of dry eye.

What about therapeutic approaches utilising our knowledge of the influence of sex in the pathogenesis of dry eye disease?

“We believe that such understanding may be translated into new insights into the physiological control of ocular tissues, as well as the generation of novel therapeutic strategies to treat DED,” Dr Sullivan said.

David A Sullivan PhD is the Chairman of the Board of Directors of the Tear Film & Ocular Surface Society (TFOS) in Boston, Massachusetts, USA, and former Associate Professor in the Department of Ophthalmology, Harvard Medical School.

david@tearfilm.org