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BLOG: How do androgen and estrogen affect dry eye? (part 2)
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Last month we learned how androgen and (to a lesser extent) estrogen levels can influence dry eye. specifically, how a decrease in systemic androgen levels can lead to meibomian gland dysfunction. With MGD, the oil layer of the tear film is insufficient, and an evaporative dry eye is induced.
I thought it would be good to review just how evaporation can lead to ocular damage.
When the tear film starts to evaporate, the water leaves, but the particles within the tears are left behind. In chemical terms, the tear film is thought of as a solution, the particles within the solution are solutes, and the water is the solvent.
In the tear film, a major portion of the solutes are salt molecules. As the solvent evaporates, the solution increases in osmolarity, meaning it has a higher solute concentration than it previously did. This helps explain why an evaporative dry eye can look so injected; the tears are simply saltier than they are supposed to be.
This high osmolarity also increases the number of inflammatory cytokines, and the dry eye snowballs. In fact, the normal cells (like proteins, lipids and mucins) in a tear film with high osmolarity can become damaged just from the being in that solution. In a hypertonic solution (here, tonicity refers to the high osmotic pressure gradient), cells will shrink because the solution/liquid inside the cell osmoses out, to help even the osmolarity imbalance. This is the reason why we prescribe topical hypertonic solution for corneal edema, to help the superficial cells osmose out their extra fluid. But in cases of dry eye, the hypertonic solution that the tear film has become worsens the situation and pulls too much water out of the epithelial cells, spurring more inflammation.
Last month we learned that aging is the biggest reason for a decrease in systemic levels of androgen. Weight gain is also a common cause. But there is another reason why these levels can decrease: anti-androgen therapy for prostate indications. A multicenter study published in 2000 looked at men taking Lupron (leuprolide acetate, Abbvie), Proscar (finasteride, Merck), Zoladex (goserelin acetate, AstraZeneca), Casodex (bicalutamide, AstraZeneca) and Eulexin (flutamide, Schering-Plough) for their prostates and found that these medications did, indeed, cause MGD. Specifically, compared to controls, these patients had much more dry eye signs and symptoms including: irregular lid margins, increase in ocular surface staining, decrease in tear break-up time and quality of meibum.
So, it would stand to reason that if decreased levels of androgen are associated with MGD, and taking anti-androgen therapy can cause dry eye, then perhaps a treatment for evaporative dry eye would be to supplement androgen levels. But knowledge of how androgen deficiency can affect the meibomian glands has been public for many years now, and the eye care market does not seem flooded with topical androgen products ... What gives?
First, it’s possible the potential of (or stigma of) androgen side effects (like increased facial/body hair growth, male-pattern baldness, breast swelling or acne) could be limiting the appeal of producing a topical therapy to pharmaceutical companies. Second, there seems to be a lot of patents for this treatment, and perhaps potential therapies are being held up?
Some compounding pharmacies will formulate testosterone eye drops and ship them to your practice, and some clinicians advocate using testosterone cream (3% to 5%) applied transdermally to the eyelids. And there is AndroGel, a medication produced by Solvay Pharmaceuticals (and then sold to AbbVie), who started heavily advertising its product for a condition they marketed as “low T.” Before this ad blitz, in 2002 sales of testosterone gels, patches, injections and tablets were $324 million per year; in 2012 it was more than $2 billion.
The FDA has issued warnings to some companies that manufacture treatment for low T about direct-to-consumer marketing of drugs that claim to cure symptoms that just about any older human would at least occasionally admit to, such as: “Do you have a decrease in libido? Do you have a lack of energy? Are you sad or grumpy? Are you falling asleep after dinner?” A decrease in androgen levels is a normal part of aging but doesn’t necessarily mean that someone should be treated for low T.
After age 30, a man’s testosterone levels typically decrease by 1% per year. Changes in weight seem to be more important than aging itself, which could be the subject of another entire article. But just because a decrease in testosterone happens often, it doesn’t mean we as doctors should ignore it.
Perhaps testosterone levels are something we should consider in our dry eye patients. I know that from now on, I am going to pay more attention to the meibomian glands of my older patients, and check to see if they’re on anti-androgen therapy. If so, then I’ll get the dry eye treatment program started sooner. And I’ll keep an open mind regarding topical androgen therapy; perhaps its future is not too distant.
References:
Connor CG, et al. Invest Ophthalmol Vis Sci. 2001;42:S30.
Krenzer KL, et al. J Clin Endocrinol Metab. 2000;85(12):4874-4882. doi:https://doi.org/10.1210/jcem.85.12.7072.
Nanavaty MA, et al. Br J Ophthalmol. 2014;98(4):567-569. doi: 10.1136/bjophthalmol-2013-304637.
Truong S, et al. Clin Exp Optom. 2014;97:324-336. doi:10.1111/cxo.12147.