The elaborate tear film ecosystem has to maintain its own delicate balance, despite influences from many outside sources and intrinsic characteristics. Dry eye is one such condition to disrupt the balance, giving rise to its newer moniker, dysfunctional tear film. It likely results from a host of factors, including hormone imbalance. 

Benefits and Risks
Androgen has been shown to regulate meibomian gland function, and any dysregulation has a profoundly adverse effect. Along with microbial invasion and duct stenosis, androgen dysregulation promotes inflammation in meibomian gland dysfunction (MGD), ultimately affecting the tear film.¹ Androgens also play a similar role in lacrimal gland function.² 

A deficiency in androgen resulting from attenuation in androgen synthesis has been documented in Sjögren’s syndrome, menopause, aging, men taking androgen blockers and in complete androgen insensitivity syndrome.² 

Multiple genes coding for androgen activity are present in ocular tissues, and research suggests androgen levels are depleted in individuals with significant MGD.^1,3  

Testosterone is the most common form of androgen.  Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione are also referred to as androgens, though they are actually converted to testosterone and could therefore be called pre-androgens.^4,5

Sex hormone deficiency also plays a key role in most dry eye disease, and studies have analyzed various methods for delivering androgen to the ocular surface.⁴ Unfortunately, investigators found topical testosterone has poor solubility and results in considerable discomfort and irritation. A transdermal orphan preparation was licensed to arGentis Pharmaceuticals, which yielded good results, as did a progesterone transdermal delivery option.³ No testosterone or progesterone preparations have yet made it to market. 

In addition to establishing efficacy, a major impediment for approval is safety. Commercial testosterone’s use is limited by cost, inconvenience, discomfort and occasional side effects—especially in women.³ Various reports show potential side effects for men with prostate disease and women with breast cancer (or those at high risk for each disease) when using hormone therapy. Although some theorize hormone supplementation enhances cancer growth, others reject this notion and show no association with increased risk.³ Regardless, a careful patient history is vital before initiating hormone therapy and, in men, a PSA blood draw and urologic exam is prudent.

Many of the side effects and safety concerns stem from oral formulations or are secondary to increased aromatase activity, elevated estradiol and its effect at the estrogen receptor. Aromatase activity increases with age, obesity, alcohol intake, insulin resistance, breast cancer, medications, processed diet and sedentary lifestyle.⁴ Although often overlooked in clinical studies, monitoring aromatase activity and symptoms of elevated estradiol is critical to the safe use of testosterone in both sexes. 

One alternative is a transdermal preparation of testosterone (3% to 10%) used once or twice daily. In addition, practitioners have used topical DHEA (.03% to 0.5%), the metabolic precursor to testosterone, from a compounding pharmacy with some reported success.³ However, results have been inconsistent, with reports of irritation. 

Play it Safe
The significance of androgen for dry eye therapy is well established, and some of us will occasionally use it in a transdermal form, mostly with female patients. However, we await additional evidence to ensure meaningful benefit with no harm when prescribing it to more patients. Further, we need a safe and effective commercial product to provide a remedy for dry eye. Although this has been part of the discourse for nearly two decades, a dearth of studies and clinical trials remains. Some practitioners will continue to use the off-label transdermal testosterone as echelon therapy, but it’s vital that this be accompanied by close monitoring for any evidence of hormonally responsive tumors.   

1. Sullivan DA, Sullivan BD, Evans JE, et al. Meibomian gland dysfunction and evaporative dry eye. Ann NY Acad Sci. 2002 June;966:211-2.
2. Sullivan DA, Yamagami H, Liu M, et al Sex steroids, the meibomian gland and evaporative dry eye. Adv Exp Med Bio. 2002;506:389-99.
3. Dawson TL. Testosterone eye drops: A novel treatment for dry eye disease. Ophthalmol Times. 2015 Nov.
4. Glaser R, Dimitrakakis C. Testosterone therapy in women: Myths and misconceptions. Maturitas. 2013;74(3):230-4.
5. Olson MC, Korb DR, Greiner JV. Evaluation of warm compress therapy for meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2003 May;44:2452.