Testosterone Ointment and Testosterone Drops for Dry Eyes
Burning, red, irritated eyes, worsen with age. For women, such dry eye symptoms worsen after menopause. Dry Eye Syndrome, which also includes reflex tearing and even itching in some patients, worsen with decreased estrogen and testosterone production in a woman’s ovaries during and after menopause. With the advent of “Computer Vision Syndrome,” extended use of our eyes on electronic devices has made the number of patients who have dry eye complaints sky rocket. Every day I see many IT programmers, mostly young men, with significant dry eye symptoms.
The photo above shows severe dry eyes with painful filaments attached to the surface of the cornea.
We also know that hormone replacement therapy (HRT) –the Estrogen-only type–in postmenopausal women (studied in a large population study of 25 665 postmenopausal women) increased risk of dry eye. However, other clinical studies have shown that estrogen supplementation improves dry eye symptoms and signs. Other studies have shown no effect. Two papers, though, did show topical estrogen applied to the surface of the eye improved tear function and symptoms (see these references)
There is also many papers noting the the role of Androgens (male hormones like Testosterone) in regulation of the lacrimal and meibomian glands. There is still not prospective controlled double blinded study showing the benefit of testosterone drops on the eye, though there have been many case reports and mini-studies without controls to say Testosterone drops and Testosterone cream applied to the base of the eyelids (where the meibomian glands are) work.
What do we know about Androgens (ie, Testosterone)?
1. They have an anti-inflammatory effect on many eye tissues like the lacrimal gland and the meibomian gland
2. They increases lacrimal gland secretion,
3. They promote the production of lipids by the meibomian glands,
4. We know that androgen deficiency may cause meibomian gland disease.
5. Topical and Systemic (taken by mouth or given by injection) Androgens improve the symptoms and signs of dry eye patients who have Sjögren’s syndrome and dry eye: shown in below studies; but these studies were not prospective or case controlled.
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- Sullivan DA. Sex and sex steroid influence on dry eye syndromes. In: Pflugfelder S,Beuerman R, Stern ME, eds. Dry eye and ocular surface disease. New York City, NY:Marcel Dekker Inc., 2004:165–90.
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6. 1 study showed Transdermal Androgen (a patch with Testosterone) improved dry eye symptoms in women with low testosterone levels.
- Nanavaty MA,
- Long M,
- Malhotra R
. Transdermal androgen patches in evaporative dry eye syndrome with androgen deficiency: a pilot study. Br J Ophthalmol 2014
7. 1 study showed Transdermal Androgen (a patch with Testosterone) improved dry eye symptoms in women with low testosterone levels and after combined androgen and estrogen therapy in postmenopausal women.
- Scott G,
- Yiu SC,
- Wasilewski D, et al
. Combined esterified estrogen and methyltestosterone treatment for dry eye syndrome in postmenopausal women. Am J Ophthalmol 2005;139:1109–10.
8. Testosterone cream applied to the eyelids normalizes tear lipid layer thickness and stability in some patients: this was shown in below study:
- Worda C,
- Nepp J,
- Huber JC, et al.
Treatment of keratoconjunctivitis sicca with topical androgen. Maturitas 2001;37:209–12.
9. Systemic antiandrogen therapy may reduce tear stability and increase meibomian gland dysfunction:
- Krenzer KL,
- Dana MR,
- Ullman MD, et al
. Effect of androgen deficiency on the human meibomian gland and ocular surface. J Clin Endocrinol Metab 2000;85:4874–82.
10. A lower serum testosterone (ie, low male hormones in your blood) is associated with and reduced tear function in postmenopausal women:
- Gagliano C,
- Caruso S,
- Napolitano G, et al
. Low levels of 17-β-oestradiol, oestrone and testosterone correlate with severe evaporative dysfunctional tear syndrome in postmenopausal women: a case–control study. Br J Ophthalmol 2014;98:371–6.
11. Estrogen hormone, in animals and in human in vitro (ie, in a petri dish) studies, decreases meibomian gland secretion and may promote inflammation:
- Sullivan DA
. Sex and sex steroid influence on dry eye syndromes. In: Pflugfelder S,Beuerman R, Stern ME, eds. Dry eye and ocular surface disease. New York City, NY:Marcel Dekker Inc., 2004:165–90.
. Estrogen and progesterone control of gene expression in the mouse meibomian gland. Invest Ophthalmol Vis Sci 2008;49:1797–808.
12. Conflicting studies have shown Estrogen can increase inflammation in the corneal surface epithelium and in the lacrimal gland (which produces the aqueous tear film layer)
AND can anti-inflammatory effects:
13. Both higher and lower circulating Estrogen levels in postmenopausal women have been associated with reduced tear function,17 ,20 and the
14. The Estrogen peak of the menstrual cycle results in increased symptoms of dry eye.
Ocular surface changes over the menstrual cycle in women with and without dry eye. Gynecol Endocrinol 2007;23:385–90.
Summary:
Many doctors use Testosterone 3%-5% cream applied to the eyelids for blepharitis (inflammation of the eyelash margin due to mites like Demodex or bacteria, which we can see easily under the microscope), which can also cause dry eyes. Some theorize that blepharitis is the result of testosterone deficiency locally to the eyelids.
Some doctors have noted a benefit to their patients of using 0.03% testosterone solubilized with hydroxyl propyl beta cyclodextrin or 0.5% concentration testosterone eye drops (see below) particularly for men with low testosterone levels. Some add 0.05% progesterone in the testosterone drops.
Most eyeMDs say they have patients who have benefitted from testosterone drops, and/or cream.
I have many patients too who feel a difference with the testosterone cream or ointment.
Still, however, we do not have a large prospective, randomized controlled study to prove any of these formulations are better than artificial tears or Xiidra or Restasis. And with millions of people suffering from debilitating dry eyes with an epidemic that is mounting daily given the rise of “Computer Vision Syndrome” (which is a real issue), we need such studies to prove the benefit of testosterone.
These studies will take, though, years to complete. And ultimately the variability of a body’s hormones is so complex, it is very possible that such studies will show mixed results. Likely the answer to the question is that for some patients, testosterone drops, cream, or ointment will help and for others it will not. It is also likely that different times in one’s life will determine the effectiveness of these treatment options. For now, the only way to know for sure if it will help you is to try testosterone cream or ointment on the eyelid margin, ointment in the eyes when formulated for the inside of the eye, and/or testosterone eye drops.
The good news is that there are no significant complications that I could find using Testosterone.
Sandra Lora Cremers, MD, FACS
Update: Jan 2017
A new issue we have encountered is many compounding pharmacies no longer make testosterone eye drops. I could not find any case report of an infection from using Testosterone drops. It could be that making Testosterone eye drops is too expensive or too risky to make. I do not know.
We are still looking for a local compounding pharmacy that can make Testosterone eye drops and cream that can be used in the eye. For now, we are prescribing Testosterone cream for the outside of the eyelid.
Email from Leiter’s:
Our apologies, Dr. Cremers, but Leiter’s is not compounding testosterone/progesterone eye drops at this time. You will need to obtain this from another pharmacy provider.Best,
Brian Rozema, RPh
Leiter’s
The below study about to be published did not show any positive effect of using testosterone transdermal (a patch) therapy on improving dry eye symptoms.
A limitation of this pilot study is the very small sample size. Also they only studied women after menopause and excluded our severe dry eye patients who have Sjögren’s syndrome.
Br J Ophthalmol. 2016 Nov 3. pii: bjophthalmol-2016-309498. doi: 10.1136/bjophthalmol-2016-309498. [Epub ahead of print]
The effects of transdermal testosterone and oestrogen therapy on dry eye in postmenopausal women: a randomised, placebo-controlled, pilot study.
Golebiowski B1, Badarudin N1, Eden J2,3, Gerrand L1, Robinson J1, Liu J2, Hampel U1,4, You J1,5, Stapleton F1.
Abstract
AIMS:
METHODS:
RESULTS:
CONCLUSIONS:
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Testosterone eye drops: A novel treatment for dry eye disease
Editor’s Note: This article is a summary of T.L. Dawson, MD’s experience with an enhanced bioavailable and non-irritating testosterone eye drop for the treatment of dry eye disease (DED). This was an informal, in-office study, using testosterone off-label as an eye drop formulation.
The sheer numbers of perimenopausal women in my practice presenting with DED suggested a sex hormone deficiency as a common denominator and, perhaps, a principal cause.
This begged the question: Had others not had similar insights and therefore directed research to a hormonal etiology?
Extensive online searches revealed to me the landmark research of David A. Sullivan, MD, Schepens Research Eye Institute, Harvard Medical School, Boston, in the 1990s. His rodent studies revealed that androgens were the key modulators of meibomian and lacrimal gland function. 1
His clinical studies indicated that androgen deficiency and the resulting DED was present in patients with Sjögrens syndrome, men taking androgen blockers, and in a genetic disorder where complete insensitivity to androgens is present (complete androgen insensitivity syndrome).
On a microbiologic level, in 2005, Frank Schirra, MD, reported a DNA receptor study that confirmed the presence of more than 1,500 genes coding for androgen activity in these tissues. 4
Clinical studies
Based on the revelations of the Sullivan research, in 2003, C.G. Connor at the Southern School of Optometry, Memphis, developed and patented a transdermal 3% androgen eyelid preparation specific for the treatment of DED. 6
He found that testosterone when given as an eye drop is effective but “the poor solubility of androgens resulted in considerable irritation and poor patient compliance.”
The transdermal preparation was licensed to an orphan drug company (arGentis Pharmaceuticals), which completed a phase II study. They reported a 68% increase in tear break-up time and a 51% increase in aqueous secretion with a 51% decrease in symptoms. They also had good results with transdermal delivery of progesterone. Neither, however, made it to market.
In 2008, Allergan commissioned a phase I study 4 with the National Institute of Health titled, “The Safety and Efficacy Study of a Testosterone Eye Drop with a Treatment of Meibomian Gland Dysfunction.”
The results after 6 months were significant, with 30% of patients with non-inspissated glands becoming asymptomatic in the androgen group versus only 8% in the control group.
DHEA was the testosterone analog used in that study. DHEA is the primary hormone produced by the adrenal and is a metabolic precursor, but only about 50% is naturally converted into testosterone. The most effective concentration in their study was 0.03%. Allergan submitted another U.S. patent application in 2012 5 and initiated a phase II study, due for completion in 2015.
The phase I study was the impetus for my own mini-office study. The intention, however, was to use an enhanced bioavailable and more tolerable aqueous soluble testosterone eye drop formulation.
Testosterone
Testosterone, when given orally in high doses to overcome first pass hepatic clearance, can risk toxicity. Parenteral dosing is therefore required, either administered daily by a transdermal or transmucosal route, or as a repository intramuscular injection every 2 weeks.
Commercial preparations of testosterone are readily available but have objectionable qualities, such as cost, inconvenience, or discomfort.
The advantage of an eye drop administration route is that it is convenient and avoids the untoward effects from a high systemic androgen load.
Primary-care physicians and gynecologists are hesitant to prescribe systemic doses of testosterone for women because of occasional cosmetically unacceptable viralization effects, such as chin hair growth or acne.
There also is resistance in the medical community to prescribing testosterone supplementation to men because of what many consider an erroneous dogma from the 1940s, based on one inadequate study and despite all recent evidence to the contrary. That assertion was that high testosterone levels enhanced prostate carcinoma growth.
Longitudinal studies have, however, repeatedly and consistently rejected that hypothesis.
I found that Leiter’s Pharmacy, one of the largest ophthalmic compounding pharmacies in the United States, dispensed an androgen eye drop.
They reported to me that it had favorable but inconsistent results but also often caused ocular irritation. It was formulated with DHEA, the metabolic precursor to testosterone in a high concentration as an emulsion. Emulsions have an inherent problem due to their high viscosity, requiring vigorous agitation to maintain concentration consistency and to avoid clogging of the dispenser bottle tip.
I collaborated with them in reformulating the hormone as testosterone and not DHEA, and in a much lower concentration with a novel and well-known aqueous solubilizer, cyclodextrin.
All sterol hormones such as the sex hormones have relatively low surface reactivity and are poorly water or lipid soluble. In an aqueous medium, they must be dispersed as a nanoparticle suspension as an emulsion.
My research revealed an ideal aqueous solubilizing compound for delivery of sterols to the eye, cyclodextrin. This was reported in a Scandinavian ophthalmologic journal in 2002. 7
Cyclodextrin has been known for more than a century and is classified by the USDA as generally recognized as safe for human use. Because of its low cost and availability in recent years, it has experienced broad applications in the food, pharmaceutical, and chemical industries. Potential drug applications of cyclodextrin have been realized and a few ophthalmic eye drops, such as Voltaren, have been formulated with it.
In 2009, I designed my own small in-office, 2-week study enrolling 12 consecutive patients (9 women and 3 men) with significant DED symptoms based on the Allergan Ocular Surface Disease Index. Pre- and post-treatment Schirmer’s and lissamine green staining measurements were obtained.
As a double-blind study, patients were issued two identical-appearing eye drop bottles, one containing only the control vehicle solution and the other, 0.03% testosterone solubilized with hydroxyl propyl beta cyclodextrin.
They were instructed to instill one drop in an eye chosen at random and the other eye drop on the fellow eye and not to cross contaminate.
After 2 weeks, they were re-examined for effects. Ten of the 12 had significant improvement in symptoms and signs.
Leiter’s then broke the code to reveal what the bottles contained. Surprisingly, improvement occurred almost equally in both eyes. I presumed that enough systemic absorption of the therapeutic drop occurred in one eye to affect the control eye.
Treatment Protocol
Although the study was statistically underpowered due to the small sample size, the beneficial results were enough for me to develop a treatment protocol. Leiter’s added this to its dispensing formulary. I decided to also include 0.05% progesterone in the formulation, based on reports also indicating beneficial effects of this hormone in decreasing dry eye symptoms.
I speculate that progesterone is effective because it is converted to testosterone in the sterol pathway and also is converted to a corticosteroid that could afford anti-inflammatory effects. Estrogen was avoided since the Woman’s Health Study revealed that women on estrogen replacement alone have a higher incidence of DED.
For any degree of dry eye, I prescribe the omega-3 fatty acid nutraceutical, eicosapentanoic acid (EPA). The beneficial effects of dietary omega-3 fatty acids in reducing DES symptoms have been reported from multiple studies. 8,9 EPA is the most effective anti-inflammatory omega-3 fatty acid and is present in high concentration in refined fish oils.
In mildly symptomatic patients, omega-3 nutraceuticals, tear substitutes, and environmental modifications may be sufficient to relieve symptoms and not require androgen replacement.
Because a testosterone eye drop is a compounded drug and therefore not usually reimbursed by insurance, I limit prescription to motivated patients with moderate to severe lissamine green staining and significant DED symptoms. I instruct them to instill one drop in each eye and, to affect some transdermal absorption, lightly massage the overflow into the lid margin and palpebral lid area.
Although twice-daily dosing is prescribed, once daily may be effective. I have found that a majority of women in the perimenopause age range of 45-60 years, or earlier, if they have had surgical menopause, have evaporative dry eye and will respond favorably to an androgen eye drop.
As they become older, I have noticed that the response may be muted because an aqueous tear deficiency develops. Sjögren’s syndrome patients and patients with other auto-immune disorders also may show less benefit from androgen treatment due to their severe tear deficiency. Cyclosporine and punctal occlusion also is usually required in these patients.
I see an increasing number of men with “male menopause” experiencing DED. Often times they have already been diagnosed with low testosterone.
If this is suspected and they are not already on supplementation, I will order a testosterone level. I have seen men with levels less than 300 ng/dl who are often symptomatic with dry eyes and sometimes symptomatic with even less than 400 ng/dl.
I prescribe a higher 0.5% concentration testosterone eye drop for men. If they have systemic symptoms of androgen deficiency such as fatigue, night sweats, or erectile dysfunction, I will refer them to their primary-care physician for transdermal or injectable testosterone supplementation rather than prescribe an eye drop formulation.
From a medico-legal standpoint, it also is prudent for them to have a current prostate exam and a PAS level drawn.
I continue to note that current literature and conferences discussing DED fail to explore the androgen connection and this avenue of treatment despite the revelations of valid scientific research.
A commercial androgen eye drop is not yet available but does appear to be in a pharmaceutical pipeline.
For patients who get inadequate relief from the usual treatment and who fit the criteria suggested, I would encourage physicians to prescribe this aqueous soluble testosterone eye drop formulated by Leiter’s Pharmacy.