Testosterone for Dry Eye Syndrome
by Jeffrey Dach MD
B was 58 years old with typical menopausal symptoms of night sweats and
hot flashes, and came to see me because of dry itchy, red eyes. The
lids sometimes swell because of the irritation. Over the years, Mrs B
had been to numerous eye doctors who gave her various drops to lubricate
the eye, antibiotic drops and steroid drops. She has been given
instructions for cleaning and irrigating the eyes. The eye drops seem
to help somewhat but the irritation always returns whenever she stops
them. Lately, the condition is getting worse and nothing seems to help.
left image: courtesy of wikimedia commons, red arrow points to
meibomian glands in edge of eye lid which secrete oil which lubricates
Low Testosterone Level
routine hormone panel showed that Mrs B had low hormone levels, and her
testosterone level was especially low. I explained to Mrs B that her dry
eye syndrome was caused by low testosterone levels,
and testosterone would help.
Cured With Testosterone, Surely You Must Be Joking, Doctor
week later, after starting her testosterone as sublingual drops, Mrs B
reported her eyes were much better. She also started a complete
bioidentical hormone program. Mrs B's ophthalmologist, Dr H, was an old
friend of mine and we would occasionally attend the same social
functions. At one of these social functions, Dr H approached to say
that a patient (no name) reported that I had cured her dry eyes with
testosterone, and surely you must be joking, Doctor. His gesture and
facial expression with his eyes rolling back were quite distinctive.
Testosterone for Dry Eyes in the Opthalmology Medical Literature
Dr H is unaware of the supportive evidence in his own specialty medical
journals. We will look at a few of these supportive articles that
recommend testosterone for evaporative dry eye syndrome. About 5 million Americans have
Dry Eye Syndrome caused by dysfunction of the lubricating glands, which
are called the lacrimal and meibomian glands. The small glands at the
upper outer eye are the lacrimal glands, and the meibomian glands are
located in the eye lid at the upper and lower edges (see diagram below).
Image :Tear system: a. tear gland / lacrimal gland, b. superior
lacrimal punctum, c. superior lacrimal canal, d. tear sac / lacrimal
sac, e. inferior lacrimal punctum, f. inferior lacrimal canal, g.
Dr David A Sullivan and Dry Eye Research
the research on testosterone and dry eyes has been done by David A
Sullivan at Schepens Eye Research Institute at Harvard Medical
Dr Sullivan Research in Mouse Model Of Sjogren's
Dr. Sullivan's early work in the 1990's involved Sjogrens syndrome, and the discovery that women with Sjögren'ssyndrome
are androgen-deficient causing meibomian gland dysfunction, tear film
instability, and the evaporative dry eye characteristic Sjogren's, which
is an autoimmune disorder. (1) Sullivan published a study in 1991 which
showed that testosterone inhibited the progression of autoimmune
disease in the lacrimal glands mice with Sjogren's. His mouse model of
Sjogren's showed that the testosterone suppressed the magnitude of
lymphocyte infiltration in the lacrimal gland 22- to 46-fold.(6)
Lacrimal and Meibomian Glands Regulated by Testosterone
In a 1999 report,
Sullivan suggested that androgens (testosterone) regulate both lacrimal
and meibomian gland function, and suggest that eye drops containing
testosterone may be safe and effective treatment for dry eyes in
Image: Chalazion, obstructed, infected meibomian gland upper eye lid.
This image is useful to give you an idea of where the glands are locared
in the lid. There are 20 - 30 small Meibomian glands located along the
edge of the upper and lower lid that secrete oil which lubricates the
surface of the eye. When one becomes obstructed, it swells up and is
called a Chalazion. Treatment is to relieve the obstruction and allow
drainage. Courtesy of wikimedia commons.
Men on Testosterone Blockers Get Dry Eyes
In 2000, Dr Sullivan reported that
men taking testosterone blockers have dry eye syndrome. Men
on testosterone blocker drug treatment for prostate cancer were found to
had poor quality of tear fluid. This was demonstrated by analyzing
the meibomian gland secretions. Their dry eye symptoms included light
sensitivity, painful and blurry eyes. Sullivan said,"the use of
anti-androgen pharmaceuticals was associated with significant changes in
the relative amounts of lipids in meibomian gland secretions. Our findings indicate that chronic androgen deficiency is associated with meibomian gland dysfunction and dry eye." (2)
In 2001, Drs Worda and Nepp from Vienna Austria reported that topically administered androgen can restore the lipid phase of the tear film, and was useful in treatment of keratoconjunctivitis sicca, medical terms for Dry Eyes. (3)
Complete Insensitivity to Androgen and Dry Eyes
Dr Sullivan turned his attention to a genetic disorder called Complete
Insensitivity to Androgen (CIAS). In this genetic disorder,
the androgen receptor is nonfunctional, and subsequently, there is
insensitivity to testosterone. Without a functioning receptor, the
normal activity of testosterone is completely blocked.
examined the tears (ie. Meibomian gland secretions), in women with CIAS
and compared them to normal controls. The patients with CIAS
had alteration in the lipid fractions of tear fluid, ( ie meibomian
gland secretions). This study was published in a 2002 report in Arch Ophthalmology (5).
Trans-Dermal Testostorone For Dry Eye Syndrome
In 2003, Dr Connor reported transdermal testosterone is safe
and effective treatment for dry eye, with the post-menopausal females
having the greatest relief of symptoms. (10)
Molecular Biology Mouse Studies of Gene Expression
In 2005, Dr Schirra et al studied the
molecular biology of testosterone, and gene expression in the meibomian
gland of mice. Dr Schirra reported that testosterone regulates the
expression of more than 1500 genes in the mouse meibomian gland
which serves to stimulate lipid and fatty acid metabolism in the
lubricating eye fluid.(11)
The Evidence is Overwhelming
sum total of the above evidence is overwhelming that testosterone plays
a key role in production of oil, the lipid component for lubricating
the eyes, and that testosterone deficiency is a treatable cause of dry
eye syndrome. The treatment is testosterone, a bioidentical hormone.
Omega 3 Fish Oil for Dry Eye Syndrome
the lubrication of the eye is an oily film, one might think that
nutritional oil consumption to be of benefit in the disorder. That is
what Dr Rahul Bhargava found in a 2013 study in the Journal of Opthalmology. Be careful to avoid the ethyl ester form of fish oil
An opthalmologist colleague reports good results with the following Omega 3 Fish Oil from PRNOmegaHealth
We also use the CO2 Super Critical Extract Omega Oil directly from Purecaps factory.
Medline List of studies showing use of Omega 3 Fish Oil Benefits Dry Eye Syndrome.
For Articles with Related content: Testosterone Information Menu
Jeffrey Dach MD
7450 Griffin Rd Suite 180/190
Davie, FL 33314
Links and References
Androgens and dry eye in Sjögren's syndrome.
Ann N Y Acad Sci. 1999 Jun 22;876:312-24. Sullivan DA et al.
Our results demonstrate that androgens regulate both lacrimal and
meibomian gland function, and suggest that topical androgen
administration may serve as a safe and effective therapy for the
treatment of dry eye in Sjögren's syndrome.
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 12 4874-4882,2000
of Androgen Deficiency on the Human Meibomian Gland and Ocular
Surface. Kathleen L. Krenzer, M. Reza Dana, M. David Ullman, Jennifer
M. Cermak, Dorothy B. Tolls, James E. Evans and David A. Sullivan
Eye Research Institute (K.L.K., M.R.D., J.M.C., D.A.S.), Brigham and
Women’s Hospital (M.R.D., J.M.C.), Department of Ophthalmology, Harvard
The purpose of this study was to determine whether
the chronic use of antiandrogen medications leads to meibomian gland
dysfunction, altered lipid profiles in meibomian gland secretions,
decreased tear film stability, and evaporative dry eye.
taking antiandrogen therapy for prostatic indications, as well as
age-related controls, were asked to complete a questionnaire that
assessed dry eye symptoms and then were given a complete anterior
segment examination. Moreover, meibomian gland secretions were obtained
from each eye and analyzed by high-performance liquid
chromatography/mass spectrometry for the relative content of
cholesterol, cholesterol esters, wax esters, diglycerides,
triglycerides, and specific molecular species in the diglyceride
Our results demonstrate that patients taking antiandrogen treatment, compared with age-related controls, had a:
significant increase in the frequency of appearance of tear film
debris, an abnormal tear film meniscus, irregular posterior lid margins,
conjunctival tarsal injection, and orifice metaplasia of the meibomian
2) significant increase in the degree of ocular surface vital dye staining; 3) significant decrease in the tear film breakup time and quality of meibomian gland secretions; and
4) significant increase in the frequency of light sensitivity, painful eyes, and blurred vision.
addition, the use of antiandrogen pharmaceuticals was associated with
significant changes in the relative amounts of lipids in meibomian gland
secretions. Our findings indicate that chronic androgen deficiency is associated with meibomian gland dysfunction and dry eye.
Maturitas. 2001 Jan 31;37(3):209-12.
Treatment of keratoconjunctivitis sicca with topical androgen.
by Worda C, Nepp J, Huber JC, Sator MO. Department of Obstetrics and
Gynecology, Division of Gynecological Endocrinology and Reproductive
Medicine, Vienna University Hospital, Währinger Gürtel 18-20, 1090,
OBJECTIVE: Androgens have been reported to
influence lipid production of sebaceous glands and even many ocular
tissues. The effect of topical androgen therapy on a 54-year-old patient
with keratoconjunctivitis sicca (KCS) and decreased lipid phase of the
tear film is reported.
METHODS: For assessment of the lipid phase
of the tear film, break up time (BUT) and lipid layer thickness (LLT)
were monitored during 6 months before treatment as well as 3 months
while using a daily topical androgen therapy.
RESULTS: During the
topical androgen therapy the pathological lipid phase of the tear film
was completely restored indicated by the normalisation of the values of
BUT and LLT.
CONCLUSION: These findings are consistent with animal experiments indicating that topical administered androgen can restore the decreased lipid phase of the tear film. This may open up new therapeutic strategies for KCS.
Sullivan research summary at Schepens Harvard Medical School
have shown that dry eye syndromes occur predominantly in women and that
estrogen replacement therapy increases the prevalence of dry eye signs
and symptoms in postmenopausal women. This latter finding is
extraordinary, given that many millions of women worldwide are
prescribed estrogen to alleviate menopausal symptoms and are therefore
at heightened risk of developing dry eye. The precise mechanism(s)
underlying the sex-related difference in, and the estrogen effect on,
dry eye prevalence is unclear. However, we hypothesize that: [a]
androgen deficiency and estrogen use are key factors in the predominance
of dry eye syndromes in women; and [b] sex, androgen and estrogen
effects are mediated through the regulation of gene expression in the
cornea and the lacrimal and meibomian glands.
Arch Ophthalmol. 2002 Dec;120(12):1689-99.
androgen insensitivity syndrome: effect on human meibomian gland
secretions. by Sullivan BD, Evans JE, Cermak JM, Krenzer KL, Dana MR,
Sullivan DA. Schepens Eye Research Institute,
determine whether androgen receptors affect the fatty acid profiles of
neutral and polar lipids in human meibomian gland secretions.
METHODS: Meibomian gland secretion samples were obtained from both eyes of
(1) women with complete androgen insensitivity syndrome, a condition
characterized by dysfunctional androgen receptors, and (2) age-matched
female and male controls.
Samples were processed for
high-performance liquid chromatography, mass spectrometry, or both and
for analysis of the mass spectra of neutral and polar lipid fatty acid
fragment ions by 3 different methods.
receptor dysfunction is associated with significant alterations in the
appearance of numerous molecular species in the neutral and polar lipid
fractions of meibomian gland secretions. The ability to detect
these differences, and to assess their nature and extent, was
facilitated by the use of several analytic approaches. Sex-related
differences exist in the expression of a variety of neutral and,
especially, polar fatty acid products in meibomian gland secretions.
CONCLUSIONS: Androgens exert
a significant effect on neutral and polar lipids in human meibomian
gland secretions, and these hormonal effects may be mediated through
Investigative Ophthalmology & Visual Science, Vol 32, 3002-3006.1991
Testosterone-induced suppression of autoimmune disease in lacrimal
tissue of a mouse model (NZB/NZW F1) of Sjogren's syndrome AC
Vendramini, C Soo and DA Sullivan Department of Ophthalmology, Harvard Medical School, Boston, MA 02114.
current investigation was designed to examine whether androgen
administration might suppress autoimmune disease in lacrimal glands of a
mouse model (NZB/NZW F1) of Sjogren's syndrome. Autoimmune, female mice
were treated with vehicle or varying concentrations of testosterone for
0, 17, 34, or 51 days, and tears, lacrimal glands, as well as
submandibular tissue, were collected from killed mice after androgen
exposure. Glands were histologically processed and evaluated with a
computer-assisted image analysis system.
Results showed that
testosterone administration induced a significant, time-dependent
decrease in the extent of lymphocytic accumulation in the lacrimal
gland. After 34-51 days of androgen therapy, the magnitude of lymphocyte infiltration had been suppressed 22- to 46-fold,
compared with that in placebo-treated tissue. This hormone effect was
associated with significant reductions in the number of focal
infiltrates, the area of individual foci, and the total quantity of
lymphocyte infiltration per lacrimal section. Testosterone exposure also
stimulated an increase in lacrimal gland weight and a rise in tear
volumes, relative to those measured in the same mice before treatment.
In addition, androgens significantly diminished the extent of lymphocyte
accumulation in submandibular tissue.
In summary, our
results demonstrate that androgen administration may inhibit the
progression of autoimmune disease in lacrimal and submandibular glands
of NZB/NZW F1 mice.
Sullivan DA et al. Ann N Y Acad Sci. 2002 Jun;966:211-22.
Androgen Deficiency, Meibomian Gland Dysfunction, and Evaporative Dry Eye
Abstract: Objective. We have recently discovered that women with primary and secondary Sjögren's syndrome are androgen-deficient. We hypothesize that this hormone insufficiencycontributes
to the meibomian gland dysfunction, tear film instability, and
evaporative dry eye that are characteristic of this autoimmune disorder.
If our hypothesis is correct, we predict: (1) that androgens regulate
meibomian gland function, control the quality and/or quantity of lipids
produced by this tissue, and promote the formation of the tear film's
lipid layer; and (2) thatandrogen deficiency, due to an
attenuation in androgen synthesis (e.g., during Sjögren's syndrome,
menopause, aging, complete androgen-insensitivity syndrome [CAIS] and
anti-androgen use), will lead to meibomian gland dysfunction andevaporative dry eye.
Experimental procedures included clinical studies, animal models, and
histological, biochemical, molecular biological, and biomedical
Results. (1) androgens regulate the meibomian gland. This
tissue contains androgen receptor mRNA, androgen receptor protein
within acinar epithelial cell nuclei, and Types 1 and 2 5a-reductase
mRNAs. Moreover, androgens appear to modulate lipid production and gene
expression in mouse and/or rabbit meibomian glands; and
(2) androgen deficiency may lead to meibomian gland dysfunction,
altered lipid profiles in meibomian gland secretions, tear film
instability, and evaporative dry eye. Thus, we have found that
anti-androgen therapy in men is associated with meibomian gland disease,
a decreased tear film breakup time, and functional dry eye.
we have discovered that androgen receptor dysfunction in women with
CAIS is associated with meibomian gland changes and a significant
increase in the signs and symptoms of dry eye. Of interest, we have also
found that androgen deficiency is associated with significant and
striking alterations in the neutral and polar lipid patterns of human
meibomian gland secretions.
Conclusions. Our findings show that the meibomian
gland is an androgen target organ and that androgen deficiency may
promote meibomian gland dysfunction and evaporative dry eye. Overall,
these results support our hypothesis that androgen deficiency may be an
important etiologic factor in the pathogenesis of evaporative dry eye
in women with Sjögren's syndrome.
Androgen Insensitivity Syndrome or AIS
(old name Testicular Feminization Syndrome or Testicular Feminisation Syndrome).
incidence of complete AIS is about in 1 in 20,000. Androgen
Insensitivity Syndrome is a phenotypic female with a chromosomal
genotype of 46,XY.The Androgen Insensitivity Syndrome has been linked to
mutations in AR, the gene for the human Androgen Receptor, located at
Xq11-12 (i.e. on the X chromosome).
The principal androgens are
testosterone and dihydrotestosterone (DHT).The androgen receptor (AR) is
a large protein of at least 910 amino acids. Each molecule consists of a
portion which binds the androgen, a zinc finger portion that binds to
DNA in steroid sensitive areas of nuclear chromatin, and an area that
Invest Ophthalmol Vis Sci 2003;44: E-Abstract 2450.
Treatment of Dry Eye with a Transdermal 3% Testosterone Cream
by C.G. Connor Optometry, Southern College of Optometry, Memphis, TN, United States
and colleagues have shown androgens play a key role in regulating the
function of both the lacrimal and meibomian glands. Previous work from
our laboratory has shown that androgenic supplemented artificial tears
were effective in relieving the symptoms of dry eye. The poor solubility
of androgens resulted in considerable irritation and poor patient
compliance. The present study employs transdermal delivery of
testosterone to treat dry eye.
Methods:Twenty eight subjects 3 males and 25 females with a mean age of 52.5 yrs that ranged from 25 to 76 yrs. with a subjective complaint of dry eye were enrolled in the study. The subjects were divided into two groups.
group received the transdermal cream alone, while the second group used
the transdermal cream supplemented with 3% testosterone. The subjects
applied the cream 2 times daily for two weeks. The groups were reversed
after two weeks of cream use. Baseline TBUT(tear breakup time) and
Schirmer test were done prior to the study and after the use of each the
two transdermal creams(control and testosterone).
TBUT was 3.83 +/- 2.07 sec, testosterone was 4.13 +/- 1.83 sec, and
cream alone was 4.53 +/- 2.2 sec. Schirmer results are 8.53 mm+/- 5.27
in 5 min baseline , 11.5 mm +/- 5.8 testosterone, and 7.8mm +/- 4.4
cream alone. ANOVA with post hoc student Newman-Keuls reveals that the
Schirmer test results with 3% testosterone is different from baseline
and cream alone at p=.05 level.
Over half the subjects reported significant improvement in dry eye symptoms with the testosterone cream.
Conclusion:Transdermal delivery of testosterone appears to be a safe and effective treatment for dry eye. The
transdermal cream allows use of increased testosterone concentration
and dramatically improves patient comfort. Post-menopausal females
perceived the greatest relief of symptoms from the treatment, while
males had the least benefit.
Investigative Ophthalmology and Visual Science. 2005;46:3666-3675.)
Control of Gene Expression in the Mouse Meibomian Gland by Frank
Schirra,1,2 Tomo Suzuki,1,2 Stephen M. Richards,1 Roderick V. Jensen,3
Meng Liu,1,2 Michael J. Lombardi,3 Patricia Rowley,3 Nathaniel S.
Treister,1,4 and David A. Sullivan1,2
From the Schepens Eye Research Institute, and the 2Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
In prior work, it has been found that the meibomian gland is an
androgen target organ, that androgens modulate lipid production within
this tissue, and that androgen deficiency is associated with glandular
dysfunction and evaporative dry eye. This study’s purpose was to test
the hypothesis that the androgen control of the meibomian gland involves
the regulation of gene expression.
METHODS. Meibomian glands were
obtained from orchiectomized mice that were treated with placebo or
testosterone for 14 days. Tissues were processed for the analysis of
differentially expressed mRNAs by using gene bioarrays, gene chips, and
real-time PCR procedures. Bioarray data were analyzed with GeneSifter
software (VizX Labs LLC, Seattle, WA).
RESULTS. The results show
that testosterone influenced the expression of more than 1590 genes in
the mouse meibomian gland. This hormone action involved a significant
upregulation of 1080 genes (e.g., neuromedin , and a significant
downregulation of 518 genes (e.g., small proline-rich protein 2A). Some
of the most significant androgen effects were directed toward
stimulation of genes associated with lipid metabolism, sterol
biosynthesis, fatty acid metabolism, protein transport, oxidoreductase
activity, and peroxisomes.
CONCLUSIONS. These findings demonstrate that testosterone
regulates the expression of numerous genes in the mouse meibomian gland
and that many of these genes are involved in lipid metabolic pathways.
Dry Eye Signs and Symptoms in Women With Premature Ovarian Failure
Janine A. Smith, MD; Susan Vitale, PhD, MHS; George F. Reed, PhD;
Shirley A. Grieshaber, RN, CRNO; Linda A. Goodman, COT; Vien H.
Vanderhoof, RN, CRNP; Karim A. Calis, PharmD, MPH; Lawrence M. Nelson,
MBA, MD Arch Ophthalmol. 2004;122:151-156.
Objective To examine
whether women with premature ovarian failure (POF) have abnormal
findings in ocular surface or tear parameters and whether they report
symptoms of ocular discomfort compared with age-matched controls.
Methods Sixty-five patients
with POF and 36 age-matched healthy controls were examined for signs
and symptoms of dry eye. The Ocular Surface Disease Index questionnaire
and the 25-item National Eye Institute Visual Function Questionnaire
(NEI-VFQ 25) were administered to the participants. Assessments of
ocular surface damage (Oxford and van Bijsterveld scores of vital dye
staining) and tear status (Schirmer tests 1 [without anesthesia] and 2
[with anesthesia] and tear breakup time) were performed.
Women with POF scored significantly worse than controls on all ocular
surface damage parameters: Oxford score (3.2 vs 1.7; P = .001),
conjunctival lissamine green (2.1 vs 1.3; P = .02), corneal fluorescein
staining (1.2 vs 0.4; P = .005), and van Bijsterveld score (2.1 vs 1.3; P
= .02). Further, the proportion of patients with POF meeting the dry
eye diagnostic criterion of a van Bijsterveld score greater than or
equal to 4 was significantly greater among women with POF than among
controls (20% vs 3%; P = .02). The POF group also tended to have worse
scores than controls on self-reported symptoms, as measured by the
overall Ocular Surface Disease Index (12.5 vs 2.1; P<.001) and the
overall NEI-VFQ (94 vs 98; P = .001) after adjustment for age and race.
Schirmer test scores and tear breakup time did not differ.
Conclusions Women with POF were more likely to exhibit ocular surface damage and symptoms of dry eye than
age-matched controls. They were not, however, more likely to have
reduced tear production. To our knowledge, this association between
ocular surface disease and POF has not been previously reported. These
data provide further evidence of the multifaceted role of sex hormones
in the health and disease of the ocular surface.
Based on data from the largest studies of dry eye to date, the Women’s
Health Study (WHS), and the Physicians’ Health Study (PHS), and other
studies,3-14 it has been estimated that about 3.23 million women and
1.68 million men, for a total of 4.91 million Americans 50 years and
older have dry eye.
lacrimal gland Tear system:
a. tear gland / lacrimal gland,
b. superior lacrimal punctum,
c. superior lacrimal canal,
d. tear sac / lacrimal sac,
e. inferior lacrimal punctum,
f. inferior lacrimal canal,
g. nasolacrimal canal
Meibomian glands are the 25-30 oil-producing glands located in both the
upper and lower eyelids that release oil slowly into the tear film.
This oil helps to stop the water in the tears from evaporating, so
helping to prevent dry eyes.
Dysfunctional meibomian glands often
cause dry eyes, one of the more common eye conditions. They may also
cause blepharitis, as the dry eyeball rubs off small pieces of skin from
the eyelid, which may get infected. Inflammation of the meibomian
glands (also known as meibomitis, meibomian gland dysfunction, or
posterior blepharitis ) causes the glands to be obstructed by thick
secretions, the resulting swelling is termed a chalazion. Besides
leading to dry eyes, the obstructions can be degraded by bacterial
lipases, resulting in the formation of free fatty acids, which irritate
the eyes and sometimes cause punctate keratitis.
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
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