Tweet
Arch Soc Esp Oftalmol vol.79 no.2 Madrid Feb. 2004
How to cite this article
EDITORIAL
--------------------------------------------------------------------------
DEFICIENCIA ANDROGÉNICA Y SÍNDROMES DE OJO
SECO
ANDROGEN DEFICIENCY & DRY EYE SYNDROMES
DAVID A. SULLIVAN, Ph. D1
Sex steroid deficiency has been linked with the development
and/or progression of a wide variety of clinical disorders, including
cardiovascular disease, obesity, osteoporosis, insulin resistance and certain
cancers (1). We hypothesize that sex steroid deficiency, specifically
that of androgens, may also be a critical etiologic factor in the
pathogenesis of dry eye syndromes.
Dry eye syndromes are a leading cause of patient visits to
ophthalmologists and are classified into two major types: aqueous-deficient
and evaporative (2). Aqueous-deficient dry eye is due to a lack of
aqueous tear secretion by the lacrimal glands. An example is Sjögren's
syndrome, an autoimmune disease that afflicts predominantly women. This
disorder is associated with extensive inflammation in lacrimal tissue, an
immune-mediated dysfunction and/or destruction of acinar and ductal
epithelial cells, and a precipitous decline in aqueous tear output.
Sjögren's syndrome may be either primary (i.e. no associated connective tissue
disease) or secondary [e.g. individuals with systemic lupus
erythematosus (SLE) or rheumatoid arthritis (RA)]. The second type of dry eye is
termed evaporative and is most often caused by meibomian gland
dysfunction and lipid insufficiency, thereby promoting increased evaporation and
reduced stability of the tear film. This form of dry eye is also
observed in Sjögren's syndrome, as well as during menopause and aging.
Researchers have estimated that meibomian gland disease may be a contributing
factor in over 2/3 of all dry eye patients (3).
The rationale for our hypothesis linking androgen deficiency with
dry eye syndromes is two-fold:
First, androgens regulate numerous aspects of the lacrimal gland,
including epithelial cell morphology, gene expression, protein
synthesis, secretory processes and immune function. Indeed, androgen action
appears to account for many of the sex-related differences that exist in
the anatomy, molecular biology, physiology and immunology of this
tissue. However, women with Sjögren's syndrome have an androgen deficiency
(4), and this hormone deficit may predispose to lacrimal gland
dysfunction, decreased tear secretion and aqueous-deficient dry eye. Consistent
with this hypothesis is the finding that androgen treatment of female
mouse models of Sjögren's syndrome causes a dramatic suppression of the
inflammation in, and a significant increase in the functional activity
of, lacrimal glands. Similarly, androgen therapy has been reported to
alleviate dry eye signs and symptoms, and stimulate tear flow, in
Sjögren's syndrome patients. The mechanism by which androgens suppress
lacrimal gland autoimmune disease appears to involve hormone binding to
nuclear receptors within epithelial cells and a consequent alteration in the
activity of specific genes and proteins in lacrimal tissue (5).
Second, the meibomian gland, like other sebaceous glands, is an
androgen target organ. Androgens control the development,
differentiation and lipid production of sebaceous glands throughout the body.
Similarly, androgens appear to regulate meibomian gland function, improve the
quality and/or quantity of lipids produced by this tissue and promote
the formation of the tear film's lipid layer. These hormone effects
appear to be mediated through androgen receptors within epithelial cell
nuclei and to involve the modulation of multiple genes, including those
related to lipid, sex steroid and other cellular metabolic pathways.
Conversely, androgen deficiency, such as occurs during menopause (decline
in secretion of ovarian androgens and adrenal androgen precursors),
aging in both sexes (decrease in the total androgen pool), autoimmune
disease (e.g. Sjögren's syndrome, SLE, RA), complete androgen insensitivity
syndrome (i.e. women with dysfunctional androgen receptors) and the use
of anti-androgen medications (e.g. for prostatic hypertrophy or
cancer), is associated with meibomian gland dysfunction, tear film instability
and a significant increase in dry eye signs and symptoms.
Androgen-deficient people also have a higher frequency of metaplasia of the
meibomian gland orifices and a reduced quality of meibomian gland secretions,
as well as significant alterations in the neutral and polar lipid
profiles of their meibomian gland secretions (i.e. relative to those of
normal male and female controls). This association between androgen
deficiency, meibomian gland dysfunction and evaporative dry eye may help to
explain why topical or systemic androgen treatment has been reported to
help restore intraglandular lipid patterns toward normal in
androgen-deficient animals, stimulate the production and secretion of meibomian
gland lipids, prolong the tear film breakup time and to decrease the signs
and symptoms of dry eye in women and men (6).
Overall, research indicates that androgen deficiency may be a
critical etiologic factor in the pathogenesis of aqueous-deficient and
evaporative dry eye syndromes during menopause, aging and certain
autoimmune diseases. Given these observations, it is possible that efforts
directed at alleviating the endocrine imbalance in ocular surface tissues
may prove beneficial as a therapy for lacrimal and meibomian gland
dysfunction and the associated dry eye in androgen-deficient individuals.
Whether this approach is useful may soon be determined by Allergan, which
is currently testing in clinical trials in the USA and Europe the
efficacy of topical androgens for the treatment of dry eye.
--------------------------------------------------------------------------
1 Schepens Eye Research Institute and Department of
Ophthalmology. Harvard Medical School, Boston, Ma, USA.
E-mail: sullivan@vision.eri.harvard.edu
Acknowlegments:
Research cited in this editorial was supported in part by grants
from United States National Eye Institute [NIH grants EY05612 & 12523],
Allergan [USA and Japan], the German Research Society DFG, the
Sjogren's Syndrome Foundation, the Massachusetts Lion's Research Fund, the
Joint Clinical Research Center of the Schepens Eye Research Institute and
the Massachusetts Eye & Ear Infirmary, and the General Clinical Research
Center at the University of Chicago Medical Center Foundation).
REFERENCES
1. Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin SX et
al. Endocrine and intracrine sources of androgens in women: inhibition
of breast cancer and other roles of androgens and their precursor
dehydroepiandrosterone. Endocr Rev 2003; 24: 152-182.
2. Lemp MA. Report of the National Eye Institute/Industry
workshop on Clinical Trials in Dry Eyes. CLAO J 1995; 21: 221-232.
3. Shimazaki J, Sakata M, Tsubota K. Ocular surface changes and
discomfort in patients with meibomian gland dysfunction. Arch Ophthalmol
1995; 113: 1266-1270.
4. Sullivan DA, Belanger A, Cermak JM, Bérubé R, Papas AS,
Sullivan RM et al. Are women with Sjögren's syndrome androgen-deficient? J
Rheumatol 2003; 30: 2413-2419.
5. Sullivan DA. Tearful relationships? Sex, hormones and
aqueous-deficient dry eye. Ocular Surface 2004; in press.
6. Sullivan DA, Sullivan BD, Evans JE, Schirra F, Yamagami H, Liu
M et al. Androgen deficiency, Meibomian gland dysfunction and
evaporative dry eye. Ann N Y Acad Sci 2002; 966: 211-222.
--------------------------------------------------------------------------------
© 2005 Sociedad Española de Oftalmología
How to cite this article
EDITORIAL
--------------------------------------------------------------------------
DEFICIENCIA ANDROGÉNICA Y SÍNDROMES DE OJO
SECO
ANDROGEN DEFICIENCY & DRY EYE SYNDROMES
DAVID A. SULLIVAN, Ph. D1
Sex steroid deficiency has been linked with the development
and/or progression of a wide variety of clinical disorders, including
cardiovascular disease, obesity, osteoporosis, insulin resistance and certain
cancers (1). We hypothesize that sex steroid deficiency, specifically
that of androgens, may also be a critical etiologic factor in the
pathogenesis of dry eye syndromes.
Dry eye syndromes are a leading cause of patient visits to
ophthalmologists and are classified into two major types: aqueous-deficient
and evaporative (2). Aqueous-deficient dry eye is due to a lack of
aqueous tear secretion by the lacrimal glands. An example is Sjögren's
syndrome, an autoimmune disease that afflicts predominantly women. This
disorder is associated with extensive inflammation in lacrimal tissue, an
immune-mediated dysfunction and/or destruction of acinar and ductal
epithelial cells, and a precipitous decline in aqueous tear output.
Sjögren's syndrome may be either primary (i.e. no associated connective tissue
disease) or secondary [e.g. individuals with systemic lupus
erythematosus (SLE) or rheumatoid arthritis (RA)]. The second type of dry eye is
termed evaporative and is most often caused by meibomian gland
dysfunction and lipid insufficiency, thereby promoting increased evaporation and
reduced stability of the tear film. This form of dry eye is also
observed in Sjögren's syndrome, as well as during menopause and aging.
Researchers have estimated that meibomian gland disease may be a contributing
factor in over 2/3 of all dry eye patients (3).
The rationale for our hypothesis linking androgen deficiency with
dry eye syndromes is two-fold:
First, androgens regulate numerous aspects of the lacrimal gland,
including epithelial cell morphology, gene expression, protein
synthesis, secretory processes and immune function. Indeed, androgen action
appears to account for many of the sex-related differences that exist in
the anatomy, molecular biology, physiology and immunology of this
tissue. However, women with Sjögren's syndrome have an androgen deficiency
(4), and this hormone deficit may predispose to lacrimal gland
dysfunction, decreased tear secretion and aqueous-deficient dry eye. Consistent
with this hypothesis is the finding that androgen treatment of female
mouse models of Sjögren's syndrome causes a dramatic suppression of the
inflammation in, and a significant increase in the functional activity
of, lacrimal glands. Similarly, androgen therapy has been reported to
alleviate dry eye signs and symptoms, and stimulate tear flow, in
Sjögren's syndrome patients. The mechanism by which androgens suppress
lacrimal gland autoimmune disease appears to involve hormone binding to
nuclear receptors within epithelial cells and a consequent alteration in the
activity of specific genes and proteins in lacrimal tissue (5).
Second, the meibomian gland, like other sebaceous glands, is an
androgen target organ. Androgens control the development,
differentiation and lipid production of sebaceous glands throughout the body.
Similarly, androgens appear to regulate meibomian gland function, improve the
quality and/or quantity of lipids produced by this tissue and promote
the formation of the tear film's lipid layer. These hormone effects
appear to be mediated through androgen receptors within epithelial cell
nuclei and to involve the modulation of multiple genes, including those
related to lipid, sex steroid and other cellular metabolic pathways.
Conversely, androgen deficiency, such as occurs during menopause (decline
in secretion of ovarian androgens and adrenal androgen precursors),
aging in both sexes (decrease in the total androgen pool), autoimmune
disease (e.g. Sjögren's syndrome, SLE, RA), complete androgen insensitivity
syndrome (i.e. women with dysfunctional androgen receptors) and the use
of anti-androgen medications (e.g. for prostatic hypertrophy or
cancer), is associated with meibomian gland dysfunction, tear film instability
and a significant increase in dry eye signs and symptoms.
Androgen-deficient people also have a higher frequency of metaplasia of the
meibomian gland orifices and a reduced quality of meibomian gland secretions,
as well as significant alterations in the neutral and polar lipid
profiles of their meibomian gland secretions (i.e. relative to those of
normal male and female controls). This association between androgen
deficiency, meibomian gland dysfunction and evaporative dry eye may help to
explain why topical or systemic androgen treatment has been reported to
help restore intraglandular lipid patterns toward normal in
androgen-deficient animals, stimulate the production and secretion of meibomian
gland lipids, prolong the tear film breakup time and to decrease the signs
and symptoms of dry eye in women and men (6).
Overall, research indicates that androgen deficiency may be a
critical etiologic factor in the pathogenesis of aqueous-deficient and
evaporative dry eye syndromes during menopause, aging and certain
autoimmune diseases. Given these observations, it is possible that efforts
directed at alleviating the endocrine imbalance in ocular surface tissues
may prove beneficial as a therapy for lacrimal and meibomian gland
dysfunction and the associated dry eye in androgen-deficient individuals.
Whether this approach is useful may soon be determined by Allergan, which
is currently testing in clinical trials in the USA and Europe the
efficacy of topical androgens for the treatment of dry eye.
--------------------------------------------------------------------------
1 Schepens Eye Research Institute and Department of
Ophthalmology. Harvard Medical School, Boston, Ma, USA.
E-mail: sullivan@vision.eri.harvard.edu
Acknowlegments:
Research cited in this editorial was supported in part by grants
from United States National Eye Institute [NIH grants EY05612 & 12523],
Allergan [USA and Japan], the German Research Society DFG, the
Sjogren's Syndrome Foundation, the Massachusetts Lion's Research Fund, the
Joint Clinical Research Center of the Schepens Eye Research Institute and
the Massachusetts Eye & Ear Infirmary, and the General Clinical Research
Center at the University of Chicago Medical Center Foundation).
REFERENCES
1. Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin SX et
al. Endocrine and intracrine sources of androgens in women: inhibition
of breast cancer and other roles of androgens and their precursor
dehydroepiandrosterone. Endocr Rev 2003; 24: 152-182.
2. Lemp MA. Report of the National Eye Institute/Industry
workshop on Clinical Trials in Dry Eyes. CLAO J 1995; 21: 221-232.
3. Shimazaki J, Sakata M, Tsubota K. Ocular surface changes and
discomfort in patients with meibomian gland dysfunction. Arch Ophthalmol
1995; 113: 1266-1270.
4. Sullivan DA, Belanger A, Cermak JM, Bérubé R, Papas AS,
Sullivan RM et al. Are women with Sjögren's syndrome androgen-deficient? J
Rheumatol 2003; 30: 2413-2419.
5. Sullivan DA. Tearful relationships? Sex, hormones and
aqueous-deficient dry eye. Ocular Surface 2004; in press.
6. Sullivan DA, Sullivan BD, Evans JE, Schirra F, Yamagami H, Liu
M et al. Androgen deficiency, Meibomian gland dysfunction and
evaporative dry eye. Ann N Y Acad Sci 2002; 966: 211-222.
--------------------------------------------------------------------------------
© 2005 Sociedad Española de Oftalmología
Comment