OPTOMETRY

REVIEW I
What causes steroid cataracts? A review of
steroid-induced posterior subcapsular cataracts

Clin Exp Optom 2002; 85: 2: 61-75

Andrew I Jobling BScHons PhD
Robert C Augusteyn BScHons PhD
DipEd FVCO
National Vision Research Institute of
Australia
Accepted for publication: 7 February
2002
Prolonged use of glucocorticoids is a significant risk factor for the development of
posterior subcapsular cataract. This places restrictions on the use of glucocorticoids in
the treatment of systemic and/or ocular inflammatory conditions as well as in organ
transplantation.
The mechanisms responsible for the opacification are unknown and no effective treat-
ment, other than surgical removal of the lens, is available. Difficulties in establishing
suitable in vivo or in vitro models have limited research in this area. Nevertheless, sev-
eral mechanisms, based on observations with other types of cataracts, have been pro-
posed. In this review, these mechanisms are evaluated in light of the evidence available.
A novel mechanism is also proposed, in which steroids do not directly act on the lens
but rather affect the balance of ocular cytokines and growth factors.

Key words: cataract, growth factors, PSC mechanisms, steroids

The proper understanding of any biologi-
cal system is important, not only from a
pure knowledge viewpoint but also in pro-
moting the development of therapies to
combat disease. In this context, the visual
system has always been of special inter-
est, because of the importance of vision
for our interactions with each other and
our environment, yet there are still many
visual and ocular functions and disorders
that remain a mystery. Loss of lens trans-
parency, cataract, which is the major
cause of world blindness, is one of these.
The World Health Organisation has re-
cently estimated that cataract accounts
for 42 per cent of bilateral blindness in
the world, in more than 20 million peo-
ple. While the incidence of blindness due
to cataract is relatively low in developed
countries, it can be as high as 72 per cent
in the developing nations.
The condition was recognised as long as
6,000 years ago and many different theo-
ries and treatments have been offered,
tested and abandoned. However, we are no
closer to understanding the changes in the
lens, which lead to this most common vi-
sion disorder, nor do we have any effective
non-surgical treatments. Epidemiological
studies and clinical observations have iden-
tified a large number of possible risk fac-
tors for cataract, ranging from the absurd,
such as marital status or educational level,
to the more credible, such as cigarette
smoking or U V exposure. Aging is the most
common risk factor, accounting for 75 per
cent of cataracts. Other significant risk fac-
tors include myopia, diabetes and the long-
term use of steroids. (General reviews on
cataracts by Ohrloff, Hockwin and Muller-
Breitenkamp*and Hardingl and a specific
review on steroid cataract by Urban and
Cotlier4 are recommended for further
information).
Several mechanisms have been pro-
posed for the changes leading to lens
opacification. These are listed in Table 1
together with brief summaries of their
major features. Each has been invoked to
explain every form of cataract observed to
date, but none provides a satisfactory ex-
planation of cataract development with
increasing age or offers hope for the de-
velopment of prophylactic measures. The
situation could be different for steroid-
induced cataracts because the specific ini-
tiating agent is known but too little defini-
tive research has been done on possible
mechanisms. Nevertheless, several theo-
ries have been advanced.

Clinical and Experimental Optometry 85.2 March 2002

61
Steroid cataracts Jobling and Augustqn
Osmotic Failure of osmotic regulatory systems due to Na,K-ATPase inactivation,
increased membrane leakiness or increased osmolality, gives rise to
localised water accumulation and refractive index fluctuations, which
produce light scatter.
Oxidative Free radical damage, especially by oxygen radicals, is caused by
increased radical production, antioxidant shortage or protective
mechanism failure. Membrane and protein damage follows.
Protein modification Oxidation, covalent addition of metabolites or other small molecules,
proteolysis and/or alterations in the environment produce conforma-
tional changes which lead to denaturation, aggregation and
insolubilisation of the lens proteins.
Metabolic disturbance Inadequate energy production, altered protein synthesis cytokine
fluctuations can lead to breakdown in protective mechanisms, including
ion pumps and antioxidant pathways, and prevent proper cell matura-
tion.
Table 1. Universal theories for cataract formation
Figure 1. Red reflex slitlamp photograph of
a steroid-inducedPSC. Notice the granular
appearance on the right side of the lens.
subcapsular cataract (PSC) (Figure 1).
STEROID CATARACT
The steroid-induced cataract appears bi-
The relationship between steroid use and laterally and is distinguishable from the
cataract was first noted by Black and col- more common types of cataract. OglesbyG
leagues in 1960.3In a study of 44 rheuma- described the clinical features of the cata-
toid arthritis sufferers, they observed that ract in a subsequent paper.
39 per cent of those who had been on sys- 'The characteristic cataract in these patients
temic steroid therapy developed posterior occupied the polar region of the postm'or cor-
Clinical and Experinlentdl Optometry 85.2 March 2002
62
tex, just within the posterior capsule, sometimes
apparently invading it and usually obliterat-
ing the postm'or zone of disjunction; it ex-
tended forward into the cortex in an irregular
fashion. Its borders were usually sharp, but
occasionally surrounded by a faint grey haze.
The fine structure consisted of tiny whitish-
yellow crystalline opacities separated by equally
small vacuoles, together appearing as a granu-
lar conglomerate, which occasionally showed
linear markings or a few larger vacuoles.
Iridescent blue, green, or red particles appeared
frequently within the mass.'
Black and colleagues5 noted a definite
dose dependent effect: the higher the ster-
oid dose, the greater the prevalence of
PSC. Also, it was observed that PSC devel-
oped only after a patient had been on high
dose steroid treatment for longer than one
year, whereas those on doses of less than
10 mg/day of prednisone or equivalent
were unlikely to develop lenticular
changes.
Since this report, numerous studies have
been made of patients with diseases such
as rheumatoid arthritis and asthma, as well
as renal and kidney transplant recipients.
All found a link between systemic steroid
use and PSC de~elopment,"'~ convincingly
refuting some early studies to the con-
t r a ~ y . ' ~The
, ' ~ direct link between steroids
and PSC is now generally accepted. How-
ever, the dosedependent nature of these
cataracts is more controversial, with some
researchersI6'* confirming Black and col-
leagues' ob~ervations,~ while others have
observed no relationship between dosage
and either the incidence or severity of
PSC.IS2'This has led some authors to sug-
gest that, while the dose of steroid is im-
portant, susceptibility of the individual or
genetic effects may also play a role in the
development of PSC.16.22
A 'safe' dose regimen of 10 mg/day
prednisone for one year was originally sug-
gested as a way of avoiding steroid-induced
PSC. However, because of the variability
in the responses of individuals to various
steroids, there can be no really 'safe' dos-
age. Regular ophthalmic examinations
would seem to be prudent.
Cataract development is not restricted
to systemic steroid use. In 1963, Valerio2'
showed that topically applied steroids

HO
Figure 2. The structure of cholesterol showing the ring
designations and the numbering of carbon atoms
could also result in PSC. This was of par-
ticular interest to ophthalmologists and
optometrists, as topical steroids are widely
used in the treatment of anterior ocular
infectionsand trauma. Several studies have
confirmed this ob~ervation.~~ Inhaled
steroids, such as those taken for asthma,
have also been implicated in PSC forma-
tionZa3 but careful, long-term monitoring
of asthmatic patients is needed to evalu-
ate this possibility.
Steroid therapy can have a more pro-
nounced effect on children, with PSC de-
velopment occurring at a faster rate and
at a lower dosage than with ad~lts.,:~~For
example, PSC has been observed in young
patients after only six months of glucocor-
ticoid ~ e a t m e n t . ~
There have been reports of cataract re-
versal following cessation of the steroid
treatment, especially in ~hildren.~ How-
ever, these are rare and once vision has
been affected, complete resolution of the
opacity is ~ n l i k e l y . ~ ~ ~
The incidence of PSC in the population
in 1966 was estimated by Spaeth and von
Sallrnann to be 0.2 per cent in young
adults, rising to 0.6 per cent in the fifth to
sixth decades. This suggests that steroid-
induced PSC was of minor significance
around that time. However, the use of
glucocorticoids has since become much
more widespread and the incidence of
steroid cataracts is expected to rise as a
result. A 1985 Oxfordshire study found
I
28
cortisol
Figure 3. Natural (cortisol) and synthetic (dexamethasone)
glucocorticoids
that steroid therapy had become the
fourth leading risk factor for cataract for-
mation, with only diabetes, myopia and
glaucoma presenting greater risks.3 Ster-
oids were estimated to be responsible for
4.7 per cent of all cataracts removed in
Oxford.
The incidence of steroid-induced cata-
ract is expected to increase further as life
expectancy increases and more people
develop conditions that can benefit from
steroid therapy. To minimise the impact
on the quality of life in the elderly, treat-
ments have to be developed to prevent or
reverse cataract development. However,
this will only be possible when we have a
thorough understanding of the mecha-
nism involved in the cataract formation.
We are still a long way from achieving this
and substantial research is required. Un-
fortunately, very little research is being
conducted now on steroid cataracts
In this article, we examine possible rea-
sons for cataract formation associated with
prolonged steroid treatment. We will be-
gin with a brief overview of steroids and
attempts to establish model systems for
studying steroid cataracts. Thereafter, we
will consider possible mechanisms
whereby steroids generate cataract.
~~ ~ ~
STEROIDS
Steroids are widespread throughout the
animal and plant world, where they have
Clinical and Experimental Optometry 85.2 March 2002
63
Steroid cataracts Jobling and Augustqn
CI$OH CH20H
I
c= 0
I
c= 0
H* CH,
dexamethasone
a myriad biological functions. In animals,
they comprise five groups: progestagens,
androgens, estrogens, mineralocorticoids
and glucocorticoids. All are derived from
cholesterol (Figure 2) but they have dif-
ferent functions and are produced in dif-
ferent tissues. Progestagens are synthe-
sised in the corpus luteum, androgens and
oestrogens in the testis and ovary, respec-
tively, and mineralocorticoids and
glucocorticoids in the adrenal cortex.
(For more detailed descriptions, see
SchroepfeP and Harnm~nd.~)
The mechanisms by which steroids me-
diate alterations in normal cell function-
ing are complex in nature and, to date,
are not fully elucidated. It is probable that
steroids, being lipid soluble, passively dif-
fuse through the plasma membranes of
target cells. Once in the cell, they bind to
receptor complexes, which consist of one
or two specific receptor protein molecules
associated with a variety of other proteins.
One such complex, the glucocorticoid
receptor, will be discussed later. The vari-
ous molecules associated with the complex
are critical in mediating the binding of
steroid to the receptor and DNA, as well
as the translocation of the steroid-receptor
complex to the nucleus.
Binding of the steroid to its specific
receptor results in a conformational
(shape) change to the receptor, so that it
can now interact with DNA. The steroid-
containing complex then binds to specific
Steroid cataracts Jobling and Augusteyn
nucleotide sequences in the cell genome,
known as hormone responsive elements
(HREs). Subsequent interaction of the
hormone with nearby DNA regulatory
elements can increase or decrease the
transcription and expression of specific
genes. There may be many steroid HREs
on many genes and some may also be re-
sponsive to other hormones or affector
molecules.
GLUCOCORTICOIDS
The major naturally occurring glucocor-
ticoid is cortisol, also known as hydrocor-
tisone (Figure 3), but metabolic deriva-
tives, such as cortisone and corticosterone
also function as hormones. Their function
appears to be in stimulating gluconeogen-
esis, the production of glucose from non-
carbohydrate carbon sources such as
amino acids. This involves promoting the
catabolism of muscle proteins, increasing
the transport of amino acids into the cell
and stimulating the syntheses of gluconeo-
genic enzymes and trans-aminases. The
glucocorticoids also have some mineralo-
corticoid activity, promoting renal sodium
reten tion.
In addition, the glucocorticoids are very
powerful anti-inflammatory and immuno-
suppressive agents. This led to their intro-
duction by Hench and c o - w ~ r k e r sas~an
~ the derivatives and compares them with
effective treatment for rheumatoid arthri-
tis in 1949. Since then, they have been
widely used for controlling inflammation
in various tissues, including the eye.414In
more recent times, glucocorticoids have
become invaluable in helping to control
rejection of organs in transplant recipi-
e n t ~The. ~ ~choice of glucocorticoid de-
pends not only on the efficacy of its anti-
inflammatory action but also on its
mineralocorticoid activity, which, unless
controlled, can result in unwanted side
effects.
The recognition of the potential ben-
efits of glucocorticoids and the subsequent
demand for reliable supplies stimulated
the production of synthetic glucocorti-
coids. Although the mechanisms of glu-
cocorticoid actions were not understood,
chemical modification allowed the genera-
tion of derivatives with improved anti-
Clinical and Experimental Optometry 85.2 March 2002
Drug Relative Equivalent Mineraiocorticoid
anti-inflammatory dose (mg) potency relative to
potency Hydrocortisone
Hydrocortisone 1 20 1
Prednisone 4 5 0.8
Cortisone 0.8 25 0.8
Prednisolone 4 5 0.8
Methylprednisoione 5 4 0.5
Triamcinolone 5 4 0
Paramethasone 10 2 0
Betamethasone 25 0.6 0
Dexamethasone 25 0.75 0
Table 2. Relative properties of some anti-inflammatory gluco-
corticoids*
* Taken from Hammondsg
inflammatory properties and reduced Models for steroid cataract
mineralocorticoid activity. In particular, One of the most useful tools in biological
introduction of a second double bond in research is an animal model and, because
Ring A (Figure 2) and substituents on car- of this, in the past significant resources
bon atoms 9 and 16 substantially altered were directed towards inducing steroid
the biological effects. Table 2 lists some of PSC in laboratory animals. Attempts to
induce such cataracts have been based on
the natural glucocorticoids. Of particular the assumption that steroids act directly
note are the synthetic glucocorticoids, on the lens. These attempts have been
betamethasone and dexamethasone largely unsuccessful.
(Figure 3), which have very high anti- In 1960, von Sallmann and colleagues5r
inflammatory activity and little mineralo- injected rats daily with dexamethasone for
corticoid activity. They provide much more 16 weeks but found no indications of lens
effective alternatives to the naturally opacification. No opacities were observed
occurring hydrocortisone. by Spencer and Andelman,5*after treat-
Adverse effects, including several ocu- ing rats for 16 weeks with triamcinolone
lar manifestations, may result from gluco- acetonide or by B e t ~ n a n , 5who
~ . ~exposed
~
corticoid use.36These are summarised in chickens to prednisolone. A major com-
Table 3. Prolonged steroid use can lead plicating factor in all these studies was the
to diabetes and its ocular complications high number of deaths due to the large
as well as elevation of intraocular pressure, steroid doses employed. Wood and co-
which can lead to optic nerve damage and w o r k e r ~observed
~~ anterior subcapsular
visual field changes.4M8 Reactivation of the cataracts in rabbits after topical applica-
herpes simplex virus is a common second- tion of steroids, three times daily for a six-
ary effect of steroid treatment,49as is a re- month period. Cortisone was the most
duction in corneal wound healing.50How- potent, while dexamethasone and pred-
ever, most common is the development of nisolone were the least. However, since the
posterior subcapsular catara~t."~ cataracts occurred in the anterior subcap
64
 Steroid cataracts Jobling and Augustqrn

sular area, they could hardly be considered

COMPLICATION MORE COMMON suitable as models for the human poste-
VEHICLE
rior subcapsular cataracts.
Gastrointestinal Oral or intravenous Only a small number of investigatorshas
gastritis ulcers succeeded in producing posterior subcap
visceral perforation sular cataract in laboratory animals.
pancreatitis
Tarkkanen and co-workerP observed PSC
nausea
increased appetite after 41 weeks subconjunctival injection of
betamethasone in two of four rabbits that
Central nervous system Oral or intravenous
headache survived out of an original cohort of seven.
convulsions However, from week 28, the rabbits devel-
pseudotumour cerebri oped diabetes, which may have been re-
psychiatric disturbances: anxiety, psychosis sponsible for the cataract formation.
Cardiovascular Oral or intravenous Bucala and colleagues58also succeeded in
hypertension producing steroid-induced PSC in rabbits
Ophthalmological Topical or oral by intravitreal injection of glucocorticoids.
glaucoma The lenticular effects were observed at
herpes simplex keratitis activation concentrations as low as 2x104 M and de-
posterior subcapsular cataracts veloped 48 to 72 hours after the injection.
central serous retinopathy
The opacities were said to be similar in
fungal or viral infection
appearance to those observed in human
Renal Oral or intravenous arthritis sufferers, as reported in the origi-
sodium retention, potassium loss
nal Black and colleagues study. N o fur-
hypokalaemic alkalosis
fluid retention ther investigations appear to have been
conducted by these authors and their
Murculoskeletal Oral or intravenous
distal wasting and weakness observations have not been reproduced
myopathy elsewhere.
osteoporosis Cataract can also be induced in the
fractures chicken, mouse, rabbit and rat foetus by
aseptic necrosis of the femur prenatal administration of glucocortic-
tendon rupture
o i d ~However,
. ~ ~ ~this is unlikely to be of
Metabolic Oral or intravenous any relevance to human postnatal steroid-
glucose intolerance induced cataract. The opacities are neither
hyperosmolar nonketotic coma
hyperlipidaemia posterior nor subcapsular but appear as
obesity supranuclear rings before engulfing the
nucleus. Furthermore, in the chick em-
Endocrine Oral or intravenous
retardation of growth in children bryo, the opacity forms 24 hours after a
secondary amenorrhoea single injection of glucocorticoid and dis-
hypothalamic-pituitary axis suppression appears 72 hours later. The transitory na-
Cushingoid state ture of this cataract makes it unlike true
glucose intolerance
steroid cataracts, which are very rarely, if
General Oral or intravenous ever, reversible.
weight gain Similar difficulties have been encoun-
hirsutism
tered in attempts to establish in nitro model
decreased wound healing
increased sweating systems, even when very high concentra-
easy bruisability tions of steroid are used. Sivak and col-
subcutaneous tissue atrophy leaguestismaintained bovine lenses in me-
increased bacterial, viral and parasitic infections dium containing 3x10. M prednisone for
three weeks. Examination with an auto-
Table 3. Complications associated with glucocorticoid treatment * mated scanning laser revealed no altera-
* Taken from Rubm and Palestine tion in focal characteristics or light scat-
ter of the lens. N o opacities were observed
by Haddad, Furman and Bella Shoreti4
after an eight-day incubation of bovine

Clinical and Experimental Optometry 85.2 March 2002

65
Steroid cataracts Jobling and Augustqrn
lenses with 1O'M methylprednisolone
acetate. By contrast, Miller, Tijerina and
Maymad5 reported cortical changes in
bovine lenses incubated for three days with
104M dexamethasone-21-phosphate. How-
ever, the changes did not resemble those
of the human steroid PSC, but were simi-
lar to those found when the lens was incu-
bated with ouabain, a potent Na+,K+-AT-
Pase inhibitor. Rat lenses maintained in a
medium containing methyl prednisolone
developed opacities within 48 hours of
exposure,66but these were similar to the
ring cataracts observed in embryonic
lenses.62
So far, it has not been possible to de-
velop a reliable model system, animal or
isolated lens, suitable for the study of
steroid-induced PSC. Cataract induction
in vivo is difficult and seems to depend not
only on the specific glucocorticoid used
but also on the schedule, dosage, vehicle
used for administration and the animal
species. Even when lenses are exposed
directly to high concentrations of steroids,
it has proved difficult to generate opaci-
ties similar to those seen in humans. Be-
cause of these difficulties, research on the
mechanism of steroid cataracts has flagged
in recent years. Only limited information
on the possible molecular events during
cataract formation has been obtained from
laboratory studies with isolated lens con-
stituents and much of this is contentious.
Nevertheless, several molecular explana-
tions have been offered for the mechanism
of steroid cataract formation. We will ex-
amine each of these theories. Thereafter,
we will explore the increasingly more at-
tractive possibility that steroids do not di-
rectly affect the lens to generate cataract.
Metabolic disturbances
Glucocorticoids can impact on cellular
metabolism by interacting directly with
enzymes, to alter their activities, or
through receptor-mediated pathways to
change the amount of enzyme being syn-
thesised by the cell. The receptor will be
discussed in detail later.
Many metabolic effects are exerted on
enzymes involved in carbohydrate metabo-
lism and, in particular, gluconeogenesis.
For this reason a number of investigations
Clinical and Experimental Optometry 85.2 March 2002
has concentrated on the metabolic effects
of glucocorticoids in the lens. Unfortu-
nately, a plethora of contradictory results
makes it difficult to come to any signifi- glucose uptake have been observed in
cant conclusions. This may, in part, be due
to the use of animals and tissues of vari-
ous ages. It has been reported that
glucocorticoids affect lens metabolism
only in young lenses.67
Both increases and decreases have been
reported for the same enzymes and meta-
bolic intermediates and the effects vary
with the steroid. For example, lactate de-
hydrogenase levels appear to increase with
dexamethasone treatment, yet remain
unaffected by hydroc~rtisone.~~ Hexoki-
nase activity was found to be unaltered by
glucocorticoids in one but inhib-
ited in other^.^^.^^ Glucose-&phosphate
dehydrogenase (GGPDH), a key enzyme
in the pentose phosphate shunt, is
inhibited by hydroc~rtisone,~~ but not by
prednisolone, d e x a ~ n e t h a s o n eor . ~ ~ Jobling and A ~ g u s t e y nfound
~ ~beta-
metha~one.~ Some
' of the differences
could be explained by the specificity of
interactions, but most appear to reflect
differences and difficulties in experimen-
tal procedures. For example, the epithe-
lium where most metabolic activity is lo-
cated represents a very small proportion
(less than one per cent) of lens mass. This
makes it very difficult to identify specific
changes in the epithelium when using
whole lenses. Culturing epithelial cells can
overcome this problem but may result in
uncharacteristic responses.
Phosphorus-31 NMR studies have re-
vealed that ATP and dinucleotide levels in
the lens decrease following a 24hour ex-
posure to d e ~ a m e t h a s o n e This
. ~ ~ would
impact on the tissue's ability to perform
energydependent processes, such as pro-
tein synthesis and ion transport, as well as
the ability to maintain antioxidant protec-
tive mechanisms. By contrast, other phos-
phate complexes, such as sugar phos-
phates, inorganic orthophosphates and
nucleoside diphosphorylsugars have
shown glucocorticoid-inducedincreases.72
What this might mean is not obvious at
present. The overall apparent effect of
glucocorticoids on lens organophosphates
observed by Greiner, Kopp and G10nek'~ Osmotic failure
led them to suggest that steroids may
66
mediate their effects via the antagonism
of lens glucose uptake or utilisation. Such
glucocorticoid induced decreases i n
other tissue^.'^^^^ However, Jobling and
Augusteyn" found that neither dexam-
ethasone nor prednisolone had any effect
on glucose uptake by cultured bovine lens
epithelial cells.
The protein synthetic machinery of the
lens also may be altered by glucocorticoids.
This occurs in other tissues due to the ster-
oid limiting the peptide chain initiation
step.76Friedburg, KrBner and Rosenstei17?
observed a decrease in lens protein syn-
thesis in the presence of &methyl pred-
nisolone acetate. However, van Venrooij,
Groeneveld and B l ~ e m e n d anoted
l ~ ~ that
dexamethasone, while causing a definite
change in cellular morphology, did not
affect the amount of protein synthesised
or the nature of the proteins produced.
~ ~ no altera-
tions in synthesis levels or patterns in cul-
tured epithelial cells exposed to dexam-
ethasone or prednisolone.
Glucocorticoids can have significant ef-
fects on cell growth and DNA/RNA syn-
thesis.79Such alterations have been ob-
served in ocular cells, with some cells, such
as retinal endothelial cells, showing growth
inhibition, while others seem to be stimu-
lated by glucocorticoids.w2 Lens epithe-
lial cells may also be under glucocorticoid
control, with decreases reported in RNA/
DNA synthesisR3and cell How-
ever, this was disputed by van Venrooij,
Groenveld and Bl0emenda1,~~who saw no
effect of dexamethasone on DNA synthe-
sis in cultured bovine capsule-lens epithe-
lium. Jobling and Augu~teyn?~ reported
the same for cultured bovine lens epithe-
lial cells.
It is difficult to come to any clear con-
clusions about the effects of glucocortic-
oids on lens metabolism, because of the
variability of the published observations.
Perhaps there are no significant effects
and the differing observations simply re-
flect the difficulties in performing these
experiments.
The appearance of intercellular clefts,
 Steroid cataracts Jobling and Augustqrn

/ oxidtion

Figure 4. Pumpleak model for maintenance of ionic balance in
the lens. K+ions diffuse out of and Na' ions into the lens. They
are pumped in or out again, respectively, by the Na+,K+-ATPase
located in the anterior epithelium. Inhibition of the pump or
increased ion fluxes due to membrane damage will lead to Na'
and water accumulation and cataract.
Figure 5. Universal mechanism for cataract formation.
Conformational changes in lens proteins (unfolding), due to a
variety of factors, can expose thiol groups, which become oxidised
to disulphides. This, together with non-specific hydrophobic
interactions,is believed to generate large protein aggregates that
scatter light.

vacuoles and swollen cells in some steroid
cataracts has led to the suggestion that
there may be glucocorticoid-induced al-
teration in lens hydration. However, again,
the data are less than convincing.
As with other tissues, the lens maintains
ion differentials between the intra- and
extracellular fluids (high K+and low Na',
internally; low K , high Na', externally)
via the action of the sodium-potassium ad-
enosine triphosphatase, Na+,K-ATPase
(Figure 4;for a review of the Na+,K+-AT-
Pase pump, the reader is directed to an
article by Skoun5).The maintenance of
ionic balance has been shown to be cru-
cial for lens transparency and alterations
in the ionic composition of the lens have
been associated with ~ a t a r a c t . ~ ~ Saltera-
uch
tions could arise from failure of the AT-
Pase pump or from increased membrane
permeability.
Early reports on the effects of steroids
on lens ion levels were equivocal. In 1962,
Harris a n d GruberH8reported that
glucocorticoids made the rabbit lens more
'leaky', allowing more Na' to enter. Some
of the effects were observed at very high,
non-physiological concentrations of ster-
oid (greater than 10-3M)and could be due
to the disruption of the lipid bilayer
through the incorporation of the hydro-
phobic steroid molecules. Intravitreal in-
jection of 6methyl-prednisolone acetate
(final concentration approximately 104M)
in guinea pigs has been found to produce
variable alterations in ion levels."
Glucocorticoid-induced modulation of
the Na+,K'-ATPase has been observed in
many tissues. For example, prednisolone
inhibits the activity in the choroid plexus:9
while dexamethasone appears to activate
the pump in rat kidney.9"This latter effect
is probably due to effects on gene expres-
sion, mediated through the glucocorticoid
receptor?' Mayman, Miller and TijerinaW
in 1979 reported an 80 per cent inhibi-
tion of calf lens Na+,Kt-ATPaseby 10"M
dexamethasone. This can be attributed to
a direct effect of the dexamethasone on
the pump, because the decrease in activ-
ity occurs long before any new protein
could be synthesised.93 The inhibition
showed a dose dependence similar to that
of ouabain, a potent Na+,K-ATPaseinhibi-
tor and resulted in a reduction in light
transmission by the lens.
By contrast, there are several reports
indicating steroids d o not influence lens
ion levels. T h e steroid derivative, 9-a-
fluorohydrocortisone, which is known to
have considerable impact on ionic flow in
the kidney, has no effect on the lens. Topi-
cal betamethasone does not alter the
pump as measured via H6Rbuptake.y4(Rb
can replace Kand be pumped into the lens
epithelium by the Na+,K-ATPase). Simi-
larly, several steroids, including pred-
nisolone hemisuccinate and dexametha-
sone produced n o alteration in n6Rb
uptake by isolated lenses, even at concen-
trations as high as 10" M.y5,96
Whether steroids can inhibit lens Na+,K'-
ATPase activity remains to be established.
However, in the absence of a clearly iden-
tifiable effect, it seems unlikely that this is
responsible for cataract. Furthermore, the
morphology of the steroid cataract, with
its localised light scatter, is unlike that of
osmotic cataracts, which are characterised
by the presence of water clefts and light
scatter throughout the lens.

Clinical and Experimental Optometry 85.2 March 2002

67
Steroid cataracts Jobling and Augusteyn

Oxidation/conformational could contribute to the development of

change the disease. Lens protein adducts have
The most commonly offered explanation been implicated in cataracts associated
for development of any type of cataract, with diabetes (reducing sugars), renal fail-
the 'universal' cataract mechanism, is that ure (cyanate, generated from urea) and
conformational change, due to some form ageing (photo-oxidation products) .'04-'06
of stress (oxidative, osmotic, metabolic), They have also been invoked as the cause
makes lens proteins susceptible to of steroid cataract.
oxidative modification. This is postulated Bucala, Fishman and CeramilO' discov-
to result in disulphide bond formation, ered that steroids, containing both a G20
pigmentation and other oxidative change carbonyl and a G21 hydroxyl group, could
as well as the generation of non-specific react with proteins to form stable adducts.
hydrophobic interactions to produce large The reaction involves formation of a Schiff
protein aggregates,which scatter light and base between amino groups in the protein
become insoluble (Figure 5). and the G20 carbonyl bond of the ster-
The oxidation explanation has been in- oid. This is followed by a Heyns rearrange-
voked for steroid cataracts, based on the ment involving the G21 hydroxyl group
idea that glucocorticoids may affect the to form a stable ketoamine product
activities of mechanisms involved in pro- (Figure 6).
tection of the lens from oxidative stress. The steroid-protein adduct reaction is
The lens contains a variety of such protec- very slow and follows first order kinetics.
tive mechanisms, including the glutath- Therefore, for a n y significant modification
ione/glutathione reductase and free
radical scavenging systems.y7Some inves-
to take place, the target proteins must be
long-lived and at high concentration. I ?
+I
M
tigators have reported decreases in the These criteria are met in the lens, leading
Lysirs f-amlrm
levels of the antioxidants, glutathione and to the suggestion that steroid adducts may
ascorbic acid, in both the lens and the accumulate and contribute to the cataract
aqueous humour, followingglucocorticoid development. The 'universal' mechanism
treatment62~y6*yRbut others have found no for cataract formation has been invoked
effect.55Loss of GSH is observed whenever to explain the subsequent opacification
the lens is stressed, in uztro or in uiuo. process, that is, the formation of steroid-
Whether the observed decrease (20 per protein adducts result in an alteration in
cent in uitro,9651 per cent in uiuo ") is re- normal protein structure (conformational Figure 6. Formation of steroid-protein
sponsible for steroid cataract remains to change), thus exposing sulphydrylgroups, adduct. The amino group in the side chain
be established. Increased lipid peroxide which are subsequently oxidised to form of lysine in the protein reacts with the ketone
has been reported in the chick embryonic intermolecular disulphide bonds. The group at carbon-20 in the steroid to form a
lens but this is probably not relevant to disulphide bonds as well as non-specific Schiff's base. The reaction is reversible but
the human condition.w Interestingly, the hydrophobic interactions are postulated becomes irreversible following a Heyns
free radical scavengers vitamin E66and to result in the formation of high molecu- rearrangement. This generates a new
N-( 2-mercaptopropionyl) glycineloOare lar weight aggregates that become insolu- aldehyde group that can react with another
known to slow steroid-induced alterations ble and produce light scatter. amino group to form a second Schiffs base.
but how they act is unclear. Some support for this idea comes from This reaction can result in crosslinking of
the observations that in uitm exposure of protein molecules.
Protein adduct formation rat and rabbit lenses to steroids results in
The nonenzymatic addition of small mol- adduct formation and o p a c i f i c a t i ~ n . ~ ~ ~ ~ ~ ~
ecules to proteins (generating protein The opacities observed in the rabbit were
adducts) is frequently observed, especially very similar to those seen in humans by
in disease.'0'J02The reaction of glucose Black and colleague^.^ Prednisolone and
with haemoglobin A to produce the modi- cortisol adducts generated in the lens were
fied haemoglobin Alc is an example of insoluble~lOsJw whereas dexamethasone
such an addition and can be used to moni- adducts are soluble.5RIncubation of iso-
tor the progress of diabetes.lo5The addi- lated rabbit lens proteins with pred-
tion of small molecules can alter the func- nisolone has been reported to generate
tion or properties of a protein and this disulphide linked, high molecular weight

Clinical and Experimental Optometry 85.2 March 2002

68
 Steroid cataracts Jobling and Augustqrn

Receptor mediated effects

Glucocorticoid effects on some cellular
activities are mediated through the gluco-
corticoid receptor, a cytosolicprotein com-
plex that binds the steroid and translocates
it to the nucleus. A diagram illustrating
the translocation mechanism is shown in
Figure 7."' Establishing if such a receptor
is in the lens is critical in evaluating the
mechanism responsible for steroid-
induced PSC. Observations in one labora-
tory have indicated that such a receptor is
Figure 7. The glucocorticoid receptor complex, which is found found in the lens and other ocular tissues
in the cytoplasm of the cell, consists of one molecule of receptor but other laboratories have been unable
protein (GR) associated with several other proteins including two to reproduce these observations.
molecules of hsp90 and one of p59. On binding of steroid, the It was reported by Weinstein and co-
complex dissociates, the receptor protein plus steroid forms a workers112.115 in the 1970s that several ocu-
dimer and this dimer translocates to the nucleus, where it binds lar tissues, including retina, iris-ciliary
to specific hormone responsive elements in the genomic DNA. body, outflow pathway and sclera exhib-
This modifies the expressionof specific genes and the subsequent ited glucocorticoid binding and cellular
synthesis of protein on the ribosomes. (Adapted from Muller and localisation consistent with the presence
Renkawitz"') of a glucocorticoid receptor. In 1978,
Southren and colleague^^'^ showed that
bovine lens epithelial extracts bound dex-
amethasone with high affinity (Kd =
8x1OY)and low capacity (550 fmoles/mg
protein). The steroid binding showed simi-
larities in temperature lability and com-
petition patterns to those of the classical
aggregates which scatter light.98However, tain insoluble steroid-protein adducts.Iog glucocorticoid receptors described in
and Jobling and Augusteynllohave shown It has been estimated that between 0.1 other tissue^."^ By contrast, bovine lens
that exposure of bovine lens proteins to and 1.34 millimoles of adduct per mole nuclear extracts exhibited saturable and
dexamethasone or prednisolone has no of polypeptide may be the pathological heat stable association of the steroid with
discernible effect on their solubility, level of adduct formation in the human protein. A later report from the same labo-
molecular weight, sulphydryl content or and result in PSC formation.5RIt is hard ratory presented autoradiographic data
conformation even though adducts were to understand how a maximum of only showing glucocorticoid binding and ap-
formed. It has also been reported that one adduct per 750 protein molecules parent localisation in the nuclei of cells in
opacities can be induced, in uitm or in uivo, could lead to large scale insolubilisation the anterior epithelium and bow regions
only if the steroid contains both the C-20 of the proteins. Much higher ratios would of the bovine lens,Il5again consistent with
carbonyl and G21 hydroxyl groups, which obtain if one assumed that the adduct is the behaviour of the classical receptor and
were considered to be necessary for located only in the region affected by the the accepted mechanism whereby gluco-
steroid-protein adduct f o r m a t i ~ n . ~ ~ ~ . "cataract,
' ~ ~ ' " ~ say one per cent of the lens, but corticoids regulate cell metabolism.
However, Dickerson, Dotzel and Clarkgfi even then the proposition is not compel- However, other observations indicate
and Jobling and Augusteynll" have ques- ling. Furthermore, it is even harder to un- that there is no receptor in the lens.
tioned these observationsand conclusions. derstand how adduct formation could be Tetrahydrocortisol, an inactive metabolite
Dickerson, Dotzel and ClarkMshowed that restricted to a small region of the lens and of cortisol, competes with dexamethasone
steroids lacking the C-21 OH group still to the posterior ends of the fibre cells to for the lens binding sitesIl5whereasit does
bound covalently to lens proteins, prob- produce the posterior subcapsular not for the glucocorticoid receptor.l16Tri-
ably through an amino group. Further- opacities. amcinolone, which is known to compete
more, they showed that non-glucocortic- There is no doubt that some steroids can for receptor sites,l"does not compete for
oids also bound to the proteins but did form adducts with lens proteins in uivo. the lens sites."5 The nuclear localisation
not cause opacities. However, it seems unlikely that this is of steroid, as described by Wenk and co-
Lenses from patients with steroid- responsible for gross alterations in lens worker~"~ was not observed in lens epithe-
induced PSC have been reported to con- proteins or in PSC. lial cells following intravenous administra-

Clinical and Experimental Optometry 85.2 March 2002

69
Steroid cataracts Jobling and Augustqrn

to anteriar chamber cell proliferation tion of dexamethasone.Il8 Recently,

f Jobling and Aug~steyn'~ showed that there
was very weak binding of dexamethasone
to soluble proteins, but this did not exhibit
the heat lability typical of receptor pro-
teins.
It was later shown that the binding was
due to non-specific interaction of steroid
with a-cry~tallin."~ Although receptor
mRNA can be detected in the
no receptor protein could be found using
specific antibodies.'lg
From the currently available data, it
would appear that there is no classical glu-
Figure 8. Lens architecture and growth: Nucleated and cocorticoid receptor in the lens, but that
metabolically active cells are found only in the anterior, equatorial non-specific binding of steroids can take
and bow regions of the lens. The majority of the tissue comprises place with some of the lens proteins. This
elongated fibre cells that lack cellular organelles, Growth factors, binding appears unlikely to have any physi-
such as FGF, in the aqueous humour induce proliferation and ological role.
migrationof anterior epithelialcells to the equatorialzone where
they differentiate into fibre cells. The fibre cells are gradually Aberrant cell behaviour
compressedinto the centre of the lens by new overlying cells and The lack of a glucocorticoid receptor and
lose their organelles in the process. the inconclusive observations on the ef-
@ epithelial cell cell migration fects of steroids on the lens have led us to
@growth factors + aqueous humour flow the idea that steroids may not act directly
on the lens to generate cataract.
One of the features of steroid cataract
appears to be the accumulation of undif-
ferentiated epithelial cells just under the
capsule at the posterior pole of the lens.
to anterbr chamber cell DrolNeratiin Such cells should be found only on the
f anterior surface of the lens mass. This sug-
gests that aberrant cell behaviour may be
involved in cataract formation. To explore
this possibility,some understanding of the
anatomy and growth of the normal lens is
required.
A simple diagram illustrating lens archi-
tecture and growth is presented in Figure
8. All lens cells are epithelial in origin.
They occur in two morphological forms,
'\
the cuboidal cells and the elongated fibre
\ undlfferentietedcells cells, reflecting two stages of cell develop-
ment. The cuboidal cells are found in a
Figure 9. Proposed mechanism for steroid cataract formation. single layer at the anterior surface of the
Reduced FGF levels and/or altered levels of other growth factors lens, directly underneath the capsule.
in the aqueoushumour,due to the effects of steroidson the ciliary They are nucleated and are the only ac-
epithelium, prevent the normal differentiation of epithelial cells tively dividing cells present in the lens.
into fibre cells. The undifferentiated cells are not packed into Apart from providing new cells, the epi-
the fibre cell mass but continue to migrate along the capsule past thelium accounts for almost all the meta-
the equatorial zone until they reach the posterior pole of the lens bolic activity required for normal lens
where they form irregular clumps of cells that scatter light. functioning. The only other nucleated and
epithelial cell cell migration metabolically active cells in the lens are
0 growth factors + aqueous humour flow those in the process of differentiating into

Clinical and Experimental Optometry 85.2 March 2002

70

fibre cells. These are located in the equa-
torial zone and bow region. The fibre cells,
which lack nuclei and cellular organelles
and are essentially metabolically dead,
constitute the vast bulk of the lens volume.
Lens growth takes place through prolif-
eration of the cuboidal epithelial cells and
continues throughout the life of the or-
ganism, slowing with age. As new cells are
formed near the equator, the adjoining
epithelial cells gradually migrate (or are
displaced) towards the equatorial regions
of the lens.Iz1Here, they undergo termi-
nal differentiation and elongation into
fibre cells, which are forced towards the
interior of the lens and compressed (Fig-
ure 8) as new cells are deposited over
them.Iz2The cells gradually lose their nu-
clei and all other intracellular organelles,
such as mitochondria, as they pass through
the bow region of the lens. Consequently,
the mature fibre cells lack the ability to
perform metabolic functions such as the
synthesis of proteins and production of
energy.
The proliferation and differentiation of
the epithelial cells are under the control
of growth factors present in the ocular
media that bathe the lens. McAvoy and
ChamberlainIz3in Sydney have identified
fibroblast growth factor-2 (bFGF) as a
major affector of lens growth and have
shown that there is a gradient of increas-
ing concentration of bFGF in the aqueous
humour from the anterior to the poste-
rior of the eye. This gradient is critical for
controlling lens cell behaviour. The low
bFGF concentration in the aqueous hu-
mour flowing over the anterior surface of
the lens is sufficient to stimulate epithe-
lial cell proliferation and migration (to-
wards the equator), while the higher con-
centrations around the equatorial region
will induce differentiation into fibre cells.
It is of interest to note that the vitreous
humour also contains high concentrations
of bFGF, which will cause differentiation
of anterior epithelial cells if the lens is re-
v e r ~ e d . ' ~More
~ . ' ~ recent
~ work has indi-
cated that there may be several other
growth factors, such as epidermal growth
factor (EGF), insulin-like growth factor
(IGF), platelet-derived growth factor
(PDGF), transforming growth factor
Clinical and Experimental Optometry 85.2 March 2002
(TGF-P) and other members of the FGF
family involved in these processes. The
sites where the growth factors originate
have not yet been established but they are
present in the aqueous humour and have
been localised in the ciliary epithelia.Iz6
Alterations in the complement of
growth factors impacting on the lens could
lead to aberrant cell behaviour and cata-
ract development. This is what one might
expect in a situation where the concen-
tration of FGF was not high enough to
stimulate differentiation of the epithelial
cells into fibre cells in the equatorial zone
or if differentiation were inhibited by an-
other cytokine. The undifferentiated cells
would continue to receive signals to mi-
grate and would pass through the equato-
rial zone. Eventually, the cells would end
up in the centre of the posterior pole,
where they would have maximum impact
on light scatter. It was shown by Hales and
co-worker~'~' that alterations in growth fac-
tors such as TGF-P will alter lens epithe-
lial behaviour and give rise to cataract-like
changes in capsular explants. Alternatively,
posterior lens cells could be induced to
create epithelial cells by retinal factors, as
shown by Coulombre and Coulombre in
their classic lens reversal experiments.lzZ
It is our hypothesis that steroid cataract
is due to an alteration in growth factors
reaching the lens and that this follows ster-
oid-induced alterations in the production
of these growth factors in other ocular tis-
sues. It is probable that the ciliary body is
the site of steroid action. The tissue pos-
sesses an extensive network of capillaries,
which ensures that systemic as well as topi-
cal steroids will be delivered to the site of
aqueous production, the non-pigmented
epithelium, where they can affect the syn-
thesis of proteins being produced for ex-
port. The epithelium contains a glucocor-
ticoid receptor and it is known to produce
a number of growth factors that are im-
portant for maintaining ocular tissues.
Production of these growth factors has
been shown to be affected by steroids. It
is proposed that steroids cause a reduc-
tion in the growth factors such as FGF,
which stimulate differentiation of lens
epithelial cells or an increase in growth
factors such as TGF-P, which inhibit this
71
Steroid cataracts Jobling and Augustqn
differentiation. When aqueous humour
containing the altered complement of
growth factors acts on the lens, prolifera-
tion and migration of anterior epithelial
cells occurs, as normal, but no differen-
tiation takes place in the equatorial zone.
As a result, cells are not incorporated into
the fibre cell mass but, instead, continue
their migration until they reach the pos-
terior pole of the lens, where they accu-
mulate forming clumps which scatter light.
The proposed mechanism is illustrated in
Figure 9.
Further work is required to establish if
this is the mechanism for steroid cataract
formation. If this turns out to be the case,
it may be possible to design drugs to
modify the ciliary body's response to ster-
oids and thereby prevent or reverse the
steroid cataract.
Possible drugs
As with most types of cataract, several sub-
stances have been investigated for their
ability to slow or halt steroid-induced PSC
formation.
Antioxidants and/or free radical scav-
engers are commonly believed to offer
protection from cataract, including those
due to steroids. Creighton and co-work-
ers&showed that vitamin E caused not only
a decrease in the incidence of steroid-
induced cataract in rats but also a decrease
in the severity of opacification. The im-
plied reason was that free radicals were
being scavenged by vitamin E, thus pre-
venting oxidative damage in the lens.
Whether this was due to a direct effect on
the pathway leading to steroid cataract
remains to be established. Nishigori and
co11eagues'"OJZR found that the free radi-
cal scavenger N-( 2-mercaptopropionyl)
glycine (MPG) as well as compounds such
as ascorbic acid and polyethylene glycol
delayed the appearance of glucocorticoid-
induced cataracts in chick embryos. How-
ever, as indicated earlier, the chick embry-
onic cataract is not a suitable model for
steroid cataract in mammals.
Aspirin (acetylsalicylic acid) has also
been proposed as a way of limiting steroid
induced opalescence.'" Aspirin is thought
to acetylate the lysine residues in lens pro-
teins, thereby preventing the binding of
Steroid cataracts Jobling and Augustqrn
glucocorticoids through their (2-20 carbo-
nyl bond and stopping the eventual disul-
phide bond formation and light scatter.
This type of protective effect has also been
suggested for other cataracts.i30However,
the justification of aspirin as a treatment
for any form of cataract has been ques-
tioned. It is highly unlikely that sufficient
aspirin can reach the lens without being
hydrolysed to salicylic acid. It is also highly
unlikely that lens proteins could remain
soluble following extensive loss of the
charged amino groups due to acetylation.
Furthermore, as mentioned earlier, it is
highly unlikely that protein modification
is the cause of steroid cataract.
Although there is a great need to de-
velop a treatment for steroid-induced PSC
or a means for preventing this unwanted
side-effect by modification of the steroid
or its vehicle, this seems a considerable way
off.Furthermore, despite the enthusiastic
claims by some researchers and market-
ing agencies, no effective treatments,
other than surgical removal of the lens,
are available for treating any form of cata-
ract.
CONCLUSION
~
The development of steroid-induced pos-
terior subcapsular cataract is complex and
much work is needed to elucidate the
mechanism. Attempts have been made to
adapt mechanisms, such as oxidation, os-
motic change and conformational change,
proposed for other types of cataract. How-
ever, the unique clinical manifestations of
steroid cataracts make it unlikely that any
of these would be applicable. Most of the
more specific theories proposed lack con-
vincing experimental or clinical support-
ing evidence.
A promising new possibility is that of
ocular growth factor imbalance leading to
aberrant cell behaviour. It is only in recent
years that the importance of growth fac-
tors in normal eye development and
growth has been recognised. The specific
factors that may be involved in cataract
formation remain to be determined. In-
vestigations on the role of various growth
factors and combinations of factors are
needed. It may then be possible to develop
an intervention strategy for preventing
cataract, thereby permitting more exten-
sive use of steroids.
ACKNOWLEDGEMENTS
Preparation of this review and some of the
research, discussed herein, were sup-
ported, in part, by the Cooperative Re-
search Centre for Eye Research and Tech-
nology. AIJ acknowledges receipt of an
Australian Postgraduate Research Award.
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Authors address:
Professor RC Augusteyn
National Vision Research Institute of
Australia
386 Cardigan Street
Carlton VIC 3053
AUSTRALIA

Clinical and Experimental Optometry 85.2 March 2002

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