C L I N I C A L A N D E X P E R I M E N TA L

INVITED REVIEW

Ocular and systemic melatonin and the influence of light

exposure

Clin Exp Optom 2019; 102: 99–108 DOI:10.1111/cxo.12824

Lisa A Ostrin OD PhD FAAO Melatonin is a neurohormone known to modulate a wide range of circadian functions,
University of Houston College of Optometry, Houston, including sleep. The synthesis and release of melatonin from the pineal gland is heavily
Texas, USA influenced by light stimulation of the retina, particularly through the intrinsically photosensi-
E-mail: lostrin@uh.edu tive retinal ganglion cells. Melatonin is also synthesised within the eye, although to a much
lesser extent than in the pineal gland. Melatonin acts directly on ocular structures to medi-
ate a variety of diurnal rhythms and physiological processes within the eye. The interactions
between melatonin, the eye, and visual function have been the subject of a considerable
body of recent research. This review is intended to provide a broad introduction for eye-
care practitioners and researchers to the topic of melatonin and the eye. The first half of
the review describes the anatomy and physiology of melatonin production: how visual
inputs affect the pineal production of melatonin; how melatonin is involved in a variety of
diurnal rhythms within the eye, including photoreceptor disc shedding, neuronal sensitivity,
and intraocular pressure control; and melatonin production and physiological roles in ret-
ina, ciliary body, lens and cornea. The second half of the review describes clinical implica-
tions of light/melatonin interactions. These include light exposure and photoreceptor
contributions in melatonin suppression, leading to consideration of how blue blockers, cata-
ract, and light therapy might affect sleep and mood in patients. Additionally, the interactions
between melatonin, sleep and refractive error development are discussed. A better under-
standing of environmental factors that affect melatonin and subsequent effects on physio-
Submitted: 3 April 2018 logical processes will allow clinicians to develop treatments and recommend modifiable
Revised: 9 July 2018 behaviours to improve sleep, increase daytime alertness, and regulate ocular and systemic
Accepted for publication: 9 July 2018 processes related to melatonin.

Key words: circadian rhythm, dopamine, intrinsically photosensitive retinal ganglion cells, light exposure, melatonin, myopia, sleep

The visual system feeds into a conscious
perception of the world. It can be assessed
through functional tests such as acuity,
contrast sensitivity, colour vision, and
visual field examination. In addition to a
role in image formation, the visual system
also has a parallel, largely unconscious
pathway, through which light exposure
influences a large number of physiological
processes, such as circadian rhythm,
sleep/wake patterns, seasonal timing and
reproduction.1,2
Melatonin is a major neuromodulatory
hormone involved in this pathway. It is
produced by the pineal gland,3 as well as
by photoreceptors4,5 and the ciliary body
epithelium.6 In both the pineal gland and
ocular tissue, melatonin synthesis and
release exhibit circadian rhythmicity, with
highest levels in darkness, and lowest
levels in the light.7 The pineal gland is the
main source of circulating melatonin,
which can diffuse into the eye via the ocu-
lar vasculature.
Melatonin plays a key role in the co-
ordination of the circadian system, which is
the underlying biological clock.8 In mam-
mals and many other species, circadian
rhythms are orchestrated by the suprachias-
matic nucleus. The circadian clock is con-
trolled by molecular oscillators which rely
on transcriptional feedback loops.9 In
humans, when external light exposures are
removed as a controlling factor, the biologi-
cal clock has a periodicity slightly greater
than 24 hours.10 The clock is synchronised
to exactly 24 hours by the solar day. In the
eye, circadian rhythmicity has been well
characterised in several processes, including
diurnal variations in intraocular pressure,
choroidal thickness, and photoreceptor sen-
sitivity and renewal.11
The relationships between vision, light
and melatonin are of increasing relevance
for health practitioners and a review on this
broad topic may be a useful background for
clinicians and researchers. This review dis-
cusses ocular and systemic roles of melato-
nin, its chronobiotic effects, and the
influence of environmental light. First, path-
ways involved in melatonin synthesis and
circadian rhythm control are discussed.
Then, the impact of artificial lighting and
electronic devices on the circadian system
and melatonin, and how these factors can
be modified through the use of ophthalmic
filters in spectacles and intraocular lenses,
are reviewed. Finally, clinical aspects of light
exposure on sleep and potential relation-
ships with myopia are considered.

© 2018 Optometry Australia Clinical and Experimental Optometry 102.2 March 2019

99
Melatonin and light exposure Ostrin
Underlying anatomy and
physiology
Melatonin synthesis, uptake and
degradation
Melatonin (N-acetyl-5-methoxytryptamine),
an indolamine, is synthesised from the pre-
cursor tryptophan, which is converted to
5-hydroxytryptophan and serotonin by
tryptophan 5-hydroxylase and L-amino acid
decarboxylase,12 and then to N-acetylserotonin
and melatonin by hydroxyindole-
0-methyltransferase (HIOMT) and arylalkyla-
mine N-acetyltransferase (AANAT).13 AANAT
and HIOMT are critical enzymatic mediators of
melatonin synthesis, with AANAT being a major
rate-limiting step. Circulating melatonin is
degraded through several pathways involving
multiple enzymatic steps, being primarily meta-
bolised in the liver, kidney, and central nervous
system.14 In humans, melatonin is rapidly meta-
bolised in the liver by hepatic cytochrome
P450,15 with a half-life of approximately
45–60 minutes,16–18 allowing measures of circu-
lating melatonin in plasma to accurately reflect
its synthesis. Melatonin is soluble in lipids and
transported in the blood via albumin binding.19
Three melatonin receptors have been
identified – MT1, MT2 and MT3.20–22 MT1
and MT2 receptors are G protein coupled
receptors with seven transmembrane
domains.23 MT1 and MT2 receptors are
expressed in the hippocampus, suprachias-
matic nucleus, eye, arteries, heart, gastroin-
testinal tract, liver, kidneys, adrenal glands,
macrophages, and blood platelets.23,24 MT1
and MT2 receptor activation leads to modu-
lation of several second messengers, includ-
ing cyclic adenosine monophosphate (cAMP)
and intracellular CA2+. The MT3 receptor is
considered an enzyme in the reductase
group, located in liver, kidney, lung, intes-
tine, muscle, and brown fat tissue.25 The
MT3 receptor is not as well described as
MT1 and MT2 receptors, and remains con-
troversial in its characterisation.
Melatonin production and release in the
pineal gland are mediated by sympathetic
innervation and the neurotransmitter nor-
epinephrine. Pineal melatonin is generated
by an endogenous oscillator, with photic
information from the eye serving to co-
ordinate synthesis and release to the light–
dark cycle.26 Light information is carried
from the retina by the intrinsically photosen-
sitive retinal ganglion cells (ipRGCs) through
the retinohypothalamic tract to the supra-
chiasmatic nucleus (Figure 1).27,28 From the
Clinical and Experimental Optometry 102.2 March 2019
100
suprachiasmatic nucleus, neurons synapse
in the paraventricular nucleus of the hypo-
thalamus, then in the upper thoracic inter-
mediolateral cell column. Pre-ganglionic
sympathetic fibres synapse in the superior
cervical ganglion, and post-ganglionic sym-
pathetic fibres synapse in the pineal gland,
whereby the rhythmic production and secre-
tion of melatonin is entrained. Studies have
shown that daytime activation of the supra-
chiasmatic nucleus suppresses melatonin
synthesis from the pineal gland via
γ-aminobutyric acid (GABA) inhibition at the
paraventricular nucleus.29
ipRGCs express the photopigment mela-
nopsin, and are considered environmental
irradiance detectors.30 Melanopsin is
directly activated by light, having a peak sen-
sitivity to short wavelengths at approxi-
mately 482 nm. Melanopsin activation
contributes to intrinsic ipRGC signalling.30
Direct photic activation of the ipRGCs
through melanopsin mediates non-visual
light responses, including circadian rhythm
entrainment and pupil size control,31 and
these functions persist even in the absence
of rod and cone photoreceptors.
Single cell recordings show that ipRGCs
exhibit sluggish sustained firing patterns that
continue after stimulus offset.32 In accordance
with these response kinetics, ipRGC activity
Paraventricular
nucleus
Suprachiasmatic
nucleus
Intrinsically
photosensitive
retinal ganglion cells
Light
Interomediolateral
column
Figure 1. Pathway from light activation of the intrinsically photosensitive retinal gan-
glion cells to pineal gland melatonin suppression
can be assessed in vivo by measuring post-
illumination pupil responses.32 Following
exposure to short wavelength light of suffi-
cient intensity to activate melanopsin, pupil
re-dilation metrics represent a measure of
ipRGC activity.33 ipRGCs also receive extrinsic
input through rod and cone pathways.34–36
Studies have shown that non-visual light
responses, such as melatonin synthesis and
circadian phase resetting, can occur through
extrinsic rod/cone signalling to the ipRGCs in
the absence of melanopsin.37,38
Ocular melatonin
Ocular sources of melatonin have been
studied in a variety of species, and although
there may be interspecies differences in
sites of melatonin synthesis and receptors,
assessing such animal models can provide
insight into human melatonin production.
In many species, including some amphib-
ians, birds and rodents, melatonin is
synthesised locally in the retina under the
control of endogenous clocks.39 Other
sources of ocular melatonin are believed to
be the non-pigmented ciliary epithelium6
and crystalline lens epithelium.40 Melatonin
contributes to several physiological pro-
cesses in the eye, including the phototrans-
duction and photoreceptor renewal in
retina,41 aqueous production and
Melatonin
Pineal gland H Circulation
N
H3CO
CH3
HN
O
Superior cervical
ganglion
© 2018 Optometry Australia

intraocular pressure modulation in the
anterior chamber,42 wound healing on the
ocular surface,43 and as an antioxidant in
the crystalline lens.44 Melatonin receptors
are found throughout the ocular tissue,
including the cornea, lens, ciliary body, ret-
ina, choroid and sclera (Figure 2).45
Retina
Retinal melatonin is synthesised by photore-
ceptors, and is believed to act locally as a
neuromodulator.46 In humans and rhesus
monkey retinae, only trace amounts of
HIOMT have been detected; therefore, retinal
synthesis may be relatively insignificant in
primates.47 However, circulating melatonin is
capable of diffusing into the eye through the
ocular vasculature. Melatonin receptors have
been localised to the retinal pigment epithe-
lium, photoreceptors, horizontal cells, bipolar
cells, amacrine cells, and ganglion cells, as
well as the inner and outer plexiform
layers.48,49 Retinal melatonin has been
shown to be metabolised locally within the
eye of the African clawed frog, Xenopus lae-
vis,50 however it is unclear if retinal metabo-
lism of melatonin occurs in mammals.
In the outer retina, melatonin activates
outer segment photoreceptor membrane
disk shedding.51 Melatonin has also been
implicated in phagocytic activity by the reti-
nal pigment epithelium to take up shed
membrane disks,52 which increases each
day after light onset for rods, and after light
offset for cones. Additionally, in humans,
melatonin protects the retinal pigment epi-
thelium from oxidative stress, which may
have protective effects against age-related
macular degeneration.53 MT receptor defi-
ciency has been shown to lead to lipofuscin
accumulation and decreased cell viability, as
Sclera (MT1, MT2)
Choroid (MT1)
Cornea
(MT1, MT2, MT3)
Retina
Lens
(MT2, MT3)
Ciliary
body (MT2) Retinal
vasculature (MT1)
Figure 2. Melatonin receptor distribution in ocular structures and in retinal cells;
note that these findings are from a variety of species including Xenopus laevis, chicks,
rabbits, rats and humans45,70
© 2018 Optometry Australia
observed in knockout mice.54 Melatonin also
plays a role in phototransduction by altering
the sensitivity of photoreceptors and bipolar
cells.55
In the inner retina, melatonin modulates
dopamine release.56,57 Dopamine mediates
light adaptation58 and circadian changes in
visual sensitivity,59 and entrains circadian
rhythms of gene expression in retinal pig-
ment epithelium, photoreceptors, and reti-
nal ganglion cells.60–65 Melatonin and
dopamine are both under circadian control,
and have antagonistic effects in the retina,
with melatonin release in darkness, and
dopamine release in response to light. Mela-
tonin inhibits dopamine release from ama-
crine cells,66 potentially through MT1
receptors, which have been identified on
dopaminergic and GABAergic amacrine cells
in guinea pigs, humans, and macaques.49,67
Light exposure stimulates the release of
dopamine from amacrine cells, which binds
to D2 and D4 receptors on photoreceptors,
inhibiting the activity of AANAT68 and modu-
lating cAMP and CA+2 levels, thereby
decreasing melatonin synthesis.69
While it has been known that melatonin
receptors are found on traditional retinal
ganglion cells,70 researchers have recently
localised MT1 and MT2 receptors to
ipRGCs.71 This finding suggests that mela-
tonin may directly influence ipRGC activity.
Potential effects of melatonin on ipRGCs
include modulating synaptic input from
bipolar and amacrine cells or regulating
melanopsin synthesis, among others. In
any case, melatonin receptor distribution
throughout the retina suggests complex
interactions between neuronal activity
involving melatonin, dopamine and
melanopsin.
Retinal pigment epithelium
(MT1, MT2)
Photoreceptors (MT1, MT2, MT3)
Horizontal cells (MT1, MT2)
Bipolar cells (MT2)
Amacrine cells (MT1, MT3)
Ganglion cells (MT1, MT2, MT3)
Melatonin and light exposure Ostrin
Ciliary body
Evidence suggests that the ciliary epithelium
is another source of ocular melatonin. Sup-
port stems from studies which have loca-
lised AANAT and HIOMT to the ciliary body
of the human eye.6 Additionally, melatonin
has been identified and quantified in aque-
ous humor,6,72,73 and metabolites of melato-
nin have been identified in the ciliary
processes.6 In rabbits, melatonin receptors
have been found on the iris and ciliary body,
and localised to the ciliary epithelium.74,75
Melatonin is believed to be involved in
aqueous secretion and in maintaining circa-
dian variations in intraocular pressure. Mel-
atonin is greatest at night, when intraocular
pressure is generally the lowest; therefore,
an inverse relationship exists between mela-
tonin and intraocular pressure. Topical
administration of melatonin and its ana-
logues have been shown to decrease intra-
ocular pressure, and thereby modify the
circadian pattern.76 The mechanism of
action is thought to be a decrease in chlo-
ride efflux and subsequent reduction in
aqueous humour formation from the non-
pigmented ciliary body epithelial cells, which
mediate fluid movement.77
Links between melatonin, aqueous
humour production and intraocular pres-
sure suggest that a role of melatonin in
glaucoma pathophysiology and therapy may
be plausible (see Rosenstein et al.78 for
review). Glaucoma is a progressive optic
neuropathy characterised by loss of retinal
ganglion cells and optic nerve changes.
Glaucomatous damage to the inner retina
has been shown to affect the ipRGCs,79
which may lead to downstream effects on
melatonin and contribute to reported
increases in sleep disorders in patients with
glaucoma.80
Cornea and ocular surface
MT1 receptor expression has been identi-
fied in corneal epithelial cells in Xenopus
laevis,79 chicks, and humans.81–84 MT2
receptors have been localised to the corneal
epithelium, stroma and endothelium in rab-
bits.43 The presence of melatonin has been
demonstrated in both rabbit and human
tears.43,85 There is evidence for several
potential roles of melatonin on the ocular
surface. Melatonin facilitates epithelial des-
quamation through modulation of tight
junction formation and dissociation of sur-
face cells.84 Melatonin has been shown to
affect corneal hydration in vitro.86 The
authors found that melatonin was required
Clinical and Experimental Optometry 102.2 March 2019
101
Melatonin and light exposure Ostrin
for normal corneal growth in vivo in chicks.86
Melatonin enhances tear secretion in
rabbits.87
With a potential role of melatonin in der-
mal wound healing88 and corneal mitotic
activity,89 investigators examined the effects
of melatonin on corneal wound healing.43 In
rabbits with epithelial defects, topical mela-
tonin and the MT2 melatonin receptor ago-
nist, IIK7, significantly increased the rate of
epithelial migration and wound closure.
However, the MT3 melatonin receptor ago-
nist, 5-MCA-NAT, had no effect on wound
healing. Therefore, melatonin, acting
through MT2 receptors, is likely implicated
in corneal wound healing.
Melatonin has also been shown to exhibit
antioxidant properties in protection of cor-
neal epithelial cells from ultraviolet
(UV) light.90 Rabbit corneal epithelial cells
treated with melatonin had decreased lipid
peroxidation and increased mitochondrial
viability compared to untreated control tis-
sue following UVB light exposure.
Lens
The role of melatonin in the crystalline lens
is at least twofold: (1) controlling transpar-
ency through homeostatic processes and
(2) reducing oxidative stress.44 In rats, mela-
tonin, a scavenger of free radicals, has been
shown to reduce cataract formation from
UVA and UVB exposure.91 Following UV
exposure, exogenously administered mela-
tonin led to decreased lipid peroxidation,
increased antioxidant enzyme activity, and
decreased CA2+, resulting in decreased cata-
ract formation.
Melatonin was originally thought to reach
the lens through absorption from the aque-
ous humour. However, recent studies sug-
gest that melatonin may also be synthesised
in human lens epithelial cells. Alkozi et al.40
reported that lens epithelial cells contain
melanopsin, with melanopsin activation by
light decreasing synthesis of melatonin.
Likewise, in darkness, lens epithelial cells
increase AANAT expression and melatonin
production. Based on the finding that lens
epithelial cells contain melanopsin and
synthesise melatonin in a light-dependent
manner, the authors suggest that it may be
possible to modulate melatonin synthesis in
the lens by altering illumination conditions,
thereby increasing antioxidant properties
and decreasing cataract formation. The
authors further speculate that modulating
melatonin synthesis by the lens at night-
time could be a method to regulate
Clinical and Experimental Optometry 102.2 March 2019
102
intraocular pressure, which may be benefi-
cial in the treatment of glaucoma. As of yet,
this speculation is unproven, but the thera-
peutic implications warrant further investi-
gation in the area.
In summary, visual processes are major
modulators of systemic melatonin produc-
tion, and melatonin is produced by and has
activity in ocular tissues. By altering those
visual inputs, it may be possible to influence
melatonin production and its systemic and
ocular effects in ways that can have clinical
and therapeutic implications. The second
half of this review will concentrate on some
of these potentially modifiable clinical
effects.
Light, melatonin and clinical
implications
In modern societies, artificial lighting greatly
affects biological rhythms. People are
increasingly exposed to excess levels of arti-
ficial light during the night-time, leading to
chronodisruption, and resulting in impaired
physiological, behavioural and biochemical
rhythms.92 Even brief exposure to bright
light during the night-time can disrupt circa-
dian patterns. Here, the influence of light
exposure, the effects of various spectral and
temporal properties of light on melatonin,
and clinical implications are discussed.
Melatonin and light exposure
Pineal melatonin synthesis and release are
directly related to light exposure, and nor-
mal circadian rhythms are dependent upon
exposure to regular light/dark patterns.
Increased night-time melatonin promotes
sleep, and decreased daytime melatonin
promotes alertness. Light is the most potent
Zeitgeber, or time-of-day cue, for regulating
circadian activity. Light exposure has been
shown to rapidly decrease the activity of
AANAT and acutely suppress the production
of melatonin.93–95 Melatonin undergoes a
sharp rise approximately one to three hours
before bed-time, which onsets in response
to dim light, known as dim light melatonin
onset (DLMO, Figure 3). Similarly, there is a
sharp fall in melatonin in response to light
onset. DLMO is considered to be a reliable,
non-invasive circadian phase marker.
Melatonin synthesis from the pineal gland
can be estimated through blood, saliva and
urine samples.96 Sample collection over a
24-hour period can provide accurate measures
of circadian phase, duration and amplitude.
Blood plasma melatonin levels are approxi-
mately three times greater than in saliva;97
however, plasma sampling can be problematic
because collection can be difficult in some sub-
jects, it is invasive, and collection often requires
trained medical personnel. Urine samples are
analysed for a metabolite of melatonin,
6-sulphatoxymelatonin, which is considered to
be a practical method to estimate melatonin
production. Saliva sampling is also a practical
method to estimate melatonin levels, and col-
lection can be conducted at home.
Photoreceptor contributions to
melatonin suppression
The contribution of rod and cone photore-
ceptors and ipRGCs to melatonin levels can
be isolated in experiments using narrow-
band light of wavelengths specific for each
photoreceptor type. Short wavelength light,
in the blue portion of the visible spectrum,
is most potent for acute suppression of mel-
atonin through activation of melanopsin
containing ipRGCs, as discussed earlier.32,98
Human studies show that red and green
light can also suppress melatonin and alter
circadian rhythm patterns,38,99 despite mini-
mal melanopsin activation, providing evi-
dence that rod and cone photoreceptors
contribute to non-visual responses to
light.100 However, the temporal properties
of rod and cone photoreceptor and ipRGC
sensitivities vary: the effects of rods and
cones on non-visual responses are more
transient, whereas the effects of ipRGCs are
of longer duration. Researchers found that
6.5 hours of either short wavelength
(460 nm, activating primarily melanopsin) or
medium wavelength (555 nm, activating the
three-cone photic system maximally) light
during the night initially suppressed melato-
nin at a similar effective dose.38 During the
second half of the light exposure period, the
sensitivity of melatonin suppression to
555 nm light decayed exponentially com-
pared to 460 nm light exposure. The results
demonstrated that rod and cone photore-
ceptors contribute substantially to circadian
photoreception, primarily acting in response
to short-duration light exposures, while mel-
anopsin expressing ipRGCs respond contin-
uously to long-duration light exposures.
Findings also suggested that red light may
only suppress melatonin when it is of suffi-
cient intensity.101
Artificial light at night
Artificial light from televisions, computers
and hand-held electronic devices has
© 2018 Optometry Australia

Light period
30
25
Change in melatonin
20
15
(pg/ml)
10
5 whether the diurnal rhythm was abolished
0
-5
-10
-15
8:00 AM 12:00 PM 4:00 PM
Figure 3. Melatonin level measured via salivary assay for a representative subject
every four hours over 24 hours. Dim light melatonin onset (DLMO) is indicated with
an arrow. (Ostrin, unpublished data).
become ubiquitous in daily life. Of impor-
tance, night-time use of electronic devices is
highly prevalent, with 90 per cent of Ameri-
cans reporting electronic device use in the
hour before bed-time.102 Computers, cell
phones and video games at night are associ-
ated with more difficulties falling asleep and
less restful sleep.102 Increasingly, light bulbs
and electronic displays use light emitting
diode (LED) light sources, which contain a
high proportion of short wavelength light
near the peak of ipRGC sensitivity. Accumu-
lating evidence suggests that LED displays
are contributing to night-time melatonin
suppression and sleep difficulties.103 Night-
time exposure to back-lit computer displays
has been shown to attenuate melatonin.104
To test the hypothesis that artificial light
in the evening suppresses night-time mela-
tonin and decreases sleep quality through
an ipRGC-dependent mechanism, a recent
study sought to investigate whether reduc-
ing short wavelength light exposure at
night-time could modulate the ipRGC-driven
pupil response, circulating melatonin levels
and sleep.105 Adult subjects wore blue-
blocking glasses for approximately four
hours before bed-time for two weeks.
Results showed that compared to baseline,
night-time melatonin significantly increased
by 58 per cent (Figure 4), objectively mea-
sured sleep duration increased an average
of 24 minutes, and ipRGC-driven pupil
responses increased. Changes in the ipRGC
pupil response, as measured in the morn-
ing, suggested that a shift in circadian phase
occurred, driven by decreased night-time
© 2018 Optometry Australia
Melatonin and light exposure Ostrin
Dark period that after 10 days, night-time melatonin
decreased from approximately 26 to
16 pg/ml, while morning melatonin
increased from 3 to 18 pg/ml, such that by
the end of sequestration, night-time and
morning melatonin levels were approaching
DLMO each other (Figure 5). Because only two
time-points were assessed, it is unclear
completely, or remained in altered pattern;
however, the results clearly demonstrate
that melatonin release is dependent on light
exposure.
8:00 PM 12:00 AM 4:00 AM Light therapy to modulate
melatonin
Time
Light therapy is a non-pharmacological
treatment that involves viewing artificial
light through a light box or visor to alter
circadian rhythms.107–109 In mood-related
disorders, such as depression, the overall
goal of light therapy is to increase the pho-
ipRGC input. Researchers concluded that toperiod, decrease daytime melatonin, and
blue-blocking glasses represent a practical increase night-time melatonin, thereby
method to combat night-time artificial light improving sleep and decreasing depressive
exposure, phase advance (move earlier) symptoms. The mechanism of action of
DLMO and improve sleep quality. light therapy is through activation of the
ipRGCs to ultimately suppress daytime mel-
Effects of constant darkness on atonin synthesis and release from the
melatonin pineal gland.110 Bright light has been used
As part of a study entitled Project Luma, two as a first-line therapy for seasonal depres-
adult subjects were sequestered into com- sions (also termed seasonal affective disor-
plete darkness for 10 days.106 During der, or SAD) and non-seasonal depression
sequestration, multiple Zeitgebers were pro- for decades as a means to modulate mela-
vided, and subjects had access to auditory- tonin and regulate mood112,113 (see Goo-
output timepieces. Saliva samples were ley111 for review). Seasonal depression is a
collected upon waking in the morning, and recurrent pattern of depressive episodes
just before bed at night. Results showed brought on by short photoperiods in winter
*
40
Before
35
After
30
Melatonin (pg/ml)
25
20
15
10
5
0
Night Morning
Figure 4. Melatonin levels measured via salivary assay at night and in the morning
before (solid bars) and after (open bars) wearing blue-blocking glasses at night-time for
two weeks. *Indicates p < 0.05. (Reprinted from Ostrin et al.105 with permission from
John Wiley & Sons).
Clinical and Experimental Optometry 102.2 March 2019
103
 Melatonin and light exposure Ostrin
35
30
y = -0.8245x + 23.163
25
Melatonin (pg/ml)
20
15
10
5 light in the short wavelength spectrum can
0 concerns that cumulative exposure to short
0 2 4 6
Day of sequestration
Figure 5. Morning and night-time salivary melatonin beginning the night subjects
were sequestered into constant darkness for 10 days (n = 2). (Unpublished data).
months.112,114 In depression, circadian
rhythm changes typically include effects on
sleep115 and hormone levels.116 Some stud-
ies have shown that patients with seasonal
depression have abnormal melatonin
levels, including increased daytime
melatonin,117 and phase delays in night-
time melatonin release,118 although results
are not consistent across all studies.119
Light therapy can also be used to help
regulate sleep and mood in jet lag or in shift
work-induced sleep disorders.111 In shift
work and in travel that spans over multiple
time zones, the timing of the light/dark cycle
is altered, leading to temporal misalign-
ments in the circadian system. This chrono-
disruption can lead to fatigue and poor
sleep quality, and has been linked to broad
physiological impairments, including
increases in gastrointestinal disorders, met-
abolic syndrome, diabetes, heart disease,
and cancer.120,121 In such cases, bright light
can be used to help reset the circadian sys-
tem to adapt to irregular light exposure pat-
terns. The timing of the bright light
exposure is critical in achieving the desired
effects from therapy. For example, night-
time shift workers are advised to undergo
light therapy in the evening to suppress
melatonin and increase night-time alertness.
In jet lag, optimal timing of light therapy
depends on the direction of travel, eastward
or westward, and number of time zones
crossed.122 For eastward travel, the circa-
dian clock must phase advance, and vice
Clinical and Experimental Optometry 102.2 March 2019
104
Subject 1 am
Subject 2 am
Subject 1 pm
Subject 2 pm
y = 0.7885x + 1.0924
8 10
versa for westward travel. Light therapy in
combination with melatonin supplements
has been shown to be beneficial in resetting
circadian time in both shift work and jet
lag.122
Cataracts and decreased light
transmission
Age-related cataract, or opacification in
the crystalline lens, is a leading cause of
reversible visual impairment. Cataracts
tend to result in a progressive yellowing of
the lens and subsequent loss of blue light
transmission due to the accumulation of
chromophores, which may impact melato-
nin patterns due to decreased light reach-
ing the ipRGCs. Investigators have sought
to understand the impacts of cataracts,
cataract surgery, and intraocular lens
properties on melatonin levels, sleep qual-
ity and daytime alertness. Shenshen et al.
evaluated the effects of cataract surgery
on salivary melatonin level and sleep qual-
ity in ageing patients receiving UV-blocking
intraocular lenses.123 Findings showed that
sleep quality improved after cataract sur-
gery, and night-time salivary melatonin
increased, with no change in timing of
DLMO, suggesting that cataract surgery
improved sleep quality via increased blue-
light transmission. In support of this the-
ory, another study reported increased
photoreception by ipRGCs following cata-
ract removal and intraocular lens
implantation.124
Blue-blocking spectacles and
intraocular lenses
Yellow-tinted lenses, which filter short wave-
length blue light, have traditionally been used
to improve contrast. More recently, evidence
suggests that night-time wear increases mel-
atonin and improves sleep, as discussed
above. With increased interest in potential
damaging effects of blue light to the retina,
the use of blue-blocking lenses, both in spec-
tacles and intraocular lenses, has been
increasing.125 Specifically, studies in animal
models and in vitro cell cultures have shown
that prolonged exposure to high-intensity
induce phototoxic retinal damage, raising
wavelength light in humans may induce reti-
nal toxicity.126 Additionally, blue-blocking
lenses are widely marketed as a strategy to
alleviate computer vision syndrome, also
known as digital eye strain, which is a group
of vision-related problems resulting from
extended electronic device use. These types
of blue-blocking technology are promoted
for full-time wear in habitual spectacles; how-
ever, long-term effects on circadian patterns,
melatonin, and in children, eye growth, are
unknown.
In an effort to understand potential
effects of blue-blocking spectacle lenses on
visual performance and sleep–wake cycles,
Lawrenson et al.126 performed a systematic
review of the literature. The authors found
limited high-quality clinical trials to support
the use of blue-blocking lenses. Addition-
ally, the studies evaluated in the review did
not address effects of blue-blocking lenses
in habitual spectacles on sleep–wake
cycles.
While the effects of full-time blue-blocking
spectacle lens wear on circadian patterns
have not yet been clarified, several studies
have investigated the effects of blue-
blocking intraocular lenses on sleep quality,
melatonin and mood.127,128 One study
found that three weeks after surgery, there
were no differences in melatonin and sleep
quality between subjects receiving neutral
versus blue-blocking intraocular lenses.124
However, after one year, subjects who
received the blue-blocking intraocular lenses
demonstrated a 50 per cent lower peak in
melatonin compared to subjects who
received the neutral intraocular lens.127 This
decrease in melatonin was attributed to a
decrease in blue light during the day due to
short wavelength absorption from the
intraocular lens.
© 2018 Optometry Australia

Other results between groups regarding
sleep and circadian rhythm were variable
and inconclusive. In another study, subjects
answered a subjective sleep quality ques-
tionnaire six months after implantation of a
clear, blue-blocking, or UV-blocking intraocu-
lar lens. Data showed that implantation of
the blue-blocking intraocular lens did not
have a negative impact on subjective sleep
quality.128 With variable results and limited
information on the effects of habitual blue-
blocking lens wear on ipRGC function,
circadian rhythms and eye growth, further
investigations are warranted.
Melatonin, sleep and refractive
error
The role of melatonin in refractive error
development is not well understood, but the
area is receiving more attention with
increasing interest in understanding associa-
tions between light exposure and refractive
error development. The prevalence of myo-
pia, or near-sightedness, has been increas-
ing, with up to 90 per cent prevalence in
some eastern Asian populations.129 While
genetics are a major risk factor for the
development of myopia, studies show that
environmental factors, such as near work
and light exposure patterns, also influence
eye growth.130 Accumulating evidence sug-
gests that increased light exposure and time
outdoors are protective of myopia.131,132
With known roles of dopamine in light adap-
tation and myopia,133,134 and reciprocal
interaction between melatonin and dopa-
mine, speculation exists whether melatonin
may also play a role in refractive error
development. Dopaminergic amacrine cells
have also been shown to have reciprocal
synapses with ipRGCs,135 which further
implicates melatonin and circadian rhythms
in myopia development.
In addition to a potential role of melato-
nin in the pathophysiology of myopia, mela-
tonin may also be altered as a result of
structural changes to the inner retina affect-
ing ipRGCs. With myopic eye growth, the ret-
ina undergoes stretching and in some cases,
retinal degenerations. Disease processes
resulting in retinal structural changes, such
as glaucoma79 and age-related macular
degeneration,136 have been shown to
reduce ipRGC activity, as assessed through
pupil responses, and may lead to subse-
quent alterations in circadian rhythms, sleep
and melatonin synthesis and release.
© 2018 Optometry Australia
Therefore, it is plausible that myopic reti-
nopathy may also lead to ipRGC damage.
A study in guinea pigs examined the
effects of monochromatic light on refractive
error and melatonin concentration.137
Guinea pigs were raised in white light, green
light, or blue light. Results showed that
guinea pigs raised in green light had signifi-
cantly higher levels of pineal gland melato-
nin, whereas guinea pigs raised in blue light
had decreased melatonin, presumably as a
result of increased ipRGC-induced melato-
nin suppression. Additionally, guinea pigs
raised in green light developed more myo-
pic refractive errors than those raised in
blue light. The authors speculated that the
increased melatonin experienced by green
light potentially induced alterations in reti-
nal growth factors or changes in ocular cir-
cadian rhythms that ultimately led to
increased eye growth.
A study in chicks showed that systemic
administration of melatonin resulted in sig-
nificant alterations in growth of several ocu-
lar tissues in both control animals and those
undergoing experimental myopia.82 Specifi-
cally, significant changes were observed in
anterior and vitreous chamber depths and
choroidal thickness in all animals receiving
melatonin. The results suggest that melato-
nin is involved in the regulation of ocular
growth diurnal rhythms, although the exact
mechanisms remain elusive.
Recent investigations have focused on the
role of circadian rhythm on refractive devel-
opment. Studies in animal models of myo-
pia show that regular intervals of light and
dark periods are essential for ocular growth
and emmetropisation. For example, con-
stant light138 and constant dark139 result in
disruptions in eye growth regulation with
subsequent refractive errors. In one study,
chicks were exposed to two hours of light
during the night.140 This brief period of light
exposure disrupted diurnal rhythms in axial
length and choroid thickness, and caused an
acute, transient stimulation in ocular growth
rate. Ultimately, animals exposed to light at
night were significantly more myopic than
those exposed to continuous darkness at
night. The authors suggested that changes
in ocular growth were potentially a result of
the acute suppression of melatonin by light
at night. These findings have implications in
how illumination at night might affect ocular
growth in children.
A controversial report showed that ambi-
ent light at night was associated with myo-
pia development in children.141 While
Melatonin and light exposure Ostrin
numerous other studies failed to replicate
these findings,142–144 the former study
raised speculation that light at night and
duration of night-time darkness could
potentially influence the emmetropisation
process in children. In young adult law stu-
dents, an association was reported between
less daily exposure to darkness and myopia
progression.145 Together, these findings
warrant further investigations into the influ-
ence of light at night and the role of circa-
dian rhythms in refractive development in
children.
Kearney et al.146 explored the relationship
between morning serum concentrations of
melatonin and dopamine with refractive
error in young adults. Results showed that
myopic individuals exhibited higher morning
serum melatonin levels than non-myopes.
On the other hand, dopamine concentration
was similar between refractive groups.
While these findings do not indicate a causal
or mechanistic relationship, they provide
further evidence of associations between
melatonin and refractive error.
Several recent studies have investigated
sleep quality between myopic and non-
myopic individuals.147–150 Ayaki et al.147
evaluated sleep in myopic children and
adults using a questionnaire. The authors
found that highly myopic children had the
poorest sleep quality, with later bedtimes
and worst subjective sleep scores. No differ-
ences in sleep were noted between refrac-
tive error groups in the adult populations.
Similarly, in a study of 3,625 Korean chil-
dren, ages 12–19 years, results demon-
strated a significant inverse relationship
with sleep duration and myopia.148 The
odds of myopia were 41 per cent less in
subjects with greater than nine hours of
sleep per night compared to those with less
than five hours of sleep per night. However,
another study found that myopic children
slept longer than non-myopic children, with
both myopia and disordered sleep being
prevalent among the subjects.151
In a recent study, using questionnaire
data in adult emmetropes and myopes,
sleep quality was reported to be ‘poor’ for
myopic subjects and ‘good’ for emmetropic
subjects.150 While morning salivary melato-
nin tended to be higher for the myopic
group, differences in melatonin level
between refractive error groups did not
reach statistical significance. Finally, a recent
study in older myopic subjects in east China
reported that myopic individuals over
60 years of age slept longer than non-
Clinical and Experimental Optometry 102.2 March 2019
105
Melatonin and light exposure Ostrin
myopic individuals, and that longer sleep
duration was associated with decreased
sleep quality.149 However, other factors may
have confounded the results on refractive
error and sleep in this population, such as
the presence of cataract, visual impair-
ments, and other disabilities.
Despite several reports of altered sleep
quality and melatonin in myopic individuals,
the mechanism behind the relationship has
yet to be elucidated. Decreased sleep dura-
tion and sleep quality in myopic subjects
could be attributed to several factors, includ-
ing stress, academic pressures, workload, and
other behavioural and psychological factors.
Another potential mechanism for decreased
sleep quality may be due to disruptions in cir-
cadian rhythms and subsequent decreases in
night-time melatonin. Initial reports evaluating
ipRGC function and refractive error have not
found a direct association between the
ipRGC-driven pupil response and myo-
pia.150,152 However, another investigation
found a significant positive correlation
between a more hyperopic refractive error
and a slower rate of pupil re-dilation to 0.1 Hz
flashing stimuli, which varied as a function of
light exposure.153 Further studies are required
to clarify these relationships.
Conclusions
Sleep and mood are interrelated and influ-
enced by environmental factors such as
light exposure. Light is the most potent cue
for entraining circadian rhythm, primarily
through ipRGC pathways to the midbrain.
As outlined in this review, melatonin is a key
neuromodulator in regulating circadian
rhythms, sleep/wake patterns and mood.
Additionally, accumulating evidence sug-
gests that melatonin serves numerous other
roles in the eye, with implications in corneal
wound healing, intraocular pressure regula-
tion, and retinal physiology.
With potential roles of light exposure and
circadian rhythm in eye growth, speculation
exists whether melatonin is implicated in
refractive error development; however, fur-
ther research is required to elucidate rela-
tionships. Light exposure, in terms of
spectral and temporal properties, repre-
sents a modifiable environmental factor,
through changes in illumination properties
or through use of ophthalmic filters, that
may help regulate disorders related to mel-
atonin synthesis and release.
Clinical and Experimental Optometry 102.2 March 2019
106
Further studies aimed at identifying the
mechanisms of action of ocular and sys-
temic melatonin in humans and under-
standing the relationships between light
exposure, dopamine and melatonin will help
to develop targeted environmental and ther-
apeutic interventions that may be beneficial
in a variety of ocular and systemic
conditions.
ACKNOWLEDGEMENTS
Special thanks to Andrew Carkeet for helpful
comments on the manuscript, Benjamin
Backus for collaboration in Project Luma,
and Sze Quan for help generating figures.
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