Current Eye Research, Early Online, 1–6, 2014

! Informa Healthcare USA, Inc.

ISSN: 0271-3683 print / 1460-2202 online
DOI: 10.3109/02713683.2014.975368

REVIEW ARTICLE

Sex, Eyes, and Vision: Male/Female Distinctions in

Ophthalmic Disorders
Alvin Eisner

Current Eye Research Editorial Board, Portland, Oregon, USA

Curr Eye Res Downloaded from informahealthcare.com by Universite De Sherbrooke on 11/19/14

ABSTRACT
There is growing recognition: (1) that sex (male and female) and sex hormones (androgens and estrogens) are
important for physiologic functions outside those pertaining expressly to reproduction, and (2) that both classes
of sex hormones are active in both sexes, and moreover are produced locally in non-gonadal tissues throughout
the body. The visual system, in addition to being of tremendous inherent importance, is unique in a very
distinctive way; it possesses an organ – the eye – having a window allowing its interior to be examined with
exquisite precision and control in both laboratory and clinical settings. Plus, many diseases manifest in the eye
or are exclusive to the eye. This special issue of Current Eye Research contains 12 review articles, each addressing
a different topical area important for Sex, Eyes, and Vision: Male/Female Distinctions in Ophthalmic Disorders.
For personal use only.

Of course, the distinctions between topical areas are blurred, and the overlap between the various lines of
knowledge and investigation likewise is substantial. Eye diseases can be both neurodegenerative and involve
altered blood flow, for instance. In fact, the thematic overlap is greater yet, in that the articles for this special
issue address matters of interest to clinicians and scientists who may identify more with women’s health or sex
& gender fields than with eye & vision fields. Nevertheless, because this special issue needs a home, the
following 12 topical areas each have here their own dedicated review: age-related maculopathy, central nervous
system function and cognition & perception, diabetic retinopathy, dry eye, glaucoma, inherited diseases, lens
and cataract, neuro-ophthalmology, ocular blood flow, ocular inflammatory disorders, optical coherence
tomography, and sex/gender eye care disparities. This overview article itself raises additional points expressly
concerning: (1) the estrogen therapy timing hypothesis, and (2) breast cancer treatment with aromatase
inhibitors.
Keywords: Estrogen, ophthalmology, sex, vision, women’s health

INTRODUCTION It is less well known that estrogens and androgens

There is a growing recognition that sex (male and
female) and sex hormones (androgens and estrogens)
are important for many physiologic functions outside
those pertaining exclusively to reproduction.1 For
some clinical areas, this importance already is broadly
appreciated. Probably the best known example con-
cerns bone health; age-related reductions of circulat-
ing estrogens are appreciated in both lay and
professional circles as contributing to losses of bone
density.2 These losses, together with sensory com-
promise,3 raise the risk of life-altering fractures,
particularly among women.4
are important for the bone health of both sexes.5
It may be less widely known yet that sex hormones
are produced in non-gonadal tissues throughout the
body, where these hormones can act locally in para-
crine, autocrine, or intracrine manners.6–13 Moreover,
all estrogens are derived from androgens or are
synthesized directly from androgens.14 The under-
lying physiology is complex and dynamic. Suffice it to
say that: (a) both sexes produce both classes of
hormones throughout an entire lifetime, and (b) it
emphatically is incorrect to equate estrogens with
female sex and androgens with male sex.15,16 It
likewise is incorrect to assume that circulating

Received 20 August 2014; revised 3 October 2014; accepted 7 October 2014; published online 20 October 2014
Correspondence: Alvin Eisner. Tel: +971 400 9855. E-mail: aeisnerphd@gmail.com

1
 2 A. Eisner
estrogens are derived entirely from endocrine sources,
even for reproductive-age women. It is true, however,
that hormonal changes occurring naturally in women
differ substantially from those of men. Moreover, the
two sexes’ uses of hormonally acting medications
differ appreciably in both health and disease. These
sex-dependent differences are important in their own
right for biological and social reasons, and they are
important operationally from the perspective of
research design.
The central nervous system (CNS)17 and cardio-
vascular system18 each synthesize and respond to sex
hormones, and changes in neural function and in
blood flow each have the capacity to impact the eye
and vision directly. There has been a tremendous
surge of research activity over the last 10–20 years
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concerning the roles of estrogen for neuroprotection
within the CNS.19 Even in the absence of insult or
pathology, visual function depends on physiologic
factors such as neurotransmitter activity (e.g. GABA
and glutamate synthesis and uptake)20 and neural
anatomy (e.g. dendritic architecture)21, which are
known to respond to changes in estrogen exposure
at non-ocular sites.22 Similarly, there has been a
wealth of research comparing cardiovascular risk
between men and women, and concerning effects of
For personal use only.
hormones on blood vessels.23 The eye’s accessibility
alone should make it a more preferred research target
than it already is for studies of estrogenic action. Not
only is the retinal vasculature observable through the
optical window, measures of ocular blood flow may
be assessed as functions of highly controlled visual
stimuli.24,25 Overall, technological advances in intrao-
cular imaging are progressing at remarkable rates,
with retinal and nerve fiber thicknesses already
routinely being measured clinically with axial preci-
sion of about 5–7 microns.26 The use of adaptive
optics, while not yet routine for the clinic, can achieve
lateral resolutions permitting imaging of individual
photoreceptors and the tiniest retinal vessels.27
Of course, many eye and vision conditions involve
neither compromised blood flow nor neurodegenera-
tion as major factors. And many inherited eye
diseases are sex-linked but apparently are influenced
little or not at all by differential exposure to sex
hormones. In contrast, eye and vision conditions
stemming from autoimmune pathologies or inflam-
matory responses can depend on past or present
levels of exposure to sex hormones, and these condi-
tions may affect the two sexes with different frequen-
cies or severities.28 Two of the more common and
better known examples are multiple sclerosis and
Sjögren’s syndrome. Although these conditions each
affect women more often than men, the former
condition seems to respond favorably to increased
exposure to estrogens,29 whereas development of the
latter may involve decreased exposure to androgens.30
Given the involvement of sex hormones or
sex-hormone balance for so many physiologic func-
tions – ranging from insulin sensitivity31 to sebaceous
gland activity32 to collagen biomechanics33 – the
ability of menopausal changes to perceptibly alter an
individual’s vision, while neither inevitable nor
necessarily immediate, should not be considered
surprising. Hence, vision change after menopause is
a thread shared by many of the review articles
comprising this special issue of Current Eye Research
devoted to ‘‘Sex, Eyes, and Vision: Male/Female
Distinctions in Ophthalmic Disorders’’.
THE REVIEW ARTICLES
This special issue contains 12 review articles, solicited
from experts in their respective fields, with most of
the articles focused on different ophthalmology
subspecialties. We thank the authors for their contri-
butions and for their patience with the review process.
The Introduction above alludes to every article,
although some of the allusions are more implicit
than others. As arranged in first-author alphabetical
order, the 12 review articles are:
(1) John Chen, Fiona Costello, Randy Kardon. Sex
disparities in neuro-ophthalmologic disorders.
(2) Janine Clayton, Alison Davis. Sex/gender dis-
parities and women’s eye health’’.
(3) Robert Handa & Robert McGivern; ‘‘Steroid
hormones, receptors, and perceptual and cogni-
tive sex differences in the visual system’’.
(4) Saradha Iragavarapu & Michael Gorin; ‘‘Gender
specific issues in hereditary ocular disorders’’.
(5) Kai Kaarniranta, Anna Machalińska, Zoltán
Veréb, Antero Salminen, Goran Petrovski &
Anu Kauppinen; ‘‘Estrogen signalling in the
pathogenesis of age-related macular
degeneration’’.
(6) Sotaro Ooto, Masanori Hangai & Nagahisa
Yoshimura; ‘‘Effects of sex and age on the
normal retinal and choroidal structures on
optical coherence tomography’’.
(7) Glen Ozawa, Marcus Bearse & Anthony Adams;
‘‘Male-female differences in diabetic
retinopathy?’’.
(8) Doreen Schmidl, Leopold Schmetterer, Gerhard
Garhöfer & Alina Popa-Cherecheanu; ‘‘Gender
differences in ocular blood flow’’.
(9) H Nida Sen, Janet Davis, Didar Ucar, Austin Fox,
Chi-Chao Chan & Debra Goldstein; ‘‘Gender
disparities in ocular inflammatory disorders’’.
(10) Shandiz Tehrani; ‘‘Gender difference in the
pathophysiology and treatment of glaucoma’’.
(11) Piera Versura, Giuseppe Giannaccare & Emilio
Campos; ‘‘Sex steroid imbalance in females and
dry eye’’.
(12) Madeleine Zetterberg & Dragana Celojevic;
‘‘Gender and cataract – the role of estrogen’’.
Current Eye Research
 Male/Female Distinctions in Ophthalmic Disorders
Together these reviews span most of the major
ophthalmology subspecialties. The article on optical
coherence tomography is the most methodologically
focused, while the article on perception and cognition
is the most concerned with parts of the brain not
visible with a slit lamp or through an ophthalmo-
scope. Each article addresses male/female differences
at the level of the person, and some include mechan-
istic information addressing roles of sex hormones
(e.g. cataract) or genetics (e.g. hereditary disorders)
or cellular signaling (e.g. macular degeneration).
Collectively, the articles address conditions and effects
for which male/female differences are widely
acknowledged (e.g. dry eye), are becoming recognized
(e.g. glaucoma), are probable (e.g. diabetic retinop-
athy), are provocative (e.g. ocular blood flow), or
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manifestly cross established clinical specialties (e.g.
neuro-ophthalmology, inflammatory disorders). Of
course, no article falls into only a single category,
and most articles contain much epidemiologic infor-
mation, quite detailed in some cases. Despite the
different phrasings in titles, there generally is insuf-
ficient information for distinguishing sex from gender
across articles.34 Of the several articles expressly
discussing social issues or behavioral differences, the
review by Clayton & Davis on sex/gender disparities
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and women’s eye health most extensively addresses
differential healthcare access and utilization.
The letters of invitation to the authors included the
following statement: ‘‘We encourage you to inject
your individual opinions if you feel a personal
perspective would serve to highlight areas of debate,
uncertainty, or future directions’’. Some of the authors
ran with (rather than from) this encouragement more
than others. In the next section of this overview, I will
follow my own suggestion and adopt a more personal
tone than usual in order to briefly illustrate a few
of the opportunities and complexities involved in
researching effects of sex and sex hormones on the
visual system. Although these illustrations are from
human-subjects research, the pertinent issues are
much broader, and the reader is encouraged to
consider the new NIH policies (rollout starting Fall
2014) regarding the inclusion of sex variables into
preclinical laboratory designs involving cells or
animals.35
SEX DIFFERENCES AND HORMONAL
CHANGE: OPPORTUNITIES AND
COMPLEXITIES FOR
HUMAN-SUBJECTS RESEARCH
Areas of research that have evolved entirely separ-
ately can come together in fruitful ways. Thus, while
this section uses as examples some work concerning
visual responses mediated via short-wavelength-sen-
sitive (SWS) cones, the themes raised have far greater
! 2014 Informa Healthcare USA, Inc.
3
generality and applicability, particularly as concerns
women’s health. For detailed information regarding
SWS-cone-mediated response, please see the March
2014 special issue of Visual Neuroscience dedicated to
Short Wavelength-Sensitive Cones and the Processing
of Their Signals.36 The two subsections presented next
address briefly two of the most pressing and contro-
versial contemporary issues in women’s healthcare.
The Timing Hypothesis
The first of these major issues centers on the purpose
and time frame of post-menopausal exogenous hor-
mone use with estrogen. The timing hypothesis (also
called the critical period [or critical window] hypoth-
esis) postulates that post-menopausal hormone ther-
apy is most effective, or is beneficial at all, when
administered sufficiently near the menopausal transi-
tion rather than many years later. This hypothesis
was developed largely as a means for reconciling
results from laboratory and observational studies
with discrepant results from the Women’s Health
Initiative,37,38 wherein women who were many years
beyond menopause and receiving hormone therapy
were unexpectedly found to be more likely to develop
cardiovascular problems or dementia than women not
receiving hormone therapy.39 In fact, the transitioning
of the longstanding expression ‘‘hormone replace-
ment therapy’’ to the more contemporary expression
‘‘hormone therapy’’ stems from some of the same
considerations as led to the timing hypothesis. That is,
for the present time at least, administration of
exogenous estrogen is recommended more as therapy
for relief of menopausal symptoms than as an elixir
for the pharmacological preservation of youth.40
Many of the reviews in this special issue report on
post-menopausal exogenous hormone use.
In 2011, Shaban Demirel and I published a paper
concerning phytoestrogen consumption and short
wavelength automated perimetry (SWAP) for post-
menopausal women.41 Although this paper appeared
in an ophthalmology journal, it probably was more
important for women’s health, particularly as relates
to the timing hypothesis.42 The results suggested that
consumption of phytoestrogens – non-steroidal estro-
gen-like compounds contained in plant sources such
as soy and flaxseed – could affect visual sensitivity
mediated via SWS cones in a way consistent with the
ability of phytoestrogens to mimic endogenous estro-
gens, albeit progressively more weakly with age until
vanishing altogether by about 60 years. This trend
further suggested (based on previous results refer-
enced in the paper) that measures of SWS-cone-
mediated response might be useful for marking age-
related changes in estrogen-receptor responsivity, and
also that diet might measurably impact at least some
neuronal responses. None of the test subjects were
 4 A. Eisner
using hormone therapy, and the subjects all met a
strict set of eligibility criteria. Hence, the results
illustrated how effects of unknown or uncontrolled
factors may impact outcomes. If diet were the
most salient factor (or even if were not), one can
readily envision how results from one population or
culture might differ from the results of another.
Phytoestrogens might even have some anti-estrogenic
properties among pre-menopausal women.43–45
There are many hidden factors capable of impact-
ing what ostensibly are straightforward male/female
comparisons. What alternative approaches might be
useful for helping to understand effects of sex or
hormonal change among people old enough to be at
some risk for age-related eye disease, yet young
enough so that excellent ocular health and visual
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function are not atypical? One approach is to assess
effects of controlled exogenous hormone administra-
tion, which in principle can be done for either sex, but
in practice is more feasible for women, who more
routinely use hormonal medications while in good
health. It would be possible, for example, to design a
protocol wherein recently post-menopausal women
are recruited for specialized visual function testing
before, during, and after a period of medically
supervised administration of exogenous estrogen.
For personal use only.
However, such a study would be operationally
challenging, and exogenous estrogen could be admin-
istered for only a relatively short duration. What other
approaches may exist? Might it be possible ethically to
assess effects of estrogen deprivation rather than
estrogen supplementation? As discussed next, the
answer is yes, and moreover, the assessments have
their own substantial clinical and scientific value.
Breast Cancer Treatment and Aromatase
Inhibition
A second controversial area in women’s health con-
cerns breast cancer. Although much of the ongoing
debate focuses on screening guidelines,46 this debate
necessarily includes both implicit and explicit consid-
erations bearing on whether and how to treat small
localized pathology in otherwise healthy women,
with risk/benefit deliberations taking into account
both short- and long-term factors.47 There is no simple
nor universally applicable answer. Some women
diagnosed with ductal carcinoma in situ (DCIS)
may even weigh the possibility that the condition
will remain non-invasive.48,49 Presently, several of the
standard-of-care options for post-menopausal women
with early-stage hormone-receptor-positive breast
cancer (including DCIS) include five years daily
administration of an aromatase inhibitor (AI) as
adjuvant therapy to reduce the risk of recurrence.50
Since endogenous estrogens are synthesized or
derived from androgens via actions of the enzyme
aromatase, many women – probably upwards of
100,000 women per year in the United States alone –
are starting treatment with AIs to reduce their
estrogen levels almost to zero.51 This sustained
period of estrogen deprivation raises several ques-
tions. The first is clinical; how is this estrogen
deprivation affecting eye health and vision during
the period of AI use, and what might be the conse-
quence in the long-term, 20 years later for example?
These are pertinent questions for most of the condi-
tions addressed in this special issue (together with
corresponding questions regarding an extended
period of tamoxifen use, now 10 rather than
5 years50). The next question is more basic; what can
we learn about the eye and vision from evaluating
people who are deprived of estrogen?
Detailed information on breast cancer medications
can be found in the Current Eye Research review article
on ‘‘Breast Cancer Medications and Vision: Effects of
Treatments for Early-Stage Disease’’ that I authored
with Shiuh-Wen Luoh in 2011.52 That article discusses
some of the essential distinctions between tamoxifen,
which is a selective estrogen receptor modulator
(SERM), and AIs, which are more aptly described as
anti-estrogens. This distinction between SERMs and
AIs is important and too often confused. The article
also discusses or references some of the various lines
of evidence relating changes in SWS-cone-mediated
response, both foveal and extrafoveal, to changes in
estrogenic activity. One of the major new develop-
ments in breast cancer treatment since 2011 concerns
the expanded use of genomic testing for predicting
risk of recurrence.53 This development already has
substantially reduced the number of women receiving
chemotherapy,54 which consequently makes assess-
ment and research of AI actions and side effects more
directly interpretable.
CONCLUSIONS
Men and women can be affected differentially by a
wide range of ophthalmic disorders, spanning most
ophthalmology subspecialties. For many of these
disorders, the influence of sex hormones and hormo-
nal change may be significant and complex yet
amenable to investigation. The collection of articles
in this special issue is intended to serve as a resource
for eye care professionals as well as health care
providers in other fields, especially those fields
pertaining to women’s health. The information hope-
fully will improve care plus provide impetus and
foundations for future basic and applied research.
DECLARATION OF INTEREST
The author reports no conflicts of interest. The author
alone is responsible for the content and writing of this
paper.
Current Eye Research
 Male/Female Distinctions in Ophthalmic Disorders
HUMAN SUBJECTS AND ANIMAL
WELFARE CONSIDERATIONS
This is a review article containing no new data from
humans or animals.
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