Association Between 17-b-Estradiol and
Interleukin-8 and Visual Field Progression in
Postmenopausal Women with Primary Angle
Closure Glaucoma
SHENGJIE LI, HAICHEN ZHANG, MINGXI SHAO, YINGZHU LI, YUNXIAO SONG, XINGHUAI SUN, AND
WENJUN CAO

PURPOSE: To investigate an association between sex
hormones and inflammatory cytokines, and to determine
whether baseline 17-b-estradiol (E2) and interleukin-8
(IL-8) are associated with visual field (VF) progression
in postmenopausal women with primary angle closure
glaucoma (PACG).

DESIGN: A prospective cross-sectional and cohort
study.

PARTICIPANTS: The cross-sectional study enrolled
200 postmenopausal women with PACG and 151 healthy
postmenopausal women as normal control subjects. A to-
tal of 105 postmenopausal women with PACG were
included and followed up for ‡2 years in the cohort study.

METHODS: All participants were evaluated for levels of
baseline sex hormones (follicle-stimulating hormone,
prolactin, progesterone, testosterone, luteinizing hor-
mone, and E2) and inflammatory cytokines (IL-1, IL-2,
IL-6, IL-8, IL-10, and C-reactive protein) and underwent
VF examinations. The cross-sectional study was conduct-
ed to establish risk factors for postmenopausal women
with PACG using logistic regression analysis. The cohort
study was designed to identify factors that could be used
to predict VF progression in postmenopausal women
with PACG using multivariate Cox regression analyses.
The main outcome measures included factors associated
with VF progression over time.

RESULTS: Decreased E2 (odds ratio 0.88 [95% confi-
dence interval {CI} 0.78-0.99], P [ .007) and increased
IL-8 (odds ratio 1.12 [95% CI 1.01-1.23], P < .001)
levels were risk factors in postmenopausal women with
PACG. A significant negative correlation was observed
Accepted for publication Apr 24, 2020.
From the Department of Clinical Laboratory (S.L., M.S., Y.L., W.C.)
and the Department of Ophthalmology and Visual Science (S.L., X.S.,
W.C.), Eye and ENT Hospital, Shanghai Medical College, the NHC
Key Laboratory of Myopia (S.L., X.S., W.C.), and the State Key
Laboratory of Medical Neurobiology (S.L., X.S., W.C.), Institutes of
Brain Science, Fudan University, Shanghai; Key Laboratory of Myopia
(S.L., X.S., W.C.), Chinese Academy of Medical Sciences; and the
Department of Clinical Laboratory (H.Z., Y.S.), Shanghai Xuhui
Central Hospital, Shanghai, China.
Inquiries to Wenjun Cao, Department of Clinical Laboratory, Eye and
ENT Hospital, Shanghai Medical College, Fudan University, Fenyang
Road 83th, Shanghai 200031, China; e-mail: wgkjyk@aliyun.com
0002-9394/$36.00 © 2020 ELSEVIER INC. ALL
https://doi.org/10.1016/j.ajo.2020.04.033
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between IL-8 levels and E2 (r [ L0.21, P [ .02).
Multivariable regression analyses revealed a significant
correlation between E2 levels and visual field mean devi-
ation (MD) (B [ L0.16, P [ .04 [95% CI L.09
to L.003) and between IL-8 levels and MD (B [ 0.36,
P < .001 [95% CI 0.01-0.02]). During follow-up, 48
(45.71%) patients showed VF progression. Lower base-
line E2 (hazard ratio 0.85 [95% CI 0.82-0.88], P [
.04) and higher baseline IL-8 levels (hazard ratio 1.01
[95% CI 1.00-1.02], P [ .004) were associated with
progression of glaucoma. Patients with lower E2 levels
had a significantly higher rate of PACG progression
(log-rank test P < .001), similar to those with higher
IL-8 levels (log-rank test P [ .04).

CONCLUSIONS: Decreased E2 and increased IL-8 levels
at baseline are significant predictors of VF progression in
postmenopausal women with PACG. (Am J
Ophthalmol 2020;217:55–67. Ó 2020 Elsevier Inc. All
rights reserved.)
P
RIMARY ANGLE CLOSURE GLAUCOMA (PACG), CHAR-
acterized by progressive retinal ganglion cell (RGC)
death and optic neuropathy, is one of the leading
global causes of irreversible blindness.1 Women, particu-
larly older women, represent the majority of PACG cases
worldwide, and contribute to the greatest burden of glau-
coma globally2,3 and in China.4,5 Female patients with
PACG are treated to slow the rate of visual field (VF) pro-
gression; however, the rate of progression is variable. Thus,
it is important to identify the risk factors associated with
this progression. The risk of developing glaucoma in
women is affected by numerous factors, including age,
menopausal stage, and sex hormones.6,7 Numerous studies
hypothesize that estrogens are neuroprotective in neurode-
generative diseases, including glaucoma.8–10 A growing
body of evidence investigating the relationship between
sex hormones and glaucoma has suggested that estrogen
may protect against damage incurred by glaucoma. Feola
and associates11 suggested that estrogen deficiency may
intensify visual impairment after ocular hypertension in
experimental glaucoma. Hulsman and associates12 reported
that early menopause is associated with a higher risk (odds
RIGHTS RESERVED. 55
 ratio [OR] 1.1-2.6) of open-angle glaucoma. Moreover, ac-
cording to a randomized controlled trial, estrogen mono-
therapy is associated with a small but significant
intraocular pressure (IOP) reduction in postmenopausal
women.6 However, no cross-sectional study has examined
the level of sex hormones in postmenopausal women
with PACG; in addition, no longitudinal study has assessed
the relationship between sex hormone levels and rates of
VF loss.
In all probability, the neuroprotective effects of estrogen
comprise a multifactorial combination of diverse neurobio-
logic and signaling mechanisms. Our previous work has
shown that levels of inflammation were significantly higher
in women with PACG than in younger women13; this led
us to hypothesize that estrogens may influence PACG via
their anti-inflammatory properties. The anti-
inflammatory action of estrogens is one of the primary rea-
sons that provide protection against central nervous system
diseases.9 Although many studies have reported that the
levels of inflammatory cytokines of patients with PACG
are significantly increased,14–16 the association between
inflammatory cytokines and VF progression of glaucoma,
and between levels of inflammatory cytokines and sex
hormones, remain unclear.
We hypothesized that decreased sex hormone concen-
trations lead to a hyperinflammatory state, leading to faster
rates of VF damage in postmenopausal women with PACG.
To test this hypothesis, we performed a cross-sectional
study to assess the levels of sex hormones in postmeno-
pausal women with PACG and to analyze the relationship
between sex hormones and inflammatory cytokines. We
also performed a prospective cohort study to assess whether
the baseline levels of sex hormones and inflammatory cyto-
kines could be used to predict VF progression of postmen-
opausal women with PACG.
METHODS
THIS STUDY WAS CONDUCTED AT THE DEPARTMENT OF
Ophthalmology and Visual Sciences, Eye and Ear Nose
and Throat (ENT) Hospital of Fudan University,
Shanghai, China. Institutional Review Board/Ethics Com-
mittee approval was obtained from the Ethics Committee
of the Eye and ENT Hospital, and the study adhered to
the principles of the Declaration of Helsinki. Informed
consent was obtained from all subjects. Both a cross-
sectional study and a prospective cohort study were
performed.

CROSS-SECTIONAL STUDY: From June 2016 to June
2018, postmenopausal women with PACG were recruited
from the Department of Ophthalmology and Visual Sci-
ences at the Eye and ENT Hospital of Fudan University.
Age-matched normal control subjects were consecutively
56 AMERICAN JOURNAL OF OPHTHALMOLOGY
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recruited from subjects who participated in yearly health
screenings during the study period. This cross-sectional
study was performed to compare the levels of sex hormones
and inflammatory cytokines between postmenopausal
women with PACG and normal subjects, and to establish
risk factors for postmenopausal women with PACG.

COHORT STUDY: This cohort study was designed to
assess whether decreased sex hormones and increased in-
flammatory cytokines, which were found in the cross-
sectional study, could be used to predict VF progression
in postmenopausal women with PACG. From June 2016
to December 2017, postmenopausal women with PACG
were recruited from the Department of Ophthalmology
and Visual Sciences at the Eye and ENT Hospital of Fudan
University. All participants visited once every 6 months to
allow regular assessment of PACG disease progression (the
minimum follow-up period was set to 24 months).

DIAGNOSTIC AND INCLUSION CRITERIA: PACG was
diagnosed by a glaucoma specialist. Previously described
diagnostic criteria were used to diagnose PACG.13,17,18
PACG was diagnosed based on narrow anterior chamber
angles with glaucomatous optic neuropathy and corre-
sponding VF loss. VF loss was determined by including a
cluster of >
_3 nonedge contiguous points on the pattern de-
viation plot, which did not cross the horizontal meridian,
and had a probability of <5% of being present in age-
matched controls (one of which was <1%); it had an
abnormal standard deviation pattern with a P < .05 occur-
ring in the normal population, and fulfilled the following
test reliability criteria: <20% fixation losses, <15% false
positives, or <15% false negatives. In addition, PACG
was diagnosed in eyes with narrow angles, elevated IOP
(IOP >21 mm Hg), having > _180 degrees of angle closure
obliterating the pigmented segment of the trabecular mesh-
work, whether synechial, appositional, segmented, or
continuous, and in cases where the degree of peripheral
anterior synechiae was too extensive to be managed by laser
peripheral iridotomy.
The inclusion criteria for PACG subjects and normal
subjects were as follows: postmenopausal women, absence
of any secondary glaucoma or any other eye disease that
could potentially affect visual acuity or the VF, absence
of any intraocular surgery within the previous 2 months,
absence of any systemic diseases including acute infectious
diseases, metabolic syndrome, autoimmune disease, or can-
cer, not taking any medications that could influence their
sex hormone levels. In this study, no patients with
PACG were treated with laser peripheral iridotomy before
entering the study. Most of the patients with PACG
received topical glaucoma medications.
In this cross-sectional study, 89 PACG and 54 normal
control subjects were excluded based on the diagnostic
and inclusion criteria; 15 patients with PACG and 8
normal control subjects who did not complete examination
SEPTEMBER 2020
 FIGURE 1. The flow chart of the cross-sectional and cohort study. IOP [ intraocular pressure; PACG [ primary angle closure
glaucoma; VCDR [ vertical cup-to-disc ratio.

or had missing information were also excluded. In the
cohort study, a total of 38 PACG subjects were excluded
based on the diagnostic and inclusion criteria. During the
follow-up period, 15 and 10 PACG subjects were excluded
and were lost to follow-up, respectively; 6 patients with
PACG with missing information were also excluded.
Finally, a total of 200 subjects with PACG and 151 normal
control subjects were enrolled in the cross-sectional study,
and a total of 105 subjects with PACG were enrolled in the
cohort study. There was no overlap between the cross-
sectional and cohort study participants. Figure 1 depicts
the flow chart of the cross-sectional and cohort studies.

EXAMINATION: Information on clinical data were ob-
tained from patients with PACG who underwent a stan-
dardized ophthalmic examination conducted by a
glaucoma specialist. This examination included the assess-
ment of the anterior chamber angle by gonioscopy (Haag-
Streit, Bern, Switzerland) and a 3-time IOP measurement
using Goldmann applanation tonometry (Haag-Streit),
which was then averaged. The fundus was analyzed using
a digital retinal camera (TRC-NW200, Topcon Medical
Systems, Oakland, New Jersey, USA). An A-scan ultra-
sound (A-Scan Pachymeter, Ultrasonic, Exton, Pennsylva-
nia, USA) was used to measure the central corneal
thickness (CCT), axial length (AL), and anterior chamber
depth (ACD), and the vertical cup-to-disc ratio (VCDR)
was evaluated by 2 doctors based on the analysis of the
fundus photographs, and then averaged. In the normal con-
trol subjects, IOP was measured using Goldmann applana-
tion tonometry (Haag-Streit); other ophthalmic
examinations were not performed.
All subjects underwent medical examinations performed
by respective specialty physicians at the Eye and ENT Hos-
pital of Fudan University. Medical examinations, including
the assessment of electrocardiograms, radiographs, liver
function, blood glucose, infectious diseases, renal function,
blood pressure, heart rate, IOP-lowering medication, body
temperature, height, and weight were performed for all sub-
jects. The BMI was calculated as the weight in kilograms
divided by the height in meters squared. A history of estro-
gen use was also ascertained.
Laboratory testing was performed at the Departments
of Clinical Laboratory, Eye and ENT Hospital of Fudan
University and Xuhui Central Hospital. Blood samples
were obtained in the morning via standard venipuncture
from the antecubital fossae (anterior elbow veins) after
subjects had fasted for 8 hours. Tubes were centrifuged
for 10 minutes at 3000 revolutions per minute. The sam-
ples were measured within 3 hours of collection. Serum
levels of sex hormones (follicle-stimulating hormone,
prolactin, progesterone, testosterone, luteinizing hor-
mone, and E2) were measured using a commercially
available kit (Roche Diagnostics GmbH, Mannheim,
Germany) by sensitive electrochemiluminescence detec-
tion. Serum levels of inflammatory cytokines (IL-1, IL-2,
IL-6, IL-8, and IL-10) were measured using a Siemens
IMMULITE1000 (Munich, Germany) chemilumines-
cence immune analyzer. C-reactive protein (CRP) levels
were measured using a Mindray BS-2000m (Shenzhen,
China) automatic biochemical analyzer. Internal con-
trols were analyzed daily over the 5-year period, with
typical monthly coefficients of variation of 2.1% to
3.8% and no significant changes in the values.

VOL. 217 ASSOCIATION BETWEEN ESTRADIOL AND IL-8 WITH VF PROGRESSION 57

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 TABLE 1. Comparison of Characteristics for Postmenopausal Women with Primary Angle Closure Glaucoma and Normal Subjects

Variable Control Group (n ¼ 151) PACG Group (n ¼ 200) t Value P Value

Age (year), mean 6 SD 64.99 6 9.32 63.43 6 10.90 1.41 .16a

BMI (kg/m2), mean 6 SD 23.77 6 15.41 23.33 6 13.56 0.28 .78a
SBP (mm Hg), mean 6 SD 128.70 6 17.29 127.27 6 19.81 0.70 .48a
DBP (mm Hg), mean 6 SD 70.64 6 9.75 70.74 6 9.94 0.09 .93a
Diabetes, n (%) 13 (8.61) 15 (7.5) 0.14 .70b
Hypertension, n (%) 42 (27.81) 48 (24) 0.66 .42b
Topical glaucoma medications, n (%)
0 – 5 (2.5) – –
1-2 – 62 (31) – –
>2 – 133 (66.5) – –
IOP (mm Hg), mean 6 SD – 20.56 6 17.68 – –
VCDR, mean 6 SD – 0.57 6 0.23 – –
CCT (mm), mean 6 SD – 541.29 6 38.88 – –
ACD (cm), mean 6 SD – 1.92 6 0.58 – –
AL (cm), mean 6 SD – 22.15 6 0.99 – –
MD (dB), mean 6 SD – 13.04 6 8.07 – –
MS (dB), mean 6 SD – 14.32 6 8.23 – –
Prolactin (ng/mL), mean 6 SD 15.19 6 10.40 15.73 6 9.82 0.26 .79a
Luteinizing hormone (mIU/mL), mean 6 SD 20.39 6 12.39 18.17 6 10.21 0.98 .33a
Testosterone (ng/mL), mean 6 SD 0.50 6 0.21 0.69 6 0.91 1.52 .13a
Follicle-stimulating hormone (mIU/mL), 34.99 6 13.69 38.73 6 15.50 1.27 .21a
mean 6 SD
Progesterone (ng/mL), mean 6 SD 1.44 6 1.93 1.29 6 3.09 3.72 <.001c
E2 (pg/mL), mean 6 SD 41.23 6 46.62 28.36 6 33.75 3.71 <.001c
IL-1 (pg/mL), mean 6 SD 5.00 6 0.03 5.86 6 5.13 1.17 .25a
IL-2 (pg/mL), mean 6 SD 405.27 6 113.12 404.53 6 134.17 0.03 .98a
IL-6 (pg/mL), mean 6 SD 2.56 6 1.10 5.06 6 35.19 2.09 .04c
IL-8 (pg/mL), mean 6 SD 24.14 6 43.38 88.48 6 248.86 6.79 <.001c
IL-10 (pg/mL), mean 6 SD 5.04 6 0.30 6.19 6 5.04 1.58 .12b
CRP (pg/mL), mean 6 SD 1.15 6 1.09 2.61 6 4.47 4.47 <.001b

ACD ¼ anterior chamber depth; AL ¼ axial length; BMI ¼ body mass index; CCT ¼ central corneal thickness; CRP ¼ C-reactive protein;
DBP ¼ diastolic blood pressure; E2 ¼ 17-b-estradiol; IOP ¼ intraocular pressure; IL ¼ interleukin; MD ¼ visual field mean deviation; MS ¼ visual
field mean sensitivity; SBP ¼ systolic blood pressure; SD ¼ standard deviation; VCDR ¼ vertical cup-disc ratio.
a
Independent samples t test.
b 2
x test.
c
Mann-Whitney U test.

VF ANALYSIS: Previously described methods were used
for VF analysis.18 The Glaucoma Department of the Eye
and ENT Hospital of Fudan University performed perime-
try in the subjects with glaucoma, unless they were unable
to see any light with both eyes open or suffered from an eye
infection. The mean deviation (MD) and mean sensitivity
of the VFs were measured using an Octopus-automated
perimeter. All patients underwent a minimum of 3 VF tests
each. After considering the learning effect of the VF tests,
the results of the first 2 tests were excluded. Only reliable (a
false positive/negative <15% and a reliability factor
<20%) and compatible VF results were included. VF
testing was performed at both baseline and every 6 months
during follow-up. Patients with PACG were required to
have >_5 reliable VF results, with a follow-up period of >2
years. Previously described methods19 were used for deter-
mination of functional PACG VF progression according
to the event-based analysis modified for Octopus perime-
try20 (satisfying >
_1 of the following criteria): 1) developing
a new scotoma of > _3 nonedge points worsening > _5 dB, or 1
nonedge point worsening > _10 dB; 2) a cluster of > _3
nonedge points with > _10 dB deterioration in a pre-
existing scotoma; 3) developing a new cluster of > _3
nonedge points with 158 around a pre-existing scotoma;
and 4) worsening of the global MD value by > _2 dB per
year. The first progressing eye of each patient was included
for analysis. If both eyes progressed at the same time, the
eye with greater progression was included.

58 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 2020

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 TABLE 2. Comparison of Clinical Characteristics in Normal Subjects, Stratified According to 17-b-Estradiol and Interleukin-8

Variable E2 <20.79 E2 >20.79 P Value IL-8 <18 IL-8 >18 P Value

a
Age (year), mean 6 SD 65.27 6 9.55 64.93 6 9.31 .87 65.48 6 9.85 63.89 6 8.04 .30a
BMI (m2/kg), mean 6 SD 22.06 6 3.10 24.13 6 16.91 .54a 24.03 6 18.27 23.15 6 3.77 .75a
SBP (mm Hg), mean 6 SD 130.57 6 17.25 128.31 6 17.34 .54a 128.77 6 17.73 128.54 6 16.43 .94a
DBP (mm Hg), mean 6 SD 69.35 6 9.98 70.91 6 9.72 .46a 70.81 6 9.78 70.26 6 9.77 .75a
Diabetes, n (%) 3 (12.5) 10 (7.87) .46b 8 (7.69) 5 (10.64) .55b
Hypertension, n (%) 9 (37.5) 33 (25.98) .25b 29 (27.88) 13 (27.66) .98b
Prolactin (ng/mL), mean 6 SD 10.21 6 5.25 15.52 6 10.60 .40c 21.46 6 11.62 13.97 6 9.83 .06c
Luteinizing hormone (mIU/mL), 16.93 6 14.38 20.62 6 12.39 .62a 21.35 6 13.09 15.46 6 6.26 .22a
mean 6 SD
Testosterone (ng/mL), mean 6 SD 0.17 6 0.07 0.52 6 0.19 .004a 0.51 6 0.20 0.41 6 0.22 .21a
Follicle-stimulating hormone (mIU/mL), 30.62 6 16.19 35.27 6 13.67 .57a 34.01 6 13.97 40.03 6 11.59 .26a
mean 6 SD
Progesterone (ng/mL), mean 6 SD 1.00 6 0.43 1.53 6 2.11 .01c 1.37 6 1.80 1.58 6 2.19 .56c
E2 (pg/mL), mean 6 SD 18.90 6 5.47 44.88 6 50.03 <.001c 45.03 6 53.83 32.69 6 18.56 .04c
IL-1 (pg/mL), mean 6 SD 5.00 6 0.00 5.01 6 0.04 .80a 5.01 6 0.04 5.00 6 0.00 .66a
IL-2 (pg/mL), mean 6 SD 392.67 6 91.09 406.17 6 115.40 .84c 405.32 6 113.57 404.75 6 125.28 .99c
IL-6 (pg/mL), mean 6 SD 2.29 6 0.64 2.61 6 1.17 .06c 2.56 6 1.14 2.53 6 1.08 .87c
IL-8 (pg/mL), mean 6 SD 61.47 6 87.65 17.17 6 22.22 .02c 9.76 6 3.47 62.60 6 70.20 <.001c
IL-10 (pg/mL), mean 6 SD 5.02 6 0.19 5.05 6 0.31 .79a 5.04 6 0.32 5.03 6 0.21 .76a
CRP (pg/mL), mean 6 SD 1.60 6 1.77 1.05 6 0.89 .02c 0.98 6 0.81 1.52 6 1.51 .005a

BMI ¼ body mass index; CRP ¼ C-reactive protein; DBP ¼ diastolic blood pressure; E2 ¼ 17-b-estradiol; IL ¼ interleukin; SBP ¼ systolic
blood pressure.
a
Independent samples t test.
b 2
x test.
c
Mann-Whitney U test.

STATISTICAL ANALYSIS: All analyses were performed
using SPSS software (version 13.0; SPSS Inc., Chicago, Il-
linois, USA). The figures were created using GraphPad
Prism 6 software (La Jolla, California, USA). The results
are presented as means 6 standard deviation (SD).
Normality was assessed using a Kolmogorov-Smirnoff
test. Independent Student t, Mann-Whitney U, Fisher
exact, and x2 tests were used to compare patient character-
istics between groups, as appropriate. The primary outcome
measure for the cross-sectional study was the OR for post-
menopausal women with PACG, and the hazard ratios
(HRs) for the progression of glaucoma, according to the
E2 or IL-8 category.
In the cross-sectional study, the associations between sex
hormones and inflammatory cytokines were analyzed using
a Spearman analysis, following which multivariate linear
regression analyses were performed. Logistic regression
analysis was performed to assess the presence of an indepen-
dent association between E2 or IL-8 and the risk of PACG.
The OR and their corresponding 95% confidence intervals
(CIs) were determined using logistic regression models,
adjusted for age, BMI, systolic blood pressure (SBP), dia-
stolic blood pressure (DBP), diabetes (yes ¼ 1, no ¼ 0), hy-
pertension (yes ¼ 1, no ¼ 0), number of topical glaucoma
medications, follicle-stimulating hormone, prolactin,
testosterone, luteinizing hormone, IL-1, IL-2, and IL-10.
We categorized study participants into 2 groups based on
their median levels of E2 and IL-8, respectively. In the
cohort study, univariate and multivariate Cox proportional
hazards analyses were used to analyze the association be-
tween baseline sex hormones and inflammatory cytokines
with PACG progression. Cox proportional hazards models
were used to obtain HRs and to identify baseline factors
that identified subjects who would be classified into the
nonprogressing PACG group during the follow-up period,
adjusted for age, BMI, SBP, DBP, diabetes (yes ¼ 1, no ¼
0), hypertension (yes ¼ 1, no ¼ 0), number of topical glau-
coma medications, VCDR, ACD, AL, CCT, IOP, MD,
follicle-stimulating hormone, prolactin, testosterone, pro-
gesterone, luteinizing hormone, IL-1, IL-2, IL-6, IL-10,
and CRP. Survival outcomes (time to confirmed VF pro-
gression) were assessed using Kaplan-Meier plots, and the
log-rank test was used to assess differences between the
curves. P < .05 was considered statistically significant.
RESULTS

CROSS-SECTIONAL STUDY: According to the screening
criteria, a total of 200 postmenopausal women with
PACG and 151 normal control subjects were enrolled in

VOL. 217 ASSOCIATION BETWEEN ESTRADIOL AND IL-8 WITH VF PROGRESSION 59

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 FIGURE 2. Univariate (A) and multivariate (B) logistic regression analyses to identify risk factors for postmenopausal women with
primary open-angle glaucoma compared with control subjects. (C) Univariate Cox proportional hazards regression analysis and (D)
multivariate Cox proportional hazards regression analysis to assess the value of baseline parameters associated with progression of
primary open-angle glaucoma. ACD [ anterior chamber depth; AL [ axial length; BMI [ body mass index; CCT [ central corneal
thickness; CI [ confidence interval; CRP [ C-reactive protein; DBP [ diastolic blood pressure; FHS [ follicle-stimulating hor-
mone; IL [ interleukin; IOP [ intraocular pressure; LH [ luteinizing hormone; MD [ mean deviation; OR [ odds ratio; SBP [
systolic blood pressure; VCDR [ vertical cup-to-disc ratio.

this study. Only 1 eye was randomly selected in cases of
bilateral PACG. Table 1 summarizes the demographic
and ocular characteristics of the PACG and control groups.
The mean serum levels of progesterone and E2 among
postmenopausal women in the PACG group were signifi-
cantly lower than those in the control group (P < .001,
Table 1). Postmenopausal women with PACG had signifi-
cantly higher levels of IL-6, IL-8, and CRP than normal
control subjects (P < .05, Table 1).
Based on the level of E2 and IL-8, the normal subjects
were categorized into E2 <20.79 and E2 >20.79 and IL-8
<18 and IL-8 >18 subgroups. Table 2 summarizes the de-
mographic and ocular characteristics of normal subjects
in the E2 and IL-8 subgroups.
Logistic regression analyses were performed to assess the
association between sex hormone and inflammatory cyto-
kine levels in postmenopausal women with PACG and
control subjects (Figure 2, A and B). Multivariate logistic
regression analyses demonstrated an association between
E2 (OR 0.88 [95% CI 0.78-0.99], P ¼ .007), CRP (OR
1.39 [95% CI 1.18-1.65], P < .001), and IL-8 (OR 1.12
[95% CI 1.01-1.23], P < .001) levels with PACG in post-
menopausal women.
Spearman analysis showed a statistically significant
negative correlation between IL-8 levels and E2
(r ¼ 0.21, P ¼ .03). In addition, there was a statistically
significant correlation between IL-8 levels and IOP (r ¼
0.18, P ¼ .01), IL-8 levels and VCDR (r ¼ 0.28, P <
.001), and IL-8 levels and MD (r ¼ 0.42, P < .001). Finally,
there was a statistically significantly correlation between
E2 levels and MD values (r ¼ 0.16, P ¼ .04, Table 3).
Furthermore, multivariable regression analyses revealed
a significant correlation between E2 levels and MD values
(B ¼ 0.16, P ¼ .04 [95% CI .09 to .003]) and IL-8
levels and MD values (B ¼ 0.36, P < .001 [95% CI 0.01-
0.02], Table 4).

COHORT STUDY: A total of 105 postmenopausal women
with PACG were included. Among them, 48 (45.71%)
showed progression of glaucoma as measured by VF.
Table 5 summarizes the demographic and ocular character-
istics of the VF progressed and VF nonprogressing groups at
baseline.
At baseline, there were no significant between-group dif-
ferences in age, BMI, SBP, DBP, diabetes, hypertension,
follow-up period, number of topical glaucoma medications,
IOP, VCDR, CCT, ACD, AL, MD, progesterone, IL-6, or
CRP (P < .05). The mean serum levels of E2 in the progres-
sion group were significantly lower than the nonprogressing
group (P < .001), and the mean level of IL-8 was

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 TABLE 3. Spearman Analysis for Associations Between Blood Levels and Ocular Parameters

Variable Progesterone E2 IL-6 IL-8 CRP

PACG subjects
IOP R ¼ 0.08 R ¼ 0.08 R ¼ 0.08 R ¼ 0.18a R ¼ 0.08
VCDR R ¼ 0.16a P ¼ .03 R ¼ 0.19a R ¼ 0.28b R ¼ 0.10
MS R ¼ 0.13 R ¼ 0.18a R ¼ 0.51b R ¼ 0.43b R ¼ 0.29b
MD R ¼ 0.14 R ¼ 0.16a R ¼ 0.50b R ¼ 0.42b R ¼ 0.29b
Normal subjects
Progesterone R ¼ 0.23b R ¼ 0.02 R ¼ 0.01 R ¼ 0.01
E2 R ¼ 0.04 R ¼ 0.21a R ¼ 0.10a
IL-6 R ¼ 0.02 R ¼ 0.16
IL-8 R ¼ 0.09

IL ¼ interleukin; E2 ¼ 17-b-estradiol; IOP ¼ intraocular pressure; VCDR ¼ vertical cup-disc ratio; MD ¼ visual field mean deviation; MS ¼
visual field mean sensitivity.
a
P < .05
b
P < .01.

significantly higher in the former group (P ¼ .003,
Table 5).
PACG subjects were categorized into >20.79 and
<20.79 and >18 and <18 groups based on the median
baseline levels of E2 and IL-8, respectively. Figure 3 repre-
sents the mean MD levels and mean change in MD be-
tween groups at different points during follow-up. In the
E2 <20.79 group, the mean MD level was significantly
higher than in the E2 >20.79 group at baseline and during
the entire follow-up period (P < .001). During the follow-
up period, the mean change in the level of MD in the
E2 <20.79 group was significantly greater than that in
the E2 >20.79 group (P < .001). The mean MD level
was significantly lower in the IL-8 <18 than in the IL-8
>18 group during the entire follow-up period (P < .001),
but not at baseline. In the IL-8 <18 group, the mean
change in the MD level was significantly smaller than those
in the IL-8 >18 group at 12, 18, and 24 months (P < .001).
To assess the value of baseline parameters associated
with progression of PACG, we performed a Cox propor-
tional hazards regression analysis (Figure 2, C and D).
Lower baseline E2 (HR 0.85 [95% CI 0.82-0.88], P ¼
.04) and higher baseline IL-8 levels (HR 1.01 [95% CI
1.00-1.02], P ¼ .004) were associated with glaucoma pro-
gression, as measured by VF on multivariate Cox analysis.
Figure 4 shows the Kaplan-Meier survival curves. The
survival analysis indicated that a significantly higher pro-
portion of patients with E2 <20.79 (log-rank test P <
.001) and IL-8 >18 experienced progression of PACG
(log-rank test P ¼ .04). Furthermore, a significantly higher
proportion of patients with E2 >20.79 and IL >18 experi-
enced progression of PACG (log-rank test P ¼ .04) than
those with E2 >20.79 and IL <18, respectively, and a
higher percentage of patients with E2 <20.79 and IL
>18 demonstrated progression of PACG (log-rank test
P ¼ .12) than those with E2 <20.79 and IL <18,
respectively.
DISCUSSION
THIS STUDY REVEALED THAT E2 LEVELS AT BASELINE WERE
decreased in postmenopausal women with PACG and glau-
coma progression, as measured by VF. Patients with
decreased baseline E2 levels had a significantly faster rate
of VF progression. Moreover, IL-8 levels at baseline were
increased in postmenopausal women with PACG and
with progression of glaucoma, as measured by VF. At base-
line, E2 levels were significantly negatively correlated with
IL-8 levels, and as measured by VF, baseline levels of E2
were more useful in predicting glaucoma progression than
IL-8. Our findings suggest that baseline E2 was associated
with glaucoma progression in postmenopausal women
with PACG. Given that VF progression plays a key role
in patients’ quality of life, this result is clinically significant
in terms of its relevance to the prevention, treatment, and
prognosis of glaucoma.
Sex hormone levels, and estrogen levels in particular, are
believed to play an important role in brain aging and
neurodegeneration, and have been regarded as major
neuroprotectants in various diseases of the central nervous
system.9,21,22 For instance, Rentz and associates23 reported
that higher E2 levels were associated with better Selective
Reminding Test performance and were marginally associ-
ated with better performance on the Face-Name Associa-
tive Memory Exam. Imtiaz and associates24 performed a
20-year follow-up study, and showed that long-term self-re-
ported postmenopausal hormone therapy was associated
with reduced Alzheimer disease risk. Zsido and associates25

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 TABLE 4. Multiple Linear Regressions for Associations Between Visual Field Mean Deviation Levels and Blood Parameters in
Postmenopausal Women with Primary Angle Closure Glaucoma

Variable B t Value P Value 95%CI

Model A
BMI 0.11 1.41 .16 0.02 to 0.14
SBP 0.09 1.13 .26 0.03 to 0.11
DBP 0.14 1.83 .08 0.01 to 0.23
Diabetes 0.04 0.47 .64 3.46 to 5.59
Hypertension 0.08 0.99 .32 4.39 to 1.44
Number of topical glaucoma medications 0.13 1.47 .14 0.04 to 0.09
Follicle-stimulating hormone 0.03 0.19 .85 0.13 to 0.16
Prolactin 0.02 0.12 .91 0.23 to 0.25
Testosterone 0.14 0.94 .35 1.33 to 3.65
Luteinizing hormone 0.04 0.28 .78 0.19 to 0.26
Progesterone 0.07 2.47 .02 0.03 to 0.01
E2 0.17 3.19 .002 0.003 to 0.001
IL-1 0.12 0.83 .41 0.64 to 0.27
IL-2 0.23 1.51 .14 0.004 to 0.03
IL-6 0.07 2.78 .006 0.05 to 0.29
IL-8 0.16 3.00 .003 0.000 to 0.001
IL-10 0.15 1.02 .32 0.23 to 0.69
CRP 0.22 4.12 <.001 0.02 to 0.05
Model B
Progesterone 0.08 0.94 .35 1.19 to 0.42
E2 0.16 2.11 .04 0.09 to 0.003
IL-6 0.16 2.15 .03 0.003 to 0.07
IL-8 0.36 4.62 <.001 0.01 to 0.02
CRP 0.19 2.58 .01 0.07 to 0.55

IL ¼ interleukin; E2 ¼ 17-b-estradiol; BMI ¼ body mass index; SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure.
Model A adjusted for age. Model B adjusted for age, BMI, SBP, DBP, diabetes (yes ¼ 1, no ¼ 0), hypertension (yes ¼ 1, no ¼ 0), number of
topical glaucoma medications, follicle-stimulating hormone, prolactin, testosterone, luteinizing hormone, IL-1, IL-2, and IL-10.

also found that low E2 levels were associated with lower
memory network covariance and worse memory perfor-
mance in midlife female women. Interestingly, we observed
similar findings; low E2 levels were associated with a higher
risk of PACG and a faster rate of glaucoma progression in
postmenopausal women. These findings indicate the
importance of E2 in brain aging and neurodegeneration.
The Rotterdam study recently showed that women who
underwent menopause before reaching the age of 45 had a
higher risk of having open-angle glaucoma (OR 2.6 [95%
CI 1.5-4.8]) and suggested that early menopause was asso-
ciated with a higher risk of open-angle glaucoma.12 Jojua
and associates26 reported that E2 levels were decreased in
women aged 45 to 65 years of age with open-angle glau-
coma. In conjunction, these current results and those of
the previous study indicate that low estrogen levels are a
risk factor for the occurrence of glaucoma. However, no
study has yet reported whether low estrogen levels were a
risk factor for PACG.
Several studies have focused on the importance of hor-
mone therapy in the development or progression of glau-
coma.27–29 A retrospective longitudinal cohort analysis
sought to determine whether the use of postmenopausal
hormones would affect the risk of primary open-angle glau-
coma.27 In this study, 2925 (1.9%) of 152 163 eligible
enrollees developed POAG, and each additional month
of E2 was associated with a 0.4% reduced risk (HR 0.99,
P ¼ .02). Moreover, Vajaranant and associates29 found
that hormone therapy containing estrogen, but not a com-
bination of estrogen and progesterone, reduced the risk of
open-angle glaucoma among African American women.
Animal models have shown that E2 eye drops protect the
RGC layer and preserve visual function.8
A previous study suggested that hormone therapy
reduced the risk of glaucoma; however, to date no study
has assessed the individual effects of E2 on glaucoma prog-
nosis, particularly in PACG. Our findings suggest that
decreased baseline E2 levels were linked to a significantly
faster rate of VF progression in postmenopausal women
with PACG. This was consistent with earlier results, which
showed that high levels of E2 could prevent the develop-
ment or progression of glaucoma. Our results lead to a crit-
ical question: what is the role of E2 in the progression of
postmenopausal women with PACG? The role of E2 in

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 TABLE 5. Baseline Demographic and Disease Characteristics of Subjects

Variable No Progression (n ¼ 57) Progression (n ¼ 48) t Value P Value

Age (year) 66.51 6 6.89 66.88 6 7.04 0.27 .79a

BMI (kg/m2) 22.42 6 3.27 23.01 6 4.02 0.82 .42a
SBP (mm Hg) 127.20 6 14.67 132.56 6 18.27 1.66 .10a
DBP (mm Hg) 70.14 6 9.81 69.60 6 9.87 0.28 .78a
Diabetes, no. (%) 5 (8.77) 4 (8.33) 0.01 .93c
Hypertension, no. (%) 16 (28.07) 17 (35.42) 0.65 .42c
Follow up period (months) 28.12 6 3.23 30.38 6 4.41 3.03 .003a
Number of topical glaucoma medications,
no. (%)
0 1 (1.75) 0 (0)
1-2 18 (31.58) 20 (41.67)
>2 38 (66.67) 28 (58.33) 1.86 .39c
IOP (mm Hg) 17.20 6 9.23 22.93 6 30.42 1.34 .18b
VCDR 0.52 6 0.21 0.53 6 0.22 0.26 .80a
CCT (mm) 541.37 6 37.25 545.52 6 41.95 0.52 .61a
ACD (cm) 1.93 6 0.61 1.94 6 0.61 0.11 .91a
AL (cm) 21.89 6 1.09 22.18 6 1.07 1.31 .19a
MD (dB) 10.17 6 6.85 11.62 6 6.78 1.08 .28a
MS (dB) 18.01 6 5.66 17.54 6 6.03 0.41 .68a
Progesterone (ng/mL) 0.81 6 0.58 0.84 6 0.59 0.27 .79b
E2 (pg/mL) 25.61 6 14.67 15.07 6 12.47 3.92 <.001b
IL-6 (pg/mL) 2.48 6 1.03 2.68 6 1.47 0.59 .56b
IL-8 (pg/mL) 21.35 6 17.36 70.52 6 119.60 3.07 .003b
CRP (pg/mL) 2.53 6 3.42 3.06 6 7.26 0.50 .62b

IL ¼ interleukin; E2 ¼ 17-b-estradiol; BMI: body mass index; SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure; IOP ¼ intra-
ocular pressure; VCDR ¼ vertical cup-disc ratio; CCT ¼ central corneal thickness; ACD ¼ anterior chamber depth; AL ¼ axial length; MD ¼
visual field mean deviation; MS ¼ visual field mean sensitivity.
a
Independent-samples t test
b
Mann-Whitney Test
c 2
x test.

preventing VF progression remains unclear. The hypothet-
ical mechanisms behind the glaucoma RGC-protective ef-
fects of estrogen include its anti-inflammatory actions,
regulation of microvasculature and blood–retinal barrier,
maintenance of mitochondrial function, free-radical scav-
enging, cellular maintenance and survival, synaptic and
structural plasticity, and impact on the cholinergic neuro-
transmitter system.9 In this study, postmenopausal women
with PACG had significantly high levels of IL-6, IL-8, and
CRP, and IL-8 and E2 levels were significantly negatively
correlated. Conversely, patients with higher IL-8 levels
had a significantly higher rate of progression of PACG.
In addition, patients with higher levels of both E2 and
IL-8 had a significantly higher rate of progression of
PACG than those with higher E2 and lower IL-8; patients
with lower E2 and higher IL-8 levels had a higher rate of
progression of PACG than those with lower E2 and lower
IL-8. The results indicate that IL-8 plays a role in the causal
pathway from E2 levels to PACG/PACG progression. In
glaucoma eyes with pseudoexfoliation, IL-8 was found to
have the highest OR, and its levels also correlated signifi-
cantly with VF defects.30 Estrogen may directly regulate cy-
tokines, partly by reducing cytokine levels in the spinal
cord.31 Several studies have also suggested that estrogen
is associated with a decreased inflammatory response.32–34
For instance, Spence and associates32 showed that estrogen
mediates its neuroprotective and anti-inflammatory effects
by decreasing the expression of the chemokines CCL2 and
CCL7 during experimental autoimmune encephalomy-
elitis, through estrogen receptor a signaling on astrocytes.
Meister and associates34 reported that urine inflammatory
scores and IL-6 decreased significantly after initiating
vaginal estrogen therapy in postmenopausal women with
recurrent urinary tract infections. Estrogen receptors a
and b are abundantly expressed throughout the eye, and
in the retina in particular.35 Therefore, E2 may directly
reduce cytokine levels in either the retina alone or
throughout the entire glaucoma-affected eye to protect
from damage to RGCs. In addition, E2 and IL-8 may influ-
ence PACG and its progression through indirect effects on
angle anatomy. Green and associates36 reported that the
sustained elevated hormonal levels during pregnancy cause

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 FIGURE 3. Comparison of the mean level of visual field mean deviation and mean change of visual field mean deviation between
groups at the different follow-up times. E2 [ 17-b-estradiol; IL-8 [ interleukin-8.

an increase in fluid outflow from the eye. Moreover,
Mookherjee and associates37 reported that lacking E2
metabolizing activity may induce myocilin upregulation
in trabecular meshwork cells; this may cause dysfunction
of the trabecular meshwork.38 Several studies observed
significantly higher levels of IL-8 in the aqueous humor
of patients with glaucoma compared with control sub-
jects,14,30 and trabecular meshwork cells are known to
secrete IL-8.39 It has also been reported that IL-8 modulates
the permeability of the Schlemm canal endothelial cells.40
These results may indicate that E2 and IL-8, may influence
PACG and its progression either directly or indirectly, by
influencing the structure of the anterior chamber angle
(the trabecular meshwork and the Schlemm canal).
The pathogenesis of glaucoma remains unclear; howev-
er, older age, elevated IOP, thinner CCT, and moderate
severity are risk factors for glaucomatous progression.41,42
However, in this study, none of the above parameters at
baseline were related to VF progression. One explanation
for this difference is that most patients with PACG
continued antiglaucoma treatment during the follow-up
period and received potentially more aggressive treatment
in response to elevated IOP, thinner CCT, and worse MD.
Thus, the antiglaucoma treatment probably eliminated
these risk factors. Second, the characteristics of the study
population differed from that of previous studies. In the
present study, the average age of postmenopausal women
with PACG was nearly 68 years; this was higher than
that of other studies.
Our study has several limitations. First, it had a relatively
short follow-up period (2 years). Second, it was conducted
in a single center; therefore, our results may be not appli-
cable to other populations. Third, in this study, the vast
majority of cases had the disease for a long duration, and

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 FIGURE 4. Kaplan-Meier curves stratified by the median value in terms of 17-b-estradiol (E2) and interleukin-8 (IL-8).

received medications. Thus, the results may have been
either affected by changes in behavior consequent to the
knowledge of their disease status, or by any kind of treat-
ment. Fourth, although baseline E2 and IL-8 levels were
associated with VF progression, E2 and IL-8 interact with
several other factors, including mediators; this does not
necessarily imply that modifying them alone will result in
protective effects. Finally, spectral-domain optical coher-
ence tomography was only performed at baseline and not
during the follow-up period. Therefore, further multicen-
tric studies on glaucoma prognosis with a longer follow-
up period are warranted. In conclusion, the results showed
that decreased E2 and increased IL-8 levels at baseline are
significant predictors of VF progression in postmenopausal
women with PACG. Moreover, there was a negative corre-
lation between the E2 and IL-8 levels. These findings sug-
gest that high levels of estrogen may retard glaucoma-
related VF progression via its anti-inflammatory effect.
Further prospective multicenter longitudinal studies are
warranted to elucidate the underlying mechanisms.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST.
Funding/Support: Supported by Shanghai Sailing Program (18YF1403500), Shanghai Municipal Commission of Health and Family Planning
(20174Y0169), Shanghai Municipal Commission of Health and Family Planning (201840050), The State Key Program of National Natural Science Foun-
dation of China (81430007), the Subject of Major Projects of National Natural Science Foundation of China (81790641), The Shanghai Committee of
Science and Technology, China (17410712500), and the Top Priority of Clinical Medicine Center of Shanghai (2017ZZ01020), Shanghai Science and
Technology Committee Foundation grant (19411964600). Financial Disclosures: The authors indicate no financial conflicts of interest. All authors attest
that they meet the current ICMJE criteria for authorship.

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