Daily fluctuations in ocular surface symptoms during the normal menstrual cycle and with the use of oral contraceptives

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The Ocular Surface journal homepage: www.elsevier.com/locate/jtos

Original Research

Daily fluctuations in ocular surface symptoms during the normal menstrual cycle and with the use of oral contraceptives Archana Bogaa,∗, Fiona Stapletona, Nancy Briggsa,b, Blanka Golebiowskia a b

School of Optometry and Vision Science, UNSW, Sydney, NSW, 2052, Australia The Mark Wainwright Analytical Centre, UNSW, Sydney, NSW, 2052, Australia

A R T I C LE I N FO

A B S T R A C T

Keywords: Estrogen Menstrual cycle Ocular surface symptoms Oral contraceptive pill Dry eye Instant symptoms assessment

Purpose: Women are more prone to ocular surface symptoms and circulating estrogen levels have been implicated. Fluctuations in estrogen during the menstrual cycle may influence ocular symptoms but existing research is incomplete and conflicting, partly due to paucity of validated questionnaires to assess daily ocular symptoms. This study aimed to evaluate daily fluctuations in ocular symptoms across a complete menstrual cycle and to compare symptoms in normally menstruating women and women using the combined oral contraceptive pill (OCP). Methods: To do this, a short online tool to assess daily symptoms was developed. 36 normally menstruating women and 36 women using the combined OCP were recruited. A two-item questionnaire, the Instant Ocular Symptoms Survey (IOSS) was developed and administered on a smartphone platform every day for 40 days. Linear mixed model analysis was used to examine differences in symptom scores over time and between groups. Results: The IOSS was found to be effective for measuring instantaneous symptoms, exhibiting good diagnostic abilities and repeatability. (AUC ± SE = 0.80 ± 0.07 and ICC = 0.75). Daily ocular symptoms showed a cyclic fluctuation across the cycle (p = 0.004) and highest symptoms were recorded on day 2 of the cycle when estrogen levels are lowest. Symptom scores were significantly higher in the OCP group (p = 0.02). Conclusions: Effects of menstrual phase and OCP use should be considered in the interpretation of ocular symptoms in clinical practice. These findings enhance the current understandings of ocular surface and systemic pain during menstrual cycle.

1. Introduction Women are more prone than men to dry eye and the associated symptoms of ocular surface discomfort throughout their life [1,2]. Sex hormone levels are likely to play an important role in dry eye and ocular pain symptoms in women, including changes in estrogen levels that occur during menopause and with the menstrual cycle [2–5]. Estrogen is shown to influence the structure and function of all ocular surface tissues and may play a role in the tear production [2,4,6]. Variations in estrogen levels during the menstrual cycle have been demonstrated to influence pain in migraine, [7] temporomandibular pain [8] and sensitivity of the lower limb to electric pain stimuli [9]. Increased systemic pain sensitivity and low pain tolerance are associated with symptoms of dry eye in women [10]. Fluctuations in estrogen levels which occur during the normal menstrual cycle may influence ocular surface symptoms and

physiology. Increased ocular discomfort and ocular surface clinical signs including reduced tear production, enhanced conjunctival epithelial cell maturation, decreased conjunctival goblet cell count and both increased and decreased corneal sensitivity, have been shown to occur during the estrogen peak at ovulation [11–13]. In contrast, other studies have reported increased symptoms during the late luteal phase [14] and no significant effects of the menstrual cycle on dry eye symptoms, tear production or osmolarity [15–17]. Studies of menstrual cycle effects on the ocular surface have been limited by small sample sizes, selective testing time points across the menstrual cycle and variations in the staging of menstrual cycle phases. The existing evidence is consequently inconsistent and incomplete. Normal estrogen levels are altered by use of the oral contraceptive pill (OCP) which suppress ovulation by lowering serum estrogen levels throughout the menstrual cycle [18,19]. OCP use has been linked to increased ocular symptoms of discomfort and dryness in contact lens

∗

Corresponding author. School of Optometry and Vision Science, University of New South Wales, NSW, 2052, Australia. E-mail addresses: [email protected] (A. Boga), [email protected] (F. Stapleton), [email protected] (N. Briggs), [email protected] (B. Golebiowski). https://doi.org/10.1016/j.jtos.2019.06.005 Received 12 December 2018; Received in revised form 20 May 2019; Accepted 17 June 2019 1542-0124/ © 2019 Published by Elsevier Inc.

Please cite this article as: Archana Boga, et al., The Ocular Surface, https://doi.org/10.1016/j.jtos.2019.06.005

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List of abbreviations IOSS OCP OCI OSDI ROC

AUC SE ICC LMM FSH LH

Instant Ocular Symptoms Survey Oral Contraceptive Pill Ocular Comfort Index Ocular Surface Disease Index Receiver Operating Characteristic

Area Under Curve Standard Error Intra Class Correlation Linear Mixed Model Follicle Stimulating Hormone Luteinizing Hormone

of 1.3 in OSDI symptom scores between the phases of the menstrual cycle determined in a previous study [14]. For 80% power at alpha = 0.05 and an effect size = 0.71, a minimum of 32 participants were required in each group. Four additional participants were recruited in each group to compensate for unexpected discontinuations during the study period.

wearers, [20–22] and increased conjunctival goblet cell count [13]. No significant effects have been reported on corneal sensitivity or tear physiology [12,23,24]. Earlier studies of ocular surface symptoms during the menstrual cycle examined fluctuation in ocular symptoms only during selected days or partial phases of the cycle. A paucity of validated questionnaires designed to assess ocular symptoms daily or instantaneously has resulted in a lack of studies which report symptoms over the entire course of the menstrual cycle. Existing dry eye questionnaires are designed to diagnose and monitor ocular surface symptoms over a longer term (one week to one month) [25]. These include commonly used questionnaires such as the Dry Eye Questionnaire (DEQ and DEQ5), [26,27] the Ocular Comfort Index (OCI) [28] and the Ocular Surface Disease Index (OSDI) [29]. This study aimed to evaluate daily fluctuations in ocular symptoms across a complete menstrual cycle and to compare symptoms in normally menstruating women and women using the combined oral contraceptive pill. In order to do this, an instant ocular surface symptoms tool was developed and validated.

2.2. Procedures 2.2.1. IOSS questionnaire validation Participants completed the IOSS plus the OSDI and OCI questionnaires online using their smartphones on the first day of the study “Visit 1”. Visit 1 could occur on any day of the menstrual cycle. The Instant Ocular Symptoms Survey (IOSS) comprises two items to elicit intensity of ocular surface dryness and discomfort (Fig. 1). The items are rephrased versions of questions 1b and 2b of the short form of the Dry Eye Questionnaire (DEQ5) [27], which were used with permission. The total IOSS score was calculated from the sum of the scores for the two items, with a maximum of 10 which represented the greatest discomfort.

2. Methods 2.2.2. Assessment of daily symptoms across the menstrual cycle Following Visit 1, participants completed the IOSS on their smartphones each day for 40 consecutive days. A period of 40 days was chosen to capture the beginning and end of one complete menstrual cycle. Participants were prompted to complete the IOSS by an SMS message sent to their mobile phone at 4 p.m. each day and were required to complete the IOSS before 8 p.m. Participants that failed to complete by 7 p.m. were prompted by a further reminder SMS. In addition to the two IOSS items, the daily questionnaire included the question “Are you menstruating today” (Fig. 1); The first day on which participants answered yes to this question was considered as Day 0 for the purposes of this study. The length of one complete menstrual cycle for each participant was calculated as the number of days from Day 0 until the start of the next menstruation. To mitigate response bias, participants were not informed of the expected outcomes, recruitment was carried out independent of their menstrual status and the question “Are you menstruating today” was asked after the symptoms questions. The time and date of each response were automatically recorded.

This was a prospective, observational, longitudinal study of normally menstruating women and those using the combined oral contraceptive pill, observed over 40 days. Questionnaire development and validation were conducted on the first day of the study and first three consecutive days of the menstrual cycle. This study was approved by the Human Research Ethics Advisory Panel, UNSW Sydney, and conducted in compliance with national legislation and the code of ethical principles for medical research involving human subjects (Declaration of Helsinki). All participants provided informed consent prior to the commencement of the study. 2.1. Participants Seventy-two participants, including 36 normally menstruating women and 36 women using the combined oral contraceptive pill were recruited into the study. Combined OCP is the more commonly used type of OCP among women with an estimated worldwide use prevalence of 8.8%–15.4% [30]. Participants included students, staff and members of the UNSW community. Participants who had severe symptoms based on the Women's Health Study questionnaire [31] and or a previous clinical diagnosis of dry eye were excluded. Regular contact lens wearers (more than 3 days per week) were excluded. Other exclusion criteria included patient-reported menstrual cycle parameters outside the normal range (defined as length of cycle 24–35 days with 4–6 menstruating days [32]), polycystic ovary syndrome, premature menopause, use of hormone-based contraception other than the combined OCP in the past three months; change in type of combined OCP within the last three months; in vitro fertilisation (IVF) treatment, pregnancy or breastfeeding in the last one year; recent use (within last three months) of ocular or systemic medication likely to affect the ocular surface (eg: anti-acne, antihistamine, corticosteroid, chemotherapy, antipsychotic and anti-depressant medication). The sample size was calculated using G*power 3.0.10 (Heinrich Heine University Düsseldorf, Germany) based on the smallest difference

2.3. Statistical analysis IOSS, OCI and OSDI data were tested for normality using the Shapiro-Wilk test (p < 0.05). SPSS Statistics (version 24, 2016. Armonk, NY, USA) was used for all analyses other than where indicated. 2.3.1. IOSS questionnaire validation Construct validity of the IOSS was assessed by examining the associations between IOSS scores and OCI and OSDI scores at Visit 1 using Spearman's rank correlation. Criterion validity of the IOSS was assessed using Receiver Operating Characteristic (ROC) curve analysis to determine its ability to classify participants without a prior diagnosis of dry eye into asymptomatic and symptomatic groups based on their responses to the Women's Health Study dry eye questionnaire [31]. ROC analysis was performed using MedCalc Statistical Software 2

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groups based on their day of the menstrual cycle at Visit 1: menstrual phase group (Days 0–5), follicular phase group (Days 6–14) and luteal phase group (Days 15–28), and differences in cross-sectional group symptom scores of IOSS, OCI and OSDI questionnaires were examined using Kruskal-Wallis analysis of variance. 2.3.2. Assessment of daily symptoms across the menstrual cycle In order to control for differences in cycle lengths and number of menstruating/bleeding days between participants, all study data was scaled to a 28-day cycle. As participants were followed for 40 consecutive days, this included more than one complete cycle and thus two measurements for some days of the cycle. Correlation due to repeated observations within the same individual was accounted for in the models, with a random effect for individual. 2.3.2.1. Model development. A Linear Mixed Model (LMM) with a random effect for person was used to analyze cyclic fluctuations in IOSS scores in the normally menstruating and OCP groups over a 28day period, using the lmer and bootMer functions in R software (version 3.3.1, 2016 - "Bug in Your Hair"). Menstrual cycle length amongst participants was rescaled to a 28-day cycle using the formula. The rescaled day values were used in subsequent analyses.

Day of cycle ⎞ Rescaled Day = ⎜⎛ ⎟ × 28 ⎝ Length of cycle ⎠ Four LMM models were developed which assessed cyclic changes in IOSS score for individual participant on the day of menstrual cycle j using cosine and sine functions. First, a model showing only linear change over time was run (Model 0) as a basis to show that a cyclic component to change was warranted. Then, three models were examined for their best fit to the study data. Model 1 considered all participants together and included a single cyclic curve for both study groups. Model 2 considered separate, parallel cyclic curves for normally-menstruating women and those using OCP. Model 3 considered the interaction between groups in addition to the change in shape of the cyclic curve of both the groups. The models developed were: Model 0: Random Intercept, Linear Change over Time

IOSSij = β0 + β1 dayij + εij Fig. 1. Smartphone layout of questionnaire administered to study participants each day. The Instant Ocular Symptoms Survey (IOSS) is a sum of the responses to questions 2 and 3.

β0 = b0i + τ0j

τ0j ∼ N (0, σ02), εij ∼ N (0, σ2)

(version 18.10.2, 2018, Ostend, Belgium) The asymptomatic group included participants who responded “never” to both symptom questions of this questionnaire. The symptomatic group included participants who responded “sometimes” or “often” but not “constantly” to at least one symptom question. The Area Under Curve (AUC) represents the accuracy of each questionnaire to separate the asymptomatic and symptomatic groups. An area of 1 represents a perfectly accurate test and 0.5 represents very poor accuracy. Agreement between repeat IOSS measurements over the first three consecutive days of the menstrual cycle (when systemic levels of estrogen are low and relatively stable), [33] was examined by calculating Intraclass Correlation Coefficient (ICC). These days in the menstrual cycle were utilized for testing repeatability to minimize the impact of variability due to factors other than a change in symptoms. ICC values between 0.0 and 0.4 are indicative of poor reliability, values between 0.4 and 0.75 indicate fair to good reliability and values 0.75–1.0 indicate excellent reliability [34]. Symptom scores determined with the IOSS and the two validated questionnaires (OCI and OSDI) at Visit 1 were compared between normally menstruating women and OCP users using the Mann-Whitney U test. Normally menstruating participants were categorized into three

Model 1: Random Intercept, Cyclic Change over Time

IOSSij = β0 + β1 cosij + β2 sinij + εij β0 = b0i + τ0j

τ0j ∼ N (0, σ02), εij ∼ N (0, σ2) Model 2: Random Intercept, Cyclic Change over Time, Main Effect of OCP Use

IOSSij = β0 + β1 cosij + β2 sinij + β3 OCPj + εij β0 = b0i + τ0j

τ0j ∼ N (0, σ02), εij ∼ N (0, σ2) Model 3: Random Intercept, Cyclic Change over Time, Time*OCP Use Interaction

IOSSij = β0 + β1 cosij + β2 sinij + β3 OCPj + β4 cosij ∗ OCPj + β5 sinij ∗ OCPj + εij

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β0 = b0i + τ0j,

was examined by testing the difference between Model 0 and Model 1 using a single curve. Relative to a model excluding fluctuation (Model 0), a model with cyclic fluctuation (Model 1) showed a better model fit. The difference in model fit was significant (p = 0.004), indicating that a cyclic model was a better fit to the IOSS data than a linear model. Second, the difference between Model 1 (a single cyclic curve) and Model 2 (2 parallel curves) was examined. The likelihood ratio test showed a significantly better fit for Model 2 versus Model 1 (p = 0.02) and no significant difference in fit between Models 2 and 3 (p = 0.79) (Table 4). Hence, Model 2 was selected to analyze the cyclic fluctuation in IOSS scores in the normally menstruating and OCP groups separately.

τ0j ∼ N (0, σ02), εij ∼ N (0, σ2) where β0 is modelled as a function of individual intercepts (b0i ) with error τ0i , which is assumed to be normally distributed with mean 0 and variance σ02 . β1 and β2 are the coefficients for the cosine and sine functions of the menstrual cycle day, β3 is the coefficient for the fixed effect of OCP use, and β4 and β5 are the coefficients for the interactions between OCP use and the cosine and sine functions. εij is the error term and is assumed to be normally distributed with a mean of 0 and variance σ 2 . For each day, the estimated mean IOSS value for the OCP group and for the normally-menstruating group was calculated from the model parameters. As the data were positively skewed, a parametric bootstrap was used to obtain percentile confidence intervals for coefficients and confidence intervals for estimated mean IOSS values. Likelihood ratio tests were used to compare model fits between Models 0 and 1, Models 1 and 2 and between Models 2 and 3.

3.2.2. Symptoms assessment The cyclic fluctuations in IOSS scores over time, with both the cosine and sine coefficients showing confidence intervals excluding 0, are presented in Fig. 4 and Table 4. The LMM analysis revealed that the maximum mean IOSS score estimated by the selected Model 2 occurred on Day 2 of the menstrual cycle in the normally menstruating group and on Day 2 of the artificial cycle in the OCP group. The highest estimated mean IOSS score in the normally menstruating group was 1.4 and in the OCP group was 2.2. The minimum estimated mean IOSS score occurred on Day 16 (normal group = 1 and OCP group = 1.9). Model 2 showed that the OCP group scored significantly higher (OCP coefficient, Model 2: 0.832, p = 0.02) than the normally menstruating group. There was no significant difference (p = 0.79, Model 3) in the shapes of the curves between the two groups as indicated by the interaction terms OCP*cosine and OCP*sine.

2.3.2.2. Symptoms assessment. The model with significantly best fit for the study data was used for analyzing the cyclic change in IOSS scores. The highest and lowest IOSS scores, differences in IOSS scores and the cyclic pattern between normally menstruating and women using the OCP was calculated using the estimated means of the model with the best fit (Model 2). 3. Results All 72 participants completed the study. Missing data occurred in 39 of the entire set of 2880 (1.35%) observations made during 40 days of the study for all participants, and all available observations were analyzed. Participant characteristics are summarised in Table 1. All 36 OCP participants were using a monophasic regimen consisting of OCP's that have the same dose of Estrogen + Progesterone throughout the treatment. They all either took placebo pills or discontinued the OCP towards the end of their cycle to allow withdrawal bleeding. The concentrations of synthetic estrogen and progesterones ranged from 20 μg to 50 μg for Ethinyl estradiol and 100 μg–500 μg for Levonorgestrel/ Norethisterone/Gestogens.

4. Discussion This paper reports a rapid, sensitive and repeatable method to effectively examine variation in instantaneous ocular symptoms using a smartphone platform. IOSS questionnaire demonstrated good construct validity, criterion validity and repeatability when compared to established dry eye questionnaires in a normal and mild to moderate dry eye population. This is the first study to assess ocular symptoms on each day of one complete menstrual cycle. The highest symptoms were reported during the menstrual phase (when estrogen levels are lowest), the lowest symptoms occurred in the early luteal phase. Ocular symptoms were higher in women using the OCP than in normally menstruating women. IOSS scores at Visit 1 demonstrated a moderate association with, and a similar ability to differentiate symptomatic participants, as previous full-length ocular symptoms questionnaires. Thus, the severity of symptoms assessed instantaneously using the IOSS was consistent with symptom reporting using the OCI and OSDI questionnaires which have a recall period of one week. IOSS exhibited good agreement between repeat measurements. This is the first ocular surface symptoms questionnaire to be validated for instantaneous assessment of symptoms. Although The Current Symptoms Questionnaire (CSQ) (reported in

3.1. IOSS questionnaire validation Construct validity of the IOSS is shown in Fig. 2. IOSS scores were moderately associated with OCI (ρ = 0.58, p < 0.001) and OSDI (ρ = 0.53, p < 0.001) scores. Criterion validity (ability to distinguish symptomatic participants) of the IOSS is demonstrated by the ROC curves predicted by the IOSS, OCI and OSDI questionnaires (Fig. 3). Estimated AUC ± SE was 0.80 ± 0.07 for IOSS, 0.87 ± 0.06 for OSDI and 0.91 ± 0.04 for OCI. An ICC of 0.75 was calculated for repeat IOSS measurements over the first 3 consecutive days during the menstrual phase. When group symptom scores at Visit 1 were compared; higher ocular symptoms were reported in the OCP group compared to the normally menstruating group using the OCI (p = 0.001) and OSDI (p = 0.001) questionnaires, but this difference was not significant using the IOSS (p = 0.12) (Table 2). No significant difference was found at Visit 1 between cross-sectional symptom scores of normally menstruating participants grouped by menstrual phase, using any of the questionnaires (p > 0.05) (Table 3).

Table 1 Participant characteristics of normally menstruating women and women using the combined oral contraceptive pill (OCP).

Number of participants Age (years)a Length of menstrual cycle or artificial cycle (days)b Number of days of menstruation or withdrawal bleedc

3.2. Assessment of daily symptoms across the menstrual cycle 3.2.1. Results of model development In order to select the best fitting and most parsimonious model, the likelihood ratio tests were performed between increasingly complicated models. First, the inclusion of a cyclic component in change over time

Normally menstruating women

Women using combined OCP

36 29.6 ± 6.0 28 (20–32)

36 25.1 ± 5.7 28 (20–35)

5 (3–7)

5 (3–7)

OCP = Oral Contraceptive Pill. a Results presented as mean and standard deviation. b, c Non-parametric data are presented as median and range. 4

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Table 2 IOSS, OCI and OSDI symptom scores at Visit 1 for the normally menstruating women and women using the combined OCP groups (median and range). Visit 1

Normally menstruating women (n = 36)

Women using combined OCP (n = 36)

p-value

IOSS score OCI score OSDI score

1 (0–7) 27 (0–40) 8.3 (0–35.4)

2 (0–7) 32.9 (15.9–47.3) 18.7 (0–70.8)

0.12 0.001 0.001

IOSS = Instant Ocular Symptoms Survey. OCI = Ocular Comfort Index. OSDI = Ocular Surface Disease Index. OCP = Oral Contraceptive Pill. Table 3 IOSS, OCI and OSDI symptom scores (median and range) for normally menstruating participants cross-sectionally categorized into 3 groups based on their day of the menstrual cycle at Visit 1: menstrual phase group (days 0–5), follicular phase group (days 6–14) and luteal phase group (days 15–28).

Fig. 2. Association between ocular symptom scores of IOSS and 2 validated questionnaires (OCI and OSDI) at Visit 1. IOSS = Instant Ocular Symptoms Survey. OCI = Ocular Comfort Index. OSDI = Ocular Surface Disease Index.

Visit 1

IOSS score OCI score OSDI score

Menstrual Phase Group

Follicular Phase Group

Luteal Phase Group

(n = 8)

(n = 13)

(n = 15)

1 (0–7) 28.6 (0–40) 4.2 (0–35.4)

1 (0–5) 27 (0–40) 8.3 (0–35.4)

0 (0–4) 27 (15.9–33.4) 8.3 (0–23)

p-value

0.84 0.92 0.81

IOSS = Instant Ocular Symptoms Survey. OCI = Ocular Comfort Index. OSDI = Ocular Surface Disease Index. Table 4 Models examined for the best fit to the study data using linear mixed model analysis to analyze fluctuations in cyclic IOSS scores of the normally menstruating and OCP groups. Model

P-value for Modela

0 1

2

3

Fig. 3. Receiver operating characteristic (ROC) curves for IOSS, OCI and OSDI ocular symptom scores illustrating how effectively asymptomatic and symptomatic participants were separated by each questionnaire. The estimated AUC ± SE values were 0.80 ± 0.07 for IOSS, 0.87 ± 0.06 for OSDI and 0.91 ± 0.04 for OCI. IOSS = Instant Ocular Symptoms Survey. OCI = Ocular Comfort Index. OSDI = Ocular Surface Disease Index. AUC = Area Under Curve. SE = Standard Error.

0.004

0.020

0.793

Term

Coefficient

Bootstrapped 95% Confidence Interval

β0

Intercept

1.854

(1.486, 2.209)

β1

Day (Linear)

−0.012

(-0.018, −0.008)

β0

Intercept

1.671

(1.288, 2.044)

β1

Cosine

0.156

(0.010, 0.206)

β2

Sine

0.077

(0.014, 0.133)

β0

Intercept

1.255

(0.784, 1.754)

β1 β2

Cosine

0.156

(0.010, 0.215)

Sine

0.076

(0.020, 0.137)

β3

OCP

0.832

(0.161, 1.532)

β0

Intercept

1.254

(0.728, 1.754)

β1

Cosine

0.177

(0.099, 0.254)

β2

Sine

0.066

(-0.018, 0.144)

β3

OCP

0.834

(0.152, 1.570)

β4

OCPaCosine

−0.042

(-0.156, 0.075)

β5

OCPaSine

0.020

(-0.091, 0.136)

IOSS = Instant Ocular Symptoms Survey. a Likelihood ratio test for difference in model fit. Each model was compared to the previous model.

agreement with one study that reported significantly higher symptoms during the late luteal phase, [14] and in contrast to other studies that found increased ocular symptoms during the estrogen peak during the follicular phase of the menstrual cycle [36], or no difference in symptoms between phases [15]. The present findings are consistent with systemic symptoms. Two daily diary studies report significantly lower symptoms of headache during ovulation in premenopausal women [37,38]. Temporomandibular pain [8] and menstrual migraine [7,38,39] are highest during the menstrual phase. Systemic pain perception also peaks in the late luteal to early menstrual phases [40]. As

abstract form only [35]) has also been validated to assess the instantaneous intensity of ocular comfort symptoms, it is not an ideal option for rapid repeated assessments as it consists of 8 items. The IOSS results confirmed that daily fluctuation in ocular symptoms occurs across the menstrual cycle. The highest ocular symptoms were reported on Day 2 of menstruation when estrogen levels are at their lowest and the lowest ocular symptoms were reported around day 16 of the menstrual cycle, which is within the ovulation period when estrogen levels are at their peak (Fig. 5). These findings are in

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Fig. 4. Linear Mixed Model 2: The daily fluctuation in estimated mean IOSS scores across a complete cycle in OCP and normally menstruating groups. The Solid curves represent the cyclic variation in symptoms in both groups and shaded areas represent the bootstrapped 95% confidence intervals. The menstrual, follicular and luteal phases in the normally menstruating group are shown as a reference. [32]. Confidence intervals for the normally menstruating group. Confidence intervals for the OCP group.

During the highest symptom reporting period (menstruation), luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone and testosterone are also at low concentrations, following a similar pattern to estrogen [41,42] and highest in concentrations during the lowest symptom reporting period (ovulation) [41,42]. While both LH and FSH show a peak in concentration at ovulation, no biological basis for any effect on symptoms of the eye has been reported [2]. Progesterone peaks only in the luteal phase, which does not match the symptom pattern seen in this study. There is no evidence for the independent effect of progesterone on ocular surface symptoms [2]. Testosterone fluctuation during the menstrual cycle is negligible; small mid-cycle peak may not be clinically significant [43]. This study showed that women using the OCP reported higher ocular symptoms than normally menstruating women across all days of the menstrual cycle. Likewise, the group comparisons using the fulllength questionnaires (OCI and OSDI) also showed higher scores for the OCP group than the normally menstruating group. The OCP suppresses estrogen levels across the menstrual cycle to prevent ovulation [44], and this may be a factor in the higher symptoms reported in the OCP

systemic pain also appears to peak during the low estrogen state of the menstrual cycle, dry eye symptoms may be a manifestation of this. The present study found a daily fluctuation in ocular symptom scores across the cycle, suggesting that a specific day to represent each phase of the menstrual cycle as per earlier studies of ocular surface symptoms may not be a sufficiently sensitive method. This was confirmed by the group results from Visit 1 which did not show an effect of the menstrual cycle phase on symptom scores. Grouping longitudinal symptom scores of different subjects into phases would dilute the effect of both high and low symptom reporting within a particular phase of the cycle. The daily comparison approach employed in this study enabled to identify time points during the menstrual cycle at which the highest and lowest symptoms occur. Sampling approaches that do not measure symptoms on each consecutive day of the cycle may not detect small changes and hence do not reflect the full extent of cyclic variation in ocular symptoms. The value of the mathematical model developed was to demonstrate that symptoms data were best described by a cyclic model which enabled comparison of differences between the normally menstruating and OCP groups.

Fig. 5. Cyclic variations in estradiol levels during a normal menstrual cycle. Redrawn from The endocrinology of the menstrual cycle: the interaction of folliculogenesis and neuroendocrine mechanisms, 1982; 38(5) pp:512 [41] During the normal menstrual cycle, systemic estrogen levels are at their lowest during menstruation (days 0–5), followed by a surge in the follicular phase (days 12–14) just before ovulation then a decline and gradual increase to another smaller broader peak during the mid-luteal phase (days 21–24). Days of the menstrual cycle were classified into menstrual phase (days 0–5), follicular phase (days 6–14) and luteal phase (days 15–28) [32]. Although ovulation is typically considered to occur on day 14, a wide variability of the ovulatory window has been confirmed to range between days 12–16 of the menstrual cycle [48].

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Acknowledgments

group. Interestingly, these women still exhibited a cyclic variation in ocular surface symptoms with a pattern similar to the normally menstruating women. Although evidence on the extent and mechanism of suppression of estrogen and other hormone levels (progesterone, LH and FSH) by the combined OCP is not consistent, some residual activity of these hormones is likely to remain across all phases of the menstrual cycle [18,45]. Low amplitude fluctuations resulting from suppressed hormone levels followed by withdrawal bleeding (pill-free period) may explain the similar pattern of fluctuation in ocular symptoms between the normally menstruating and OCP groups. Reduced androgen levels, specifically testosterone, which occur due to combined OCP use [46] may also effect an increase in symptoms [2]. The effects of OCP use on symptoms of dry eye have not been extensively studied. Three previous studies have examined the effects of OCP use [15,23,24] and reported no impact on ocular symptoms or tear physiology. However, increased frequency of ocular symptoms was reported with OCP use in a study of contact lens wearers [20]. As the study limited to recruitment of population with no symptoms and mild to moderate symptoms of dry eye, participants mostly made use of the actual IOSS scores 0 to 5. Future studies could be designed to validate the IOSS in a dry eye population that includes severe symptoms of dry eye. Sex hormones, including estrogens and androgens, have been implicated in symptoms and signs of dry eye in women, [6] and monitoring the levels of these hormones across the menstrual cycle could be considered in future studies. A daily collection of serum was not logistically possible in this study due to its invasive nature, but assessment of local hormone levels in tears using recently developed methods may be a promising future approach [47]. Another potential area to examine would be a daily fluctuation of clinical signs of dry eye across the menstrual cycle. To our knowledge, this is the only study to look at the effects of a complete menstrual cycle and OCP use on ocular comfort symptoms and to report the highest symptoms during the lowest estrogen levels. Effects of the menstrual cycle may be more pronounced in dry eye and contact lens patients hence clinical examination should include recording information about the day of their menstrual cycle and contraceptive use. Clinicians suspecting the effect of the menstrual cycle on ocular symptoms should consider re-assessing patients during another phase of the menstrual cycle. They could also provide appropriate advice regarding the management of dry eye symptoms and contact lens care during the menstrual phase where symptoms are likely to be greatest. Increased symptom reporting should be expected in OCP users.

The authors would like to acknowledge the help of Professor Carolyn Begley from the School of Optometry at Indiana University in providing permission to use two items from the short form of the Dry Eye Questionnaire DEQ5. Special thanks to the study participants for their valuable time to contribute to the study. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jtos.2019.06.005. References [1] Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II definition and classification report. Ocul Surf 2017;15:276–83. https://doi.org/10. 1016/j.jtos.2017.05.008. [2] Sullivan DA, Rocha EM, Aragona P, Clayton JA, Ding J, Golebiowski B, et al. TFOS DEWS II sex, gender, and hormones report. Ocul Surf 2017;15:284–333. https://doi. org/10.1016/j.jtos.2017.04.001. [3] Golebiowski B, Badarudin N, Eden J, You J, Hampel U, Stapleton F. Does endogenous serum oestrogen play a role in meibomian gland dysfunction in postmenopausal women with dry eye? Br J Ophthalmol 2017;101:218–22. https://doi. org/10.1136/bjophthalmol-2016-308473. [4] Truong S, Cole N, Stapleton F, Golebiowski B. Sex hormones and the dry eye. Clin Exp Optom 2014;97:324–36. https://doi.org/10.1111/cxo.12147. [5] Golebiowski B, Badarudin N, Eden J, Gerrand L, Robinson J, Liu J, et al. The effects of transdermal testosterone and oestrogen therapy on dry eye in postmenopausal women: a randomised, placebo-controlled, pilot study. Br J Ophthalmol 2017;101:926–32. https://doi.org/10.1136/bjophthalmol-2016-309498. [6] Gibson EJ, Stapleton F, Wolffsohn JS, Golebiowski B. Local synthesis of sex hormones: are there consequences for the ocular surface and dry eye? Br J Ophthalmol 2017;101:1596–603. https://doi.org/10.1136/bjophthalmol-2017-310610. [7] MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A. Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen. Neurology 2006;67:2154–8. https://doi.org/10.1212/01.wnl.0000233888.18228.19. [8] LeResche L, Mancl L, Sherman JJ, Gandara B, Dworkin SF. Changes in temporomandibular pain and other symptoms across the menstrual cycle. Pain 2003;106:253–61. https://doi.org/10.1016/j.pain.2003.06.001. [9] Tassorelli C, Sandrini G, Proietti Cecchini A, Nappi RE, Sances G, Martignoni E. Changes in nociceptive flexion reflex threshold across the menstrual cycle in healthy women. Psychosom Med 2002;64:621–6. https://doi.org/10.1097/01.PSY. 0000021945.35402.0D. [10] Vehof J, Kozareva D, Hysi PG, Harris J, Nessa A, Williams FK, et al. Relationship between dry eye symptoms and pain sensitivity. JAMA Ophthalmol 2013;131:1304–8. https://doi.org/10.1001/jamaophthalmol.2013.4399. [11] Riss B, Binder S, Riss P, Kemeter P. Corneal sensitivity during the menstrual cycle. Br J Ophthalmol 1982;66(2):123–6https://doi.org/10.1136/bjo.66.2.123. [12] Millodot M, Lamont A. Influence of menstruation on corneal sensitivity. Brit J Ophthal 1974:752–6https://doi.org/10.1136/bjo.58.8.752. [13] Connor CG, Flockencier LL, Hall CW. The influence of gender on the ocular surface. J Am Optom Assoc 1999;70:182–6. [14] Versura P, Fresina M, Campos EC. Ocular surface changes over the menstrual cycle in women with and without dry eye. Gynecol Endocrinol 2007;23:385–90. https:// doi.org/10.1080/09513590701350390. [15] Chen SP, Massaro-Giordano G, Pistilli M, Schreiber CA, Bunya VY. Tear osmolarity and dry eye symptoms in women using oral contraception and contact lenses. Cornea 2013;32:423–8. https://doi.org/10.1097/ICO.0b013e3182662390. [16] Feldman F, Bain J, Matuk AR. Daily assessment of ocular and hormonal variables throughout the menstrual cycle. Arch Ophthalmol 1978;96:1835–8. https://doi. org/10.1001/archopht.1978.03910060347010. [17] Oliver M, Walsh G, Tomlinson A, Mcfadyen A, Hemenger RP. Effect of the menstrual cycle on corneal curvature. Ophthal Physiol Opt 1996;16https://doi.org/10. 1016/0275-5408(96)00013-0. [18] Van Heusden AM, Fauser BCJM. Residual ovarian activity during oral steroid contraception. Hum Reprod Update 2002;8:345–58. https://doi.org/10.1093/ humupd/8.4.345. [19] Rivera R, Yacobson I, Grimes D. The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am J Obstet Gynecol 1999;181:1263–9. https://doi.org/10.1016/S0002-9378(99)70120-1. [20] Brennan NA, Efron N. Symptomatology of HE MA contact lens wear. Invest Ophthalmol Vis Sci 1989;66:834–8. https://doi.org/10.1097/00006324198912000-00006. [21] Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II epidemiology report. Ocul Surf 2017;15:334–65. https://doi.org/10.1016/j.jtos. 2017.05.003. [22] Ruben M. Contact lenses and oral contraceptives. Br Med J 1966:1110https://www. ncbi.nlm.nih.gov/pmc/articles/PMC1843971/pdf/brmedj02548-0074a.pdf. [23] Tomlinson A, Pearce EI, Simmons PA, Blades K. Effect of oral contraceptives on tear physiology. Ophthalmic Physiol Opt 2001;21:9–16. https://doi.org/10.1016/

5. Conclusions In summary, IOSS is a short and repeatable instrument that effectively measures instantaneous ocular symptoms on a smartphone platform. Increased severity of ocular dryness and discomfort were reported during the low estrogen level phase of the normal menstrual cycle and in women using the OCP. These findings suggest that fluctuation in systemic estrogen levels plays a role in the regulation of tear and ocular surface physiology. The effects of menstrual phase and OCP use should be considered in the interpretation of dry eye symptoms and contact lens discomfort in clinical practice. These findings enhance the current understandings of ocular surface and systemic pain during the menstrual cycle. Funding sources Archana Boga was supported by the Australian Postgraduate Award (APA) Scholarship from the University of New South Wales (UNSW). Conflicts of interest The authors have no conflicting interests to declare. 7

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