Hormone Replacement Therapy and Dry Eye Syndrome (2024)

ContextPostmenopausal hormone replacement therapy (HRT) use is common in theUnited States. Some research suggests that estrogen may have detrimental effectson the tear film and could influence the development of dry eye syndrome,but few data are available on this relationship.

ObjectiveTo determine the relationship of HRT and dry eye syndrome.

Design, Setting, and ParticipantsThe Women's Health Study, a large cohort study in which 25665postmenopausal women provided information about use of HRT at baseline (1992),12, and 36 months and dry eye syndrome at 48 months.

Main Outcome Measures(1) Clinically diagnosed dry eye syndrome, as reported by participants;(2) severe symptoms (both ocular dryness and irritation either constantlyor often); and (3) either clinically diagnosed dry eye syndrome or severesymptoms, compared between women who used HRT vs those who did not.

ResultsFor the combined end point of either clinically diagnosed dry eye syndromeor severe symptoms, the multivariable-adjusted odds ratios were 1.69 (95%confidence interval [CI], 1.49-1.91) for estrogen use alone and 1.29 (95%CI, 1.13-1.48) for estrogen plus progesterone/progestin use compared withno HRT use. Each 3-year increase in the duration of HRT use was associatedwith a significant 15% (95% CI, 11%-19%) elevation in risk of clinically diagnoseddry eye syndrome or severe symptoms. Results were similar for the combinedend point of clinically diagnosed dry eye syndrome and severe symptoms.

ConclusionsThese data suggest that women who use HRT, particularly estrogen alone,are at increased risk of dry eye syndrome. Physicians caring for women whoare taking or considering HRT should be apprised of this potential complication.

Dry eye syndrome, or keratoconjunctivitis sicca, damages the ocularsurface and can cause debilitating symptoms of dryness and irritation, whichmay result in psychological comorbidity and reduced work capacity.^1-4 Dry eyesyndrome is associated with an enhanced risk of corneal infection, and, whensevere, can cause permanent visual impairment.^2,3Treatments for dry eye syndrome are generally costly and inadequate, and manypatients are unable to find satisfactory relief from their symptoms.⁵ Finally, dry eye syndrome accounts for a substantialburden on the health care system,⁵ comprisingone of the leading causes of patient visits to both ophthalmologists and optometrists.²

Hormone replacement therapy (HRT) is used by an estimated 38% of postmenopausalwomen in the United States.⁶ It has been shownto have a clear role in the treatment of a variety of menopausal symptoms,⁷ and may confer other health benefits.^8-11However, some deleterious effects of HRT are increasingly recognized,^12-14 and estrogen mayhave adverse effects on the ocular surface.^15-17Despite this, virtually no data are available on the relationship of HRT anddry eye syndrome. Therefore, we examined this relationship in the Women'sHealth Study.

The Women's Health Study is a randomized trial among 39876 healthprofessionals (aged 45 to 84 years in 1992) to assess the benefits and risksof aspirin and vitamin E in the prevention of cardiovascular disease and cancer.¹⁸ Women were also initially randomized to beta carotene,but this component of the trial was terminated after an average treatmenttime of 22.8 months. To be eligible for the Women's Health Study, women musthave been postmenopausal or have no intention of becoming pregnant. At baseline,all participants were free of cancer (except possibly nonmelanoma skin cancer),myocardial infarction, stroke, transient cerebral ischemia, liver disease,renal disease, peptic ulcer, or gout. Women using anticoagulants, corticosteroids,or supplements of vitamins A, E, or beta carotene were also excluded. Participantscompleted annual questionnaires reporting health-related exposures and anyhealth outcomes experienced over the previous year.

At baseline, participants reported demographic information includingage, race/ethnicity, educational level, and household income, as well as adetailed medical history and information on lifestyle factors. Women reportedtheir HRT use at baseline and at 12 and 36 months of follow-up. We classifiedpostmenopausal women by their use at 36 months as either never or ever usersof HRT. We further classified ever users as using estrogen alone, or estrogencombined with progesterone/progestins based on their most recent use pattern.

On the 4-year follow-up questionnaire we included 3 questions to assessdry eye syndrome: How often do your eyes feel dry (not wet enough)? How oftendo your eyes feel irritated? and Have you ever been diagnosed by a clinicianas having dry eye syndrome? The 2 questions pertaining to symptoms had possibleanswers of constantly, often, sometimes, or never. These 2 questions alonewere previously found to have a sensitivity of 60% coupled with a specificityof 94% compared with clinical diagnosis of dry eye syndrome, and to providenearly the same predictability as a 14-item questionnaire.¹⁹

We defined 3 outcome measures for dry eye syndrome. We defined clinicallydiagnosed dry eye syndrome as a self-reported diagnosis of dry eye syndromeby a clinician, and severe symptoms as a report of both dryness and irritationeither constantly or often. We also formed a composite end point of eithera previous clinical diagnosis or severe symptoms of dry eye syndrome.

We used χ² tests to examine the relationship of HRT withseveral potential determinants of its use as well as with dry eye syndrome.We then constructed multivariable logistic regression models (separate modelsfor each definition of dry eye syndrome) to obtain odds ratios (ORs) and 95%confidence intervals (CIs) to estimate the effects of estrogen use only, andestrogen plus progesterone/progestin. We initially adjusted for age in 5-yearcategories and, since subjects were participants in a randomized trial, randomizedtreatment assignments (aspirin vs placebo, vitamin E vs placebo, and betacarotene vs placebo). We then extended the models to account for predictorsof HRT, as well as other medical conditions that may have influenced the prevalenceof dry eye syndrome.

Although our primary analysis was restricted to postmenopausal women,we also fit models in which premenopausal women formed the reference group.In additional analyses, we fit models to examine whether the dose of estrogenor progesterone/progestin or duration of HRT were related to dry eye syndrome.

There is evidence that androgens are protective against dry eye syndrome.^20,21 Since women who had oophorectomywould be expected to have lower androgen levels²²and to be more likely to take HRT, we also conducted separate analyses amongwomen based on oophorectomy history.

Finally, to address the issue of the timing of the onset of dry eyesyndrome relative to initiation of HRT, we conducted an additional analysisfor the end point of clinically diagnosed dry eye syndrome, in which we excludedwomen who were diagnosed with dry eye syndrome prior to the initiation ofHRT. In this analysis, we chose an index date of 10 years prior to our assessmentof dry eye syndrome and excluded all women with a date of diagnosis priorto this index date. Beginning from the index date, we then constructed a seriesof consecutive 1-year intervals, which included data from all women who remainedfree of dry eye syndrome at the beginning of the interval. We used data onduration of HRT to estimate the time of initiation of therapy to determineeach participants' HRT status at the beginning of each interval, and dataon the date of diagnosis of dry eye syndrome to assign the diagnosis to theinterval in which it occurred. We used Cox proportional hazards models toobtain estimates of the relative risk and 95% CI associated with HRT.

Information about dry eye syndrome was provided by 36995 (93%)of the 39876 women enrolled in the Women's Health Study. Among the womenwith data on dry eye syndrome, 25665 (69%) were postmenopausal. We excludedfrom further analyses 156 women who were taking either vagin*l estrogen orprogesterone alone, as well as 120 women for whom data on HRT were unavailable.Of the remaining 25389 women, 61.1% had ever taken HRT and 90% of thesewomen were current users. As expected, HRT was related to a number of demographicand social characteristics, being more common among younger women, women whoidentified themselves as either white or Asian, and women with higher levelsof education and household income (Table1). Use of HRT also varied by geographic region with the highestprevalence in the West, and the lowest levels in the Northeast. Women whohad taken HRT were also more likely to have had an eye examination in thepast 2 years.

Use of HRT was significantly related to the prevalence of dry eye syndrome(Figure 1). Considering the prevalenceof either clinically diagnosed dry eye syndrome or severe symptoms, womenwho never used HRT had the lowest prevalence (5.9%). Women who used estrogenalone had the highest prevalence (9.1%), and women who used a combinationof estrogen plus progesterone/progestin had a prevalence that was intermediatebetween never users and users of estrogen alone (6.7%). Relationships weresimilar for severe symptoms and clinically diagnosed dry eye syndrome.

After adjusting for age and randomized treatment assignments, HRT wasstill significantly associated with clinically diagnosed dry eye syndromefor estrogen alone (OR, 1.70 [95% CI, 1.49-1.95] and for estrogen and progesterone/progestinOR, 1.30 [95% CI, 1.12-1.50]); severe symptoms (OR, 1.72 [95% CI, 1.46-2.03]and OR, 1.24 [95% CI, 1.04-1.48]); and the combined end point of either clinicallydiagnosed dry eye syndrome or severe symptoms (OR, 1.69 [95% CI, 1.51-1.90]and OR, 1.27 [95% CI, 1.12-1.44]), respectively. Further adjustment for race/ethnicity,geographic region, educational level, household income, and frequency of eyeexaminations had little impact on these findings. Additional adjustment fordiabetes mellitus, hypertension, rheumatoid arthritis, and other connectivetissue diseases also had no effect (Table2). Compared with no HRT use, the multivariable-adjusted ORs forthe combined end point of clinically diagnosed dry eye syndrome or severesymptoms were 1.69 (95% CI, 1.49-1.91) for estrogen use alone and 1.29 (95%CI, 1.13-1.48) for estrogen plus progesterone/progestin use.

In models that included premenopausal women as the reference group,the multivariable-adjusted ORs for clinically diagnosed dry eye syndrome orsevere symptoms were 1.02 (95% CI, 0.86-1.22) for postmenopausal women whonever used HRT; 1.71 (95% CI, 1.46-2.00) for postmenopausal women who usedestrogen alone; and 1.29 (95% CI, 1.10-1.51) for postmenopausal women whoused estrogen plus progesterone/progestin.

In models examining dose, the risk of dry eye syndrome was elevatedcompared with nonusers in all women who took estrogen, including women whoused less than 1 mg/d, the lowest prescribed doses (multivariable-adjustedOR, 1.73 [95% CI, 1.25-2.41]), and there was no clear dose-response relationship.Use of progesterone/progestin in combination with estrogen resulted in lowerrisks of dry eye syndrome compared with those associated with use of estrogenalone regardless of progesterone dose. For example, in women taking the lowestdoses of progesterone/progestin in combination with the lowest doses of estrogen,the multivariable-adjusted OR was reduced from 1.73 for estrogen alone to1.31 (95% CI, 0.80-2.14) for the combination. Duration of HRT was significantlyassociated with a multivariable-adjusted 15% higher risk (95% CI, 11%-19%)of dry eye syndrome for each 3-year increase in the duration of HRT use.

Among the subgroup of postmenopausal women without a history of oophorectomy,the multivariable-adjusted ORs for the end point of clinically diagnosed dryeye syndrome or severe symptoms were 1.38 (95% CI, 1.04-1.83) for estrogenalone and 1.32 (95% CI, 1.14-1.54) for estrogen plus progesterone/progestin.Among postmenopausal women with a history of oophorectomy, the multivariable-adjustedORs were 1.53 (95% CI, 1.24-1.89) for estrogen alone and 1.24 (95% CI, 0.79-1.94)for estrogen plus progesterone/progestin.

Finally, in models examining the timing of the initiation of HRT relativeto the diagnosis of dry eye syndrome, we observed a higher incidence of clinicallydiagnosed dry eye syndrome among women who were free of clinically diagnoseddry eye syndrome at the time they began using HRT (multivariable-adjustedrelative risk, 1.48 [95% CI, 1.27-1.72] for estrogen alone; relative risk,1.15 [95% CI, 0.97-1.37] for estrogen plus progesterone/progestin).

In this study, postmenopausal women who used HRT had higher prevalencesof dry eye syndrome than never users (estrogen alone, 69%; estrogen plus progesterone/progestin,29%). Adjusting for age and other factors, postmenopausal women who had neverused HRT did not differ from premenopausal women in the prevalence of dryeye syndrome. The relationship of HRT and dry eye syndrome was consistentfor all definitions of dry eye syndrome used in the present study, and heldfor clinically diagnosed cases diagnosed after the initiation of therapy.The longer the duration of HRT, the higher the risk of dry eye syndrome.

Since we were not able to determine if initiation of HRT preceded theonset of dry eye syndrome, the relationships we observed may reflect a highertendency of women with dry eye syndrome to be prescribed HRT. However, giventhe lack of evidence of any beneficial effect of replacement hormones in thiscontext, its prescription specifically for dry eye syndrome is not likelyto be common and certainly cannot be considered a standard of practice. Moreover,when we excluded cases that were clinically diagnosed prior to the initiationof HRT, we continued to observe a significantly elevated risk of subsequentdry eye syndrome among women who took exogenous estrogen. Although we couldnot address the issue of timing for our analysis based on dry eye symptoms,the similarity of our findings for symptoms compared with clinically diagnosedcases as well as the consistently stronger relationship with estrogen aloneand significant increased risk with longer duration HRT use argue againstthis as a major source of bias. These factors, and the fact that participantswere unaware of our hypothesis when they provided information about HRT useand dry eye syndrome (collected at different times and on different questionnaires),also argue against the possibility that women taking HRT were more likelyto think that such therapy caused dry eye syndrome and therefore were morelikely to report dry eye symptoms.

Residual confounding is a concern in any epidemiological study. In thepresent study, we were not able to control for factors such as contact lensuse or use of other medications that might lead to an increased frequencyof dry eye syndrome. However, given the high prevalence of HRT and the magnitudeof the observed effects, any extraneous factor would need to be prevalentas well as strongly related to both HRT and dry eye syndrome to explain theobserved associations. With regard to contact lens use, in a subgroup of 393women, we determined that HRT was not associated with contact lens use (26.8%of never users wore contact lenses vs 24.8% of HRT users), making residualconfounding by this factor unlikely. Moreover, control for medical conditionssuch as hypertension, diabetes, rheumatoid arthritis, and other connectivetissue diseases had little impact on our findings.

An additional consideration relates to our use of a questionnaire-basedassessment of dry eye syndrome, although there is consensus among both researchers² and clinicians^23,24that ascertainment of dry eye symptoms provides important information. Infact, assessment of symptoms was determined to be the single most importanttest for dry eye syndrome identified by clinicians in practice.^23,24An expert panel also identified these symptoms to be the sine qua non of dryeye syndrome.² This seems appropriate sinceocular surface damage rarely reaches clinical importance in the absence ofsymptoms,²⁵ and a major goal of therapy fordry eye syndrome is the relief of debilitating symptoms. Moss et al²⁶ identified expected relationships when using self-reporteddry eye syndrome in epidemiological studies. In the present study, we useda validated questionnaire to assess symptoms of dry eye syndrome, and strictcriteria to identify women as having dry eye syndrome based on symptoms alone.We also assessed previous clinical diagnoses of dry eye syndrome, which shouldhave helped us identify participants with treated dry eye syndrome who hadreceived some relief from their symptoms, as well as cases with only mildersymptoms. Because we were not able to examine study participants, however,estimates could have been biased by a higher likelihood of diagnosis amongwomen using HRT, although controlling for more frequent eye examinations didnot have any impact on our findings. This explanation also seems unlikelygiven the significant relationship of HRT with symptoms alone, the strongereffect of estrogen taken alone, and the significant increase in risk withlonger duration of HRT use.

Despite the common occurrence of dry eye syndrome, basic epidemiologicaldata are limited. Clinical observations suggest, and most epidemiologicalstudies^26-28 support,that dry eye syndrome is more common in women, a finding that would be consistentwith either a detrimental effect of estrogen or a beneficial role of androgens,^1,21 or both. Indeed, it may be the balanceof androgens and estrogen that is important in determining risk of dry eyesyndrome. Since women with oophorectomy would be expected to have lower androgenlevels²² and are also more likely to be prescribedestrogen replacement, we were concerned that low androgen levels might haveconfounded the relationship of exogenous estrogen with dry eye syndrome. However,when we looked separately among the subgroups of women based on history ofoophorectomy, we observed elevated risks of dry eye syndrome associated withestrogen in each subgroup, suggesting that these relationships were not likelyto be purely a consequence of confounding by low androgen levels.

There are few epidemiological studies that directly assess the potentialrelationship of exogenous estrogen use with dry eye syndrome, and none thathas examined the relationship in as much detail as the present study. Twostudies^26,27 reported that therewas no statistically significant relationship of HRT with the presence ofself-reported dry eye symptoms. However, the data were not actually presentedin either study, estrogen and estrogen plus progesterone/progestin were notexamined separately, and it is unlikely that either study had sufficient statisticalpower to detect an association of the magnitude we observed.

Strengths of the present study include its large sample size and theprevalent use of HRT, which provided a high degree of precision for our estimatesof an association with dry eye syndrome. We also used a validated questionnaire-basedassessment of dry eye symptoms with high specificity for identifying subjectswith dry eye syndrome. In addition, we obtained information on clinical diagnosesof dry eye syndrome from our population of knowledgeable female health professionals,and reporting of medical diagnoses has proven reliable among such populations.^29,30 Information on HRT was obtained withoutknowledge of dry eye status (and vice-versa). The results of the present studyconsistently showed a higher prevalence of dry eye syndrome among women whoused HRT, regardless of the way in which we defined dry eye syndrome. As wouldbe expected if the relationship were real rather than spurious, similar findingswere observed for clinically diagnosed dry eye syndrome, severe symptoms,or either condition. Moreover, there was a significant trend of increasingprevalence of dry eye syndrome with longer duration of HRT use.

Basic research suggests that sex hormone levels may influence both thelacrimal and meibomian glands.^15,21Laboratory and preliminary clinical studies suggest that whereas androgenshave a beneficial influence on lacrimal and meibomian gland function,^15,21 estrogen may play a role in exacerbatingdry eye syndrome.^{15-17,21,31,32}Given our findings as well as the known inhibitory effects of estrogen onother sebaceous glands,³³ further study ofthe effects of estrogen on the function of the meibomian gland—a largesebaceous gland containing estrogen receptors³⁴—wouldbe interesting. Moreover, the apparently beneficial modifying effect of progesterone/progestinon the relationship of estrogen with dry eye syndrome requires further study.

In summary, the present study suggests that postmenopausal women whouse HRT have a higher prevalence of dry eye syndrome compared with those whohave never used HRT, and this is particularly true of women who used estrogenalone. Given these findings and the high prevalence of HRT in the United States,further studies of the effects of sex-steroid hormones on dry eye syndromeare recommended. Meanwhile, physicians caring for women who are taking orare considering HRT should be informed of the potential increased risk ofdry eye syndrome with this therapy.