Dry eye in post-menopausal women using hormone replacement therapy

Maturitas 56 (2007) 257–262

Dry eye in post-menopausal women using hormone replacement therapy Uzeyir Erdem a,∗ , Ozlem Ozdegirmenci b , Emine Sobaci b , G¨ung¨or Sobaci a , Umit G¨oktolga c , Selim Dagli a a

Department of Ophthalmology, Gulhane Military Medical Faculty, 06018 Etlik, Ankara, Turkey b T.C.S.B Etlik Women Hospital, Ankara, Turkey c Department of Obstetrics & Gynecology, Gulhane Military Medical Faculty, Ankara, Turkey

Received 12 February 2006; received in revised form 22 August 2006; accepted 25 August 2006

Abstract Purpose: To evaluate the effect of hormone replacement therapy (HRT) on dry eye in post-menopausal women. Methods: Forty post-menopausal women with dry eye (20 patients, group 1) and without dry eye (20 patients, group 2), and planning to receive HRT (estrogen plus progesterone), were recruited as the study groups. Forty age-matched untreated women were enrolled as controls (group 3 with dry eye, 5 patients; group 4 without dry eye, 35 patients). Patients having at least one of the symptoms (dryness, itching, photophobia, foreign body sensation, and tearing) together with two of the tests with positive results for dry eye (tear film break-up time (BUT), fluorescein staining of the cornea, analysis of the meibomian gland, and Schirmer I test) in both eyes were considered dry eye positive. Hormonal assay for follicle stimulating hormone, luteinizing hormone, estradiol, and free testosterone was performed. Dry eye statuses in the groups were evaluated statistically. Results: Four patients with incomplete follow-up data were excluded. HRT use increased estrodiol levels in the groups. Mean ages of patients (50.2 ± 4.8 and 50.7 ± 3.9 years, and 50.0 ± 4.6 and 53.0 ± 3.9 years) were similar (p = 0.67). Duration of menopause in groups 1 and 2 (3.2 ± 2.2 and 1.4 ± 1.2 years; p = 0.01), and in groups 3 and 4 (3.0 ± 1.6 and 1.7 ± 1.3 years; p = 0.014) were different. At the third month examinations, all of the patients in group 1, and 11 patients (61.1%) in group 2 had dry eye (p = 0.003). Conclusion: Duration of menopause and use of HRT may increase the incidence of dry eye in post-menopausal woman. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Hormone replacement therapy; Dry eye; Menopause

1. Introduction ∗ Corresponding author. Tel.: +90 312 3237835; fax: +90 312 3045850. E-mail address: [email protected] (U. Erdem).

Dry eye is one of the leading reasons for patient visits to ophthalmologists [1–5]. It has been recognized that hormones might have an impact on the incidence

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and course of dry eye syndrome, especially in the postmenopausal women [6]. Hormone replacement therapy (HRT) is the administration of estrogens and progesterones to post-menopausal women. Its use is common in the modern world. There is controversy in the literature regarding the risks and benefits of HRT on dry eye [7,8]. This study was undertaken to determine the effect of HRT on dry eye syndrome in post-menopausal women.

2. Methods Twenty post-menopausal women with dry eye (group 1) and 20 without dry eye (group 2) planning to receive HRT (estrogen plus progesterone) were recruited as the study groups. Forty age-matched postmenopausal women, untreated with HRT were enrolled as controls. The control subjects were subdivided into two groups according to dry eye status (group 3 with dry eye; and group 4 without dry eye). Before enrollment in the study, complete gynecologic and ophthalmologic evaluations of patients have completed. Inclusion criteria were: duration of spontaneous menopause is at least 1 year before the first examination, absence of contraindications for HRT treatment, no medical history of dry eye syndrome or allergic ocular disease prior to menopause, no use of medicine that have adverse effect on the hormone levels and the tests for dry eye, including eye drops, and no use of contact lens and cigarette smoking. None of the patients in the study group had received any hormonal therapy before the study. Exclusion criteria were: systemic and ocular diseases, which required any kind of medical or surgical treatment with adverse effect on the tests for dry eye during the follow-up period, and incomplete followup data. The research complies with the Declaration of Helsinki of the World Medical Association, and informed consent was obtained from each subject after a full explanation of the procedures. All patients in the study group received HRT, which was composed of 0.625 mg/day conjugated estrogen and 5 mg/day medroxyprogesteron acetate in a continuous combined regimen (Premelle® , Wyeth). In all groups, blood samples (10 ml) were collected for the assessment of serum sex hormone levels. Serum estradiol (E2) levels were evaluated using

radioimmunoassay (Immunotech, France). Serum freetestosterone levels were determined with the radioimmunoassay by Count-A-Count analyzer (Radim, Italy). Serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured by the immunoradiometric assay (Immunotech, Prague). Serum hormone levels (FSH, LH, estradiol, and free testosterone) were measured before and 3 months after HRT. Since beneficial effect from HRT on dry eye was suggested by the others [9–11], no dry eye medication was given to the patients in the group 1. The patients in group 3 were treated with a conventional medication, tear substitutes, for dry eye during the 3 months of follow-up. The symptoms, which were common in dry eye states, dryness, itching, foreign body sensation, tearing, and photophobia, were taken into consideration for diagnostic purposes. Dry eye was confirmed by means of a set of tests performed in successive manner: tear film break-up test, fluorescein staining of the cornea, analysis of the meibomian gland by slit lamp, and the Schirmer test. A fluorescein strip (Flourescein Strips Chauvin, Lab. Chauvin, Aubenas, France) was applied in the lower eyelid fornix, and the patient asked to blink three times and look straightforward. The breakup time of the tear film observed under cobalt blue filtered light of the slit lamp microscope was recorded with a stopwatch. The mean of three consecutive tear break-up tests was taken into consideration, and that of 5 s or less was considered abnormal [12]. After a dry fluorescein strip was touched lightly to the infero-temporal fornix, fluorescein staining of cornea was graded as grade 0, no staining; grade 1, mild staining, limited to less than 1 third of the cornea; grade 2, staining between grades 1 and 3; grade 3, severe staining on half or more of the cornea. Fluorescein staining of the cornea was considered abnormal if it was one or more [2]. The meibomian gland dysfunction observed under slit lamp microscopy was graded as grade 0, no obstruction; grade 1, plugging with translucent serous secretion when the lid margin is compressed; grade 2, plugging with waxy or viscous secretion when the lid margin is compressed; grade 3, plugging with no secretion when the lid margin is compressed. Any meibomian gland dysfunction (grade 1 or more) was considered abnormal [2]. Three minutes after oxybuprocain (Benoxinate® ) instillation and

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Table 1 Distributions of age and menopause duration in the groups Groups

Age

Duration of menopause

Mean (years)

p

Mean (years)

p

Study group HRT(+) 1. Dry eye(+) 2. Dry eye(−)

50.2 ± 4.8 50.7 ± 3.9

>0.05

3.2 ± 22 1.4 ± 12

0.01

Control group HRT(−) 3. Dry eye(+) 4. Dry eye (−)

50.0 ± 4.6 53.0 ± 3.9

>0.05

3.0 ± l.6 1.7 ± 13

0.014

Table 2 The distribution of dry eye states in study and control groups Groups

Initial exam No. of cases

Dry eye

No. of cases

Dry eye

Study HRT(+)

20 20

20 0

18a 18a

18 11

Control HRT(−)

5 35

5 0

5 35

0 0

a

Third month exam

p

0.003 1.0

Two patients with incomplete follow-up data one in each study group (groups 1 and 2) were excluded from the study.

drying it, Schirmer with anesthesia test for basal secretion was applied with a filter strip (SNO* Strips, Lab. Chauvin, Aubenas, France) located inferior-temporally without touching the cornea and considered abnormal if wetting of the strip was 5 mm or less in 5 min [2,13]. These tests were performed in the same time interval from 9 a.m. to 11 a.m. at the same environment having the temperature ranging 21 ◦ C to 25 ◦ C, by a well-trained physician. The ophthalmic and gynecologic examinations, the questionnaire and the tests for dry eye were also performed 3 months after starting the ¨ O, ¨ UG). These HRT by the same examiners (UE, SD, O tests results including hormonal assay were recorded, kept confidential, and evaluated by other physicians (ES, GS). Patients having at least one of the symptoms together with two of the tests with positive results for dry eye in both eyes were considered dry eye positive. All tests were repeated after 3 months. All statistical analyses were performed with SPSS/PC 11.0 (SPSS Inc., Chicago, IL). Mann– Whitney U test, Kruskall–Wallis variance analysis, and Fischer exact test were used for statistical evaluations. A p value of <0.05 was considered statistically significant.

3. Results Age and menopause duration in the groups, and distribution of dry eye states in the study and the control groups are shown in Tables 1 and 2, respectively. Distribution of dry eye states in the study and the control groups, and age and menopause duration in the groups are shown in Tables 1 and 2, respectively. Clinical test results and hormone profiles are shown in Table 3.

4. Discussion Changes in hormone profile have been known to be associated with increased risk of some ocular disease [14,15]. The relationship between hormone levels and tear production is obviously complex, but it is still unclear how the different sexual hormones orchestrate to regulate the functional activity of these tissues [16]. Whether this relationship is related to changes directly on the ocular surface or on the lachrymal and meibomian glands is, so far, unknown. Impairment in the regulation of lachrymal secretion seems to play a prominent role in the pathogenesis

1.1 1.8 0.1 3.3 4.3 0.1 ± ± ± ± ± ± 5.6 7.3 0.2 38.2 40.1 1.4 1.1 1.9 0.1 3.9 2.7 0.1 ± ± ± ± ± ± 5.7 7.0 0.2 39.5 38.4 1.7 0.9 0.9 0.1 2.7 3.4 0.2 ± ± ± ± ± ± ± ± ± ± ± ± 4.1 4.2 2.5 39.5 37.2 1.6 1.1 1.3 0.4 2.2 10.6 0.1 ± ± ± ± ± ± a

Two patients with incomplete follow-up data were excluded from the study.

5.2 7.1 1.3 31.2 63.4 1.2 ± ± ± ± ± ± 5.5 7.4 0.3 37.2 35.4 1.5 0.9 0.5 0.3 4.1 11.1 0.1 ± ± ± ± ± ± 3.2 4.0 2.1 37.2 56.9 l.l Schirmer with anesthesia (mm) BUT (s) Meibomian dysfunction (grade) LH (␮/ml) Estradiol (pg/ml) Free testosterone (pg/ml)

3.9 4.1 2.2 39.6 32.8 1.7

± ± ± ± ± ±

1.1 0.9 0.2 4.3 7.2 0.1

3 months after HRTa

1.3 2.1 0.2 2.1 6.2 0.2

3 months after HRTa

Before study

0.8 0.7 0.2 3.3 3.7 0.1

4.1 4.2 0.2 33.2 37.4 1.6

Before HRT Before HRT

Before study

Group 3 (with dry eye), n = 5 Group 2 (without dry eye), n = 20 Group 1 (with dry eye), n = 20

3 months after

Controls Study (patients on HRT)

Table 3 Clinical findings, dry eye test results, and serum hormone levels in the groups

3 months after

U. Erdem et al. / Maturitas 56 (2007) 257–262

Group 4 (without dry eye), n = 35

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of post-menopausal ophthalmic symptomatology [17]. Mathers et al. found a different relationship between hormone levels and tear production in pre and post-menopausal women. In premenopausal women, the serum testosterone levels were correlated negatively with tear production, whereas estrogen levels correlated positively. In post-menopausal women, the correlations were reversed, with higher testesteron levels associated with increased tear function and higher estrogen levels with reduced tear function [18]. In this study, all except 2 of the post-menopausal women had lower estrogen levels before HRT that was increased to normal at the third month follow-up. Testosterone levels remained within normal limits throughout the study. In a case-control study, Sullivan et al have shown that Sjogren’s syndrome (SS) was not associated with significant alterations in the serum concentrations of testosterone, androstenedione, estrone, or 17␤-estradiol. They have shown that SS were androgen-deficient [19]. The hormone levels in the beginning were similar in the study and the control groups in our study. Therefore, we do not have an explanation for presence of dry eye in some patients on the basis of hormone levels in this study. We have to consider that in post-menopausal women, all estrogens and nearly all androgens are made locally in peripheral target tissues from the inactive adrenal steroid precursor dehydroepiandrosterone (DHEA) (peripheral formation of sex steroids or intracrinology), and that circulating levels of human sex steroid hormones, particularly those of testosterone, have little physiological meaning [20]. We found significant difference in duration of menopause between patients with and without dry eye. This unusual finding may be explained by declining secretion of DHEA by the adrenals with age or peripheral (eye) tissue-specific steroidogenic enzymes, which may be a common etiological factor in dry eye development in post-menopausal women. We think this subject deserves further researches. In our study, it is remarkable that none of the patients in group 1 (who had dry eye before HRT) recovered from dry eye and 61% of patients in group 2 (who had no dry eye before HRT) developed dry eye, after 3 months of HRT use. On the other hand, all of the patients in group 3 had relief of symptoms and/or signs of dry eye and none of the patients group 4 developed dry eye during follow-up of 3 months. These results support the notion that higher estro-

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gen levels reached by use of HRT may lead to dry eye. Previous studies found improvements in tear functions with estrogen based HRT [9–11]. Although decline in contrast sensitivity are common finding in post-menopausal women [21], Guaschino et al. showed that HRT improved contrast sensitivity function significantly [10]. A large cohort assessing the relation between HRT use and dry eye syndrome found that post-menopausal women using HRT were appeared to be at increased risk of dry eye syndrome by 30–70%, depending on the type of HRT. It was found that the risk increased with the length of HRT use. They also showed that the longer the duration of HRT use, the higher the risk of dry eye syndrome. Risk rose by 15% for every 36 months of HRT use. The prevalence was lowest in new users (5.7%), highest in those on estrogen alone (9.1%), and 6.7% in patients who were on combination (estrogen–progesterone) therapy. This implied that progesterone/progestin seemed to have a protective effect with regard to dry eye in that study [7]. All patients in our study used combined drug for HRT, and none of the patients had beneficial effect from this combination. Even worse, adverse effect from HRT was evident, particularly in the group 2 without dry eye in the beginning of the study. The estradiol transdermal estrogen replacement therapy, a continuous estrogen replacement therapy, has been shown to induce keratitis sicca and ocular idiosyncratic reactions [22]. In addition, HRT use in post-menopausal women may complicate the ophthalmic procedures by development of dry eye [23] to the tissue-specific change induced by HRT. We believe that these controversies can be clarified in controlled clinical trials with longer-term follow-ups. Our treatment period (3 months) seems to be relatively shorter. This was because of occurrence of new dry eye cases in group 2, and lack of expected relief of dry eye from HRT in group 1 at the third month control. The differences between the studies may probably come from the patient characteristics, study design, drug composition, and inclusion and evaluation criteria. It is known that diagnosis of dry eye syndrome is complicated in that there are not two separate distinct groups of patients, with and without dry eye syndrome, but sliding scales of susceptibility, frequency of occurrence, and severity. Since symptoms and signs of dry eye can be induced by environmental conditions, we

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adhered to apply the tests in the same conditions, by the same examiner, and tried to refrain from subjective evaluation such as symptom questionnaire. The lack of placebo arm might have biased our results with regard to ocular symptomatology. Our patients had no previous HRT use or HRT-related drug use at the study entry. They had also no medical history of dry eye-related symptoms or treatments before menopause. The prevalence of dry eye in our menopausal women untreated with HRT was 12.5%. Surveys of the prevalence of dry eye in general population have been often relied upon questionnaires to elicit symptoms of dry eye. A well designed survey identified an increase in prevalence of dry eye with age from 5.7% among women less than 50 years to 9.8% among women aged more than 75 years [1]. To avoid from subjectivity as much as possible, we lowered the cut-off values of the tests to their minimums reported in the literature. Additionally, we defined the patients as dry eye positive if they had involvement in both eyes with abnormal test results. There is only one clinical trial that showed moderate improvement for dry eye from estradiol ointment in post-menopausal women [24]. In this study, we expected some relief of dry eye as suggested by the others [9–11] in the group 1, and applied HRT instead of tear substitutes, and found that oral administration of HRT causes dry eye. Unfortunately, there is no large scale or multi-center, controlled clinical trial on the use of estrogen or progestin as a potential therapy for dry eye. In conclusion, the results of this study suggests that duration of menopause and HRT use in menopausal women may increase the incidence of dry eye, although a direct cause and effect relationship remains to be established. Acknowledgement The author has no proprietary or commercial interest in any product or concept discussed in this article. References [1] Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003;136:318–26. [2] Lin PY, Tsai SY, Cheng CY, Liu CH, Chou P, Hsu WM. Prevalence of dry eye among an elderly Chinese population in Tai-

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