28 November, 2016: 

From time to time, we have to remind ourselves and the health-care providers that estrogen and the other sex steroids are actually involved in all the body organs, and that their physiological effects are not limited to fertility, treatment of menopausal symptoms, or cardiovascular and bone protection. Menopause Live has addressed in the past the effects of estrogen on other tissues and bodily functions, such as the skin, the voice or hearing. This time, I put the eye and sight into this context. A small, but double-blind, placebo-controlled study (n = 40, age 63.9 ± 5.1 years, 13.2 ± 6.3 years postmenopause) investigated the outcomes of estrogen, testosterone or their combination in hysterectomized women with dry eyes [1]. The results demonstrated estrogen-related worsening in dryness intensity after 8 weeks of estradiol gel 1 mg/g as compared to placebo; 1% testosterone cream showed a neutral effect, but a combination of the two hormones led to a significant increase in tear secretion.

Comment

Dry eye syndrome, also known as keratoconjunctivitis sicca, is a common condition which is the result of low production of tears or too quick evaporation. Symptoms include irritation, redness, discharge, easily fatigued eyes and blurred vision. This can result from meibomian gland dysfunction, allergies, autoimmune disorders, pregnancy, local surgery, smoking, conjunctival infections and other etiologies. Among relevant medications that may cause dry eyes are anti-depressants, which are frequently prescribed in midlife and beyond. Postmenopausal hormone replacement (HRT) has been mentioned in this framework as well. However, there seems to be some controversy in regard to the impact of HRT on dry eyes.

Several previous studies concluded that estrogen has favorable effects on dry eyes. Sator and colleagues examined 64 women with dry eyes who started HRT because of menopausal complaints [2]. A comparison of visual analog scores at 4 months in the women who received 17β-estradiol eye drops versus those who received a tear substitute demonstrated a statistically significant difference in all observed ocular symptoms (p < 0.0001). The Schirmer's test revealed a significant difference of results before and after treatment in the estradiol group (p < 0.0001); no significant difference was found in the comparator group. Yet, in another recent study, larger than the above index one, but not including a placebo arm, prolonged HRT use seemed to increase the risk of dry eyes [3]. This cross-sectional study (n = 360 postmenopausal women, with or without dry eyes, both users or non-users of HRT) found that there was a significant variation in the severity levels of dry eyes based on dosage levels (< 1 and > 1 mg/day) across women using HRT (p  <  0.0001), and a significant variation in the severity levels of dry eyes based on duration levels 12, 36, and 48 months across women using HRT (p  <  0.0001). The Women's Health Study showed negative effects of HRT in 25,665 postmenopausal women, who either received hormones or were non-users at baseline, and were followed for up to 48 months [4]. The multivariable-adjusted odds ratios 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 compared with no HRT use. Each 3-year increase in the duration of HRT use was associated with a significant 15% elevation in risk of clinically diagnosed dry eye syndrome or severe symptoms.

Other ocular issues that were examined in relation to HRT included cataract, glaucoma and macular degeneration. A meta-analysis on cataract types demonstrated a significantly decreased risk of nuclear cataract in the current HRT group (OR 0.72, 95% CI 0.61–0.85) and borderline reduced risk of nuclear cataract in ever HRT group (OR 0.80, 95% CI 0.64–1.01) as compared with the non-HRT group [5]. Several studies showed that lifetime exposure to estrogen was associated with the risk of open-angle glaucoma [6]. While prolonged use of oral contraceptives reduced the risk of glaucoma on the one hand, and early menopause was associated with an increased risk of glaucoma on the other hand, specific data on HRT and glaucoma are lacking. An effect of HRT on the retina may be the result of either direct neuroprotection or augmentation of blood flow in the local microvascular bed. In an ancillary study to the Women's Health Initiative clinical trial, treatment with CEE alone or CEE + P did not affect early- or late-stage age-related macular degeneration, but CEE + P reduced the risk of soft drusen and neovascular macular degeneration [7]. For further reading, a nice summary of some of the above-mentioned issues (eye diseases in the context of age, gender and menopause) was published earlier this year in Maturitas [8].

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Golebiowski B, Badarudin N, Eden 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 2016 Nov 3. Epub ahead of print
   http://www.ncbi.nlm.nih.gov/pubmed/27811278 
2. Sator MO, Joura EA, Golaszewski T, et al. Treatment of menopausal keratoconjunctivitis sicca with topical oestradiol. Br J Obstet Gynaecol 1998;105:100–2
   http://www.ncbi.nlm.nih.gov/pubmed/9442170
3. AlAwlaqi A, Hammadeh M. Examining the relationship between hormone therapy and dry-eye syndrome in postmenopausal women: a cross-sectional comparison study. Menopause 2016;23:550-5
   http://www.ncbi.nlm.nih.gov/pubmed/27003590 
4. Schaumberg DA, Buring JE, Sullivan DA, et al. Hormone replacement therapy and dry eye syndrome. JAMA 2001;286:2114–19
   http://www.ncbi.nlm.nih.gov/pubmed/11694152 
5. Lai K, Cui J, Ni S, Zhang Y, He J, Yao K. The effects of postmenopausal hormone use on cataract: a meta-analysis. PLoS One 2013;8:e78647
   http://www.ncbi.nlm.nih.gov/pubmed/24205286 
6. Dewundara SS, Wiggs JL, Sullivan DA, Pasquale LR. Is estrogen a therapeutic target for glaucoma? Semin Ophthalmol 2016;31:140-6
   http://www.ncbi.nlm.nih.gov/pubmed/26959139 
7. Haan MN, Klein R, Klein BE, et al. Hormone therapy and age-related macular degeneration: the Women's Health Initiative Sight Exam Study. Arch Ophthalmol 2006;124:988-92
   http://www.ncbi.nlm.nih.gov/pubmed/16832022 
8. Zetterberg M. Age-related eye disease and gender. Maturitas 2016;83:19-26
   http://www.ncbi.nlm.nih.gov/pubmed/26508081