Hormones and Dry Eye Syndrome

An Update on What We Do and Don't Know

Eduardo Melani Roch; Flavio Mantelli, Luis Fernando Nominato; Stefano Bonini


Curr Opin Ophthalmol. 2013;24(4):348-355. 

In This Article

Sex Hormones

Dry eye syndrome prevalence is much higher among women and aging is a risk factor for this condition. This realization suggests that sex hormones are key factors on this condition and output during menopause could worsen DES, whereas sex hormone replacement therapy (SHRT) may instead attenuate this condition. However, epidemiologic studies are not supportive of this idea as DES incidence in women on SHRT is even greater than that in individuals not undergoing such treatment.[9] Specifically, they showed that there is instead a higher incidence of DES among older women on SHRT, especially those using estrogen alone. As a matter of fact, with longer-term SHRT use, DES frequency and symptomology increased.[9] These findings disagree with other studies in which menopause was found to be a risk factor for DES, but SHRT was instead of some benefit in those cases.[10,11] On the contrary, another epidemiologic study confirmed that SHRT is a DES risk factor [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.0–2.5].[12] This study agrees with other observations indicating that estrogen therapy in women triggered or worsened the onset of DES and/or Sjögren's syndrome.[13–15]

A possible explanation for these conflicting conclusions is that the outcome of SHRT depends on estrogen dosage; age of the individuals when therapy is first initiated, namely, estrogen may be only beneficial in younger persons, whereas detrimental and/or pro-inflammatory in postmenopausal women; and type and combination of SHRT applied. It has been demonstrated that estrogen administered at physiological doses is supportive of lacrimal gland function and preservation of anterior ocular surface health at early ages, but at higher doses and/or in combination with other hormonal supplements would be injurious and/or induce inflammation. Elderly women would be more susceptible to these aforementioned limitations of SHRT. This expectation was confirmed by a study showing that higher estrogen levels correlated with declines in tear secretion in women older than 60 years, whereas in women who were in their fourth decade tear output instead improved.[16,17]

Moreover, some studies showed that DES symptoms identified with the ocular surface disease index (OSDI) questionnaire worsened with SHRT using drospirenone and estradiol, but Schirmer test and tear film break-up time (TFBUT) improved after 6 months of treatment. This dichotomy suggests that it is difficult to arrive at a meaningful conclusion regarding the safety and or efficacy of DES treatment as it is a multifactorial disease. Furthermore, any comparative study based on only one or a few parameters monitored for just a limited time is inadequate for deciding how to manage this disease.[14,18]

Women with Sjögren's syndrome are deficient in certain types of androgen such as dihydrotestosterone and dehydroepiandrosterone (DHEA), but present with similar levels of testosterone and estrogen compared to age-matched controls.[19] Systemic treatment of Sjögren's syndrome patients with DHEA only partially reverse its lower saliva levels, despite marked increase in the blood level of DHEA.

Endometriosis is a gynecological disease whose pathophysiology involves higher estrogen levels. There are recent conflicting reports addressing the association of Sjögren's syndrome with this disease and therefore with estrogen.[20,21]

Such differences support the notion of the uncertainty of the SHRT in treating DES ( Table 2 ). SHRT is problematic because sex hormone action is affected by endocrine production levels, circulating hormonal levels of total and free forms, peripheral tissue hormonal conversion, target cell receptor and enzymatic affinity, interactions with effects of other stimuli, and final physiologic action of thousands of genes regulated by sex hormones in tissues responsible for tear film and ocular surface health maintenance. Those aforementioned factors are also known as intracellular or intracrine hormonal phenomena in peripheral tissues. Their involvement is not completely understood and may also account for variable findings in regard to the association between changes in sex hormonal levels and DES.[22,23,24]

Therefore, therapeutic testing on an individual basis is necessary in menopausal women to verify whether or not SHRT is beneficial in treating DES. Moreover, to confirm sex hormone dysfunctional involvement in DES, a clinical gynecologic investigation maybe complemented by measuring the following sex hormone serum levels: total testosterone, free testosterone, 17-hydroxiprogesterone, dihydroepiandrosterone sulfate (SDHEA), in the early follicular phase of the menstrual cycle. In addition, thyroid function tests as described below and prolactin levels are also useful to eliminate other endocrine diseases. Those tests can be complemented by ultrasonographic ovary analysis.