Topical estradiol effectively treats postmenopausal dry eye, study shows

A patented application of this hormone showed promise in a phase 2 study. A phase 3 multicenter trial is about to begin.

Issue: December 1, 2001

ByVirginia Lubkin, MD, FACS

A topical estradiol derivative may be an effective treatment for classical dry eye syndrome in postmenopausal women. The Aborn Eye Research Center at the New York Eye and Ear Infirmary in New York City has completed a phase 2 Food and Drug Administration trial of a patented version of estradiol, an estrogenic hormone.

The term “dry eye” describes a variety of conditions of diverse origin that affect the tear film and/or the ocular surface. The high incidence of dry eye in postmenopausal women worldwide demands a clear definition of the syndrome. Thus, the term “keratoconjunctivitis sicca” may have limited value, since the inflammatory component may not be the primary manifestation. Another controversy is the association of Sjögren’s syndrome as a cause of dry eye, since the incidence of Sjögren’s is minuscule compared with straightforward postmenopausal dry eye.

Postmenopausal dry eye

Postmenopausal dry eye syndrome has frustrated patients, researchers and clinicians by the paucity of successful treatments and until more recently, the difficulty in assessing efficacy of treatment modalities. The hallmark of treatment has been tear replacement therapy, and most efforts have focused on devising artificial lubricants, which either mimic the human tear film or present a more sophisticated hypo-osmolar version of the tear film.

Unfortunately, as dry eye syndrome progresses beyond the mild stage, this common therapy becomes less effective, and more viscous preparations are needed for added ocular surface protection. In the case of artificial lubricants, improvement of the reduced tear volume is fleeting at best and marginally improves the quality of tears.

Various studies have shown that postmenopausal dry eye is clearly not limited to aqueous deficiency and inflammatory changes of the ocular surface and lacrimal gland. Estrogen deficiency may lead to sebaceous gland alteration, so further destabilization of the tear film occurs due to meibomian gland dysfunction.

Studies have shown that estrogen receptor mRNA are present in the lacrimal gland, meibomian gland, lids, palpebral and bulbar conjunctiva, cornea and other anterior ocular surfaces. Their presence may indicate that dry eye syndrome may be under complex hormonal influence. Based on the clinical observation that dry eye syndrome is prevalent in the menopausal and perimenopausal population, a hormonal etiology is implicated. The literature is replete with recent research touting the roles of estrogen, testosterone and progesterone as modulatory factors in the pathogenesis of the dry eye syndrome.

Topical estrogens

My colleagues and I developed the concept for our trial by observing the standard gynecological method for treatment of postmenopausal vaginal dryness — avoiding large doses of oral or transdermal systemic estrogen and using local intravaginal ointments or creams of estrogen derivatives.

In addition, a study of the behavior of conjunctival cells in menstrual women revealed consistent cellular cycling with rotation of the menstrual cycle. Further investigations revealed that estrogen receptors in the conjunctiva are present but markedly few, leading to the conclusion that the dosage of oral or parenteral estrogens would have to be undesirably high, increasing the risks of unwanted side effects.

There are long-observed anecdotal reports that the use of oral estrogens at hormone replacement therapy (HRT) doses do not show significant relief of dry eye symptomatology. While the incidence of postmenopausal dry eye is high, affecting millions in our aging female population, it is rarely pursued or mentioned by gynecologists.

Interestingly, there are numerous premenopausal women who have difficulty in wearing contact lenses, and in many cases have been found to have abnormally low blood hormonal levels.

The study

This FDA phase 2 study included 44 postmenopausal women with dry eye and not on HRT during the trial. The study was a randomized, double-masked, parallel-group, placebo-controlled study of topical estradiol eye drops. The placebo used was the vehicle, which is an artificial tear supplement.

Given the lack of a “gold standard” that both diagnoses and monitors treatment effect, a battery of tests was used to assess the effectiveness of the estradiol drops in treatment of postmenopausal dry eye syndrome. Tear osmolarity, rose bengal staining, tear breakup time, and Schirmer testing were combined to form an overall objective assessment of the subjects. Subjective scores were performed and the significance of each subjective symptom was evaluated in terms of its occurrence in this patient population. Finally, in recognition of the importance of subject impression and satisfaction, summary statements were collected from all study participants.

The study results of these measures indicated a strong trend for estradiol drops to significantly improve both objective parameters and hallmark symptoms. The Aborn Eye Research Center at the New York Eye and Ear Infirmary is about to begin a phase 3 FDA multicenter trial to further study the safety and efficacy of topical estradiol treatment of postmenopausal dry eye syndrome.

For Your Information:

Virginia Lubkin, MD, FACS, principal investigator for this study, is Director of the Aborn Eye Research Center and honorary senior attending surgeon, The New York Eye and Ear Infirmary, and an associate clinical professor, The Mount Sinai Medical Center, NY. She can be reached at New York Eye and Ear Infirmary, 310 E. 14th St., Aborn Eye Research, New York, NY 10003; (212) 979-4463; fax: (212) 979-4574; e-mail: aborn@nyee.edu. Dr. Lubkin holds the patent for the topical application of estradiol in the treatment of dry eye syndrome, and has a financial interest in the estradiol eye drop for treatment of dry eye.