Gender and androgen imbalances are keys to dry eye

Decreased androgens and aqueous tear production and increased evaporative tear loss result in inflammation of the ocular surface.

EVANSTON, Ill. — Gender and androgen imbalances may be at the root of dry eye.

“The mechanisms that produce dry eye are not only a gender imbalance but also an androgen imbalance, and this results in inflammatory changes in the ocular surface,” said Marian S. Macsai, MD, chief of the division of ophthalmology at Evanston Hospital. She spoke about dry eye as a gender imbalanced surface disorder.

Over the past 5 years it has become recognized that tear production is the result of interaction of the cornea, lacrimal gland and brain — or the integrated ocular surface/lacrimal gland functional unit, in the words of Dr. Macsai.

“Afferent sensory nerve impulses from the ocular surface and nasal mucosa synapse in the brain stem with efferent, autonomic, secretory nerve impulses that enervate the lacrimal gland. Stimulation of this reflex loop results in the delivery of the tear fluid and proteins on demand to the ocular surface,” she said.

The key and the cause

So what is the key to unlocking the mystery of the dry eye?

“We know that 90% of patients who develop Sjögren's syndrome are women, and numerous studies have demonstrated that, in fact, there is a higher incidence of dry eye in women as we age,” Dr. Macsai said.

She reported that the cause of dry eye can be separated into two basic underlying etiologies: decreased aqueous tear production and increased evaporative tear loss.

“In our search for the cause of dry eye, androgen-sensitive ocular tissues have been identified. These include the lacrimal gland and the meibomian gland,” she said.

“Under normal circumstances, circulating androgens provide an anti-inflammatory environment within the lacrimal gland. In the presence of a normal level of circulating androgens, circulating T-cells find no inflammatory signals and undergo apoptosis, or programmed cell death, as they leave the tissue. However, at menopause there is a distinct drop in the level of circulating androgens, and if this drop is below threshold, the lacrimal gland is left vulnerable to inflammation.”

In this setting, any condition that would stimulate tear production can now initiate neurogenic inflammation in the lacrimal gland.

“When stimulated, the epithelial cells in the lacrimal gland secrete cytokines and antigens that subsequently attract more circulating T-cells, and because of these inflammatory signals, apoptosis of the circulating T-cells is aborted and the activated T-cells accumulate in the lacrimal gland,” Dr. Macsai said.

The activated T-cells secrete pro-inflammatory cytokines that recruit additional T-cells to the tissue of the lacrimal gland, and the inflammatory process is accelerated as the T-cells gather in the lacrimal gland.

“Due to this inflammatory process and the T-cells that gather in the lacrimal gland, the epithelial cells in the lacrimal gland undergo apoptosis,” she said.

The tears that are secreted contain pro-inflammatory cytokines and further initiate inflammation at the ocular surface.

“As a result, the inflammation in the cornea and conjunctival epithelium increases as the volume of tears decreases and the tear composition changes. Therefore, decreased tear production and clearance result in inflammation of the ocular surface,” she said.

The androgen connection

Androgens affect both the lacrimal and meibomian glands and consequently will alter the tear film.

“The androgens stimulate the Meibomian glands to produce lipids, which maintain tear film stability and prevent tear film evaporation. When androgens decrease below threshold, there is a distinct correlation with the presence of meibomian gland dysfunction in the evaporative dry eye,” Dr. Macsai said.

Inflammation from these increased androgen levels results in decreased aqueous tear production due to decreased function of the lacrimal gland, and increased evaporative tear loss due to decreased function of the meibomian glands. However, she stressed, the question of which androgens are responsible for this process has not yet been answered.

“Testosterone, prolactin and estrogen have all been suspected, but no one individual hormone has been identified as the etiology. Most likely a combination effect is the source of the problem,” she said.

Decreased androgen levels exist in menopausal women, in aging men and women, in patients with Sjögren's syndrome and other autoimmune diseases and in patients with complete androgen insensitivity syndrome. In all of these conditions, Dr. Macsai noted, dry eyes may be present.

“Further research will hopefully define the role of androgen imbalance in ocular surface disease and elucidate whether androgen replacement, topical or systemic, may reverse this inflammatory process,” she said.

For Your Information:
  • Marian S. Macsai, MD, can be reached at Evanston Northwestern Healthcare, Division of Ophthalmology, Evanston, IL 60201; (847) 657-1936; fax: (847) 657-1949; e-mail: mmacsai@enh.org.