New Light on Cataracts
Authors: Trivedi Bijal P. 
Published: August 2003

Add another ailment to the mischief caused by waning estrogen concentrations. A new study in mice suggests that cataracts are members of the club that already includes osteoporosis, heart disease, cognitive declines, mood swings, and hot flashes (see
"More Than a Hot Flash"
). The findings might prod exploration of estrogen as a cataract therapy.

The discovery of estrogen receptors in the lens and retina in the late 1990s suggested that the hormone might act in the eye, and epidemiological studies reinforce this notion. After menopause, when estrogen concentrations sink, the incidence of cataracts in women overtakes that in men. Moreover, women taking tamoxifen, a strong estrogen inhibitor, are particularly prone to cataracts.
Vicki Davis, an endocrinologist at Cedars-Sinai Medical Center in Los Angeles, was investigating the role of estrogen in bone when she glimpsed its effects on vision. Davis engineered two types of mice by adding mutant estrogen receptor genes and control switches designed to disrupt estrogen's function only in bone. The extra DNA landed in different spots in the two genomes.
The control switch Davis employed--a shortened version of one that flicks on a bone-specific gene--misbehaved, and the mice produced the mutant estrogen receptor in many tissues, including the eye. When the females from one strain hit puberty and began producing estrogen, their eyes turned white, indicating that they had cataracts. Littermates without the mutant gene had clear eyes.
Intrigued, Davis shifted her focus from bone to eye. Although females of the second strain and males of both strains didn't develop cataracts from naturally occurring estrogen, their eyes turned cloudy after treatment with a potent synthetic version of the hormone diethylstilbestrol (DES). Perhaps individuals of the first strain make more of the mutant receptor than those of the second strain do because the DNA snippet lies in a more active part of the genome, Davis speculates. This situation might explain why females in the second strain require a more robust hormone jolt to provoke cataract formation. Together, the results suggest that estrogen depletion usually encourages cataracts, Davis proposes--even though that model is counterintuitive at first glance.
In the animals carrying the altered receptor, estrogen is used to block estrogen signaling, whereas under normal circumstances the hormone activates it. Estrogen receptors pair up when the hormone is present, and the receptor duo then binds to DNA, turning genes on and off. Davis suggests that the mutant receptor can hook up with another receptor, but the team cannot bind its DNA targets, some of which are required to keep the lens clear. Age-related drops in estrogen production also thwart receptor coupling and might have a similar effect.
Earlier studies hinted that estrogen is important for lens clarity, says Deborah Carper, who studies mechanisms of cataract formation in the aging eye at the U.S. National Eye Institute in Bethesda, Maryland. But Davis's work provides evidence that blocking estrogen signaling in a live animal can cause cataracts, she says. Already known for its multiple roles, estrogen keeps dazzling onlookers with its versatility.
--Bijal P. Trivedi

V. L. Davis, C.-C. Chan, T. J. Schoen, J. F. Couse, G. J. Chader, K. S. Korach, An estrogen receptor repressor induces cataract formation in transgenic mice.
Proc. Natl. Acad. Sci. U.S.A.
, 24 June 2002 [e-pub ahead of print].
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