Women have a higher incidence of cataracts, and epidemiologic data suggest that the increased risk may be caused by a lack of estrogen in postmenopausal years. We have examined the effects of estrogen on methylnitrosourea (MNU)-induced cataractogenesis in Sprague-Dawley rats. Animals were ovariectomized, injected with MNU, and treated with estradiol or estrone by a continuous-release, subcutaneous Silastic implant, or they received an empty Silastic implant (no hormone). In the no-hormone group, rats developed opaque lenses approximately 6 months after MNU treatment. By 8 months, 74% (14͞19) of the no-hormone rats had evident opacity in one or both eyes by simple gross inspection; 58% (22͞38) of the eyes in this group were opaque. Estradiol or estrone treatment reduced the incidence of cataractous eyes to 12% or 25%, respectively. Lenses were examined under a dissecting microscope for light transmission. The lenses of the group treated with no hormone had light transmission of 26% ؎ 9.2%, whereas lenses from the estradiol-treated animals had light transmission of 72% ؎ 5.8%. Histological examination revealed that the anterior cortices of the opaque lenses were disrupted and showed the hallmark signs of age-related cataracts; in addition, some eyes that appeared clear by macroscopic examination showed the early histologic signs of cataractogenesis. It was demonstrated with reverse transcription-PCR that lens cells express both ␣ and  types of estrogen receptor, suggesting that the protective effects of the hormones may be a direct, receptor-mediated phenomenon. Thus, the MNU-treated, ovariectomized rat serves as a model for age-related cataractogenesis, and observation of a clear protective effect of estrogens in this system supports the implications of epidemiologic data.More than 75% of people Ն75 years old have some degree of lens opacification (1), and it is estimated that Ͼ50% of blindness is caused by cataracts (2). Age-related cataracts can be classified according to their anatomic location within the lens: cortical, nuclear, posterior, or mixed (3). Women exhibit an increased incidence of cataracts compared with agematched men (4-7), mainly because of a higher rate of cortical cataracts (8, 9). Thus, age-related cataracts present a significant health problem, one that exhibits a sexual dichotomy.Epidemiologic evidence suggests that estrogens may protect against cataracts. Although women are at a higher risk of developing cataracts than are men, this increased risk comes after menopause, when estrogen levels have waned (9, 10). In one study of 544 women, early onset of menopause was associated with a 2.9-fold risk of developing cataracts (11). Moreover, the results of three small epidemiologic studies suggest that postmenopausal estrogen replacement therapy reduces the incidence of cataracts (12)(13)(14). The role of estrogen in modifying the onset of age-related cataractogenesis requires suitable experimental models for further study.Results of animal studies have produced conflicting observation...