The Effects of Estrogen and Androgen on Tear Secretion and Matrix Metalloproteinase-2 Expression in Lacrimal Glands of Ovariectomized Rats

PURPOSE: Previous studies have shown that ovariectomy (OVX) induces lacrimal gland regression and that androgens are implicated. This study explored the effects of estrogen and androgen on tear secretion and matrix metalloproteinase 2 (MMP-2) expression in lacrimal glands of ovariectomized rats. METHODS: Sixty-four adult female Wistar rats were randomly divided into three groups (control, sham operated, and OVX). Bilateral OVX was performed in the OVX group. After 5 months, the OVX group was further divided into six subgroups receiving topical ophthalmic or systemic treatment with corn oil vehicle, estradiol, or testosterone for 6 weeks. Schirmer test (SIT), assessment of tear film breakup time (BUT), corneal fluorescein staining, and measurement of estradiol and testosterone levels were performed before OVX and 1, 2, 3, 4, and 5 months after OVX, as well as after 6 weeks of treatment. Lacrimal glands were assessed for MMP-2 mRNA and protein expression. RESULTS: The mean (SD) tear film BUT decreased from 10.53 (0.79) to 9.98 (1.00) seconds (P < 0.01) in the first month after OVX, and the mean (SD) SIT result decreased by 50% from 7.32 (1.61) to 3.39 (1.15) mm (P < 0.01) in the third month after OVX. The mean (SD) corneal fluorescein staining score increased from 0.35 (0.11) to 6.02 (1.34) (P < 0.05) in the fourth month after OVX. The values increased or decreased in parallel with the time course (P < 0.01). In serum, ovariectomy resulted in a mean (SD) decline in estradiol levels from 44.38 (9.78) to 23.00 (3.78) pg/mL (P < 0.01), and the mean (SD) testosterone levels decreased from 2.42 (0.26) to 1.87 (0.15) ng/mL (P < 0.05). The mean (SD) estradiol level was elevated to 35.38 (3.34) pg/mL by systemic estradiol administration for 6 weeks, which also led to further mean (SD) decreases in tear film BUT from 5.28 (0.81) to 3.65 (0.55) seconds (P < 0.01) and in SIT result from 2.19 (1.01) to 1.47 (0.85) mm (P < 0.05), as well as a higher mean (SD) corneal fluorescein staining score from 7.39 (1.34) to 9.89 (1.27) (P < 0.05). However, the mean (SD) testosterone level was increased to 3.53 (0.67) ng/mL by systemic testosterone administration for 6 weeks. As a result, the mean (SD) tear film BUT increased from 5.08 (0.40) to 6.03 (1.48) seconds (P < 0.05), and the mean (SD) SIT result increased from 2.38 (1.20) to 3.66 (1.90) mm (P < 0.05). The mean (SD) corneal fluorescein staining score declined from 7.45 (0.73) to 4.56 (1.21) (P < 0.05). In the nontreated OVX group, the mean (SD) MMP-2 mRNA (0.66 [0.10]) and protein (0.55 [0.13]) expression in lacrimal glands was significantly increased compared with that in the sham-operated group (0.50 [0.09] and 0.40 [0.07], respectively) (P < 0.05). Systemic estradiol administration further increased the mean (SD) MMP-2 mRNA (0.83 [0.10]) and protein (0.69 [0.12]) expression (P < 0.05), while systemic testosterone administration decreased the mean (SD) MMP-2 mRNA (0.12 [0.04]) and protein (0.27 [0.07]) expression (P < 0.01). Topical ophthalmic administration of two sex hormones had no effect on the mean (SD) MMP-2 mRNA (0.59 [0.12] for estradiol and 0.57 [0.14] for testosterone) or protein (0.49 [0.11] for estradiol and 0.46 [0.13] for testosterone) expression (P > 0.05). CONCLUSIONS: Ovariectomy-induced ocular surface impairment may be associated with androgen deficiency. A pathogenetic role for estrogen in dry eye may involve upregulation of MMP-2 expression, while androgen suppresses MMP-2 expression.