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

Abstract

Citation: Song X, Zhao P, Wang G, Zhao X. The effects of estrogen and androgen on tear secretion and matrix metalloproteinase-2 expression in lacrimal glands of ovariectomized rats. Invest Ophthalmol Vis Sci. 2014;55:745-751. DOI:10.1167/iovs. 12-10457 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 ( 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.

Hypercalcemia Leads to Delayed Corneal Wound Healing in Ovariectomized Rats

“…Cell adhesion and proliferation were similar for cells incubated in medium containing any Ca 2+ level in the range of 4-12 mg/dL. On the other hand, cell viability was significantly decreased by incubation in medium containing [8][9][10][11][12] 30) and Berridge et al reported the high Ca 2+ levels can lead to cell death. 31) Taken together, these findings suggest that the viability of corneal epithelium cells is decreased under high Ca 2+ conditions (over 8 mg/dL) as are observed in the lacrimal fluid of OVX rats, and that a decrease in the viability of corneal epithelial cells may be the cause of delay in corneal wound healing in OXV rats.…”

“…In addition, the decrease in estrogen secretion following menopause is related to the prevalence of several disorders within the area innervated by the trigeminal nerve. 9,10) The ocular surface is an integrated unit comprising the corneal and conjunctival epithelia, meibomian glands, main and accessory lachrymal glands, and trigeminal neurons. It has been reported that a decrease in estrogen level results in dry eye in animal models.…”

“…It has been reported that a decrease in estrogen level results in dry eye in animal models. 9,10) Hypercalcemia is also observed in the some postmenopausal women due to the reduced function of Ca 2+ regulation. 8) Hypercalcemia may lead to increased Ca 2+ contents in the lacrimal fluid, and affect the cornea.…”

“…11,12) In addition, OVX rats show a decrease in the secretion of lacrimal fluid; the pathogenetic role for estrogen in dry eye involves the upregulation of matrix metalloproteinase 2 (MMP-2) expression. 9) Some changes in the biological characteristics of OVX rats may correspond to those of human osteoporosis. In this study, we investigated the effect of Ca 2+ levels in lacrimal fluid on the rate of corneal wound healing in OVX rat debrided corneal epithelium.…”

Estrogen receptor (ER)-α, β and progesterone receptor (PR) mediates changes in relaxin receptor (RXFP1 and RXFP2) expression and passive range of motion of rats’ knee

“…Meanwhile, high level of E 2 was reported to cause increased anterior tibia dislocation in rats during pregnancy (Charlton et al, 2001). The mechanisms underlying E 2 and P 4 effects on knee laxity are not well understood, however evidences suggested that these effects could be mediated via changes in collagen turnover (Song et al, 2014), modulation of enzymes activity involved in collagen metabolism (Shan et al, 2013) as well as response of tissues toward relaxin via changes in the amount of receptor expressed (Dehghan et al, 2014a,b).…”