The Effect of L-Thyroxine Supplementation on Retinal Vascular Development in Neonatal Rats

Abstract

Purpose: Thyroxine (T4) plays a role in neuroretinal maturation, but little is known regarding its role in retinal vascularization. The neonatal rat retina is incompletely vascularized at birth, providing a model for the human premature infant retina and for retinopathy of prematurity (ROP). We hypothesized that T4 supplementation would accelerate vascular development of normal neonatal rat retina. Methods: Two hundred twenty Sprague-Dawley rats were raised in litters of 10 in room air and received either 0.05 μ g/g, 0.5 μ g/g, or 1.0 μ g/g of intraperitoneal T4 or saline control beginning on day 1 of life for 3 days, 7 days, or 3 days followed by 4 days recovery. Rats were sacrificed on either day 4 or day 8 of life. Left eyes were fixed, retinae dissected and ADPase-stained. Flat mounted retinae were digitized and total retinal areas and retinal vascular density were evaluated in a masked manner. Serum T4, thyroid stimulating hormone (TSH), and insulin-like growth factor-1 (IGF-1) were measured at each time point. Results: Retinal vascular density was reduced in animals receiving daily 1 μ g/g T4 compared with saline controls after 3 days of T4 (16.8 ± 1.4 vessels/mm vs. 18.3 ± 1.3 vessels/mm, p = 0.04) and 7 days of T4 (14.4 ± 1.3 vessels/mm vs. 16.8 ± 1.1 vessels/mm, p < 0.0006). However, retinal vascular density returned to normal after 3 days of treatment and 4 days of recovery. Vascularized retinal area was reduced in animals receiving 1 μ g/g T4 for 3 days followed by 4 days recovery compared with saline controls (85 ± 6% vs. 92 ± 3%, p = 0.002). At lower doses of T4 (0.05 μ g/g and 0.5 μ g/g for 3 or 7 days) and at 1 μ g/g T4 for 7 days, there was no effect on vascularized retinal area. Serum T4 levels were increased, with corresponding TSH suppression, after T4 treatment for 3 or 7 days. Serum IGF-1 levels were unaffected by T4 supplementation. Conclusions: Systemic T4 supplementation at 1 μ g/g per day was detrimental to retinal vascular development in neonatal animals. If these effects are paralleled in human neonates, T4 supplementation might increase, rather than decrease, the risk of developing ROP. Further work on the role of T4 in the pathogenesis of ROP is warranted.

KEYWORDS:

• insulin-like growth factor 1
• retina
• ROP
• thyroxine
• vasculogenesis