Archived, thyroid and pituitary biopsies from dogs with sulfamethoxazole (SMZ)-induced hypothyroidism were examined for changes in histologic morphology. Dogs were treated alternately with SMZ (30 mg/kg BID) and placebo for 6-week periods in a crossover design.

Random fields were examined on thyroid sections under microscopy. Morphometric analysis was done using MetaMorph® software. Relative proportions of follicular epithelial cells compared with colloid-filled lumina were estimated by subtracting cumulative cross-sectional area of colloid-filled follicles from total area of each field. In pituitary samples, thyrotrophs were detected by immunohistochemical staining, using an anti-canine TSH antibody. TSH-positive pituitary cells were counted in 6 random fields on each slide.

Colloid-containing follicles were markedly smaller and numbers of epithelial cells were greater in dogs following SMZ (N= 6) vs. placebo (N= 6). The median and interquartile range (IQR) of the percentage of thyroid tissue populated by epithelial cells in SMZ-treated dogs was 77.9 (IQR 64.5-91.3) vs. 32.0 (IQR 24.9-39.1) in placebo-treated dogs. The difference between the groups was significant (P = 0.014). SMZ-induced changes were reversed following 6 weeks of placebo. The median number of TSH-positive pituitary cells per field was significantly greater (P < 0.001) on biopsies from SMZ-treated (median 28.5; IQR 12.5-44.5; N = 3) vs. placebo-treated dogs (median 5.0; IQR 0.0-12.25; N = 3).

Our results demonstrate that SMZ-induced hypothyroidism is characterized by reversible thyroid follicular epithelial hyperplasia and colloid collapse. An increased population of pituitary thyrotrophs in SMZ-treated dogs supports recent reports of transdifferentiation of pituitary cells in response to hormonal needs.