Effects of Flutamide Therapy on Craniofacial Growth and Development in a Model of Craniosynostosis

Abstract

Research has implicated the faulty regulation of transforming growth factor beta signaling as one mechanism for premature calvaria suture fusion. Androgens have been shown to increase the expression and activity of the transforming growth factor beta, resulting in increased osteoblast proliferation and differentiation and possibly premature suture fusion. The present study was designed to test the hypothesis that flutamide, an androgen receptor-blocking agent, would "rescue" a coronal suture destined to fuse and improve craniofacial growth in a familial rabbit model of craniosynostosis. Thirty rabbits with delayed-onset, coronal suture synostosis were examined via longitudinal cephalometry. The rabbits were divided into 4 groups: (1) sham surgical controls (n = 10), (2) bovine serum albumin (500 ng) protein controls (n = 6), (3) flutamide diluent controls (n = 6), and (4) flutamide (15 mg dissolved in ethanol) experimental group (n = 8). At 10 days of age, radiopaque amalgam markers were implanted in all rabbits on either side of the coronal suture to monitor sutural growth. At 25 days of age, the bovine serum albumin, ethanol, and flutamide were combined with a slow-resorbing collagen vehicle and injected subperiosteally above the coronal suture into the respective groups. Although results revealed a slight but significant increase in coronal suture marker separation in flutamide-treated rabbits compared with controls at 42 days of age, few significant differences were noted for craniofacial growth and intracranial volume among groups. Results suggest that androgen receptor-blocking using flutamide may only provide a transient rescue to suture fusion in this model. Further research is needed to investigate the effects of hormones on suture development and maintenance.