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Purpose: The aim of this study was to test the hypothesis that the dose of estrogen replacement therapy may have an influence on the clinical, radiographic, and histopathologic changes within the temporomandibular joint (TMJ)., Materials and Methods: A prospective experimental study was conducted in 12 mature ovariectomized dogs. Dogs were randomly allocated into 1 of 4 groups (OVX-E0, dogs that did not receive any estrogen replacement therapy; OVX-E0.5, dogs that received 0.15 mg/kg of estradiol; OVX-E1, dogs that received 0.3 mg/kg of estradiol; and OVX-E2, dogs that received 0.6 mg/kg of estradiol); dogs were evaluated clinically for 12 weeks; and contact radiographic and histopathologic examinations of the TMJ were performed just after euthanasia., Results: Radiographic examination of the TMJ in the OVX-E0 group showed narrowing of the joint space with marginal osteophyte formation along the mandibular condyle. The OVX-E0.5 group showed mild widening of the joint space with no remarkable changes within the mandibular fossa or condyle. The OVX-E1 group was free of radiographic changes within the TMJ. High doses of estrogen in the OVX-E2 group showed marked flattening of the mandibular condyle and fossa with sclerosis of the subchondral bone. Histopathologic sections in the OVX-E0 group showed thin compact bone with scanty, less organized lacunae. The OVX-E0.5 group showed compact bone of medium thickness with large osteons and disorganized lacunae. The OVX-E1 group showed thick compact bone with reduced intertubercular spaces and organized lacunae. The OVX-E2 group showed thin bone with reduced trabecular and increased intertrabecular thickness. The collagen content did not change significantly among the 4 groups, whereas its quality changed significantly (P < .05)., Conclusions: Estrogen dosage is potentially a key regulator of bone metabolism within the TMJ. Estrogen replacement therapy exhibited an inverted U-shaped beneficial effect. Estrogen depletion as well as high doses of estrogen resulted in clinical, radiographic, and histopathologic changes within the TMJ. Estrogen replacement therapy should be prescribed at the optimum dose when indicated as hormonal replacement therapy., (Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)