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We used a neonatal mouse model to examine the histogenesis of uterine adenomyosis, and to test whether adenomyosis is due to an abnormality in myometrial differentiation, or in extracellular matrix proteins expression. We also studied the effects of tamoxifen and estradiol on uterine development, myometrial differentiation, and organization. Female CD1 pups were treated with oral tamoxifen (1 mg/kg) (nZ27) or estradiol (0.1 mg/kg) (nZ24) from age 1 to 5 days. Uteri from control (nZ27) and treated mice were obtained on days 2, 5, 10, 15, and 42 of age. We examined the sections histologically, using image analysis and immunohistochemistry for a-smooth muscle actin (a-SMA), desmin, vimentin, laminin, fibronectin, and estrogen receptor-a. Following tamoxifen exposure, all uteri showed adenomyosis by 6 weeks of age (seen as early as day 10). The inner myometrium showed thinning, lack of continuity, disorganization, and bundling. a-SMA expression was normal. Desmin expression normally showed a wave of maturation that was absent in tamoxifen-treated mice. In the estradiol group, adenomyosis was not observed. All uterine layers were normally developed, but hypertrophied. The inner myometrium retained its circular arrangement. There was no difference in the localization of laminin or fibronectin between groups (laminin expression was reduced in the tamoxifen treated uteri). Vimentin could not be detected in all groups. Our results suggest that the development of the inner myometrium is particularly sensitive to estrogen antagonism, and can be affected by steroid receptors modulation. Disruption of the inner myometrium may play a role in the development of uterine adenomyosis.

Background and Aim: To study the characteristics of the inner (IM) and outer (OM) myometrium in the presence and absence of uterine adenomyosis. Methods: Case control blinded comparison carried out in a university department. Morphometric features of the myometrium were studied in uteri from pre- and postmenopausal women with and without uterine adenomyosis as the sole pathology. Uteri were also divided according to the phase of the cycle and examined using immunohistochemistry and image analysis. Results: Cell density and total nuclear area were statistically significantly greater in the IM compared to OM, in pre- and postmenopausal women, in both the adenomyosis and control uteri. The difference in nuclear size was statistically significant only in the premenopausal group. The change from the IM to the OM in cell density and total nuclear area was gradual with no distinct zonation. Examined features did not vary with cycle phase. Both the IM and OM in adenomyosis exhibited lower cell density and larger nuclei compared to controls. In adenomyosis, immunostaining for α-smooth muscle actin, desmin and Ki-67 was consistent with myometrial hyperplasia and hypertrophy. Conclusions: There are clear differences between the IM and the OM but the transition is gradual, with no distinct zonation. Adenomyosis is characterised by reduced cell density, and increased nuclear size and features of hyperplasia and hypertrophy that are not confined to the IM.

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