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. 2011 Nov;85(5):954-64.
doi: 10.1095/biolreprod.111.091470. Epub 2011 Jul 6.

Uterine gland formation in mice is a continuous process, requiring the ovary after puberty, but not after parturition

Affiliations

Uterine gland formation in mice is a continuous process, requiring the ovary after puberty, but not after parturition

C Allison Stewart et al. Biol Reprod. 2011 Nov.

Abstract

Uterine gland formation occurs postnatally in an ovary- and steroid-independent manner in many species, including humans. Uterine glands secrete substances that are essential for embryo survival. Disruption of gland development during the postnatal period prevents gland formation, resulting in infertility. Interestingly, stabilization of beta-catenin (CTNNB1) in the uterine stroma causes a delay in gland formation rather than a complete absence of uterine glands. Thus, to determine if a critical postnatal window for gland development exists in mice, we tested the effects of extending the endocrine environment of pregnancy on uterine gland formation by treating neonatal mice with estradiol, progesterone, or oil for 5 days. One uterine horn was removed before puberty, and the other was collected at maturity. Some mice were also ovariectomized before puberty. The hormone-treated mice exhibited a delay in uterine gland formation. Hormone-treatment increased the abundance of uterine CTNNB1 and estrogen receptor alpha (ESR1) before puberty, indicating possible mechanisms for delayed gland formation. Despite having fewer glands, progesterone-treated mice were fertile, suggesting that a threshold number of glands is required for pregnancy. Mice that were ovariectomized before puberty did not undergo further uterine growth or gland development. Finally, to establish the role of the ovary in postpartum uterine gland regeneration, mice were either ovariectomized or given a sham surgery after parturition, and uteri were evaluated 1 wk later. We found that the ovary is not required for uterine growth or gland development following parturition. Thus, uterine gland development occurs continuously in mice and requires the ovary after puberty, but not after parturition.

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Figures

FIG. 1.
FIG. 1.
Uterine gland development is delayed when the endocrine environment of pregnancy is extended. The experimental design to determine the effects of neonatal hormone treatment on postnatal and postpubertal uterine gland development is shown (A), as is the histological comparison of mice at 3 and 8 wk of age that were treated neonatally with oil, E2, or P4 (BG). Tissues were obtained from the same animal at different time points (i.e., B and E). Gland numbers were obtained from uterine cross-sections at 3 and 8 wk (H). Arrowheads indicate gland development in E2- or P4-treated mice at 8 wk. An asterisk (*) indicates significantly fewer endometrial glands in hormone-treated mice compared to age-matched, oil-treated mice (P < 0.0001). Data are shown as the mean ± SEM. myo, myometrium; St, stroma. Bar = 100 μm.
FIG. 2.
FIG. 2.
Hormone treatment alters epithelial differentiation and cell proliferation as early as PD10. Histological analysis (AC) and immunofluorescence localization of H3S10ph (DF) and ACTA (GI) in the uteri of oil-, E2-, and P4-treated mice at PD10 are shown. White arrows (E) indicate proliferating cells; asterisks (H, I) indicate disorganization of E2 smooth muscle layers and ACTA within the P4 endometrium. IC, inner circular myometrium; myo, myometrium; OL, outer longitudinal myometrium; St, stroma. Bar = 100 μm. J) H3S10ph-positive cells within the epithelial layer were quantitated; *P < 0.0001.
FIG. 3.
FIG. 3.
CTNNB1 and ESR1 are more abundant in the endometrium of hormone-treated mice. Immunofluorescence localization of CTNNB1 and ESR1 in the uteri of oil-treated (A, D, G, and J), E2-treated (B, E, H, and K), and P4-treated (C, F, I, and L) mice at 3 and 8 wk are shown. Gland development is normal in Ex3Esr1KO mice at PD10 (N) compared with wild-type (WT) controls (M). White arrows indicate CTNNB1 in the shallow stroma (B and C) and ESR1 in the LE and shallow stroma (H and I) at 3 wk. No differences were observed at 8 wk. myo, myometrium; St, stroma. Bar = 50 μm (AL) and 100 μm (M and N).
FIG. 4.
FIG. 4.
P4-treated mice were fertile despite having fewer glands. Uterine histology of mice following the breeding trial (AC) is shown, as are uterine gland numbers (D) from mice treated with oil, E2, or P4 neonatally and placed with males for 12 wk at maturity. Data are shown as the mean ± SEM. St, stroma. Bar = 100 μm. *P < 0.001.
FIG. 5.
FIG. 5.
Uterine growth and gland development require ovarian hormones after puberty. The experimental design to determine the role of the ovary and steroid hormones on postpubertal gland development (A) is shown, as is the histological comparison of mice at 3 and 8 wk of age that were treated neonatally with oil, E2, or P4 and ovariectomized at 3 wk (BG). Tissues were obtained from the same animal at different time points (i.e., B and E). Arrows indicate uterine glands. Uterine gland numbers were quantified (H), and an asterisk (*) indicates significant differences in gland number within the same treatment groups (P < 0.001). Data are shown as the mean ± SEM. myo, myometrium; St, stroma. Bar = 200 μm.
FIG. 6.
FIG. 6.
Uterine growth and gland regeneration occur independently of ovarian hormones following parturition. The experimental design (A) and histological comparison (B) of dams subjected to either sham surgery (Sham) or ovariectomy (Ovx) at PPD0.5 and collected at PPD8 are shown. Uterine horn length (C) and gland numbers (D) were quantified. No difference was found in uterine horn length (P = 0.6), but fewer glands were found in Ovx uteri. Data are shown as the mean ± SEM. St, stroma. Bar = 100 μm. *P < 0.001.

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