Tris(4-hydroxyphenyl)ethane (THPE), a trisphenol compound, is antiestrogenic and can retard uterine development in CD-1 mice

ABSTRACT There is emerging evidence that early uterine development in humans is an important determinant of conditions such as ontogenetic progesterone resistance, menstrual preconditioning, defective deep placentation and pre-eclampsia in young adolescents. A key observation is the relative infrequency of neonatal uterine bleeding and hormone withdrawal at birth. The origin of the uterus from the fusion of the two paramesonephric, or Müllerian, ducts was described almost 200 years ago. The uterus forms around the 10th week of foetal life. The uterine corpus and the cervix react differently to the circulating steroid hormones during pregnancy. Adult uterine proportions are not attained until after puberty. It is unclear if the endometrial microbiome and immune response—which are areas of growing interest in the adult—play a role in the early stages of uterine development. The aim is to review the phases of uterine development up until the onset of puberty in order to trace the origin of abnormal development and to assess current knowledge for features that may be linked to conditions encountered later in life. The narrative review incorporates literature searches of Medline, PubMed and Scopus using the broad terms individually and then in combination: uterus, development, anatomy, microscopy, embryology, foetus, (pre)-puberty, menarche, microbiome and immune cells. Identified articles were assessed manually for relevance, any linked articles and historical textbooks. We included some animal studies of molecular mechanisms. There are competing theories about the contributions of the Müllerian and Wolffian ducts to the developing uterus. Endometrium features are suggestive of an oestrogen effect at 16–20 weeks gestation. The discrepancy in the reported expression of oestrogen receptor is likely to be related to the higher sensitivity of more recent techniques. Primitive endometrial glands appear around 20 weeks. Features of progestogen action are expressed late in the third trimester. Interestingly, progesterone receptor expression is higher at mid-gestation than at birth when features of endometrial maturation are rare. Neonatal uterine bleeding occurs in around 5% of neonates. Myometrial differentiation progresses from the mesenchyme surrounding the endometrium at the level of the cervix. During infancy, the uterus and endometrium remain inactive. The beginning of uterine growth precedes the onset of puberty and continues for several years after menarche. Uterine anomalies may result from fusion defects or atresia of one or both Müllerian ducts. Organogenetic differentiation of Müllerian epithelium to form the endometrial and endocervical epithelium may be independent of circulating steroids. A number of genes have been identified that are involved in endometrial and myometrial differentiation although gene mutations have not been demonstrated to be common in cases of uterine malformation. The role, if any, of the microbiome in relation to uterine development remains speculative. Modern molecular techniques applied to rodent models have enhanced our understanding of uterine molecular mechanisms and their interactions. However, little is known about functional correlates or features with relevance to adult onset of uterine disease in humans. Prepubertal growth and development lends itself to non-invasive diagnostics such as ultrasound and MRI. Increased awareness of the occurrence of neonatal uterine bleeding and of the potential impact on adult onset disease may stimulate renewed research in this area.

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The effects of tamoxifen and estradiol on myometrial differentiation and organization during early uterine development in the CD1 mouse

Reproduction ◽

10.1530/rep-09-0054 ◽

2009 ◽

Vol 138 (2) ◽

pp. 341-350 ◽

Cited By ~ 32

Author(s):

Mohamed K Mehasseb ◽

S C Bell ◽

M A Habiba

Keyword(s):

Extracellular Matrix ◽

Image Analysis ◽

Steroid Receptors ◽

Smooth Muscle Actin ◽

Estrogen Receptor Α ◽

Matrix Proteins ◽

Muscle Actin ◽

Uterine Adenomyosis ◽

Circular Arrangement ◽

Uterine Development

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) (n=27) or estradiol (0.1 mg/kg) (n=24) from age 1 to 5 days. Uteri from control (n=27) 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 α-smooth muscle actin (α-SMA), desmin, vimentin, laminin, fibronectin, and estrogen receptor-α. 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. α-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.

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A comparative study of the corpus luteum

Reproduction Fertility and Development ◽

10.1071/rd9950303 ◽

1995 ◽

Vol 7 (3) ◽

pp. 303 ◽

Cited By ~ 26

Author(s):

RT Gemmell

Keyword(s):

Corpus Luteum ◽

Luteal Phase ◽

Secretory Granules ◽

Hormonal Control ◽

Egg Laying ◽

Oestrous Cycle ◽

Corpora Lutea ◽

Embryonic Diapause ◽

Alternative Reproductive Strategy ◽

Uterine Development

The corpus luteum (CL) is a transitory organ which has a regulatory role in reproduction. Sharks, amphibians and reptiles have corpora lutea that produce progesterone which influences the rate of embryonic development. The egg-laying monotremes and the two major mammalian groups, eutherian and marsupial, have a CL that secretes progesterone. Most eutherians have allowed for the uterine development of their young by extending the length of the oestrous cycle and the CL or placenta actively secretes progesterone until birth. Gestation in the marsupial does not extend beyond the length of an oestrous cycle and the major part of fetal development takes place in the pouch. Where the extension of the post-luteal phase in the eutherian has allowed for the uterine development of young, the marsupial has extended the pre-luteal phase of the oestrous cycle and has evolved an alternative reproductive strategy, embryonic diapause. The mechanism for the secretion of hormones from the CL has been controversial for many years. Densely-staining secretory granules have been observed in the CL of sharks, marsupials and eutherians. These granules have been reported to contain relaxin, oxytocin or mesotocin, and progesterone. A hypothesis to suit all available data is that all hormones secreted by the CL are transported within such granules. In conclusion, although there are obvious differences in the mode of reproduction in the two main mammalian groups, it is apparent that there is a great deal of similarity in the hormonal control of regression of the CL and parturition.

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