The development of the human uterus: morphogenesis to menarche

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.

High incidence of Mayer-Rokitansky-Küster-Hauser syndrome syndrome in third-generation DES women

“…The early phase, known as the initiation of the Müllerian (paramesonephric) ducts (MDs), takes place during J o u r n a l P r e -p r o o f weeks 8 and 9 of pregnancy (from the first day of the last menstrual period) in the undifferentiated XX or XY embryo. MDs originate at the apical part of the mesonephros (primitive kidney) and elongate caudally along Wolff's excretory (mesonephric) ducts [3]. From a genetic point of view, the initiation of MDs does not depend on chromosomal sex and involves genes independent of sex steroids, such as PAX2, LHX1, TCF2, DMRT1, and WNT-4, -7A, and -9B, and those encoding retinoic acid αand β-receptors [3] (Fig.…”

Investigation of infertility using endometrial organoids

“…Canonical Wnt/β-catenin signalling is essential for the development of the human uterus ( Habiba et al 2021 ). The WNT pathway also plays a role in adulthood as it regulates endometrial cell proliferation and homeostasis after menstruation.…”

Development and Carcinogenesis: Roles of GATA Factors in the Sympathoadrenal and Urogenital Systems

“…As for reproductive systems, WDs give rise to the upper male genital tract, such as the epididymis, vas deferens, and seminal vesicles. In females, Müllerian duct gives rise to the oviduct and uterus [ 36 ].…”

“…Biomedicines 2021, 9, x FOR PEER REVIEW 6 of 11 deferens, and seminal vesicles. In females, Müllerian duct gives rise to the oviduct and uterus [36].…”