Cyclic processes in the uterine tubes, endometrium, myometrium, and cervix: pathways and perturbations

Abstract

This review leads the 2023 Call for Papers in MHR: 'Cyclical function of the female reproductive tract' and will outline the complex and fascinating changes that take place in the reproductive tract during the menstrual cycle. We will also explore associated reproductive tract abnormalities that impact or are impacted by the menstrual cycle. Between menarche and menopause, women and people who menstruate living in high-income countries can expect to experience ∼450 menstrual cycles. The primary function of the menstrual cycle is to prepare the reproductive system for pregnancy in the event of fertilization. In the absence of pregnancy, ovarian hormone levels fall, triggering the end of the menstrual cycle and onset of menstruation. We have chosen to exclude the ovaries and focus on the other structures that make up the reproductive tract: uterine tubes, endometrium, myometrium, and cervix, which also functionally change in response to fluctuations in ovarian hormone production across the menstrual cycle. This inaugural paper for the 2023 MHR special collection will discuss our current understanding of the normal physiological processes involved in uterine cyclicity (limited specifically to the uterine tubes, endometrium, myometrium, and cervix) in humans, and other mammals where relevant. We will emphasize where knowledge gaps exist and highlight the impact that reproductive tract and uterine cycle perturbations have on health and fertility.

Keywords: cervix; endometrium; fallopian tube; fertility; menstrual cycle; menstruation; myometrium; uterine tube.

Figure 1.

Cyclical ovarian hormone production and changes in uterine tube, endometrial, myometrial, and endocervical tissue composition and structure during the menstrual cycle. (A) During the proliferative phase oestradiol (E₂) is the dominant ovarian hormone. Following ovulation, the corpus luteum secretes high levels of progesterone (P) which subsequently fall in the absence of pregnancy, triggering the end of the menstrual cycle and onset of menstruation. A single columnar epithelium lines the uterine tube mucosa (B and C) which contains lymphoid and myeloid cells, including uterine natural killer (uNK), plasma, and dendritic cells. During the proliferative phase (B), epithelial cells express estrogen receptors (ER)-α and -β and progesterone receptor (PR)-A and E₂ induces increased epithelial cell height and cilia activity. In the secretory phase, epithelial PR-A is reduced and E₂ induced epithelial changes are lost. The uterine lumen (D and E) is lined by the endometrial epithelial luminal epithelium (LE) covering the multi-cellular stromal compartment of the endometrium which is internal to the muscular myometrium. The glandular epithelium (GE) invaginates from the LE into the endometrial stroma. During the proliferative (D) phase, E₂ induces endometrial cell (GE and stroma) proliferation via ERα and ERβ. ER expression in the myometrial myocytes is maximal during the proliferative phase. PR-A expression in myocytes is consistent throughout the menstrual cycle. Androgen receptors (AR) are also present in stromal fibroblasts during the proliferative phase. During the secretory phase (E), ER decline in the glandular epithelium and stroma, although ERβ levels are maintained in the stroma. During the period of endometrial receptivity (window of implantation, WOI), the endometrium undergoes significant transformation: (i) the luminal epithelium undergoes epithelial–mesenchymal transition, including loss of tight junctions and adherens junctions, with enzymatic clearance of the glycocalyx and the appearance of pinopods; (ii) the glandular epithelium becomes highly secretory, with released factors acting on the luminal epithelium or blastocyst to promote implantation; and (iii) stromal cells in the endometrium undergo ‘decidualization’ in response to P₄ and factors released from decidualized stromal cells. In the absence of P₄ and E₂, menses (iv) and endometrial breakdown is initiated. There is an influx of immune cells into the endometrial stroma, vasoconstriction of spiral arteries, and breakdown and shedding of the functional layer of the endometrium. The endocervix joins the vagina to the uterus and is comprised of mucin-secreting columnar epithelium overlaying a dense fibro-muscular stroma made up of connective and elastic tissues and smooth muscle. During the proliferative phase (F), mucin secretion increases with rising E₂ and infiltrating immune cell numbers drop. During the secretory phase (G), mucin secretion reduces with increasing P₄ and infiltrating immune cell numbers increase. Figure created with BioRender.com.