Anjana R. Nair and Hugh S. Taylor1
(1)
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
Hugh S. Taylor
Email: hugh.taylor@yale.edu
Abstarct
Menstruation is a result of the profound tissue remodeling that occurs each month in reproductive-aged women. After withdrawal of steroid hormone support, the functionalis layer of the endometrium undergoes extensive changes, resulting in complete tissue breakdown. With each menstrual cycle, most of the endometrium is completely shed at menses and subsequently regenerated. Menstruation is seen in only a few animals that have hemochorial placentation. In hemochorial placentation, trophoblasts invade the maternal blood vessels and chorionic villi are in direct contact with maternal blood. Thus the invasive nature of hemochorial placenta requires a correspondingly defensive uterus. In pregnancy, under the influence of progesterone, the endometrial stroma undergoes extensive decidualization. Decidualization limits trophoblastic invasion; however, protection from invasive trophoblasts requires the development of a barrier, a process that results in terminal differentiation. This differentiated state is renewable only by regeneration from progenitor cells located in the basalis layer of the endometrium; a strategy that requires monthly bleeding events and introduces multiple potential opportunities for mechanistic failure and the emergence of abnormal uterine bleeding. An appreciation of normal endometrial physiology as it pertains to the regulation of menstruation is essential to understand disorders of menstruation.
Menstruation is a result of the profound tissue remodeling that occurs each month in reproductive-aged women. After withdrawal of steroid hormone support, the functionalis layer of the endometrium undergoes extensive changes, resulting in complete tissue breakdown. With each menstrual cycle, most of the endometrium is completely shed at menses and subsequently regenerated. Menstruation is seen in only a few animals that have hemochorial placentation. In hemochorial placentation, trophoblasts invade the maternal blood vessels and chorionic villi are in direct contact with maternal blood. Thus the invasive nature of hemochorial placenta requires a correspondingly defensive uterus. In pregnancy, under the influence of progesterone, the endometrial stroma undergoes extensive decidualization. Decidualization limits trophoblastic invasion; however, protection from invasive trophoblasts requires the development of a barrier, a process that results in terminal differentiation. This differentiated state is renewable only by regeneration from progenitor cells located in the basalis layer of the endometrium; a strategy that requires monthly bleeding events and introduces multiple potential opportunities for mechanistic failure and the emergence of abnormal uterine bleeding. An appreciation of normal endometrial physiology as it pertains to the regulation of menstruation is essential to understand disorders of menstruation.
The Endometrium During the Menstrual Cycle
The endometrium is composed of the basalis and functionalis layers. The basalis layer is deep and adjacent to the myometrium, while the functionalis layer comprises the superficial two-thirds of the endometrium. The functionalis is divided into stratum compactum and stratum spongiosum. The stratum compactum is a superficial thin layer with gland necks and dense stroma, while the stratum spongiosum is the deeper part of functionalis composed of glands and loosely arranged stroma. Only the functionalis layer of endometrium is shed with each cycle. The basalis layer contains the progenitor cells that regenerate the functionalis layer in each cycle. Endometrial tissue responds to sex steroid hormones produced in the follicular and luteal phases of the ovarian cycle. The menstrual cycle is divided into proliferative and secretory phases, and cytoarchitectural and molecular differences between the phases reflect endometrial responses to cyclic changes in ovarian hormone exposure.
Proliferative Phase
The functional layer (upper 2/3) of the endometrium is shed during each menstrual cycle. By the end of menstruation, the endometrial lining is about 2 mm thick and is composed of epithelial cells that arise from the glands in the basalis layer and migrate to the denuded surface of the endometrium. Of note, the thin epithelialized basalis layer seen in early menstrual cycle is similar to the endometrial cytoarchitecture observed in postmenopausal women and also in women with hypothalamic amenorrhea. The initial repair of the endometrial surface, an event critical for the regeneration, occurs before cessation of menses and prior to the rise in estradiol [1, 2]. A measurable increase in endometrial thickness does not commence until this process is complete.
Estradiol, produced by the ovaries on approximately day 4 or 5 (D4 or 5) of the cycle, induces growth and proliferation of the endometrium. The epithelial and stromal cells undergo mitoses and multiply, thus causing the glands to increase in length, while the stromal cells grow and expand the extracellular matrix [3]. Some of the surface epithelial cells commonly seen near the tubal ostia and endocervix become ciliated at this time.
Endometrial growth can be viewed using ultrasound, measuring the total width of the opposed endometrial epithelial surfaces (also known as the trilaminar endometrial stripe). There is rapid growth of the endometrium from cycle D4 or 5. Endometrial thickness begins from a nadir of approximately 4.5 mm on cycle D4 and increases linearly to a plateau of approximately 10 mm on cycle D9 or 10 [4]. The cessation of endometrial growth occurs before estradiol levels reach their peak and prior to the onset of secretory phase progesterone production, thereby indicating that nonsteroidal factors limit the growth of endometrium.
Amenorrhea in some women results from chronic anovulation, which can be associated with unopposed estrogen exposure and disordered endometrial growth. Although some anovulatory women may have thickened endometrium, they do not experience the continued rapid growth of endometrial tissue seen in the normal proliferative phase. The endometrium does not grow indefinitely and the average endometrial thickness is rarely greater than 11 mm [5]. Obviously, unopposed estrogen is not sufficient to produce continued endometrial growth, again suggesting the existence of factors that limit the extent of proliferation. The cellular mechanisms responsible for dysfunctional endometrial growth observed in anovulatory women are still poorly understood. Nonetheless, the observed pathophysiology of the endometrium in anovulatory women likely reflects dysregulation of modulators of endometrial repair and growth cessation which promotes long-term stabilization under anovulatory conditions or estrogen deficiency.
Secretory Phase
Secretion of progesterone after ovulation causes complete cessation of endometrial epithelial proliferation. Estrogen receptors expressed by the endometrial epithelial cells during the proliferative phase are downregulated by progesterone action, thus attenuating estrogen’s proliferative effect. Progesterone exposure induces sub-nuclear glycogen-rich vacuoles to appear on approximately (D16) of the cycle and inhibits epithelial cell mitosis by D17. The vacuoles become supranuclear on D18 and secretions are found in the gland lumen by D19–20. Peak secretory activity is seen by D20–21 [6–10]. These changes are essential for conception and the generation of an endometrial surface receptive to blastocyst attachment.
Progesterone provokes profound stromal fibroblast changes characterized by cellular enlargement, as well as laminin and type 4 collagen accumulation [11, 12]. In the luteal phase, type 4 collagen and laminin are present in the extracellular space of the endometrial stroma and the basement membrane of glands and blood vessel walls. Even though Collagen types 1, 3, and 6, and laminin are present in the endometrium throughout the menstrual cycle, their ratios change with prolonged exposure to progesterone (i.e., type 3:1 decreases and type 5:1 increases) [13]. The endometrium also makes large quantities of prolactin and IGF-binding proteins (IGFBP-1). These changes in response to progesterone result in dramatic alterations in both the extracellular matrix and secretory products of the endometrium.
Stromal edema is apparent by D20–23 and in the few days immediately preceding menstruation, the stroma becomes infiltrated by natural killer cells, macrophages, and T cells. In contrast, continuous progesterone exposure results in endometrial atrophy and thinning, gland narrowing, and vasculature abnormalities characterized by the creation of sinusoids and hyperplasic endothelial cells. This endometrial histology characterizes women with amenorrhea due to chronic progestin exposure.
Endometrial Growth Regulation
Numerous growth factors as well as ovarian steroid hormones regulate the growth of the endometrium during the menstrual cycle.
Ovarian Steroids
The endometrium responds to the ovarian steroids estrogen and progesterone; these two hormones are the only extrinsic signals necessary to drive a normal uterine menstrual cycle and are in fact sufficient to do so. The proliferative phase of the cycle is mainly mediated by the effects of estrogens. Estrogen receptor alpha (ERα, also known as ESR1) and estrogen receptor beta (ERβ, also known as ESR2) are transcribed from different genes and have distinct expression patterns. ESR2 is expressed in the endometrium throughout the menstrual cycle [14]. ERS1 varies throughout the menstrual cycle and is expressed by both epithelial and stromal cells during the proliferative phase [14]. Estrogen receptors are largely lost in the epithelium after progesterone exposure. There is also evidence that estrogen signaling may be transmitted through non-classic estrogen receptors, including the membrane receptor G-coupled receptor 30 (GRP30); however, this remains controversial.
The effects of progesterone on the uterus are mediated through progesterone receptors A (PR-A), B (PR-B), and C (PR-C). Each is a homologous protein transcribed from different promoters of the same gene [15–17]. Epithelial and stromal cells express PR-A and PR-B in the proliferative phase. In the luteal phase, only the stromal cells express PR-A and PR-B (PR-A is predominant), while the expression of both the receptors are downregulated in the epithelial cells [18, 19]. PR expression in stromal cells is unaffected by chronic exposure to long-acting progestational agents [20].
Growth Factors
A large number of mitogenic growth factors are secreted by the endometrium, modulating sex steroid action on the endometrium. These peptide molecules can initiate the activation of a cascade of intracellular pathways by binding to their cognate membrane bound receptors (Fig. 2.1).
Fig. 2.2
Endometrial growth factors. Relative amounts of growth factor (top) and growth factors receptor (bottom) mRNA and protein levels in the human endometrium during the menstrual cycle. Levels illustrated are relative to levels during the early proliferative phase. CSF-1 colony-stimulating factor-1; EGF epidermal growth factor; FGF fibroblast growth factor; IGF-1 insulin-like growth factor-1; IL-1 interleukin-1; LIF leukemia-inhibiting factor; PDGF platelet-derived growth factor; TGF transforming growth factor. From Guidice L, Saleh W (Trends Endocrinol Metab 1995;6:60–69) with permission
Epidermal growth factor (EGF) is expressed by the epithelial cells during the proliferative phase and by stromal cells during secretory phase of the cycle [21, 22]. The levels of EGF are stable throughout the menstrual cycle. EGF can either synergize with estradiol or act independently to stimulate epithelial cell growth. EGF stimulation indirectly leads to ERα activation and the expression of downstream targets of this receptor [23, 24]. EGF may mediate the proliferative effects on epithelial cells seen in the endometrium during the early follicular phase when estradiol levels are generally very low. Transforming growth factor alpha (TGFα), a member of the EGF family, binds the same receptor as EGF and achieves peak levels during the mid-cycle. TGFα is also thought to mediate the proliferative actions of estrogen on the endometrium.
Fibroblast growth factors (FGF) comprise a family of approximately nine members and of these, FGF-1, -2, -4, and -7 are expressed in human endometrium. Epithelial cells produce FGF-1 and -2 during the proliferative and secretory phases of the menstrual cycle. Stromal cells express FGF-2 in the proliferative phase, where it is proposed to induce mitosis and DNA synthesis [25–28].
Insulin-like growth factors (IGF)-1 and -2 are produced at high levels by epithelial and stromal cells throughout the menstrual cycle. Endometrial stromal fibroblast proliferation is induced by IGF-1 [29, 30]; however, both IGF-1 and -2 can also promote differentiation. IGF-1 production is upregulated by estradiol and it mediates estrogen’s effect on endometrial growth. IGF-2 is involved in mediating differentiation of cells in response to progesterone effects. Their effects are mediated by binding to IGFBP-1. IGFBP-1 is one of six homologous proteins that specially modulate the mitogenic and metabolic effects of IGF-1 and -2. Both IGFBP-I protein and mRNA have been localized to the pre-decidual stromal cells in late secretory-phase endometrium and to decidual cells during pregnancy.
Multiple other relevant cytokines and growth factors have been described including keratinocyte growth factor (KGF), a member of the FGF family. KGF is expressed at higher levels in the stromal cells and during the secretory phase. It is proposed to mediate epithelial–stromal signaling [31]. Platelet-derived growth factor (PDGF) is secreted by stromal cells and platelets. It is localized to the stromal cells and stimulates stromal cell proliferation and angiogenesis. Tumor necrosis factor α (TNFα) activity in the endometrium is higher in the proliferative and mid-secretory phases. It has multiple influences on cell growth. TNFβ is mitogenic, angiogenic, immunomodulatory, and inflammatory in its actions.
While the list provided is far from complete, it serves to illustrate the complexity of cellular communication that is needed to maintain normal endometrial physiology. It makes sense that disequilibrium within this intricate network of cellular pathways could result in devastating consequences that affect menstrual cycles and implantation, and/or predispose some women to the development of neoplasia.
Endometrial Stem cells
In order for the epithelium and stroma to be completely renewed in each menstrual cycle, there must be a continuous pool of progenitor cells available to replenish and rebuild the endometrium. Hormonally, responsive stem cells residing in the basalis are hypothesized to be the source of progenitor cells that are committed to developing into specific types of differentiated cells, e.g., epithelial, stromal, and vascular. These resident stem cells are hypothesized to allow the rapid cyclic regeneration of the endometrium. However, there was no direct evidence to confirm this hypothesis until 2004. In that year, two reports from different laboratories provided evidence to support the hypothesis that local stem cells provided progenitor cells for cyclic endometrial renewal [32–34].
Human endometrium contains small populations of epithelial and stromal stem cells responsible for cyclic regeneration of endometrial glands and stroma. Notably, these cells exhibit clonogenicity. Consistent with this concept, small numbers of epithelial (0.22%) and stromal cells (1.25%) will initiate colonies and exhibit high proliferative potential in vitro. These cells comprise the local progenitor stem cells that are destined to give rise to most of the endometrium in each menstrual cycle.
Endometrial regeneration from multipotent stem cells derived from the bone marrow was recently demonstrated in bone marrow transplant recipients; donor-derived endometrial epithelial cells and stromal cells were detected in endometrial samples of bone marrow recipients. Histologically, these cells appeared to be endometrial epithelial and stromal cells and they also express appropriate markers of endometrial cell differentiation. These findings strongly suggest that bone marrow may also be an extrauterine source for endometrial stem cells [33, 35–37]. Moreover, these observations suggest that cyclic mobilization of bone marrow-derived stem cells may be a normal physiologic process. Interestingly, male donor-derived bone marrow transplant cells were found in the uterine endometrium of recipient female mice, and although rare, these cells differentiated into epithelial and stromal cells [38]. Endometrial stem cells are likely derived from a common stem cell found in both men and women. More recently, another group showed that bone marrow transplants-derived endothelial progenitors also contribute to the formation of new blood vessels in the endometrium [39].
The repopulation of endometrium with bone marrow-derived stem cells may be important to normal endometrial physiology and may also help to explain the cellular basis for the high rates of long-term failure following conservative alternatives to hysterectomy such as endometrial ablation or resection. Alternatively, endometrial regeneration may be incomplete in women with deficient stem cell reserves or defective recruitment of stem cells after injury, thereby increasing the risk for poor outcomes including Asherman’s syndrome.
Endometrial Vessels
Since menstruation is a form of tissue remodeling where the lining of the uterine cavity is shed regularly, it is of utmost importance that the vasculature of the endometrium also be capable of regeneration. Nowhere outside the reproductive tract do vessels undergo this dramatic and regular regeneration. Angiogenesis and development of the microvasculature system within the endometrium may be the key event for normal endometrial cycling, as proliferation and subsequent maturation of the endometrium are dependent on delivery of local oxygen and nutrients to the tissue [40].
Endometrial Vascular Supply
Arcuate arteries arise from the uterine arteries in the myometrium. The arcuate arteries divide just inside the border of the endometrium and give rise to numerous straight arterioles that supply the lower third of the endometrium. These vessels continue as the spiral arteriole and supply the functional two-thirds of the endometrium. Endometrial blood vessels have abundant smooth muscle cells and just beneath the surface of the endometrium, the capillaries are fenestrated. The venules from the area drain into the uterine vein [41–44]. A sketch of the endometrial vascular system can be found in Fig. 2.1.
Fig. 2.1
Schematic presentation of the endometrial vascular system. The primate endometrium is comprised of the stratum basalis (s. basilis) and stratum functionalis (s. functionalis). Uterine arteries branch within the myometrium to yield the arcuate and radial arteries. The radial artery branches within the s. basilis to yield numerous straight and spiral arterioles in the lower third of the endometrium. Spiral arterioles provide the vascular blood supply to the s. functionalis through a vast network of fenestrated capillaries
Regulation of Endometrial Vessel Growth
Menstruation results in open vessels that need to be repaired in order to control bleeding. The blood vessels begin to regenerate at the end of menstruation and continue into the proliferative phase of the menstrual cycle. Balances between factors that stimulate and inhibit angiogenesis regulate endometrial shedding and regeneration. Numerous angiogenic factors have been described by several investigators and include EGF [23], TGFα, TGFβ, TNFα, FGF-1, FGF-2, PDGF, and vascular endothelial growth factor (VEGF) [45, 46] Fig. 2.2. Appropriate angiogenesis is required for cessation and regulation of menstrual flow. Disorders of blood vessel function and repair may contribute to abnormal uterine bleeding.
Several specific factors involved in endometrial endothelial regeneration are well studied. VEGFs are heparin-binding 30–45 kDa molecules that are potent mitogens. VEGFs are proposed to have a crucial role in the development of vascular endothelium and thus formation of new blood vessels [47, 48]. Of the five different variants of VEGF, VEGF 121 and 165 isoforms are the predominant forms that regulate endometrial angiogenesis.
VEGF-A is produced in the glandular and luminal epithelium as well as in the stroma in the proliferative phase of the cycle. In the secretory phase of the menstrual cycle, only the epithelial cells continue to express VEGF-A [49, 50]. Several studies suggest that VEGF is hormonally regulated. Estradiol is thought to increase VEGF release; however, the exact role of ovarian hormones in the regulation of VEGF expression and function is not clear. [51]
Menstruation
Menstruation is the occurrence of bleeding when progesterone is withdrawn from an estrogen- and progestin-primed uterus. While progesterone withdrawal occurs in all species with an estrus cycle, only a very few menstruate, suggesting the existence of unique regulatory mechanisms in the endometrium of these species. The cellular events that follow withdrawal of steroid support can be divided into four types and are described below.
Loss of Vascular Integrity
Spiral arterioles are unique to menstruating species. The classic studies conducted more than 50 years ago by Markee demonstrated that steroid (estrogen/progesterone) withdrawal produced severe vasoconstriction of the endometrial spiral arterioles lasting 4–24 h [52]. The vasoconstriction is followed by vasodilatation in these vessels, causing increased blood flow. Ischemic damage induced by the vasoconstriction causes blood to flow out of the vessels to the epithelial surface. The interruption of blood supply and the acute tissue hemorrhage culminate in shedding of the superficial functional layer of the endometrium.
Several vasoactive agents likely mediate the response to steroid withdrawal. Local prostaglandin (PG) production is proposed to affect endometrial vasoregulation by increasing the ratio of the vasodilatory PGE2 relative to the vasoconstrictor PGF2α at menstruation [53]. Nitric oxide (NO), a vasodilator, is also locally synthesized in the endometrium and may have a role in regulating vascular tone [54]. VEGF may affect the induction of NO synthesis. Molecular studies of endometrial NOS expression, as well as animal experiments with NOS inhibitors, indicate that NO plays an important role in endometrial functions such as endometrial receptivity, implantation, and menstruation. Endothelins are also potent vasoconstrictors. Cameron et al. have shown that endometrium is rich in these molecules as well as their cognate receptors, thereby regulating bleeding during menstruation [55]. Many of these agents have yet to be explored in the treatment of abnormal uterine bleeding.
It is important to appreciate that prior to overt vascular breakdown and menstruation, an inflammatory process ensues and vasospasm prompts tissue degeneration. Leukocytes are recruited to the endometrium, where they make up nearly 50% of the tissue just prior to menstruation. Chemokines involved in endometrial tissue breakdown include molecules such as IL-8, which are produced by the endometrium after progesterone withdrawal. These molecules in turn attract various leukocytes to the uterus. Myeloid cells are particularly abundant and release pro-inflammatory cytokines at this time, as well as multiple other molecules involved in tissue degradation.
Matrix Metalloproteins (MMPs) and Tissue Breakdown
The endometrial matrix consists of the collagen, laminin, gelatin, fibronectin, proteoglycans, and hyaluronic acid. In addition to spiral arteriolar vasoconstriction, enhanced matrix degradation is a key mechanism that contributes to the onset of menstruation. MMPs regulate the degradation of all of the components of the extracellular matrix. Endometrial stroma expresses MMP 1, 2, 3, and 10, while epithelium expresses MMP 7. A plethora of MMPs are produced by leukocytes as well. MMPs are generally secreted in an inactive form. Pro-MMPs are made in increasing numbers prior to menstruation in response to local signals as well as progesterone withdrawal. A tightly regulated balance among MMP production, activation, and inhibition controls the activity of MMPs and hence tissue integrity. MMPs are also regulated by tissue inhibitors of MMPs (TIMPs). Withdrawal of progesterone at menstruation leads to increased MMP production and activation as well as release of TIMPs, thus causing matrix degradation. The degradation of tissue matrix results in massive tissue destruction, loss of structural integrity, and vascular disruption. These events have an even more profound effect than the vascular events previously described. The endometrium is sloughed along with blood coming from the destroyed endometrial vasculature [56].
Mechanisms have evolved to prevent premature clotting during the initial phase of endometrial shedding [57]. Hemostasis is achieved after menstruation by coagulation in the basal endometrium. Tissue breakdown induced by MMPs activates endometrial platelets and results in coagulation of blood. Coagulation abnormalities in various disease states will lead to an increase in menstrual blood loss.
Endometrial Re-epithelialization
Endometrial epithelial cells from the basal glands cover the denuded surface of the endometrium on D2 of the cycle. The epithelial cells migrate and spread to cover the endometrial surface. Of note, re-epithelialization at this time does not reflect mechanisms that involve clonal expansion or a significant effect of estrogen. It is unclear if migrating cells are epithelial stem cells and whether loss of cell–cell contact stimulates this migration.
Vascular Repair
Repair of the endometrial vessels is a crucial event in cyclic shedding of the uterine lining. Endothelial cells sprout from the ruptured arterioles and venules in the basal layer of endometrium and recruit pericytes and smooth muscle cells [58, 59]. VEGF plays an important initial role, inducing recruitment and proliferation of endothelial cells, and forming tubules and tight junctions between cells [60, 61]. Intense vasoconstriction of spiral arterioles prior to onset of bleeding induces local tissue ischemia in the endometrium. This hypoxia induces VEGF expression via hypoxia-inducible factor α [62]. Recruitment of pericytes and smooth muscle cells for maturation of the vessels follows endothelial cell recruitment.
Summary
An endometrium, receptive to embryo implantation, is prepared and shed each month during the menstrual cycle. A woman typically will have about 500 menstrual cycles in her lifetime. Disorders of the menstruation are a common problem and one of the most frequent indications for medical care in a reproductive-aged woman. Precisely regulated tissue degradation, controlled hemorrhage, and rapid hemostasis and repair are required for normal menstruation. A thorough understanding of the mechanisms that underlie this process is important to understand the basis and treatment of disorders in this complex physiologic process.
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