Complete re-epithelialization of the surface coincides with cessation of bleeding. DNA tracing studies have shown that increased DNA synthesis is confined to the basal layer of the body and fundus of the uterus and the adjacent isthmic and peritubal-ostial endometrial mucosa, all of which remain intact during menstruation.
This increase occurs only after complete denudation of the basal layer by cycle day 3.
The postmenstrual endometrium is repaired by cellular migration and replication of surface epithelial cells. These features are consistent with ameboid contraction-expansion-mediated motility. Typically, the regenerative surface epithelium is devoid of cells involved in DNA synthesis or mitoses Fig. Surface epithelial cells supported by tightly packed stromal cells.
Both lack DNA synthesis as evidenced by negative immunostaining reaction for Ki x Endometrial stromal cells modulate the growth, steroid hormone action, and functional differentiation of the epithelial cells. The basement membrane provides anchorage and participates in the control of proliferation and migration of epithelial cells as well as in their differentiations. An essential component of epithelial regeneration is provided by stromal cells which aggregate in cellular 'balls' beneath the regenerative surface epithelium Fig.
Menstrual endometrium, cycle days 3 and 4. Note dense stromal cell aggregates beneath the regenerative surface epithelium arrow x Tenascin, an extracellular matrix protein, is immunolocalized around proliferative endometrial glands and is believed to enhance epithelial cell migration and proliferation during periods of postmenstrual repair by inhibiting cell attachments to fibronectin.
Pathology Outlines - Dating of endometrium
After the initial epithelial spread, cell division and migration operate simultaneously until a confluent surface layer has been regenerated by cycle day 5. The sudden increase in nucleic acid synthesis and a very short DNA-synthesis phase of the regenerative cells result in accelerated tissue turnover. These characteristics of migration and accelerated tissue turnover explain the spectacularly rapid wound healing capability of the human endometrium.
DNA and ultrastructural data do not support the concept that the regenerative endometrium derives directly from persistent secretory spongiosa or stromal fibroblasts of the endometrium. Indeed, during cycle days 3 and 4, despite increased DNA activity, plasma levels of estrogens and progesterone receptors are low and unchanged from the premenstrual values. By immunostaining, the regenerative surface epithelium and underlying stromal cells are seen to be depleted of receptors for estradiol and progesterone Fig.
Immunostaining for ER is negative in regenerative surface epithelium arrow and the immediately underlying stromal cells. In contrast, the endometrial glands and stromal cells in the deeper layer immunostained strongly for ER and PR not shown. The findings suggest that the early phase of regeneration is independent of hormonal influence x Experimental endometrial regeneration in the rabbit has shown that proliferation kinetics and morphologic alterations of the regenerative but estrogen-deprived atrophic endometrium associated with ovariectomy are similar to those in animals with intact ovaries.
These changes are accompanied by an increase in plasma levels of estrogens and progesterone receptors and a slight decrease in serum pituitary hormones, alterations that are consistent with target cell sensitivity and response to preovulatory estradiol. The preovulatory endometrium demonstrates proliferative changes in the glands, stromal cells, and vascular system Fig. The glands have relatively narrow lumens, pseudostratified nuclei and mitotic figures, and the stroma is cellular and slightly edematous x The glands acquire numerous mitoses and gradually become longer and larger, with convoluted shapes.
The stroma becomes vascularized. These changes take place under the stimulatory action of estradiol, which stimulates the DNA-promoter enzyme, thymidylate synthetase.
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Endometrial growth during the pre-ovulatory phase is further substantiated by immunohistochemical tracing methods. The most often used proliferation markers are the DNA S-phase Ki Mib-1 molecule , the anti-apoptotic bcl-2, and the tumor suppressor gene p Both the gland and stromal cell nuclei stain strongly and diffusely for Ki, so do occasional endothelial cells of endometrial capillaries x Cytoplasmic membrane staining for bcl-2 is seen in endometrial gland cells and occasional stromal cells x Immunostaining for p53 is mainly confined to nuclei of stromal cells x Increased proliferation leads to a considerable thickening of the endometrial mucosa.
It is interesting to note that the endometrium demonstrates geographic variations in its response to hormonal stimuli. Maximum DNA synthesis is observed in the fundus and body of the uterus, whereas the isthmic and cornual regions contain comparatively lower values. Also, nuclear DNA activity is higher in the upper third than in the lower two thirds of the functional layer. This zonal variation in sensitivity of endometrial tissue to hormonal influence may be related to different physiologic functions: Whether differences in hormonal responses are due to dissimilar vascular supply of the upper and lower layers or to the intrinsic, heterogeneous nature of the endometrial tissue in terms of receptor content, or to both, remains to be determined.
Maximum DNA synthesis during the midproliferative phase of the cycle i. Increased nuclear DNA synthesis and mitotic activity in gland cells correlate with high levels of nucleolar organizer regions.
According to animal studies, DNA synthesis decreases rather than increases after 2 days of estrogen administration. Inhibition of nucleic acid synthesis is apparently not related to loss of estradiol receptors or nuclear translocation of estradiol receptors, but rather, presumably, to accumulation of the chalone-like inhibitors of DNA synthesis. This hypothesis is attractive, but it remains to be tested.
In addition to tissue proliferation, estradiol promotes the development of free and bound ribosomes, mitochondria, golgiosomes and primary lysosomes in gland cells and presumably in stromal cells. Biochemically, these organelles each provide for protein matrix, energy, and synthesis of various enzymes. Some of these enzymes, including glucosephosphatase, hexokinase, pyruvate kinase, and lactate dehydrogenase, are involved in carbohydrate metabolism. Concentrations of estradiol receptors and progesterone receptors increase in both the blood and the endometrium during the proliferative phase of the cycle see Fig.
Another characteristic feature of proliferative-surface and gland-lining cells is an increase in the number of cilia and microvilli. These decrease considerably during the secretory phase, suggesting that endometrial ciliogenesis and microvillogenesis are estrogen dependent. Ciliated cells are especially numerous around gland openings. It has been suggested that this peculiar distribution and strong-forward and slow-recovery ciliary beat pattern facilitate mobilization and distribution of endometrial secretions during the luteal phase of the cycle.
Intracytoplasmic filaments serve as a cytoplasmic 'skeleton' in gland and stromal cells. Gland cells have cytokeratin- and vimentin-positive intracytoplasmic filaments, whereas endometrial stromal cells stain strongly for vimentin, smooth muscle-related antigens and CD Fig. Proliferative endometrium, cycle day Interglandular stromal cells strongly and diffusely immunostain for CD x Lymphoid aggregates resembling follicles may be seen in the endometrial stroma, particularly in the basal layer and during the proliferative phase of the cycle.
They are unlikely to play a significant role, if any, in the local secretory immune system. Indeed, endometrial epithelial cells synthesize negligible amounts of immunoproteins, 2 and IgG-containing plasma cells are absent in normal endometrium.
The Endometrial Cycle
The observations are consistent with the sterile nature of normal endometrium. The two main mechanisms of endometrial vessel formation have been suggested to occur via intussusception and sprouting.
In the latter, endothelial cell activation, degradation of basement membrane, migration and proliferation lead to formation of tubules, stabilization of pericytes, and extracellular matrix formation. Pericytes may, in fact, play a significant role in angiogenesis and regulation of blood flow. The cycling endometrium requires repeated, rapid, short-term proliferation and rapid arrest of neovascularisation.
Angiogenesis in the endometrium is regulated and controlled by a multitude of promoters and inhibitors, all of which are believed to be under the influence of estradiol and progesterone during the menstrual cycle. The most important promoter of endothelial growth via mitosis is the vascular endothelial growth factor VEGF. During the postovulatory, or secretory, phase the estradiol-primed endometrium is under progestagenic stimulation and undergoes secretory differentiation.
Because similar changes may be produced by estrogens alone in the absence of ovulation, variably sized subnuclear vacuoles in a mitotically active endometrium are not considered specific to ovulation. The most reliable histologic alterations that are considered specific to ovulation are seen on the POD 3 or 17 th day of the cycle. Both phenomena involve every cell in a given gland Fig.
Histologic dating of the endometrium: accuracy, reproducibility, and practical value.
Day 17 POD 3 secretory endometrial glands with S-shaped configuration, subnuclear vacuolization, and palisading of nuclei in middle of lining epithelium x At the transmission electron microscopic level, ovulation may be recognized by the appearance of giant mitochondria and the so-called nucleolar channel system in gland cells. They are presumably produced by the infolding of the nuclear membranes under progesterone stimulation. During the first four postovulatory days, both the glandular and stromal cells are engaged in DNA synthesis and mitotic activity although to a much lower degree than is seen in the preovulatory and proliferative endometrium Fig.
Similarly, other proliferative markers such as bcl-2 and tumor suppressor gene p16 are only rarely seen, if at all Fig. Postovulatory endometrium, POD 3 cycle day Immunostaining for Ki in glands and stromal cells is reduced from that seen in the preovulatory endometrium X Immunostaining for p16 is absent from cells lining an 'S'-shaped gland x These findings indicate reduced proliferative activity and an increase in accumulation of intracytoplasmic glycogen.
The glands are engaged in intracellular but not yet in active extracellular secretion of glycoproteins. On POD 5 and 6 cycle days 19 and 20 , the intracellular secretory products are extruded into the glandular space by apocrine-type secretion. This is characterized by protrusions and eventual detachment of the apical portion of cells containing glycoproteins. Transudation of plasma from circulating blood in the endometrial mucosa also contributes to uterine secretory fluids. The peak of intraglandular secretions on POD 7 cycle day 21 coincides with the time of implantation of the free blastocyst if fertilization has taken place in this cycle.
Nucleic acid synthesis by gland cells ceases as apocrine secretory activity is initiated by POD 5 cycle day 19 Fig. Postovulatory day 11 cycle day Immunostaining for the proliferation marker Ki is confined to predecidual stromal cells as DNA synthesis is shut off within secretory-type endometrial gland cells x Immunostaining for ER is present in both gland and stromal predecidual cells but of less intensity than in proliferative endometrim x Immunostaining for PR is confined exclusively to predecidual stromal cells indicating arrest in E2-dependent glandular growth x This correlates with total lack of mitoses in the glands during the mid and late periods of the secretory phase.
It has been suggested that in mice, progesterone induces the epithelial cells to enter a nondividing G0 stage of the cell cycle during decidualization. For accurate dating purposes from cycle day 21 POD 7 onwards, the pathologist relies on changes in the stroma, rather than in the glands.
These include edema, coiling of spiral arterioles, and predecidualization of the stroma. Endometrial vascular proliferation at the implantation site is related to the blastocyst rather than to histamine or PGE2. The blastocyst has a unique biologic property that is shared only with tumor cells producing the so-called angiogenesis factor, a substance capable of inducing growth of new capillaries.
Receptors for human chorionic gonadotropin and luteinizing hormone are present in vascular smooth muscle cells and endothelium, suggesting their possible role in regulating blood flow. Although decidualized cells have receptors for estradiol, its role in this process, if any, is not clear. This change consists of cytonuclear enlargement with tetraploid nuclei resulting in plump, liver-like epithelioid cells. Predecidualization not pseudodecidualization is accompanied by an increase in nuclear DNA synthesis, mitotic activity, and the formation of a pericellular laminin substance.
Consequently, predecidual cells are relatively independent of the growth-inhibitory effect of progesterone.