Histology_Ross

Histology_Ross. The cell mass resulting from the series of mitotic divisions is known as a morula (L. morum, mulberry), and the individual cells are known as blastomeres. During the third day after fertilization, the morula, which has reached a 12to 16cell stage and is still surrounded by the zona pellucida, enters the uterine cavity. The morula remains free in the uterus for about a day while continued cell division and development occur. The early embryo gives rise to a blastocyst, a hollow sphere of cells with a centrally located clump of cells. This inner cell mass will give rise to the tissues of the embryo proper; the surrounding layer of cells, the outer cell mass, will form the trophoblast and then the placenta (Fig. 23.17).


Histology_Ross

Histology_Ross. Fluid passes inward through the zona pellucida during this process, forming a fluid-filled cavity, the blastocyst cavity. This event defines the beginning of the blastocyst. As the blastocyst remains free in the uterine lumen for 1 or 2 days and undergoes further mitotic divisions, the zona pellucida disappears. The outer cell mass is now called the trophoblast, and the inner cell mass is referred to as the embryoblast. Implantation occurs during a short period known as the implantation window. The attachment of the blastocyst to the endometrial epithelium occurs during the implantation window, the period when the uterus is receptive for implantation of the blastocyst. This short period results from a series of programmed actions of progesterone and estrogens on the endometrium.


Histology_Ross

Histology_Ross. Antiprogesterone drugs such as mifepristone (RU-486) and its derivatives compete for the receptors in the endometrial epithelium, thus blocking hormone binding. The failure of progesterone to gain access to its receptors prevents implantation, thus effectively closing the window. In the human, the implantation window begins on day 6 after the LH surge and is completed by day 10. As contact is made with the uterine wall by the trophoblastic cells over the embryoblast pole, the trophoblast rapidly proliferates and begins to invade the endometrium. The invading trophoblast differentiates into the syncytiotrophoblast and the cytotrophoblast.  The cytotrophoblast is a mitotically active inner cell layer producing cells that fuse with the syncytiotrophoblast, the outer erosive layer.  The syncytiotrophoblast is not mitotically active and consists of a multinucleate cytoplasmic mass; it actively invades the epithelium and underlying stroma of the endometrium.


Histology_Ross

Histology_Ross. Through the activity of the trophoblast, the blastocyst is entirely embedded within the endometrium on about the 11th day of development. (Further development of the syncytiotrophoblast and cytotrophoblast is described in the section on the placenta.) FIGURE 23.17 • Schematic diagrams of sectioned blastocysts. a. A human blastocyst at about 4.5 days of development showing formation of the inner cell mass. b. A monkey blastocyst at about 9 days of development. The trophoblastic cells of the monkey blastocyst have begun to invade the epithelial cells of the endometrium. In humans, the blastocyst begins to invade the endometrium at about the fifth or sixth day of development. c. A human blastocyst at 14 days after implantation. At this stage, the trophoblast cells have differentiated into syncytiotrophoblasts and cytotrophoblasts.


Histology_Ross

Histology_Ross. The syncytiotrophoblast has well-developed Golgi complexes, abundant sER and rER, numerous mitochondria, and relatively large numbers of lipid droplets. These features are consistent with the secretion of progesterone, estrogens, hCG, and lactogens by this layer. Recent evidence indicates that cytotrophoblast cells may also be a source of steroid hormones and hCG. After implantation, the endometrium undergoes decidualization. During pregnancy, the portion of the endometrium that undergoes morphologic changes is called the decidua or decidua graviditas. As its name implies, this layer is shed with the placenta at parturition. The decidua includes all but the deepest layer of the endometrium. The stromal cells differentiate into large, rounded decidual cells (see page 850). The uterine glands enlarge and become more coiled during the early part of pregnancy and then become thin and flattened as the growing fetus fills the uterine lumen.


Histology_Ross

Histology_Ross. Three different regions of the decidua are identified by their relationship to the site of implantation (Fig. 23.18):  The decidua basalis is the portion of the endometrium that underlies the implantation site. The decidua capsularis is a thin portion of en dometrium that lies between the implantation site and the uterine lumen.  The decidua parietalis includes the remaining en dometrium of the uterus. By the end of the third month, the fetus grows to the point that the overlying decidua capsularis fuses with the decidua parietalis of the opposite wall, thereby obliterating the uterine cavity. By the 13th day of development, an extraembryonic space, the chorionic cavity, has been established (see Fig. 23.17c).


Histology_Ross

Histology_Ross. By the 13th day of development, an extraembryonic space, the chorionic cavity, has been established (see Fig. 23.17c). The cell layers that form the outer boundary of this cavity (i.e., the syncytiotrophoblast, cytotrophoblast, and extraembryonic somatic mesoderm) are collectively referred to as the chorion. The innermost membranes enveloping the embryo are called the amnion (see Fig. 23.18). The endometrium of the cervix differs from the rest of the uterus.


Histology_Ross

Histology_Ross. The cervical mucosa measures about 2 to 3 mm in thickness and differs dramatically from the rest of the uterine endometrium in that it contains large, branched glands (Fig. 23.19 and Plate 98, page 884). It also lacks spiral arteries. The cervical mucosa undergoes little change in thickness during the menstrual cycle and is not sloughed during the period of menstruation. During each menstrual cycle, however, the cervical glands undergo important functional changes that are related to the transport of spermatozoa within the cervical canal. The amount and properties of the mucus secreted by the gland cells vary during the menstrual cycle under the influence of the ovarian hormones. At midcycle, the amount of mucus produced increases 10-fold. This mucus is less viscous and appears to provide a more favorable environment for sperm migration. The cervical mucus at other times in the cycle restricts the passage of sperm into the uterus. Thus, hormonal mechanisms ensure that ovulation and


Histology_Ross

Histology_Ross. a more favorable environment for sperm migration. The cervical mucus at other times in the cycle restricts the passage of sperm into the uterus. Thus, hormonal mechanisms ensure that ovulation and changes in the cervical mucus are coordinated, thereby increasing the possibility that fertilization will occur if freshly ejaculated spermatozoa and the ovum arrive simultaneously at the site of fertilization in the uterine tube.


Histology_Ross

Histology_Ross. Blockage of the openings of the mucosal glands results in the retention of their secretions, leading to formation of dilated cysts within the cervix called Nabothian cysts. Nabothian FIGURE 23.18 • Development of the placenta. This schematic drawing shows growth of the uterus during human pregnancy and development of the placenta and its membranes. Note that there is a gradual obliteration of the uterine lumen and disappearance of the decidua capsularis as the definitive placenta is established. (Modified from Williams J. Am J Obstet Gynecol 1927;13:1.) cysts develop frequently but are clinically important only if numerous cysts produce marked enlargement of the cervix. The transformation zone is the site of transition between vaginal stratified squamous epithelium and cervical simple columnar epithelium.


Histology_Ross

Histology_Ross. The transformation zone is the site of transition between vaginal stratified squamous epithelium and cervical simple columnar epithelium. The portion of the cervix that projects into the vagina, the vaginal part or ectocervix, is covered with a stratified squamous epithelium (Fig. 23.20). An abrupt transition between this squamous epithelium and the mucus-secreting columnar epithelium of the cervical canal, the endocervix, occurs in the transformation zone that during the reproductive age of the woman is located just outside the external os (Plate 98, page 884). Before puberty and after menopause, the transformation zone resides in the cervical canal (Fig. 23.21). Metaplastic changes in this transformation zone constitute precancerous lesions of the cervix. Metaplasia (Gr.


Histology_Ross

Histology_Ross. Metaplastic changes in this transformation zone constitute precancerous lesions of the cervix. Metaplasia (Gr. í, change in form) represents an adoptive and reversible response to persistent injury of the epithelium caused by chronic infections. It results from a reprogramming of epithelial stem cells that begin to differentiate into new cell lineage. Within the cervical canal (endocervix) it is manifested as a replacement of the simple columnar epithelium with fully mature stratified squamous epithelium (Fig. 23.22). The cervical epithelial cells are constantly exfoliated into the vagina. Stained preparations of the cervical cells (Papanicolaou [Pap] smears) are used routinely for screening and diagnosis of precancerous and cancerous lesions of the cervix. The developing fetus is maintained by the placenta, which develops from fetal and maternal tissues.


Histology_Ross

Histology_Ross. The developing fetus is maintained by the placenta, which develops from fetal and maternal tissues. The placenta consists of a fetal portion, formed by the chorion, and a maternal portion, formed by the decidua basalis. The two parts are involved in physiologic exchange of substances between the maternal and fetal circulations. The uteroplacental circulatory system begins to develop around day 9, with development of vascular spaces called trophoblastic lacunae within the syncytiotrophoblast. Maternal sinusoids, which develop from capillaries of the maternal side, anastomose with the trophoblastic lacunae (Fig. 23.23). The differential pressure between the arterial and venous channels that communicate with the lacunae establishes directional flow from the arteries into the veins, thereby establishing a primitive uteroplacental circulation. Numerous pinocytotic vesicles present in the syncytiotrophoblast indicate the transfer of nutrients from the maternal vessels to the embryo.


Histology_Ross

Histology_Ross. Proliferation of the cytotrophoblast, growth of chorionic mesoderm, and blood vessel development successively give rise to the following.  Primary chorionic villi are formed by the rapidly proliferating cytotrophoblast. They send cords or masses of cells into the blood-filled trophoblastic lacunae in the syncytiotrophoblast (see Fig. 23.17b). The primary villi appear between days 11 and 13 of development.  Secondary chorionic villi are composed of a central core of mesenchyme surrounded by an inner layer of cytotrophoblast and an outer layer of syncytiotrophoblast. They develop at about day 16 when the primary chorionic villi become invaded by loose connective tissue from chorionic mesenchyme. The secondary villi cover the entire surface of the chorionic sac (Fig. 23.23a).


Histology_Ross

Histology_Ross.  Tertiary chorionic villi are formed by the end of the third week as the secondary villi become vascularized by blood vessels that have developed in their connective tissue cores (Fig. 23.23b and Plate 100, page 888). As the tertiary villi are forming, cytotrophoblastic cells in the villi continue to grow out through the syncytiotrophoblast.


Histology_Ross

Histology_Ross. FIGURE 23.19 • Photomicrograph of a human cervix. This H&E–stained specimen is from a postmenopausal woman. Its lower portion projects into the upper vagina where an opening, the external os, leads to the uterus through the cervical canal. The surface of the cervix is covered by stratified squamous epithelium (SSE) that is continuous with the epithelial lining of the vagina. An abrupt transition from stratified squamous epithelium to simple columnar epithelium (SCE) occurs at the entry to the cervical canal. In this specimen, the stratified epithelium has extended into the canal, an event that occurs with aging. Mucus-secreting cervical glands are seen along the cervical canal. These are simple branched tubular glands that arise as invaginations of the epithelium lining the canal. Frequently, the glands develop into nabothian cysts as a result of retention of mucous secretion by blockage of the gland opening. The material marked by the X is mucus secreted from the cervical glands. 10.


Histology_Ross

Histology_Ross. When they meet the maternal endometrium, they grow laterally and meet similar processes growing from neighboring villi. Thus, a thin layer of cytotrophoblastic cells called the trophoblastic shell is formed around the syncytiotrophoblast. The trophoblastic shell is interrupted only at sites where maternal vessels communicate with the intervillous spaces. Future growth of the placenta is accomplished by interstitial growth of the trophoblastic shell. FIGURE 23.20 • Stratified squamous epithelium of the ectocervix. The stratified squamous epithelium and underlying fibrous connective tissue within the lower rectangle in Figure 23.22 is shown here at higher magnification. The more mature epithelial cells have a clear cytoplasm (arrowheads), a reflection of their high glycogen content. Also, note the connective tissue papillae protruding into the epithelium (arrows). The bulk of the cervix is made up of dense, fibrous connective tissue with relatively little smooth muscle. 120.


Histology_Ross

Histology_Ross. FIGURE 23.21 • Transformation zone of the cervix. The site of the squamocolumnar junction from the upper rectangle in Figure 23.19 is shown here at higher magnification. Note the abrupt change from stratified squamous epithelium to simple columnar epithelium (arrow). Neoplastic changes leading to development of cervical cancer most frequently begin in this transformation zone. Within the connective tissue are the branched, mucus-secreting cervical glands (CG) composed of a simple columnar epithelium that is continuous with the lining epithelium of the cervical canal. 120. FIGURE 23.22 • Metaplastic stratified squamous epithelium of the cervical canal. This photomicrograph shows an island of the fully mature stratified squamous epithelium surrounded by the simple columnar epithelium normally found in the cervical canal. 450. (Courtesy of Dr. Fabiola Medeiros, Mayo Clinic.)


Histology_Ross

Histology_Ross. Several types of cells are recognized in the connective tissue stroma of the villi: mesenchymal cells, reticular cells, fibroblasts, myofibroblasts, smooth muscle cells, macrophages, and fetal placental antigen–presenting cells, historically also known as Hofbauer cells (Fig. 23.24 and Plate 100, page 888). Fetal placental antigen–presenting cells are the specific villous macrophages of fetal origin that participate in the placental innate immune reactions. In response to antigen, they proliferate and upregulate specific surface receptors that recognize and bind to a variety of pathogens. Like other antigen-presenting cells, if stimulated, they increase the number of MHC II (major histocompatibility complex) molecules on their surface.


Histology_Ross

Histology_Ross. They are more common in the early placenta. The vacuoles in these cells contain lipids, glycosaminoglycans, and glycoproteins. Recent studies of HIV-infected placentas indicate that HIV is primarily localized within the fetal placental antigen–presenting cells and in the syncytiotrophoblast. Early in development, the blood vessels of the villi become connected with vessels from the embryo. Blood begins to circulate through the embryonic cardiovascular system and the villi at about 21 days. The intervillous spaces provide the site of exchange of nutrients, metabolic products and intermediates, and wastes between the maternal and fetal circulatory systems.


Histology_Ross

Histology_Ross. During the first 8 weeks, villi cover the entire chorionic surface, but as growth continues, villi on the decidua capsularis begin to degenerate, producing a smooth, relatively avascular surface called the chorion laeve. The villi adjacent to the decidua basalis rapidly increase in size and number and become highly branched. This region of the chorion, which is the fetal component of the placenta, is called the chorion frondosum or villous chorion. The layer of the placenta from which the villi project is called the chorionic plate (Plate 99, page 886).


Histology_Ross

Histology_Ross. During the period of rapid growth of the chorion frondosum, at about the fourth to fifth month of gestation, the fetal part of the placenta is divided by the placental (decidual) septa into 15 to 25 areas called cotyledons. Wedge-like placental septa form the boundaries of the cotyledons, and because they do not fuse with the chorionic plate, maternal blood can circulate easily between them. Cotyledons are visible as the bulging areas on the maternal side of the basal plate. The decidua basalis forms a compact layer known as the basal plate that is the maternal component of the placenta. maternal sinusoid syncytiotrophoblast cytotrophoblast cytotrophoblastic shell tertiary villus developing vessels in wall of chorionic sac intervillus space


Histology_Ross

Histology_Ross. maternal sinusoid syncytiotrophoblast cytotrophoblast cytotrophoblastic shell tertiary villus developing vessels in wall of chorionic sac intervillus space FIGURE 23.23 • Schematic diagrams of sections through a developing human embryo. a. This drawing shows the chorionic sac and placenta at 16 days of development. b. The same embryo at 21 days of development. The diagrams illustrate the separation of the fetal and maternal blood vessels by the placental membrane, which is composed of the endothelium of the capillaries, mesenchyme, cytotrophoblast, and syncytiotrophoblast. Vessels within this part of the endometrium supply blood to the intervillous spaces. Except for relatively rare rupturing of capillary walls, which is more common at delivery, fetal blood and maternal blood do not mix. Fetal and maternal blood are separated by the placental barrier.


Histology_Ross

Histology_Ross. Fetal and maternal blood are separated by the placental barrier. Separation of the fetal and maternal blood, referred to as the placental barrier, is maintained primarily by the layers of fetal tissue (Fig. 23.25). Starting at the fourth month, these layers become very thin to facilitate the exchange of products across the placental barrier. The thinning of the wall of the villus is caused in part by the degeneration of the inner cytotrophoblast layer. At its thinnest, the placental barrier consists of the:  Syncytiotrophoblast Discontinuous inner cytotrophoblast layer  Basal lamina of the trophoblast Connective (mesenchymal) tissue of the villus Basal lamina of the endothelium  Endothelium of the fetal placental capillary in the tertiary


Histology_Ross

Histology_Ross. This barrier bears a strong resemblance to the air–blood barrier of the lung, with which it has an important parallel function, namely, the exchange of oxygen and carbon dioxide—in this case between the maternal blood and the fetal blood. It also resembles the air–blood barrier by having a particular type of macrophage in its connective tissue— in this instance, the fetal placental antigen–presenting cells (Hofbauer cell). FIGURE 23.24 • Photomicrographs of a human placenta. a.


Histology_Ross

Histology_Ross. This H&E–stained specimen shows the amniotic surface (A), the chorionic plate (CP), and, below, the various-sized profiles of the chorionic villi (CV ). These villi emerge from the chorionic plate as large stem villi and branch into the increasingly smaller villi. Blood vessels (BV ) are evident in the larger villi. The smallest villi contain capillaries where exchange takes place. 60. Upper inset. This higher magnification shows the simple cuboidal epithelium of the amnion and the underlying connective tissue. 200. Lower inset. This higher magnification shows a cross-sectioned villus containing several larger blood vessels and its thin surface syncytiotrophoblast layer. 200. b. This H&E–stained specimen shows the maternal side of the placenta. The stratum basale (SB), the part of the uterus to which some of the chorionic villi (CV ) anchor, is seen at the bottom of the micrograph. Also evident is a stromal connective tissue (CT ) component, part of the stratum basale, to which many


Histology_Ross

Histology_Ross. to which some of the chorionic villi (CV ) anchor, is seen at the bottom of the micrograph. Also evident is a stromal connective tissue (CT ) component, part of the stratum basale, to which many of the chorionic villi are also attached. Within the stratum basale and the connective tissue stroma are clusters of cells, the decidual cells (arrows), which arose from connective tissue cells. 60. Inset. Decidual cells seen at higher magnification. 200.


Histology_Ross

Histology_Ross. FIGURE 23.25 • Human placental barrier in a third trimester of the pregnancy. This high magnification electron micrograph shows the thinnest layer of a fully developed placental barrier (section does not include cytotrophoblast cells that form a discontinuous layer in the human placenta). The lumen of intervillous space containing maternal erythroblasts (ME) (to the left ) is separated from the fetal capillary space containing fetal erythroblasts (FE) (to the right ). The intervillous space is lined by the multinucleated syncytiotrophoblast (Syn). Its surface contains microvilli projecting into maternal blood space. The cytoplasm of syncytiotrophoblast contains multiple nuclei (N) and has an abundance of transport vesicles, rER, and sER, mitochondria, and occasional lipid droplets. The syncytiotrophoblast rests on the basal lamina (TBL), which is separated by the thin layer of the connective tissue (CT ) from the basal lamina (EBL) of the fetal endothelial cells (FEn). 11,000.


Histology_Ross

Histology_Ross. The syncytiotrophoblast rests on the basal lamina (TBL), which is separated by the thin layer of the connective tissue (CT ) from the basal lamina (EBL) of the fetal endothelial cells (FEn). 11,000. (Courtesy of Dr. Holger Jastrow.)


Histology_Ross

Histology_Ross. The placenta is the site of exchange of gases and metabolites between the maternal and fetal circulation. Fetal blood enters the placenta through a pair of umbilical arteries (Fig. 23.26). As they pass into the placenta, these arteries branch into several radially disposed vessels that give numerous branches in the chorionic plate. Branches from these vessels pass into the villi, forming extensive capillary networks in close association with the intervillous spaces. Gases and metabolic products are exchanged across the thin fetal layers that separate the two bloodstreams at this level. Antibodies can also cross this layer and enter the fetal circulation to provide passive immunity against a variety of infectious agents—for example, those of diphtheria, smallpox, and measles. Fetal blood returns through a system of veins that parallel the arteries except that they converge on a single umbilical vein.


Histology_Ross

Histology_Ross. Maternal blood is supplied to the placenta through 80 to 100 spiral endometrial arteries that penetrate the basal plate. Blood from these spiral arteries flows into the base of the intervillous spaces, which contain about 150 ml of maternal blood that is exchanged three to four times per minute. The blood pressure in the spiral arteries is much higher than that in the intervillous spaces. As blood is injected into these spaces at each pulse, it is directed deep into the spaces. As the pressure decreases, the blood flows back over the surfaces of the villi and eventually enters endometrial veins also located in the base of the spaces.


Histology_Ross

Histology_Ross. Exchange of gases and metabolic products occurs as the blood passes over the villi. Normally, water, carbon dioxide, metabolic waste products, and hormones are transferred from the fetal blood to the maternal blood; water, oxygen, metabolites, electrolytes, vitamins, hormones, and some antibodies pass in the opposite direction. The placental barrier does not exclude many potentially dangerous agents such as alcohol, nicotine, viruses, drugs, exogenous hormones, and heavy metals. Therefore, during pregnancy, exposure to or ingestion of such agents should be avoided to reduce the risk of injury to the embryo or fetus. Before the establishment of blood flow through the placenta, the growth of the embryo is supported in part by metabolic products that are synthesized by or transported through the trophoblast. The syncytiotrophoblast synthesizes glycogen, cholesterol, and fatty acids, as well as other nutrients used by the embryo.


Histology_Ross

Histology_Ross. The placenta is a major endocrine organ producing steroid and protein hormones. The placenta also functions as an endocrine organ, producing steroid and peptide hormones as well as prostaglandins that play an important role in the onset of labor. Immunocytochemical studies indicate that the syncytiotrophoblast is the site of synthesis of these hormones. The steroid hormones progesterone and estrogen have essential roles in the maintenance of pregnancy. As pregnancy proceeds, the placenta takes over the major role in the secretion of these steroids from the corpus luteum. The placenta produces enough progesterone by the end of the eighth week to maintain pregnancy if the corpus luteum is surgically


Histology_Ross

Histology_Ross. FIGURE 23.26 • Schematic diagram of mature human placenta. The sagittal section of the uterus (left) with the developing embryo shows the most common location of the placenta. The mature placenta (right) is divided into cotyledons by placental septa that are formed by outgrowths of the decidua basalis. Maternal blood enters the placenta through numerous endometrial spiral arteries that penetrate the basal plate. As the blood enters the cotyledon, it is directed deep into the intervillous spaces (red arrows). It then passes over the surface of the villi, where exchange of gases and metabolic products occurs. The maternal blood finally leaves the intervillous space (black arrows) through endometrial veins. The fetal blood enters the placenta through the umbilical arteries that divide into a series of radially disposed arteries within the chorionic plate. Branches from the vessels pass into the main stem villi and there form extensive capillary networks. The veins within the villi then


Histology_Ross

Histology_Ross. a series of radially disposed arteries within the chorionic plate. Branches from the vessels pass into the main stem villi and there form extensive capillary networks. The veins within the villi then carry the blood back through a system of veins that parallels the fetal arteries.


Histology_Ross

Histology_Ross. removed or fails to function. In the production of placental estrogen, the fetal adrenal cortex plays an essential role, providing the precursors needed for estrogen synthesis. Because the placenta lacks the enzymes needed for the production of estrogen precursors, a cooperative fetoplacental (endocrine) unit is established. Clinically, the monitoring of estrogen production during pregnancy can be used as an index of fetal development.


Histology_Ross

Histology_Ross. The following peptide hormones are secreted by the placenta:  Human chorionic gonadotropin (hCG) is required for implantation and maintenance of the pregnancy. Its synthesis begins around day 6, even before the syncytiotrophoblast is formed. HCG exhibits extensive (about 85%) sequence homology to LH, which is required for ovulation and maintenance of the corpus luteum during the menstrual cycle. Similar to the work of LH during the menstrual cycle, hCG maintains the corpus luteum during early pregnancy. HCG also possesses marked homology to pituitary thyroid-stimulating hormone (TSH), which may account for hyperthyroidism in pregnancy by stimulating the maternal thyroid gland to increase secretion of tetraiodothyronine (T4). Measurement of hCG is used to detect early pregnancy and assess pregnancy viability. Two other clinical conditions that increase the blood levels of hCG include trophoblastic diseases and ectopic pregnancies.


Histology_Ross

Histology_Ross.  Human chorionic somatomammotropin (hCS), also known as human placental lactogen (hPL), is closely related to human growth hormone. Synthesized in the syncytiotrophoblast, it promotes general growth, regulates glucose metabolism, and stimulates mammary duct proliferation in the maternal breast. The effects of hCS on maternal metabolism are significant, but the role of this hormone in fetal development remains unknown.  IGF-I and IGF-II are produced by and stimulate proliferation and differentiation of the cytotrophoblast.  Endothelial growth factor (EGF) exhibits an age-dependent dual action on the early placenta. In the 4to 5-week-old placenta, EGF is synthesized by the cytotrophoblast and stimulates proliferation of the trophoblast. In the 6to 12-week-old placenta, synthesis of EGF is shifted to the syncytiotrophoblast; it then stimulates and maintains the function of the differentiated trophoblast.


Histology_Ross

Histology_Ross.  Relaxin is synthesized by decidual cells and is involved in the “softening” of the cervix and the pelvic ligaments in preparation for parturition.  Leptin is synthesized by the syncytiotrophoblast, particularly during the last month of gestation. Leptin appears to  FOLDER 23.4 Clinical Correlation: Fate of the Mature Placenta at Birth


Histology_Ross

Histology_Ross. The mature placenta measures about 15 to 20 cm in when the placenta attaches too deeply into the uterine wall diameter and 2 to 3 cm in thickness, covers 25% to 30% but does not penetrate the myometrium. Placenta increta of the uterine surface, and weighs 500 g to 600 g at term. (about 15% of all cases) occurs when the placental villi The surface area of the villi of human placenta is estimated penetrate deep into the muscular layer of the myometrum. to be about 10 m2. The microvilli on the syncytiotrophoblast In the remaining 10% of all cases, placenta percreta pen-increase the effective area for metabolic exchange to more etrates through the entire uterine wall and attaches to an-than 90 m2. After birth, the uterus continues to contract, other organ such as the bladder, rectum, intestines, or reducing the luminal surface and inducing placental separa-large blood vessels. It is the most serious complication of tion from the uterine wall. The entire fetal portion of the


Histology_Ross

Histology_Ross. intestines, or reducing the luminal surface and inducing placental separa-large blood vessels. It is the most serious complication of tion from the uterine wall. The entire fetal portion of the pla-placentation and may cause rupture of the uterus and other centa, fetal membranes, and the intervening projections of complications related to its attachment. A retained abnordecidual tissue are released. During uncomplicated labor, mal placenta or placental fragments may cause massive the placenta separates from the uterine wall and is delivered postpartum bleeding and need to be manually removed. approximately 30 minutes after birth. Placenta increta and percreta are often treated by perform-


Histology_Ross

Histology_Ross. One of the most severe complications of labor results ing a hysterectomy. from abnormal placentation (abnormal attachment of After physiologic delivery of the placenta, the endomethe placenta on uterine wall). If decidual tissue during im-trial glands and stroma of the decidua basalis regenerate. plantation is disrupted, the placenta invades deep into the Endometrial regeneration is completed by the end of the uterine wall. This may cause one of the three clinical condi-third week postpartum except at the placental site, where tions, known as placenta accreta, placenta increta, or pla-regeneration usually extends for another three weeks. Durcenta percreta. Classification depends on the severity and ing the first week after delivery, remnants of the decidua deepness of the placental attachment. Placenta accreta, are shed and constitute the red-brown uterine discharge accounting for approximately 75% of all cases, occurs known as lochia rubra.


Histology_Ross

Histology_Ross. regulate maternal nutrient storage to the nutrient requirements of the fetus. It is also involved in transporting nutrients across the placental barrier from mother to the fetus.  Other growth factors stimulate cytotrophoblastic growth (e.g., fibroblast growth factor, colony-stimulating factor [CSF-1], platelet-derived growth factor, and interleukins [IL-1 and IL-3]) or inhibit trophoblast growth and proliferation (e.g., tumor necrosis factor). The vagina is a fibromuscular tube that joins internal reproductive organs to the external environment. The vagina is a fibromuscular sheath extending from the cervix to the vestibule, which is the area between the labia minora. In a virgin, the opening into the vagina may be surrounded by the hymen, folds of mucous membrane extending into the vaginal lumen. The hymen or its remnants are derived from the endodermal membrane that separated the developing vagina from the cavity of the definitive urogenital sinus in the embryo.


Histology_Ross

Histology_Ross. The vaginal wall (Fig. 23.27) consists of the following.  An inner mucosal layer has numerous transverse folds or rugae (see Fig. 23.1) and is lined with stratified squamous epithelium (Fig. 23.28). Connective tissue papillae from the underlying lamina propria project into the epithelial layer. In humans and other primates, keratohyalin granules may be present in the epithelial cells, but under normal conditions, keratinization does not occur. Therefore, nuclei can be seen in epithelial cells throughout the thickness of the epithelium.  An intermediate muscular layer is organized into two sometimes indistinct, intermingling smooth muscle layers, an outer longitudinal layer, and an inner circular layer. The outer layer is continuous with the corresponding layer in the uterus and is much thicker than the inner layer. Stria ted muscle fibers of the bulbospongiosus muscle are present at the vaginal opening (Plate 101, page 890).


Histology_Ross

Histology_Ross.  An outer adventitial layer is organized into an inner dense connective tissue layer adjacent to the muscularis and an outer loose connective tissue layer that blends with the adventitia of the surrounding structures. The inner layer contains numerous elastic fibers that contribute to the elasticity and strength of the vaginal wall. The outer layer contains numerous blood and lymphatic vessels and nerves. The vagina possesses a stratified, squamous nonkeratinized epithelium and lacks glands. The lumen of the vagina is lined by stratifed squamous, nonkeratinized epithelium. Its surface is lubricated mainly by mucus produced by the cervical glands. The greater and lesser vestibular glands located in the wall of the vaginal vestibule produce additional mucus that lubricates the vagina. Glands are not present in the wall of the vagina. The epithelium of the vagina undergoes cyclic changes during the menstrual cycle. Under the influence of estrogens, during the follicular


Histology_Ross

Histology_Ross. FIGURE 23.27 • Photomicrograph of a human vagina. This low-magnification H&E–stained specimen of the vaginal wall shows two of three layers of the vagina: the mucosal layer and the muscular layer (the outer layer, the adventitia, is not included). The mucosal layer consists of a stratified squamous epithelium and the underlying connective tissue. The epithelial connective tissue boundary is typically very irregular, with prominent papillae projecting into the undersurface of the epithelium. The muscular layer is seen only in part; it consists of irregularly arranged bundles of smooth muscle cells. Also, the deep region of the connective tissue contains a rich supply of blood vessels that supply the various layers of the vaginal wall. 40. phase, the epithelial cells synthesize and accumulate glycogen as they migrate toward the surface. Cells are continuously desquamated, but near or during the menstrual phase, the superficial layer of the vaginal epithelium may be shed.


Histology_Ross

Histology_Ross. The lamina propria exhibits two distinct regions. The outer region immediately below the epithelium is a highly cellular loose connective tissue. The deeper region, adjacent to the muscular layer, is denser and may be considered a submucosa. The deeper region contains many thin-walled veins that simulate erectile tissue during sexual arousal. Numerous elastic fibers are present immediately below the epithelium, and some of the fibers extend into the muscular layer. Many lymphocytes and leukocytes (particularly neutrophils) are found in the lamina propria and migrate into the epithelium. Solitary lymphatic nodules may also be present. The number of lymphocytes and leukocytes in the mucosa and vaginal lumen dramatically increases around the time of menstrual flow. The vagina has few general sensory nerve endings. The sensory nerve endings that FIGURE 23.28 • Photomicrograph of the vaginal mucosa.


Histology_Ross

Histology_Ross. FIGURE 23.28 • Photomicrograph of the vaginal mucosa. This micrograph, a higher magnification of Figure 23.27, shows the stratified squamous epithelium and mature cells with small pyknotic nuclei. Note a single layer of basal cells and two or three layers of cells undergoing differentiation (with eosinophilic cytoplasm). Projections of the connective tissue papillae into the epithelium give the connective tissue–epithelial junction an uneven appearance. The tips of these projections often appear as isolated structures surrounded by epithelium (arrows). 180. are more plentiful in the lower third of the vagina are probably associated primarily with pain and stretch sensations. The female external genitalia consist of the following parts, which are collectively referred to as the vulva and have a stratified squamous epithelium as follows.  The mons pubis is the rounded prominence over the pubic symphysis formed by subcutaneous adipose tissue.


Histology_Ross

Histology_Ross.  The mons pubis is the rounded prominence over the pubic symphysis formed by subcutaneous adipose tissue.  The labia majora are two large longitudinal folds of skin, homologous to the skin of the scrotum, that extend from the mons pubis and form the lateral boundaries of the urogenital cleft. They contain a thin layer of smooth muscle that resembles the dartos muscle of the scrotum and a large amount of subcutaneous adipose tissue. The outer surface, like that of the mons pubis, is covered with pubic hair. The inner surface is smooth and devoid of hair. Sebaceous and sweat glands are present on both surfaces (Fig. 23.29).  The labia minora are paired, hairless folds of skin that border the vestibule and are homologous to the skin of the


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Histology_Ross. The examination of Pap smears is a valuable diagnostic tool in evaluating the vaginal and cervical mucosae (Fig. F23.5.1). The superficial epithelial cells are scraped from the mucosa, spread on a glass slide, fixed, and then stained with the Papanicolaou stain (a combination of hematoxylin, orange G, and eosin azure). Examination of the Pap smear provides valuable diagnostic information about the epithelium regard-ing pathologic changes, response to hormonal changes dur-ing the menstrual cycle, and the microbial environment of the vagina. The synthesis and release of glycogen by the epithelial cells of the uterus and vagina are directly related to changes in the pH of vaginal fluid. The pH of the fluid, which is normally low, around pH 4, becomes more acid near midcycle as Lactobacillus acidophilus, a lactic acid–forming bacterium in the vagina, metabolizes the se-creted glycogen. An alkaline environment can favor the growth of infectious agents such as Staphylococci, Corynebacterium


Histology_Ross

Histology_Ross. a lactic acid–forming bacterium in the vagina, metabolizes the se-creted glycogen. An alkaline environment can favor the growth of infectious agents such as Staphylococci, Corynebacterium vaginale, Trichomonas vaginalis, and Candida albicans, causing an abnormal increase in vaginal transexudates and inflammation of the vaginal mucosa and vulvar skin known as vulvovaginitis. These pathologic con-ditions are readily diagnosed with Pap smears. Specific antimicrobial agents (antibiotics, sulfonamides) are used to-gether with nonspecific therapy (acidified 0.1% hexetidine gel) to restore the normal low pH in the vagina and thus pre-vent the growth of these agents. In addition, cervicovaginal Pap smears are widely used for diagnosis of early cervical cancer as well as endome-trial carcinoma. Because cervical lesions may exist in a noninvasive stage for as long as 20 years, the abnormal cells shed from the epithelium are easily detected with a Pap smear examination. Microscopic examination


Histology_Ross

Histology_Ross. cervical lesions may exist in a noninvasive stage for as long as 20 years, the abnormal cells shed from the epithelium are easily detected with a Pap smear examination. Microscopic examination of these cells permits differentiation between normal and abnormal cells, determines their site of origin, and allows classifying cellular changes related to the spread of the disease. The Pap smear is an extremely effective and in-expensive screening method in preventing cervical can-cer. Most of the cell abnormalities detected by Pap smears are in the precancerous stage, which allows the clinician to implement appropriate therapy.


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Histology_Ross.  FOLDER 23.5 Clinical Correlation: Cytologic Pap Smears aabba b FIGURE F23.5.1 • Photomicrographs of cervical smears. a. Negative cervical smear. The surface squamous cells reveal small pyknotic nuclei and abundant cytoplasm. Other cells in the micrograph include red blood cells and neutrophils. 600. b. Abnormal smear. Many of the cells in this specimen contain large nuclei with no evidence of pyknosis (arrows). The cytoplasm is relatively scant. Other cells exhibit a more normal appearance with pyknotic nuclei and more surrounding cytoplasm (arrowheads). Neutrophils are also present. 600. penis. Abundant melanin pigment is present in the deep cells of the epithelium. The core of connective tissue within each fold is devoid of fat but does contain numerous blood vessels and fine elastic fibers. Large sebaceous glands are present in the stroma.


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Histology_Ross.  The clitoris is an erectile structure that is homologous to the penis. Its body is composed of two small erectile bodies, the corpora cavernosa; the glans clitoris is a small, rounded tubercle of erectile tissue. The skin over the glans is very thin, forms the prepuce of the clitoris, and contains numerous sensory nerve endings.  Vestibule. The vestibule is lined with stratified squamous epithelium. Numerous small mucous glands, the lesser vestibular glands (also called Skene’s glands), are present primarily near the clitoris and around the external urethral orifice. The large, paired greater vestibular glands (also called Bartholin’s glands) are homologous to the male bulbourethral glands. These tuboalveolar glands are


Histology_Ross

Histology_Ross. FIGURE 23.29 • Photomicrograph of the inner surface of the labia majora. This low-power H&E–stained specimen of the labia majora’s inner surface shows its nonkeratinized epithelium (Ep) and abundant sebaceous glands (SG). Two sebaceous ducts (SD) are also evident. Note the continuity of the duct epithelium with the epithelium of the skin and the sebaceous gland epithelium. At this magnification, several smooth muscle bundles can just barely be discerned (arrows).


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Histology_Ross. about 1 cm in diameter and are located in the lateral wall of the vestibule posterior to the bulb of the vestibule. The greater vestibular glands secrete lubricating mucus. The ducts of these glands open into the vestibule near the vaginal opening. If the duct of the Bartholin’s gland becomes obstructed, it usually dilates and fills with a secretion produced by the gland. This condition, known as Bartholin’s cyst, may become infected within a few days, causing severe pain, redness, and enlargement of the involved labia majora. Purulent material in Bartholin’s abscess usually requires surgical incision with drainage or complete excision. Numerous sensory nerve endings are present in the external genitalia:  Meissner’s corpuscles are particularly abundant in the skin over the mons pubis and labia majora.


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Histology_Ross. Numerous sensory nerve endings are present in the external genitalia:  Meissner’s corpuscles are particularly abundant in the skin over the mons pubis and labia majora.  Pacinian corpuscles are distributed in the deeper layers of the connective tissue and are found in the labia majora and in association with the erectile tissue. The sensory impulses from these nerve endings play an important role in the physiologic response during sexual arousal.  Free nerve endings are present in large numbers and are equally distributed in the skin of the external genitalia.


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Histology_Ross.  Free nerve endings are present in large numbers and are equally distributed in the skin of the external genitalia. The mammary glands, or breasts, are a distinguishing feature of mammals. They are structurally dynamic organs, varying with age, menstrual cycle, and reproductive status of the female. During embryologic development, growth and development of breast tissue occur in both sexes. Multiple glands develop along paired epidermal thickenings called mammary ridges (milk lines) that extend from the developing axilla to the developing inguinal region. In humans, normally only one group of cells develops into a breast on each side. An extra breast (polymastia) or nipple (polythelia) may occur as an inheritable condition in about 1% of the female population. These relatively rare conditions may also occur in men. In females, mammary glands develop under the influence of sex hormones.


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Histology_Ross. In females, mammary glands develop under the influence of sex hormones. Until puberty, both females and males mammary glands develop in similar fashion. At the onset of puberty in males, testosterone acts on the mesenchymal cells to inhibit further growth of the mammary gland. In the same time, the mammary glands in women undergo further development under hormonal influence of estrogen and progesterone. Estrogen stimulates mesenchymal cells further development. The mammary gland increases in size, mainly due to the growth of interlobular adipose tissue. The ducts extend and branch into the expanding connective tissue stroma. Proliferation of epithelial cells is controlled by interactions between the epithelium and the specialized intralobular hormone-sensitive loose connective tissue stroma. By adulthood, the complete ductal architecture of the gland has been established.


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Histology_Ross. The mammary glands remain in inactive state until pregnancy, during which the mammary glands assume their complete morphologic and functional maturation. This occurs in response to estrogens and progesterone initially secreted from the corpus luteum and later from placenta, prolactin from pituitary gland, and gonadocorticoids produced by adrenal cortex. By the end of pregnancy, secretory vessicles are found in the epithelial cells, but milk production is inhibited by high levels of progesterone. The actual initiation of milk secretion occurs immediately after birth and is induced by prolactin (PRL) secreted by the adenohypophysis. The ejection of the milk from the breast is stimulated by oxytocin released from the neurohypophysis. With the change in the hormonal environment at menopause, the glandular component of the breast regresses or involutes and is replaced by fat and connective tissue. In men, some additional development of the mammary glands normally occurs after puberty, and


Histology_Ross

Histology_Ross. the glandular component of the breast regresses or involutes and is replaced by fat and connective tissue. In men, some additional development of the mammary glands normally occurs after puberty, and the glands remain rudimentary.


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Histology_Ross. Constant hormonal exposure and genetic predisposition are the major risk factors for the development of breast cancer. It is the most common malignancy in women in the United States. Each year an estimated nearly FIGURE 23.30 • Schematic drawing of the human breast as seen during lactation. The breast is composed largely of terminal duct lobular units (TDLUs) containing branched tubuloalveolar glands. TDLUs are contained within an extensive connective tissue stroma and variable amounts of adipose tissue. (Modified from Warwick R, Williams PL, eds. Gray’s Anatomy, 35th ed. Edinburgh: Churchill Livingstone, 1973.) 200,000 women (and also 1,700 men) are diagnosed with breast cancer. Most breast cancers are linked to hormonal exposure (which increases with age, early menarche, late menopause, and with older age of a first full-term pregnancy). About 5% of all breast cancers are attributable to mutation in autosomal dominant breast cancer genes (BRCA1 and BRCA2).


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Histology_Ross. Mammary glands are modified tubuloalveolar apocrine sweat glands. The tubuloalveolar mammary glands, derived from modified sweat glands in the epidermis, lie in the subcutaneous tissue. The inactive adult mammary gland is composed of 15 to 20 irregular lobes separated by fibrous bands of connective tissue. They radiate from the mammary papilla, or nipple, and are further subdivided into numerous lobules known as terminal duct lobular units (TDLUs) (Fig. 23.30). Some of the fibrous bands, called suspensory or Cooper’s ligaments, connect with the dermis. Abundant adipose tissue is present in the dense connective tissue of the interlobular spaces.


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Histology_Ross. Each gland ends in a lactiferous duct that opens through a constricted orifice into the nipple. Beneath the areola, the pigmented area surrounding the nipple, each duct has a dilated portion, the lactiferous sinus. Near their openings, the lactiferous ducts are lined with stratified squamous keratinized epithelium. The epithelial lining of the duct shows a gradual transition from stratified squamous to two layers of cuboidal cells in the lactiferous sinus and finally to a single layer of columnar or cuboidal cells through the remainder of the duct system.


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Histology_Ross. The epidermis of the adult nipple and areola is highly pigmented and somewhat wrinkled and has long dermal papillae invading into its deep surface (Fig. 23.31). It is covered by keratinized stratified squamous epithelium. The pigmentation of the nipple increases at puberty, and the nipple becomes more prominent. During pregnancy, the areola becomes larger and the degree of pigmentation increases further. Deep to the areola and nipple, bundles of smooth muscle fibers are arranged radially and circumferentially in the dense connective tissue and longitudinally along the lactiferous ducts. These muscle fibers allow the nipple to become erect in response to various stimuli.


Histology_Ross

Histology_Ross. The areola contains sebaceous glands, sweat glands, and modified mammary glands (glands of Montgomery). These glands have a structure intermediate between sweat glands and true mammary glands, and they produce small elevations on the surface of the areola. It is believed that Montgomery glands produce a lubricating and protective secretion that changes the skin’s pH and discourages microbial growth. Numerous sensory nerve endings are present in the nipple; the areola contains fewer sensory nerve endings. Terminal duct lobular unit (TDLU) of the mammary gland represents a cluster of small secretory alveoli (in lactating gland) or terminal ductules (in inactive gland) surrounded by intralobular stroma.


Histology_Ross

Histology_Ross. Successive branching of lactiferous ducts leads to the terminal duct lobular unit (TDLU). Each TDLU represents a grapelike cluster of small alveoli that forms a lobule (Fig. 23.32) and consists of the following.  Terminal ductules are present in the inactive gland. Dur ing pregnancy and after birth, epithelium of the terminal ductules, which is lined by secretory cells, differentiates into fully functional secretory alveoli producing milk.  The intralobular collecting duct carries alveolar secre tions into the lactiferous duct.  The intralobular stroma is specialized hormonally sensi tive loose connective tissue that surrounds the terminal ductules and alveoli. The intralobular connective tissue contains little adipose cells.


Histology_Ross

Histology_Ross. Glandular epithelial and myoepithelial cells are the most important cells associated with mammary ducts and lobules. Glandular epithelial cells line the duct system, whereas myoepithelial cells lie deep within the epithelium between the epithelial cells and the basal lamina. These cells, arranged in a basketlike network, are present in the secretory portions of the gland. In routine hematoxylin and eosin (H&E) preparation, the myoepithelial cells are more apparent in the larger ducts. However, in the immunocytochemical preparation, their discontinuous, basketlike arrangement is better visualized within the alveoli (Fig. 23.33). Contraction of myoepithelial cells assists in milk ejection during lactation. Recent immunoﬂuorescence studies have proven that breast progenitor cells found in the ductular epithelium give rise to both glandular cells of the alveoli and myoepithelial cells. The morphology of the secretory portion of the mammary gland varies with the menstrual cycle.


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Histology_Ross. FIGURE 23.31 • Photomicrographs of a section through the female nipple. a. This low-magnification micrograph of an H&E–stained sagittal section through the nipple shows the wrinkled surface contour, a thin stratified squamous epithelium, and associated sebaceous glands (arrows). The core of the nipple consists of dense connective tissue, smooth muscle bundles, and the lactiferous ducts that open at the nipple surface. 6. b. The wall of one of the lactiferous ducts is shown here at higher magnification. Its epithelium is stratified cuboidal, consisting of two-cell layers. As it approaches the tip of the nipple, it changes to a stratified squamous epithelium and becomes continuous with the epidermis. 175. c. A higher magnification of the sebaceous gland from the rectangle in a. Note how the glandular epithelium is continuous with the epidermis (arrows), and the sebum is being secreted onto the epidermal surface. 90. d. A higher magnification showing bundles of smooth muscle in


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Histology_Ross. how the glandular epithelium is continuous with the epidermis (arrows), and the sebum is being secreted onto the epidermal surface. 90. d. A higher magnification showing bundles of smooth muscle in longitudinal and cross-sectional profiles. 350.


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Histology_Ross. In the inactive gland, the glandular component is sparse and ductules appear as cords formed by the cuboidal-shaped epconsists chiefly of duct elements (Fig. 23.34 and Plate 102, ithelial cells with little or no lumen. During the luteal phase, page 892). During the menstrual cycle, the inactive breast the epithelial cells increase in height, and lumina appear in undergoes slight cyclic changes. Early during the follicular the ducts as small amounts of secretions accumulate. Also, phase, the intralobular stroma is less dense, and terminal fluid accumulates in the connective tissue. This is followed by


Histology_Ross

Histology_Ross. FIGURE 23.32 • Terminal Duct Lobular Unit a. This schematic diagram shows components of the terminal duct lobular unit (TDLU). Terminal ductules and intralobular collecting duct are surrounded by a specialized hormonally sensitive loose connective tissue called intralobular stroma. TDLU are separated from each other by interlobular stroma containing variable amount of dense irregular connective tissue and adipose tissue. In active mammary glands, terminal ductules differentiate into milk-producing alveoli. b. This photomicrograph shows the TDLU from an inactive mammary gland. The clear area in the upper part of the image represents adipose cells. 120. FIGURE 23.33 • Myoepithelial cells in the mammary gland.


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Histology_Ross. FIGURE 23.33 • Myoepithelial cells in the mammary gland. This imunofluorescence image is obtained from mammary gland of lactating mouse two days post-parturition. The mouse carried a transgene composed of the smooth muscle -actin promoter conjugated to enhance green fluorescent protein (GFP) reaction. Three-dimensional organization of myoepithelial cells is visualized in green color due to the expression of the promoter transgene in myoepithelial cells. The tissue was also stained red with antibody against smooth muscle -actin conjugated directly with CY3 fluorescent dye. The orange color staining results from overlapping of the green and red staining. The cells on the surface of the terminal duct lobular unit are stained orange, while those deeper in the tissue stained only green because the antibody did not penetrate deep into the tissue. Note a small intralobular duct that merges into the larger lactiferous duct. 600. (Courtesy Dr. James


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Histology_Ross. J. Tomasek, University of Oklahoma Health Science Center.) abrupt involution and apoptosis during the last few days of menstrual cycle before onset of menstruation. Mammary glands undergo dramatic proliferation and development during pregnancy. The mammary glands exhibit a number of changes in preparation for lactation. These can be examined by the trimester of pregnancy.  First trimester is characterized by elongation and branching of the terminal ductules. The lining epithelial and myoepithelial cells proliferate and differentiate from breast progenitor cells found in epithelium of terminal ductules. Myoepithelial cells proliferate between the base of the epithelial cells and the basal lamina in both the alveolar and ductal portions of the gland.


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Histology_Ross.  Second trimester is characterized by differentiation of alveoli from the growing ends of the terminal ductules. The development of the glandular tissue is not uniform, and variation in the degree of development is seen even within a single lobule. The cells vary in shape from flattened to low columnar. Plasma cells, lymphocytes, and eosinophils infiltrate the intralobular connective tissue stroma as the breast develops (Plate 103, page 894). At this stage, amount of glandular tissue and mass of the breast increases mainly due to the growth of the alveoli (Fig. 23.35).


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Histology_Ross.  Third trimester commences maturation of the alveoli. The epithelial glandular cells become cuboidal with nuclei positioned at the basal cell surface. They develop an extensive rER; secretory vesicles and lipid droplets appear in the cytoplasm. The actual proliferation of the interlobular stromal cells declines and subsequent enlargement of the breast occurs through hypertrophy of the secretory cells and accumulation of secretory product in the alveoli. The changes in glandular tissue during pregnancy are accompanied by a decrease in the amount of connective tissue and adipose tissue. Both merocrine and apocrine secretion are involved in production of milk.


Histology_Ross

Histology_Ross. Both merocrine and apocrine secretion are involved in production of milk. The secreting cells contain abundant granular endoplasmic reticulum, a moderate number of large mitochondria, a supranuclear Golgi apparatus, and a number of dense lysosomes (Fig. 23.36). Depending on the secretory state, large lipid droplets and secretory vesicles may be present in the apical cytoplasm. The secretory cells produce two distinct products that are released by different mechanisms.  Merocrine secretion: The protein component of the milk is synthesized in the rER, packaged into membrane-limited secretory vesicles for transport in the Golgi apparatus, and released from the cell by fusion of the vesicle’s limiting membrane with the plasma membrane.


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Histology_Ross.  Apocrine secretion: The fatty or lipid component of the milk arises as lipid droplets free in the cytoplasm. The lipid coalesces to form large droplets that pass to the apical region of the cell and project into the lumen of the acinus. The droplets are invested with an envelope of plasma membrane as they are released. A thin layer of cytoplasm is trapped between the plasma membrane and lipid droplet and is released with the lipid, but the cytoplasmic loss in this process is minimal.


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Histology_Ross. The secretion released in the first few days after childbirth is known as colostrum. This premilk is an alkaline, yellowish secretion with a higher protein, vitamin A, sodium, and chloride content and a lower lipid, carbohydrate, and potassium content than milk. It contains considerable amounts of antibodies (mainly secretory IgA) that provide the newborn with some degree of passive immunity. The antibodies in the colostrum are believed to be produced by the lymphocytes and plasma cells that infiltrate the loose connective tissue of the breast during its proliferation and development and are secreted across the glandular cells as in salivary glands and intestine. As these wandering cells decrease in number after parturition, the production of colostrum stops, and lipid-rich milk is produced. Hormonal Regulation of the Mammary Gland


Histology_Ross

Histology_Ross. The initial growth and development of the mammary gland at puberty occur under the influence of estrogens and progesterone produced by the maturing ovary. Under hormonal influence, the TDLUs develop and differentiate into dynamic functional units. Subsequent to this initial development, slight changes in the morphology of the glandular tissue occur during each ovarian cycle. During the follicular phase of the menstrual cycle, estrogen in the circulation stimulates proliferation of the lactiferous duct components. After ovulation in the luteal phase, progesterone stimulates growth of alveoli; intralobular stroma become edematous. Clinically, during the luteal phase, women perceive tenderness and a progressive increase of breast tissue mass. During pregnancy, the corpus luteum and placenta continuously produce estrogens and progesterone, causing a massive increase in TDLUs. It is now believed that the growth of the mammary glands also depends on the presence of prolactin, which is


Histology_Ross

Histology_Ross. continuously produce estrogens and progesterone, causing a massive increase in TDLUs. It is now believed that the growth of the mammary glands also depends on the presence of prolactin, which is produced by the adenohypophysis; hCS, which is produced by the placenta; and adrenal glucocorticoids.


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Histology_Ross. FIGURE 23.34 • Photomicrograph of an inactive mammary gland. a. This low-magnification H&E–stained specimen shows several lobules within the dense connective tissue of the breast. The epithelial component consists of a branching duct system that makes up the lobule. The clear areas (arrows) are adipose cells. 60. b. A higher magnification of the area in the rectangle of a. The epithelial cells of the ducts are columnar and exhibit interspersed lymphocytes (arrows) that have entered the epithelium. The surrounding stained material (arrowheads) represents the myoepithelial cells (MEp) and collagen bundles in the adjacent connective tissue. 700. Lactation is under the neurohormonal control of the adenohypophysis and hypothalamus.


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Histology_Ross. Lactation is under the neurohormonal control of the adenohypophysis and hypothalamus. Although estrogen and progesterone are essential for the physical development of the breast during pregnancy, both of these hormones also suppress the effects of prolactin and hCS, the levels of which increase as pregnancy progresses. Immediately after birth, however, the sudden loss of estrogen and progesterone secretion from the placenta and corpus luteum allows prolactin to assume its lactogenic role. Production of milk also requires adequate secretion of growth hormone, adrenal glucocorticoids, and parathyroid hormones.


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Histology_Ross. The act of suckling during breast-feeding initiates sensory impulses from receptors in the nipple to the hypothalamus. The impulses inhibit the release of prolactin-inhibiting factor, and prolactin is then released from the adenohypophysis. The sensory impulses also cause the release of oxytocin in the neurohypophysis. Oxytocin stimulates the myoepithelial cells that surround the base of the alveolar secretory cells and the base of the cells in the larger ducts, causing them to contract and eject the milk from the alveoli and the ducts. In the absence of suckling, secretion of milk ceases, and the mammary glands begin to regress and atrophy. The glandular tissue then returns to an inactive condition. Involution of the Mammary Gland


Histology_Ross

Histology_Ross. Involution of the Mammary Gland The mammary gland atrophies or its specialized stroma involutes after menopause. In the absence of ovarian hormone stimulation, the secretory cells of the TDLUs degenerate and disappear, leaving only ducts to create a histologic pattern that resembles that of male breast. The connective tissue also demonstrates degenerative changes, marked by a decrease in the number of fibroblasts and collagen fibers, and loss of elastic fibers.


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Histology_Ross. FIGURE 23.35 • Photomicrograph of an active mammary gland during late pregnancy. a. This low-magnification H&E–stained specimen shows the marked proliferation of the duct system giving rise to the secretory alveoli that constitute the major portion of the lobules. The intralobular ducts are difficult to identify because their epithelium also secretes. Outside the lobules is a large excretory duct. 60. b. A higher magnification of an area in a. The secretory alveolar cells are mostly cuboidal here. A myoepithelial cell (mEp) as well as a number of plasma cells (arrows) can be identified in the adjacent loose connective tissue. 700.  FOLDER 23.6 Clinical Correlation: Cervix and Human Papillomavirus (HPV) Infections


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Histology_Ross. Human papillomavirus (HPV) is the most common and cancer of the penis in men. Most HPV-associated sexually transmitted virus in the United States. More than lesions can be diagnosed by microscopic examination of 40 HPV types are known to infect the urogenital and anal smears or biopsies. In difficult cases, ancillary techniques regions of men and women, targeting the stratified squa-such as in situ hybridization can help to confirm the diagnosis mous epithelium of the perineal skin or mucous mem-(Fig. F23.6.1). Recently, two vaccines (Cervarix and Garbranes. Most women will be infected by HPV in their dasil) have become available to protect women against the lifetime, but only a small percentage (5%–10%) will de-types of HPV that cause most cervical cancers. Cervarix is velop a persistent infection and the associated risk of cer-designed to prevent infections from HPV types 16 and 18 vical cancer. Of the approximately 40 sexually transmitted and contains recombinant noninfectious


Histology_Ross

Histology_Ross. infection and the associated risk of cer-designed to prevent infections from HPV types 16 and 18 vical cancer. Of the approximately 40 sexually transmitted and contains recombinant noninfectious viruslike particles HPV types, most (90%) cause genital warts rather than (VLPs) from both virus types. Gardasil contains a mixture of cervical cancer and so are called low-risk HPV types (e.g., recombinant VLPs from HPV types 6, 11, 16, and 18. Nei-HPV types 6 and 11). Low-risk HPV types tend to infect ther vaccine is therapeutic (i.e., they do not clear prior in-mature epithelial cells and lead to genital warts or mild fection), but both lead to the development of specific cervical dysplasia. HPV types 16 and 18 are the most immunity against HPV infections. The vaccines are most efcommon high-risk HPV types and are associated with 70% fective for girls and young women between ages 9 and 26 of cervical cancers. High-risk HPV types usually infect di-who have had no prior HPV exposure and who


Histology_Ross

Histology_Ross. HPV types and are associated with 70% fective for girls and young women between ages 9 and 26 of cervical cancers. High-risk HPV types usually infect di-who have had no prior HPV exposure and who complete viding cells, cause moderate to severe cervical dysplasia or the three-injection immunization protocol before initiation carcinomas, and are linked to anal cancer, vulvar cancer, of sexual activity.


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Histology_Ross.  FOLDER 23.6 Clinical Correlation: Cervix and Human Papillomavirus (HPV) Infections (Cont.) FIGURE F23.6.1 • Photomicrograph of in situ hybridization of a human cervical biopsy showing HPV infection. a. This low-magnification photomicrograph shows stratified squamous epithelium of the cervix hybridized with DNA probes to HPV types 6 and 11 and counterstained with nuclear fast red. Note that the majority of infected cells are mature cells located in the upper layers of the stratified squamous epithelium of the ectocervix. 120. b. This higher-magnification photomicrograph shows viral particles stained purple within the nuclei of infected cells. 225. (Courtesy of Dr. Fabiola Medeiros, Mayo Clinic.)


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Histology_Ross. FIGURE 23.36 • Photomicrographs and diagram of a lactating mammary gland. a. Low-magnification micrograph of a fast greenosmium–stained section of a lactating mammary gland. Portions of several large lobules and an excretory duct are seen. Many of the alveoli exhibit a prominent lumen, even at this magnification. 60. b. A higher magnification of an area in a shows lipid droplets (black circular profiles) within the secretory cells of the alveoli as well as in the alveolar lumina. The arrows indicate plasma cells within the interstitial spaces. 480. c. Diagram of a lactating mammary gland epithelial cell. (Redrawn after Bloom W, Fawcett DW. A Textbook of Histology, 10th ed. Philadelphia: WB Saunders, 1975.) and infertility. This effect is caused by high levels of serum prolactin, which suppress secretion of LH. Ovulation usually for 2 to 3 years, lactational amenorrhea is the principal means of birth control.  FOLDER 23.7 Functional Considerations: Lactation and Infertility


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Histology_Ross.  FOLDER 23.7 Functional Considerations: Lactation and Infertility Almost 50% of fully breast-feeding women exhibit lacta-resumes after 6 months or earlier with a decrease in suckling tional amenorrhea (lack of menstruation during lactation) frequency. In cultures in which breast-feeding may continue The arteries that supply the breast are derived from the thoracic branches of the axillary artery, the internal thoracic artery, and anterior intercostal arteries. Branches of the vessels pass primarily along the path of the alveolar ducts as they reach capillary beds surrounding the alveoli. Veins basically follow the path of the arteries as they return to the axillary and internal thoracic veins. Lymphatic capillaries are located in the connective tissue surrounding the alveoli. The larger lymphatic vessels drain into axillary, supraclavicular, or parasternal lymph nodes.


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Histology_Ross. Lymphatic capillaries are located in the connective tissue surrounding the alveoli. The larger lymphatic vessels drain into axillary, supraclavicular, or parasternal lymph nodes. The nerves that supply the breast are anterior and lateral cutaneous branches from the second to sixth intercostal nerves. The nerves convey afferent and sympathetic fibers to and from the breast. The secretory function is primarily under hormonal control, but afferent impulses associated with suckling are involved in the reflex secretion of prolactin and oxytocin. This page intentionally left blank.


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Histology_Ross. The ovaries are small, paired, ovoid structures that exhibit a cortex and medulla when sectioned. On one side is a hilum for the transit of neu-rovascular structures; on this same side is a mesovarium that joins the ovary to the broad ligament. The functions of the ovary are the produc-tion of ova and the synthesis and secretion of estrogen and progesterone. In the cortex are numerous primordial follicles that are present at the time of birth and that remain unchanged until sexual maturation. The oogonia in these follicles are arrested in prophase of the first meiotic division. At puberty, under the influence of pituitary gonadotropins, the ovaries begin to undergo the cyclical changes designated the ovarian cycle. During each cycle, the ovaries normally produce a single oocyte that is ready for fertilization. At the beginning of the ovarian cycle, under the influence of pituitary follicle-stimulating hormone (FSH), some of the primordial follicles begin to undergo changes that lead


Histology_Ross

Histology_Ross. for fertilization. At the beginning of the ovarian cycle, under the influence of pituitary follicle-stimulating hormone (FSH), some of the primordial follicles begin to undergo changes that lead to the development of a mature (Graafian) follicle. These changes include a proliferation of follicular cells and enlargement of the follicle. Although several primordial follicles begin these developmental changes, usually only one reaches maturity and yields an oocyte. Occasionally, two follicles will mature and ovulate, leading to the possibility of dizygotic twin development. The dis-charge of the oocyte and its adherent cells is called ovulation. At ovulation, the oocyte completes the first meiotic division. Only if fertilization occurs does the oocyte complete the second meiotic division. Whether or not fertilization occurs, the other follicles that began to proliferate in the same cycle degenerate, a process referred to as atresia.


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Histology_Ross. Cortex, ovary, monkey, H&E ×120. The cortex of an ovary from a sexually mature individual is shown here. On the surface, there is a single layer of epithelial cells designated the germinal epithelium (GEp). This epithelium is continuous with the serosa (peritoneum) of the mesovarium. Contrary to its name, the epithelium does not give rise to the germ cells. The germinal epithelium covers a dense fibrous connective Early primary follicles, ovary, monkey, H&E ×450. When a primordial follicle begins the changes leading to the formation of a mature follicle, the layer of squamous follicular cells becomes cuboidal, as in this figure. In addition, the follicular cells proliferate and become multilayered. A follicle Primordial follicles, ovary, monkey, H&E ×450.


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Histology_Ross. Primordial follicles, ovary, monkey, H&E ×450. This figure shows several primordial follicles at higher magnification. Each follicle consists of an oocyte surrounded by a single layer of squamous follicular cells (F). The nucleus (N) of the oocyte is typically large, but the oocyte itself is so Late primary follicle, ovary, monkey, H&E ×450. The primary follicle in this figure shows a multilayered mass of follicular cells (FC) surrounding the oocyte. The innermost layer of follicular cells is adjacent to a thick eosinophilic layer of extracellular homogeneous material called the zona pellucida (ZP). At this stage of development, the oocyte has also enlarged slightly. The entire structure surrounded by the zona pellucida is actually the oocyte.


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Histology_Ross. tissue layer, the tunica albuginea (TA); under the tunica albuginea are the primordial follicles (PF ). It is not unusual to see follicles at various stages of development or atresia in the ovary. In this figure, along with the large number of primordial follicles, there are four growing follicles (SF ), an atretic follicle (AF ), and part of a large follicle on the right. The region of the large follicle shown in the figure includes the theca interna (TI ), granulosa cells (GC ), and part of the antrum (A). undergoing these early changes is called a primary follicle. Thus, an early primary follicle may still be unilaminar, but it is surrounded by cuboidal cells, and this distinguishes it from the more numerous unilaminar primordial follicles that are surrounded by squamous cells.


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Histology_Ross. large that the nucleus is often not included in the plane of section, as in the oocyte marked X. The group of epithelioid-appearing cells (arrowhead) are follicular cells of a primordial follicle that has been sectioned in a plane that just grazes the follicular surface. In this case, the follicular cells are seen en face. Surrounding the follicles are elongate cells of the highly cellular connective tissue, referred to as stromal cells. The stromal cells surrounding a secondary follicle become disposed into two layers designated the theca interna and the theca externa. As seen in figure above stromal cells become epithelioid in the cell-rich theca interna (TI). A, antrum AF, atretic follicle F, follicle cells, primordial FC, follicle cells GEp, germinal epithelium N, nucleus of oocyte PF, primordial follicles SF, growing follicles TA, tunica albuginea TI, theca interna X, oocyte showing only cytoplasm ZP, zona pellucida arrowhead, follicle cells seen en face KEY


Histology_Ross

Histology_Ross. Atresia of follicles is a regular event in the ovary, beginning in embryonic life. In any section through the postpubertal ovary, follicles of various stages can be seen undergoing atresia. In atresia, the initial changes involve pyknosis of the nuclei of the follicular cells and dissolution of their cytoplasm. The follicle is then invaded by macrophages and other connective tissue cells. The oocyte degenerates, leaving behind the prominent zona pellucida. This may fold inward or collapse, but it usually retains its thickness and staining characteristics. When included in the plane of section, a distorted zona pellucida serves as a reliable diagnostic feature of an atretic follicle. In atresia of large, nearly mature follicles, cells of the theca interna remain to form clusters of epithelioid cells in the ovarian cortex. These are referred to collectively as interstitial glands and continue to secrete steroid hormones. Secondary follicles, ovary, monkey, H&E ×120.


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Histology_Ross. Two follicles growing under the influence of FSH are shown in figure on left. The more advanced follicle is a secondary follicle. The oocyte in this follicle is surrounded by several layers of follicular cells (FC) that, at this stage, are identified as granulosa cells. At a slightly earlier time, small lakes of fluid formed 874 between the follicular cells, and these lakes have now fused into a well-defined larger cavity called the follicular antrum (FA), which is evident in the figure. The antrum is also filled with fluid and stains with the periodic acid-Schiff (PAS) reaction, although only lightly. The substance that stains with the PAS reaction has been retained as an eosinophilic precipitate in the antra of the secondary follicles shown here and in figure on right. Immediately above the obvious secondary follicle is a slightly smaller follicle. Because no antral spaces are evident between the follicular cells, it is appropriate to classify it as a primary follicle. In both


Histology_Ross

Histology_Ross. above the obvious secondary follicle is a slightly smaller follicle. Because no antral spaces are evident between the follicular cells, it is appropriate to classify it as a primary follicle. In both follicles, but particularly in the larger follicle with the antrum, the surrounding stromal cells have become altered to form two distinctive layers designated theca interna (TI) and theca externa (TE). The theca interna is a more cellular layer, and the cells are epithelioid. When seen with the electron microscope, they display the characteristics of endocrine cells, particularly steroid-secreting cells. In contrast, the theca externa is a connective tissue layer. Its cells are more or less spindle shaped.


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Histology_Ross. In figure on right, a later stage in the growth of the secondary follicle is shown. The antrum (FA) is larger, and the oocyte is off to one side, surrounded by a mound of follicular cells called the cumulus oophorus. The remaining follicular cells that surround the antral cavity are referred to as the membrana granulosa (MG), or simply granulosa cells. Atretic follicle, ovary, monkey, H&E ×65. marked by arrows in adjacent figure on right. The two larger, more advanced follicles do not display the remains of a zona pellucida, but they do display Atretic follicles (AF) are shown here and at higher magnificaother features of follicular atresia. tion in adjacent figure on right. The two smaller atretic follicles can be identified by virtue of the retained zona pellucida (ZP) Atretic follicles, ovary, monkey, H&E ×120.


Histology_Ross

Histology_Ross. tion in adjacent figure on right. The two smaller atretic follicles can be identified by virtue of the retained zona pellucida (ZP) Atretic follicles, ovary, monkey, H&E ×120. In atresia of a more advanced follicle, the follicular cells tend to degenerate more rapidly than the cells of the theca interna, and the basement membrane separating the two becomes thickened to form a hyalinized membrane, the glassy membrane. Thus, the glassy membrane (arrows) separates an outer layer of remaining theca interna cells from the degenerating inner follicular cells. The remaining theca interna cells may show cytologic integrity (RTI); these intact theca cells remain temporarily functional in steroid secretion. AF, atretic follicle FA, antrum of follicle FC, follicle cells MG, membrana granulosa RTI, remaining theca interna cells TE, theca externa TI, theca interna ZP, zona pellucida arrowhead, persisting theca interna cells arrows, glassy membrane KEY


Histology_Ross

Histology_Ross. After the oocyte and its immediately surrounding cells (i.e., the cells of the cumulus oophorus) are discharged from the mature ovarian follicle (ovulation), the remaining follicle cells (membrana granulosa) and the adjacent theca interna cells differentiate into a new functional unit, the corpus luteum. The cells of the corpus luteum, luteal cells, rapidly increase in size and become filled with lipid droplets. A lipid-soluble pigment in the cytoplasm of the cells, lipochrome, gives them their yellow appearance in fresh tissue. Electron micrographs of the luteal cells demonstrate that they have features typical of steroid-secreting cells, namely, abundant smooth endoplasmic reticulum and mitochondria with tubular cristae. Two types of luteal cells are identified: Large, centrally located granulosa lutein cells are derived from the granulosa cells; smaller, peripherally located theca lutein cells are derived from the theca interna. A rich vascular network is established in the corpus


Histology_Ross

Histology_Ross. granulosa lutein cells are derived from the granulosa cells; smaller, peripherally located theca lutein cells are derived from the theca interna. A rich vascular network is established in the corpus luteum into which progesterone and estrogen are secreted by the lutein cells. These hormones stimulate growth and differentiation of the uterine endometrium to prepare it for implantation of a fertilized ovum.


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Histology_Ross. Corpus luteum, ovary, human, H&E ×20. This figure shows ovarian cortex shortly after ovulation. The arrowhead points toward the surface of the ovary at the site of ovulation. The cavity (FC) of the former follicle has been invaded by connective tissue (CT). The membrana granulosa has become plicated, and the granulosa cells, now transforming into cells of the corpus luteum, are called granulosa lutein cells (TC). The plication of the membrana granulosa begins just before ovulation and Corpus luteum, ovary, human, H&E ×65 (on left) and ×240 (on right).


Histology_Ross

Histology_Ross. A segment of the plicated corpus luteum is shown in figure on left at higher magnification. As noted above, the main cell mass is composed of granulosa lutein cells (GLC). On one side of this cell mass is the connective tissue (CT) within the former follicular cavity; on the other side are the theca lutein cells. The granulosa lutein cells contain a large spherical nucleus (see, also, GLC, in figure on right) and a large amount of cytoplasm. The cytoplasm contains yellow pigment (usually not evident in routine H&E sections), hence the name, corpus luteum. Theca lutein cells (TLC) also contain a spherical nucleus, but the cells are smaller than the granulosa lutein cells. Thus, when identifying the two-cell types, aside from location, note that the nuclei of adjacent theca lutein cells generally appear to be closer to each continues as the corpus luteum develops. As the corpus luteum becomes more plicated, the former follicular cavity becomes reduced in size. At the same time, blood


Histology_Ross

Histology_Ross. appear to be closer to each continues as the corpus luteum develops. As the corpus luteum becomes more plicated, the former follicular cavity becomes reduced in size. At the same time, blood vessels (BV) from the theca of the follicle invade the former cavity and the transforming membrana granulosa cells. Cells of the theca interna follow the blood vessels into the outermost depressions of the plicated structure. These theca interna cells become transformed into cells of the corpus luteum called theca lutein cells.


Histology_Ross

Histology_Ross. Corpus luteum, ovary, human, H&E ×20. A portion of a fully formed corpus luteum is shown here. Most endocrine cells are the granulosa lutein cells (GLC). These form a folded cell mass that surrounds the remains of the former follicular cavity (FC). External to the corpus luteum is the connective tissue of the ovary (CT). Keep in mind that the theca interna was derived from the connective tissue stroma of the ovary. The location of theca lutein cells (TLC) reflects this origin, and these cells can be found in the deep outer recesses of the glandular mass, adjacent to the surrounding connective tissue. other than nuclei of adjacent granulosa lutein cells. The connective tissue (CT) and small blood vessels that invaded the mass of granulosa lutein cells can be identified as the flattened and elongated components between the granulosa lutein cells.


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Histology_Ross. The changes whereby the ruptured ovarian follicle is transformed into a corpus luteum occur under the influence of pituitary luteinizing hormone. In turn, the corpus luteum itself secretes progesterone, which has a profound effect on the estrogen-primed uterus. If pregnancy occurs, the corpus luteum remains functional; if pregnancy does not occur, the corpus luteum regresses after having reached a point of peak development, roughly 2 weeks after ovulation. The regressing cellular components of the corpus luteum are replaced by fibrous connective tissue, and the structure is then called a corpus albicans.


Histology_Ross

Histology_Ross. BV, blood vessels CT, connective tissue FC, former follicular cavity GLC, granulosa lutein cells TC, granulosa cells transforming into corpus luteum cells TLC, theca lutein cells KEY 878 The uterine tubes (oviducts, Fallopian tubes) are joined to the uterus and extend to the ovaries, where they present an open flared end (abdominal ostium) for entry of the ovum at ovulation. The oviduct undergoes cyclical changes along with those of the uterus, but these are not nearly as pronounced. The epithelial cells increase in height during the middle of the cycle, just about the time the ovum will be passing through the tube, and become reduced during the premenstrual period. Some of the epithelial cells are ciliated. The epithelial cells depend on the ovaries for their viability. Not only does the number of ciliated cells increase during the follicular phase of the ovarian cycle, but also removal of the ovaries leads to atrophy of the epithelium and loss of ciliated cells. The uterine tube


Histology_Ross

Histology_Ross. the number of ciliated cells increase during the follicular phase of the ovarian cycle, but also removal of the ovaries leads to atrophy of the epithelium and loss of ciliated cells. The uterine tube varies in size and degree of mucosal folding along its length. The mucosal folds are evident in its distal portion, the infundibulum, as it nears the open end. Near the opening, the tube flares outward and is called the infundibulum. It has fringed folded edges called fimbria. The infundibulum leads proximally to the ampulla, which constitutes about two thirds of the length of the oviduct, has the most numerous and complex mucosal folds, and is the site of fertilization. Mucosal folds are least numerous at the proximal end of the oviduct, near the uterus, where the tube is narrow and referred to as the isthmus. A uterine or intramural portion measures about 1 cm in length and passes through the uterine wall to empty into the uterine cavity. Fertilization of the ovum usually occurs in the


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Histology_Ross. to as the isthmus. A uterine or intramural portion measures about 1 cm in length and passes through the uterine wall to empty into the uterine cavity. Fertilization of the ovum usually occurs in the distal portion of the ampulla. For the first several days of development, as it navigates the complex pathway created by the mucosal folds, the embryo is transported proximally by the beating of the cilia of the ciliated epithelial cells and by peristaltic contractions of the well-developed muscularis layer that underlies the mucosa.


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Histology_Ross. Uterine tube, human, H&E ×40. A cross section through the ampulla of the uterine tube is shown here. Many mucosal folds project into the lumen (L), and the complicated nature of the folds is evident by the variety of profiles that is seen. In addition to the mucosa (Muc), the remainder of the wall consists of a muscularis (Mus) and connective tissue. The muscularis consists of smooth muscle that forms a relatively thick layer of circular fibers and a thinner outer layer of longitudinal fibers. The layers are not clearly delineated, and no sharp boundary separates them. Mucosal fold, uterine tube, human, H&E ×160; inset ×320.


Histology_Ross

Histology_Ross. The area enclosed by the rectangle in figure above is shown here at higher magnification. The specimen shows a longitudinal section through a lymphatic vessel (Lym). In other planes of section, the lymphatic vessels are difficult to identify. The for tuitously sectioned lymphatic vessel is seen in the core of the mucosal fold, along with a highly cellular connective tissue (CT) and the blood vessels (BV) within the connective tissue. The epithelium lining the mucosa is shown in the inset. The ciliated cells are readily identified by the presence of well-formed cilia (C). Nonciliated cells, also called peg cells (PC), are readily identified by the absence of cilia; moreover, they have elongate nuclei and sometimes appear to be squeezed between the ciliated cells. The connective tissue (CT) contains cells whose nuclei are arranged typically in a random manner. They vary in shape, being elongated, oval, or round. Their cytoplasm cannot be distinguished from the intercellular material


Histology_Ross

Histology_Ross. contains cells whose nuclei are arranged typically in a random manner. They vary in shape, being elongated, oval, or round. Their cytoplasm cannot be distinguished from the intercellular material (inset). The character of the connective tissue is essentially the same from the epithelium to the muscularis, and for this reason, no submucosa is described.


Histology_Ross

Histology_Ross. PLATE 95 BV, blood vessels C, cilia CT, connective tissue Ep, epithelium L, lumen Lym, lymphatic vessel Muc, mucosa Mus, muscularis PC, peg cells KEY 880 The uterus is a hollow, pear-shaped organ with a thick wall and, in the nonpregnant state, a narrow cavity. The uterine wall is composed of a mucosa, referred to as the endometrium; a muscularis, referred to as a myometrium; and, externally, a serosal cover, the perimetrium. The myometrium consists of smooth muscle and connective tissue and contains the large blood vessels that give rise to the vessels that supply the endometrium. The uterus undergoes cyclical changes that are largely manifested by changes that occur in the endometrium. If implantation of an ovum does not occur after preparation for this event, the state of readiness is not maintained, and much of the endometrium degenerates and is sloughed off, constituting the menstrual flow. The part of the endometrium that is lost is referred to as the stratum functionale; the


Histology_Ross

Histology_Ross. not maintained, and much of the endometrium degenerates and is sloughed off, constituting the menstrual flow. The part of the endometrium that is lost is referred to as the stratum functionale; the part that is retained is called the stratum basale. The stratum basale is the deeper part of the endometrium and adjoins the myometrium. The myometrium also undergoes changes associated with implantation of a zygote. In the nonpregnant uterus, the smooth muscle cells are about 50 m in length; during pregnancy, they undergo enormous hypertrophy, often reaching more than 500 m in length. In addition, new muscle fibers develop after division of existing muscle cells and division and differentiation of undifferentiated mesenchymal cells. The connective tissue also increases to strengthen the uterine wall. Fibroblasts increase by division and secrete additional collagen and elastic fibers. After parturition, the uterus nearly returns to its normal size. Most muscle fibers return to their normal


Histology_Ross

Histology_Ross. wall. Fibroblasts increase by division and secrete additional collagen and elastic fibers. After parturition, the uterus nearly returns to its normal size. Most muscle fibers return to their normal size, and some degenerate. Collagen secreted during pregnancy is digested by the very cells that secreted it, the fibroblasts. Similar, but less pronounced, proliferation and degeneration of fibroblasts and collagen occur in each menstrual cycle.


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Uterus, human, H&E ×25; inset ×120.

Histology_Ross. Uterus, human, H&E ×25; inset ×120.


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Histology_Ross. After the stratum functionale (SF) is sloughed off, resurfacing of the raw tissue occurs. The epithelial resurfacing comes from the glands that remain in the stratum basale (SB). The gland epithelium simply proliferates and grows over the surface. This figure shows the endometrium as it appears when resurfacing is complete. The area inscribed in the upper small rectangle is shown at higher magnification in the inset on the right. Note the simple columnar epithelium (SEp) that covers the endometrial surface and its similarity to the glandular epithelium (Gl). The endometrium is relatively thin at this phase and over half of it consists of the stratum basale. The area inscribed by the lower small rectangle, located in the region of the stratum basale, is shown at higher magnification in the inset in figure below. The glandular epithelium of the deep portion of the glands is similar to that of the endometrial surface. Below the endometrium is the myometrium (M), in which a number of


Histology_Ross

Histology_Ross. the inset in figure below. The glandular epithelium of the deep portion of the glands is similar to that of the endometrial surface. Below the endometrium is the myometrium (M), in which a number of large blood vessels (BV) are present.


Histology_Ross

Histology_Ross. Endometrium, proliferative phase, uterus, human, H&E ×25; inset ×120. Under the influence of estrogen, the various components of the endometrium proliferate (proliferative phase), so that the total thickness of the endometrium is increased. As shown in this figure, the endometrial glands (Gl) become rather long and follow a fairly straight course within the stratum functionale (SF) to reach the surface. The stratum basale (SB) remains essentially unaffected by the estrogen and appears much the same as in above figure. In this figure, the stratum functionale (SF), on the other hand, has increased in thickness and constitutes about four fifths of the endometrial thickness. BV, blood vessels Gl, endometrial glands M, myometrium SB, stratum basale SEp, surface epithelium SF, stratum functionale KEY


Histology_Ross

Histology_Ross. After estrogen brings about the uterine events designated the proliferative phase another hormone, progesterone, influences additional uterine changes that constitute the secretory phase of the uterine cycle. This hormone brings the endometrium to a state of readiness for implantation, and as a consequence of its actions, the thickness of the endometrium increases further. There are conspicuous changes in the glands, primarily in the stratum functionale, where the glands take on a more pronounced corkscrew shape and secrete mucus that accumulates in sacculations along their length. The vasculature of the endometrium also proliferates and degenerates in each menstrual cycle. Radial arteries enter the stratum basale of the endometrium from the myometrium and give rise to small, straight arteries that supply the stratum basale and continue into the endometrium to become the highly coiled spiral arteries. Arterioles derived from the spiral arteries supply the stratum functionale. The


Histology_Ross

Histology_Ross. arteries that supply the stratum basale and continue into the endometrium to become the highly coiled spiral arteries. Arterioles derived from the spiral arteries supply the stratum functionale. The distal portion of the spiral arteries and the arterioles are sloughed with the stratum functionale during menstruation. Alternating contraction and relaxation of the basal portions of the spiral arteries prevent excessive blood loss during menstruation.


Histology_Ross

Uterus, human, H&E ×25.

Histology_Ross. Uterus, human, H&E ×25.