3 days after fertilization, the morula enters the lumen of the uterus.

•Once in the uterus, the cells of the morula rearrange themselves to form a hollow structure, the blastocyst, whose fluid-filled cavity also houses a small cluster of cells, the inner cell mass (embryoblasts) responsible for the formation of the embryo.

•Approximately 5 to 6 days after fertilization, the cells at the periphery of the blastocyst, the trophoblasts, proliferate and initiate the process of implantation into the endometrium. By the ninth day, implantation is complete.

•As the trophoblasts proliferate, they form an inner cellular layer, the cytotrophoblast, and an outer syncytial layer, the syncytiotrophoblast.

The syncytiotrophoblasts will initiate the formation of the embryonic portion of the placenta.

In response to the invasion of the syncytiotrophoblasts, the endometrium will initiate the formation of the maternal portion of the placenta.

Placenta

During pregnancy, the uterus participates in the formation of the placenta, a highly vascular structure that permits the exchange of various materials between the maternal and fetal circulatory systems (see Graphic 17-2). It must be stressed that the exchange occurs without the commingling of the maternal and fetal bloods and that the placenta is derived from both maternal and fetal tissues. The roles of the trophoblasts and the endometrium are as follows:

•The syncytiotrophoblasts and cytotrophoblasts form the chorion, the precursor of the chorionic plate from which the chorionic villi will arise.

•The endometrium in contact with the chorion becomes modified to form the decidua with its three regions:

Decidua basalis, the richly vascularized maternal portion of the placenta that induces the trophoblasts to form the chorionic villi.

Decidua capsularis, the tissue separating the lumen of the uterus from the embryo and will be known as the chorion laeve, and

Decidua parietalis, the endometrial tissue between the uterine lumen and the myometrium.

Initially, the chorionic villi are slender structures and are known as primary villi. Once they are invaded by mesenchymal cells and fetal capillary networks, they become more substantial and their population of cytotrophoblasts decreases because they become incorporated into the syncytiotrophoblasts; in this manner, the primary villi become known as secondary villi.

F E M A L E R E P R O D U C T I V E S Y S T E M 409

•As the placenta is forming, the decidua basalis develops large, blood-filled vascular channels, known as lacunae, and the secondary villi protrude into these “lakes” of maternal blood, supplied by maternal arterioles and drained by maternal venules.

•Secondary villi grow into these lacunae and some of the villi contact and fuse with the decidua basalis (anchoring villi), whereas other secondary villi (free villi) resemble fingers that are immersed in water.

The fetal capillary beds of the anchoring and free villi are located adjacent to the syncytiotrophoblasts and lie in close proximity of the maternal blood in the lacunae.

Oxygen and nutrients in the maternal blood diffuse through the villi to reach the fetal capillaries.

Carbon dioxide and waste products in the fetal blood also diffuse through the villi to reach the maternal blood in the lacunae.

The exchange of gases and material occurs by passing through the placental barrier whose components are listed in Table 17-3.

In addition to its role in the delivery of nutrients and oxygen to the fetus and exchanging it for the fetal waste products, the placenta also manufactures hormones and factors necessary for the maintenance of pregnancy and the delivery of the fetus (see Table 17-4).

VAGINA

The vagina, an 8- to 9-cm long muscular sheath, extending from the cervix of the uterus to the vestibule, is adapted for the reception of the penis during copulation and for the passage of the fetus from the uterus during birth. The wall of the vagina is composed of three layers: the mucosa, muscularis, and the adventitia.

•The mucosa consists of a stratified squamous epithelium and a loose, fibroelastic connective tissue layer, the lamina propria.

TABLE 17-3 • Components of the Placental Barrier

Endothelial cells of the fetal capillary

Basal lamina of the fetal endothelium

Connective tissue of the secondary villus

Basal lamina of the cytotrophoblasts

Cytotrophoblasts

Syncytiotrophoblasts

Frequently, in a virgin, the external orifice of the vagina is partially occluded by the hymen, a thin, somewhat vascular connective tissue membrane, covered on both sides by stratified squamous epithelium.

•The muscularis is composed of a mostly longitudinally disposed smooth muscle layer interspersed with some circularly arranged fibers. At its external orifice, the muscularis of the vagina possesses a sphincter, composed of circularly arrayed smooth muscle fibers.

•The adventitia is a dense fibroelastic connective tissue that affixes the vagina to the surrounding pelvic connective tissue.

EXTERNAL GENITALIA

The external genitalia, composed of labia majora, labia minora, clitoris, and vestibular glands, are also referred to as the vulva. These structures are richly innervated and function during sexual arousal and copulation.

MAMMARY GLANDS

The mammary glands, highly modified sweat glands, are identical in males and females until the onset of puberty, when, due to hormonal influences, the female breasts develop.

•The mammary gland is composed of numerous individual compound glands, each of which is considered a lobe.

Each lobe is drained by a lactiferous duct that delivers milk, the secretion of the mammary glands, onto the surface of the nipple.

•The pigmented region of the skin surrounding the nipple, known as the areola, is richly endowed by sweat, sebaceous, and areolar glands.

•During pregnancy, several hormones interact to promote the development of the secretory units of the mammary gland. Cells of the terminal interalveolar ducts proliferate to form secretory alveoli.

The hormones involved in promoting this process are progesterone, estrogen, and human chorionic mammotropin from the placenta and lactogenic hormone (prolactin) from the acidophils of the adenohypophysis.

•Alveoli and terminal interalveolar ducts are surrounded by myoepithelial cells that contract as a result of the release of oxytocin from the neurohypophysis (in response to suckling), forcing milk out of the breast (milk ejection reflex).

Milk is composed of water, proteins, lipids, and lactose.

However, milk secreted during the first few days (colostrum) is different, in that it is rich in vitamins, minerals, lymphoid cells, and proteins, especially immunoglobulin A, providing antibodies for the neonate for the first few months of life.

The Papanicolaou (Pap) smear is performed as part of routine gynecological examination to examine stained exfoliative cells of the lining of the cervix and vagina. Evaluation of the smeared cells permits the recognition of precancerous conditions as well as cancer of the cervix. An annual smear test is recommended since cervical cancer is relatively slow growing and the Pap smear is an extremely cost-effective procedure that has been responsible for the early detection of cervical cancer and for saving lives of affected individuals.

Gonorrhea

Gonorrhea is a sexually transmitted bacterial infection caused by the gram-negative diplococcus Neisseria gonorrhoeae. In the United States, over a million cases of gonorrhea occur annually. Frequently, this sexually transmitted disease is responsible for pelvic inflammatory disease (PID) and for acute salpingitis.

Pelvic Inflammatory Disease

PID an infection of the cervix, uterus, fallopian tubes, and/or ovary, is usually a sequel to microbial infection. Individuals suffering from PID exhibit tenderness and pain in the lower abdominal region, fever, unpleasantsmelling vaginal discharge, and episodes of abnormal bleeding.

Adenomyosis

Adenomyosis is a common condition in which the endometrial glands invade the myometrium and cause the uterus to enlarge, occasionally becoming two or three times its normal dimensions. In most women, adenomyosis has no symptoms, and it is only on gynecological examination that the condition is discovered. When it becomes symptomatic, the woman is usually between 35 and 50 years of age, she may experience pain during intercourse, and she notices an increase in menstrual flow as well as bleeding between periods. Although the condition is benign, if the symptoms are severe and uncontrollable, hysterectomy may be indicated.

Endometriosis is distinguished by the presence of ectopic endometrial tissue dispersed to various sites along the peritoneal cavity. Occasionally, the tissues may migrate to extraperitoneal areas, including the eyes and brain. The etiology of this disease is not known. In some cases the lesions of endometriosis involve small cysts attached separately or in small clumps on the visceral or parietal peritoneum.

This photomicrograph is from the fallopian tube of a female patient with endometriosis. Observe that uterine glands and stroma occupy the lumen of the oviduct. (Reprinted with permission from Mills SE, Carter D, et al., eds. Sternberg’s Diagnostic Surgical Pathology, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010, p. 2377.)

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Endometrial Carcinoma

Endometrial carcinoma is a malignancy of the uterine endometrium usually occurring in postmenopausal women. The most common type of endometrial cancer is adenocarcinoma. Since during the early stages the cancer cells do not invade the cervix, Pap smears are not very effective in diagnosing this disease until it has entered its later stages. The major symptom of endometrial cancer is abnormal uterine bleeding.

Hydatidiform Mole

Occasionally, an ovum does not develop normally and instead of becoming a fetus forms a mass of tissue that

initially mimics pregnancy, or in some patients, after delivery, remnants of placental tissue may proliferate. Known as a hydatidiform mole, these growths increase in size much faster than would a fetus. When the physician does not hear a heartbeat, the patient’s abdomen swells more than expected, and the patient complains of vomiting and severe nausea, a hydatidiform mole should be suspected. This is especially true in individuals who complain of a vaginal discharge of grape-like clusters of tissue. In most of the cases, the hydatidiform mole resorbs on its own. Only in about 20% of the cases does it become invasive, and in very rare cases does it becomes malignant (then it is known as a choriocarcinoma).

Paget’s Disease of the Nipple

Paget’s disease of the nipple usually occurs in elderly women and is associated with breast cancer of ductal origin. Initially, the disease manifests as scaly or crusty

nipple frequently accompanied by a fluid discharge from the nipple. Usually, the patient has no other symptoms and frequently neglects the condition.

System Reproductive Female • 1-17 GRAPHIC

Cycle Hormonal and Placenta• 2-17 GRAPHIC

ary • Ov1-17 PLATE

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FIGURE 1. Ovary. Monkey. Plastic section. ×14.

The ovary is subdivided into a medulla (Me) and a cortex (Co). The medulla houses large blood vessels (BV) from which the cortical vascular supply is derived. The cortex of the ovary contains numerous ovarian follicles, most of which are very small (arrows); a few maturing follicles have reached the Graafian follicle (GF) stage. The thick, fibrous connective tissue capsule, tunica albuginea (TA), is shown to advantage; the germinal epithelium (GE) is evident occasionally. Observe that the mesovarium (Mo) not only suspends the ovary but also conveys the vascular supply to the medulla. A region similar to the boxed area is presented at a higher magnification in Figure 2.

FIGURE 3. Primary follicles. Monkey. Plastic section. ×270.

Primary follicles differ from primordial follicles not only in size but also in morphology and number of follicular cells. The unilaminar primary follicle of the inset (×270) displays a single layer of cuboidal follicular cells (FC) that surround the relatively small primary oocyte (PO), whose nucleus (N) is clearly evident. The multilaminar primary follicle displays a primary oocyte (PO) that has increased in size. The follicular cells (FC) now form a stratified layer around the oocyte, being separated from it by the intervening zona pellucida (ZP). The stroma (St) is being reorganized around the follicle to form the theca interna (TI). Note the presence of a basal membrane (BM) between the follicular cells and the theca interna.

FIGURE 2. Ovary. Monkey. Plastic section. ×132.

This photomicrograph is a higher magnification of a region similar to the boxed area of Figure 1. Observe that the germinal epithelium (GE) covers the collagenous capsule, the tunica albuginea (TA). This region of the cortex (Co) houses numerous primordial follicles (PF). Observe that the connective tissue of the ovary is highly cellular and is referred to as the stroma (St). Inset. Ovary. Cortex. Monkey. Plastic section. ×540. The primordial follicle is composed of a primary oocyte (PO), whose nucleus (N) and nucleolus (arrow) are evident. Observe the single layer of flat follicular cells (FC) surrounding the oocyte. The tunica albuginea (TA) and the germinal epithelium (GE) are also shown to advantage in this photomicrograph.

FIGURE 4. Secondary follicle. Rabbit. Paraffin section. ×132.

Secondary follicles are very similar to primary multilaminar follicles, the major difference being their larger size. Moreover, the stratification of the follicular cells (FC) has increased, displaying more layers, and more important, a follicular fluid (FF) begins to appear in the intercellular spaces, which coalesces into several Call-Exner bodies. Note also that the stroma immediately surrounding the follicular cells is rearranged to form a cellular theca interna (TI) and a more fibrous theca externa (TE).

Luteum Corpus and vary • O2-17 PLATE

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FIGURE 1. Graafian follicle. Paraffin section. ×132.

The Graafian follicle is the most mature of all ovarian follicles and is ready to release its primary oocyte in the process of ovulation. The follicular fluid (FL) fills a single chamber, the antrum, which is surrounded by a wall of granulosa (follicular) cells known as the membrana granulosa (MG). Some of the granulosa cells, which surround the primary oocyte (PO), jut into the antrum as the cumulus oophorus (CO). Observe the basal membrane (BM), which separates the granulosa cells from the theca interna (TI). The fibrous theca externa (TE) merges almost imperceptibly with the surrounding stroma. The boxed area is presented at a higher magnification in Figure 2.

FIGURE 3. Corpus luteum. Human. Paraffin section. ×14.

Subsequent to ovulation, the Graafian follicle becomes modified to form a temporary structure, the corpus hemorrhagicum, which will become the corpus luteum. The cells comprising the membrana granulosa enlarge, become vesicular in appearance, and are referred to as granulosa lutein cells (GL), which become folded; the spaces between the folds are occupied by connective tissue elements, blood vessels, and cells of the theca interna (arrows). These theca interna cells also enlarge, become glandular, and are referred to as the theca lutein cells. The remnants of the antrum are filled with fibrin and serous exudate that will be replaced by connective tissue elements. A region similar to the boxed area is presented at a higher magnification in Figure 4.

FIGURE 2. Graafian follicle. Cumulus oophorus. Paraffin section. ×270.

This photomicrograph is a higher magnification of the boxed area of Figure 1. Observe that the cumulus oophorus houses the primary oocyte (PO), whose nucleus (N) is just visible in this section. The zona pellucida (ZP) surrounds the oocyte, and processes (arrows) of the surrounding follicular cells extend into this acellular region. The single layer of follicular cells appears to radiate as a crown at the periphery of the primary oocyte and is referred to as the corona radiata (CR). Note the basal membrane (BM) as well as the theca interna (TI) and the theca externa (TE).

FIGURE 4. Corpus luteum. Human. Paraffin section. ×132.

This photomicrograph is a higher magnification of a region similar to the boxed area of Figure 3. The granulosa lutein cells (GL) of the corpus luteum are easily distinguished from the connective tissue (CT) elements, since the former display round nuclei (N), mostly in the center of large round cells (arrowheads). The center of the field is occupied by a fold, housing theca lutein cells (TL) amid numerous connective tissue (CT) and vascular (BV) elements. A region similar to the boxed area is presented at a higher magnification in Figure 1 of the next plate.

Oviduct and vary • O3-17 PLATE

Microscopy Electron and Light viduct, • O4-17 PLATE

erus • Ut5-17 PLATE

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FIGURE 1. Uterus. Follicular phase. Human. Paraffin section. ×14.

The uterus is a thick-walled organ whose wall consists of three layers. The external serosa (or in certain regions, adventitia) is unremarkable and is not presented in this photomicrograph. The thick myometrium (My) is composed of smooth muscle, subdivided into three poorly delineated layers: outer longitudinal (OL), middle circular (MC), and inner longitudinal (IL). The endometrium

(En) is subdivided into a basal layer (B) and a functional layer

(F). The functional layer varies in thickness and constitution and passes through a sequence of phases during the menstrual cycle. Note that the functional layer is in the process of being built up and that the forming glands (GL) are straight. The deeper aspects of some of these glands display branching (arrow). The boxed area is presented at a higher magnification in Figure 2.

FIGURE 3. Uterus. Luteal phase. Human. Paraffin section. ×14.

The myometrium (My) of the uterus remains constant during the various endometrial phases. Observe its three layers, noting especially that the middle circular layer of smooth muscle is richly vascularized and is therefore frequently referred to as the stratum vasculare (SV). The endometrium (En) is richly endowed with glands (GL) that become highly tortuous in anticipation of the blastocyst that will be nourished by secretions of these glands subsequent to implantation. A region similar to the boxed area is presented at a higher magnification in Figure 4.

FIGURE 2. Uterus. Follicular phase. Human. Paraffin section. ×132.

This photomicrograph is a higher magnification of the boxed area of Figure 1. Note that the functional layer (F) of the endometrium is lined by a simple columnar epithelium (Ep) that is displaying mitotic activity (arrows). The forming glands (GL) also consist of a simple columnar epithelium (Ep) whose cells are actively dividing. The stroma (St) is highly cellular, as evidenced by the numerous connective tissue cell nuclei visible in this field. Note also the rich vascular supply (BV) of the endometrial stroma.

FIGURE 4. Uterus. Early luteal phase. Human. Paraffin section. ×132.

This photomicrograph is a higher magnification of a region similar to the boxed area of Figure 3. The functional layer of the endometrium is covered by a simple columnar epithelium (Ep), separating the endometrial stroma (St) from the uterine lumen (L). Note that the glands (GL), also composed of simple columnar epithelium, are more abundant than those in the follicular phase (Figure 2, above). Observe also that these glands appear more tortuous and are dilated and their lumina contain a slight amount of secretory product (arrow).

erus • Ut6-17 PLATE

Vagina and Placenta• 7-17 PLATE

Gland y Mammar• 8-17 PLATE