Histology_Ross

Histology_Ross. Mucosal folds, seminal vesicle, human, H&E 220. This higher magnification of the mucosal folds reveals the epithelium (Ep) and the underlying loose connective tissue or lamina propria (LP). The epithelium is described as pseudostratified. It is composed of low columnar or cuboidal cells and small, round basal cells. The latter are randomly inter spersed between the larger principal cells, but they are relatively sparse. the surface, the mucosal ridges appear as “villi.” In some areas, particularly the peripheral region of the lumen, the interconnecting folds of the mucosa appear as alveoli. Each of these chambers is, however, simply a pocket-like structure that is open and continuous with the lumen. The mucosa is subtended by a very cellular loose connective tissue (CT) that, in turn, is surrounded by smooth muscle (SM).


Histology_Ross

Histology_Ross. The seminal vesicles are paired elongated sacs. Each vesicle consists of a single tube folded and coiled on itself with occasional diverticula in its wall. The upper extremity ends as a cul-de-sac; the lower extremity is constricted into a narrow straight excretory duct that joins and empties into its corresponding ductus deferens. For this reason, the epithelium may not be readily recognized as pseudostratified. In some areas, the epithelium appears thick (arrowhead) and, based on the disposition of the nuclei, would seem to be multilayered. This is due to a tangential section of the epithelium and is not a true stratification. The lamina propria of the mucosa is composed of a very cellular connective tissue containing some smooth muscle cells and is rich in elastic fibers. PLATE 91 KEY CT, connective tissue Ep, epithelium LP, lamina propria SM, smooth muscle arrowhead, oblique section of epithelium arrows, mucosal arches


Histology_Ross

Histology_Ross. OVERVIEW OF THE FEMALE REPRODUCTIVE SYSTEM / 830 OVARY / 831 Ovarian Structure / 832 Follicle Development / 833 Ovulation / 837 Capacitation and Fertilization / 840 Atresia / 843 Blood Supply and Lymphatics / 845 Innervation / 845 UTERINE TUBES / 845 UTERUS / 848 Cyclic Changes During the Menstrual Cycle / 850 Implantation / 852 Cervix / 853 PLACENTA / 854 VAGINA / 860 EXTERNAL GENITALIA / 861 MAMMARY GLANDS / 863 Hormonal Regulation of the Mammary Gland / 866 Involution of the Mammary Gland / 867 Blood Supply and Lymphatics / 870 Innervation / 870 Folder 23.1 Clinical Correlation: Polycystic Ovarian Disease / 839 Folder 23.2 Clinical Correlation: In Vitro Fertilization / 844 Folder 23.3 Functional Considerations: Summary of Hormonal Regulation of the Ovarian Cycle / 846 Folder 23.4 Clinical Correlation: Fate of the Mature Placenta at Birth / 860 Folder 23.5 Clinical Correlation: Cytologic Pap Smears / 862 Folder 23.6 Clinical Correlation: Cervix and Human Papillomavirus (HPV)


Histology_Ross

Histology_Ross. Clinical Correlation: Fate of the Mature Placenta at Birth / 860 Folder 23.5 Clinical Correlation: Cytologic Pap Smears / 862 Folder 23.6 Clinical Correlation: Cervix and Human Papillomavirus (HPV) Infections / 868 Folder 23.7 Functional Considerations: Lactation and Infertility / 870


Histology_Ross

Histology_Ross. The female reproductive system consists of internal sex organs and external genital structures. The internal female reproductive organs are located in the pelvis, and the external genital structures (external genitalia) are situated in the anterior part of the perineum known as the vulva.  The internal female reproductive organs are the ovaries, uterine tubes, uterus, and vagina (Fig. 23.1). They are contained mainly within the pelvic cavity and in the perineum.  The external genitalia include the mons pubis, labia majora and minora, clitoris, vestibule and opening of the vagina, hymen, and external urethral orifice. The mammary glands are included in this chapter because their development and functional state are directly fundus of uterus body of uterine portion isthmus of mesosalpinx ampulla of of uterine tube uterine tube uterine tube suspensory ligament of ovary ovary ligament of ovary mesometrium perimetrium


Histology_Ross

Histology_Ross. FIGURE 23.1 • Schematic drawing of female internal sex organs. This drawing shows the posterior view of the female internal sex organs. Part of the wall of the uterus, uterine tube, and vagina has been removed to reveal their internal structure. Note the three distinct layers of the uterine wall: the inner layer, the endometrium lining the uterine cavity; the middle and thickest layer, the myometrium; and the outer layer, the perimetrium, which is the peritoneal covering of the uterus. related to the hormonal activity of the female reproductive system. Similarly, the placenta is included because of its functional and physical relationship to the uterus in pregnancy. Female reproductive organs undergo regular cyclic changes from puberty to menopause.


Histology_Ross

Histology_Ross. The ovaries, uterine tubes, and uterus of the sexually mature female undergo marked structural and functional changes related to neural activity and changes in hormone levels during each menstrual cycle and during pregnancy. These mechanisms also regulate the early development of the female reproductive system. The initiation of the menstrual cycle, referred to as the menarche, occurs in females between 9 and 14 years of age (the mean age of menarche is 12.7 years) and marks the end of puberty and the beginning of the reproductive life span. During this phase of life, the menstrual cycle averages about 28 to 30 days in length. Between 45 and 55 years of age (the mean age is 51.4 years), the menstrual cycle becomes infrequent and eventually ceases. This change in reproductive function is referred to as the menopause or climacterium (commonly called the “change of life”). The ovaries cease their reproductive function of producing oocytes and their endocrine function of producing


Histology_Ross

Histology_Ross. is referred to as the menopause or climacterium (commonly called the “change of life”). The ovaries cease their reproductive function of producing oocytes and their endocrine function of producing hormones that regulate reproductive activity. Other organs (e.g., vagina and mammary glands) show varying degrees of reduced function, particularly secretory activity.


Histology_Ross

Histology_Ross. Production of gametes and steroid hormones are the two major functions of the ovary. The ovaries have two interrelated functions: gametogenesis (the production of gametes) and steroidogenesis (the production of steroids). In women, the production of gametes is called oogenesis. Developing gametes are called oocytes; mature gametes are called ova. Two major groups of steroid hormones—estrogens and progestogens—are secreted by the ovaries.  Estrogens promote the growth and maturation of internal and external sex organs and are responsible for the female sex characteristics that develop at puberty. Estrogens also act on mammary glands to promote breast development by stimulating ductal and stromal growth and accumulation of adipose tissue.


Histology_Ross

Histology_Ross.  Progestogens prepare the internal sex organs, mainly the uterus, for pregnancy by promoting secretory changes in the endometrium (discussed in the section on cyclic changes in the endometrium). Progestogens also prepare the mammary gland for lactation by promoting lobular proliferation. FIGURE 23.2 • Schematic drawing of a section through the ovary. This drawing shows stages of follicular development from the early primary follicle to the mature (Graafian) follicle. The maturation of the follicles occurs in the direction of the arrow. Changes in the follicle after ovulation lead to development of the corpus luteum and eventually the corpus albicans. Note the highly coiled blood vessels in the hilum and medulla of the ovary. Both hormones play an important role in the menstrual cycle by preparing the uterus for implantation of a fertilized ovum. If implantation does not occur, the endometrium of the uterus degenerates and menstruation follows.


Histology_Ross

Histology_Ross. In nulliparas (women who have not borne children), the ovaries are paired, almond-shaped, pinkish white structures measuring about 3 cm in length, 1.5 cm in width, and 1 cm in thickness. Each ovary is attached to the posterior surface of the broad ligament by a peritoneal fold, the mesovarium (see Fig. 23.1). The superior (or tubal) pole of the ovary is attached to the pelvic wall by the suspensory ligament of the ovary, which carries the ovarian vessels and nerves. The inferior (or uterine) pole is attached to the uterus by the ovarian ligament. This ligament is a remnant of the gubernaculum, the embryonic fibrous cord that attaches the developing gonad to the floor of the pelvis. Before puberty, the surface of the ovary is smooth, but during reproductive life it becomes progressively scarred and irregular because of repeated ovulations. In postmenopausal women, the ovaries are about one-fourth the size observed during the reproductive period.


Histology_Ross

Histology_Ross. The ovary is composed of a cortex and a medulla. A section through the ovary reveals two distinct regions:  The medulla or medullary region is located in the central portion of the ovary and contains loose connective tissue, a mass of relatively large contorted blood vessels, lymphatic vessels, and nerves (Fig. 23.2).  The cortex or cortical region is found in the peripheral portion of the ovary surrounding the medulla. The cortex contains the ovarian follicles embedded in a richly cellular connective tissue (Plate 92, page 872). Scattered smooth muscle fibers are present in the stroma around the follicles. The boundary between the medulla and cortex is indistinct. “Germinal epithelium” instead of mesothelium covers the ovary.


Histology_Ross

Histology_Ross. The surface of the ovary is covered by a single layer of cuboidal and, in some parts, almost squamous cells. This cellular layer, known as the germinal epithelium, is continuous with the mesothelium that covers the mesovarium. The term germinal epithelium is a carryover from the past when it was incorrectly thought to be the site of germ cell formation during embryonic development. It is now known that the primordial germ cells (both male and female) are of extragonadal origin and that they migrate from the embryonic yolk sac into the cortex of the embryonic gonad, where they differentiate and induce differentiation of the ovary. A dense connective tissue layer, the tunica albuginea, lies between the germinal epithelium and the underlying cortex (Plate 92, page 872). Tumors that arise from the epithelial surface of the ovary account for more than 70% of ovarian cancers. The origin of surface epithelial tumors may be related to repeated disruption and repair of the germinal


Histology_Ross

Histology_Ross. arise from the epithelial surface of the ovary account for more than 70% of ovarian cancers. The origin of surface epithelial tumors may be related to repeated disruption and repair of the germinal epithelium that occurs during ovulations.


Histology_Ross

Histology_Ross. Ovarian follicles provide the microenvironment for the developing oocyte.


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Histology_Ross. Ovarian follicles of various sizes, each containing a single oocyte, are distributed in the stroma of the cortex. The size of a follicle indicates the developmental state of the oocyte. Early stages of oogenesis occur during fetal life when mitotic divisions massively increase the number of oogonia (see the section on oogenesis). The oocytes present at birth remain arrested in development at the first meiotic division (see page 92). During puberty, small groups of follicles undergo cyclic growth and maturation. The first ovulation generally does not take place for a year or more after menarche. A cyclic pattern of follicular maturation and ovulation is then established that continues in parallel with the menstrual cycle. Normally, only one oocyte reaches full maturity and is released from the ovary during each menstrual cycle. Obviously, the maturation and release of more than one egg at ovulation may lead to multiple zygotes. During the reproductive life span, a woman produces only


Histology_Ross

Histology_Ross. the ovary during each menstrual cycle. Obviously, the maturation and release of more than one egg at ovulation may lead to multiple zygotes. During the reproductive life span, a woman produces only about 400 mature ova. Most of the estimated 600,000 to 800,000 primary oocytes present at birth do not complete maturation and are gradually lost through atresia, the spontaneous death and subsequent resorption of immature oocytes. This process begins as early as the fifth month of fetal life and is mediated by apoptosis of cells surrounding the oocyte. Atresia reduces the number of primary oocytes in a logarithmic fashion throughout life from as many as 5 million in the fetus to less than 20% of that number at birth. The oocytes that remain at menopause degenerate within a few years.


Histology_Ross

Histology_Ross. Histologically, three basic types of ovarian follicles can be identified on the basis of developmental state:  primordial follicles; growing follicles which are further subcategorized as pri mary and secondary (or antral) follicles; and mature follicle or Graafan follicles. Some histologists and clinicians identify additional stages in the continuum of follicular development. In the cycling ovary, follicles are found at all stages of development, but primordial follicles predominate. The primordial follicle is the earliest stage of follicular development.


Histology_Ross

Histology_Ross. The primordial follicle is the earliest stage of follicular development. Primordial follicles first appear in the ovaries during the third month of fetal development. Early growth of the primordial follicles is independent of gonadotropin stimulation. In the mature ovary, primordial follicles are found in the stroma of the cortex just beneath the tunica albuginea. A single layer of squamous follicle cells surrounds the oocyte (Fig. 23.3 and Plate 92, page 872). The outer surface of the follicle cells is bounded by a basal lamina. At this stage, the oocyte and the


Histology_Ross

Histology_Ross. FIGURE 23.3 • Primordial follicle. a. Schematic drawing of a primordial follicle shows the oocyte arrested in prophase of the first meiotic division. The oocyte is closely surrounded by a single layer of squamous follicle cells. The outer surface of these cells is separated from the connective tissue by a basal lamina. The ooplasm contains characteristic organelles, as seen with the electron microscope, including a Balbiani body, annulate lamellae, and small spherical mitochondria. b. This photomicrograph of primordial follicles shows the oocytes surrounded by a single layer of flattened follicle cells (FC). Usually, the nucleus (N) of the oocyte is in an eccentric position. Two oocytes in which the nucleus is not included in the plane of section are indicated (X ). Similarly, there are two follicles (arrows) in which the follicle cells are revealed in face or tangential view and the enclosed oocytes are not included in the section. 640.


Histology_Ross

Histology_Ross. surrounding follicle cells are closely apposed to one another. The oocyte in the follicle measures about 30 m in diameter and has a large, eccentric nucleus that contains finely dispersed chromatin and one or more large nucleoli. The cytoplasm of the oocyte, referred to as ooplasm, contains a Balbiani body (Fig. 23.3a). At the ultrastructural level, the Balbiani body is revealed as a localized accumulation of Golgi membranes and vesicles, endoplasmic reticulum, numerous mitochondria, and lysosomes. In addition, human oocytes contain annulate lamellae, and numerous small vesicles are scattered throughout the cytoplasm along with small, spherical mitochondria. Annulate lamellae resemble a stack of nuclear envelope profiles. Each layer of the stack includes pore structures that are morphologically identical to nuclear pores. The primary follicle is the first stage in the development of the growing follicle.


Histology_Ross

Histology_Ross. As a primordial follicle develops into a growing follicle, changes occur in the oocyte, in the follicle cells, and in the adjacent stroma. Initially, the oocyte enlarges, and the surrounding flattened follicle cells proliferate and become cuboidal. At this stage—that is, when the follicle cells become cuboidal— the follicle is identified as a primary follicle. As the oocyte grows, it secretes specific proteins that are assembled into an extracellular coat called the zona pellucida. It appears between the oocyte and the adjacent follicle cells (Fig. 23.4). The zonal pellucida in humans is composed of three classes of sulfated acidic zona pellucida (ZP) glycoproteins termed ZP-1 (80 to 120 kilodaltons), ZP-2 (73 kilodaltons), and ZP-3 (59 to 65 kilodaltons). Of the three, the most important is the ZP-3, which functions as the spermatozoa-binding receptor and inducer of the acrosome reaction (see page 841); ZP-2 is believed to act as a secondary spermatozoa-binding protein, and ZP-1 has


Histology_Ross

Histology_Ross. is the ZP-3, which functions as the spermatozoa-binding receptor and inducer of the acrosome reaction (see page 841); ZP-2 is believed to act as a secondary spermatozoa-binding protein, and ZP-1 has not yet been functionally characterized. In the light microscope, zona pellucida is clearly visible as a homogeneous and refractile layer that stains deeply with acidophilic stains and with the periodic acid–Schiff (PAS) reagents (Plate 92, page 872). It is first apparent when the oocyte, surrounded by a single layer of cuboidal or columnar follicle cells, has grown to a diameter of 50 m to 80 m.


Histology_Ross

Histology_Ross. Follicle cells undergo stratification to form the granulosa layer of the primary follicle. Through rapid mitotic proliferation, the single layer of follicle cells gives rise to a stratified epithelium, the membrana granulosa (stratum granulosum), surrounding the oocyte. The follicle cells are now identified as granulosa cells. The basal lamina retains its position between the outermost layer of the follicle cells, which become columnar, and the connective tissue stroma. During follicular growth, extensive gap junctions develop between granulosa cells. Unlike Sertoli cells in the testis, however, the basal layer of the granulosa cells does not possess elaborate tight junctions (zonulae occludentes), indicating the absence of a blood–follicle barrier. Movement of nutrients and small informational macromolecules from the blood into the follicular fluid is essential for normal development of the ovum and follicle. Connective tissue cells form the theca layers of the primary follicle.


Histology_Ross

Histology_Ross. Connective tissue cells form the theca layers of the primary follicle. As the granulosa cells proliferate, stromal cells immediately surrounding the follicle form a sheath of connective tissue cells, known as the theca folliculi, just external to the basal PRIMARY FOLLICLE stromal cells forming zona pellucida oocyte a follicle cells bbbbb FCFCFCFCFC FIGURE 23.4 • Early primary follicle. a. Schematic drawing of a primary follicle in an early stage of development. Note the formation of the zona pellucida between the oocyte and the adjacent follicle cells. A single layer of cuboidal follicle cells surrounds the growing oocyte. b. Photomicrograph of a primary follicle. Note the distinct layer of follicle cells (FC) surrounding the oocyte. 640.


Histology_Ross

Histology_Ross. LATE PRIMARY FOLLICLE granulosa cells stratum granulosum cortical granules oocyte cytoplasm granulosa cells microvilli of oocyte gap junction basal lamina zona pellucida process of granulosa cell theca folliculi a bbbbb GCGCGCGCGC ZPZPZPZPZP FIGURE 23.5 • Late primary follicle. a. Schematic drawing of a late primary follicle shows a multilayered mass of granulosa cells (differentiated from follicle cells) surrounding the oocyte. Note that the innermost layer of granulosa cells is adjacent to the zona pellucida, and the outermost layer of these cells rests on the basal lamina, which is adjacent to the stromal cells now called the theca folliculi. The Balbiani body at this stage reorganizes into multiple Golgi units, and cortical granules appear in the cytoplasm. The wedge-shaped enlargement depicts the ultrastructure of an oocyte and adjacent follicle cells. Numerous microvilli from the oocyte and slender processes from the granulosa cells extend into the zona pellucida that surrounds


Histology_Ross

Histology_Ross. depicts the ultrastructure of an oocyte and adjacent follicle cells. Numerous microvilli from the oocyte and slender processes from the granulosa cells extend into the zona pellucida that surrounds the oocyte. Processes of the granulosa cells contact the plasma membrane of the oocyte. b. Photomicrograph of a late primary follicle (monkey). Multiple layers of granulosa cells (GC) can be seen surrounding the primary oocyte. The zona pellucida (ZP) is present between the oocyte and follicle cells. 160.


Histology_Ross

Histology_Ross. lamina (Fig. 23.5). The theca folliculi further differentiates into two layers:  The theca interna is the inner, highly vascularized layer of cuboidal secretory cells (Plate 93, page 874). The fully differentiated cells of the theca interna possess ultrastructural features characteristic of steroid-producing cells. Cells of the theca interna possess a large number of luteinizing hormone (LH) receptors. In response to LH stimulation, they synthesize and secrete the androgens that are the precursors of estrogen. In addition to secretory cells, the theca interna contains fibroblasts, collagen bundles, and a rich network of small vessels typical of endocrine organs.  The theca externa is the outer layer of connective tissue cells. It contains mainly smooth muscle cells and bundles of collagen fibers.


Histology_Ross

Histology_Ross.  The theca externa is the outer layer of connective tissue cells. It contains mainly smooth muscle cells and bundles of collagen fibers. Boundaries between the thecal layers and between the theca externa and surrounding stroma are not distinct. However, the basal lamina between the granulosa layer and the theca interna establishes a distinct boundary between these layers. It separates the rich capillary bed of the theca interna from the granulosa layer, which is avascular during the period of follicular growth. Maturation of the oocyte occurs in the primary follicle.


Histology_Ross

Histology_Ross. Maturation of the oocyte occurs in the primary follicle. The distribution of organelles changes as the oocyte matures. Multiple, dispersed Golgi elements derived from the single Balbiani body of the primordial oocyte become scattered in the cytoplasm. The number of free ribosomes, mitochondria, small vesicles, and multivesicular bodies and the amount of rough-surfaced endoplasmic reticulum (rER) increase. Occasional lipid droplets and masses of lipochrome pigment may also be seen. The oocytes of many species, including mammals, exhibit specialized secretory vesicles known as cortical granules (see Fig. 23.5a). They are located just beneath the oolemma (oocyte’s plasma membrane). The granules contain proteases that are released by exocytosis when the ovum is activated by the sperm (discussed in the section on fertilization).


Histology_Ross

Histology_Ross. Numerous irregular microvilli project from the oocyte into the perivitelline space between the oocyte and the surrounding granulosa cells as the zona pellucida is deposited (see Fig. 23.5). At the same time, slender processes from the granulosa cells develop and project toward the oocyte, intermingling with oocyte microvilli and, occasionally, invaginating into the oocyte plasma membrane. The processes may contact the plasma membrane but do not establish cytoplasmic continuity between the cells. The secondary follicle is characterized by a fluid-containing antrum. The primary follicle initially moves deeper into the cortical stroma as it increases in size, mostly through proliferation of the granulosa cells. Several factors are required for oocyte and follicular growth:  Follicle-stimulating hormone (FSH) Growth factors (e.g., epidermal growth factor [EGF],


Histology_Ross

Histology_Ross. When the stratum granulosum reaches a thickness of 6 to 12 cell layers, fuid-flled cavities appear among the granulosa cells (Fig. 23.6). As the hyaluronan-rich fluid called liquor folliculi continues to accumulate among the granulosa cells, the cavities begin to coalesce, eventually forming a single, crescent-shaped cavity called the antrum. The follicle is now identified as a secondary follicle or antral follicle (Plate 93, page 874). The eccentrically positioned oocyte, which has attained a diameter of about 125 m, undergoes no further growth. The inhibition of growth is achieved by the presence of a small, 1to 2-kilodalton peptide called oocyte maturation inhibitor (OMI), which is secreted by the granulosa cells into the antral fluid. A direct correlation is observed between the size of the secondary follicle and OMI concentration. The concentration is highest in small follicles and lowest in mature follicles. The follicle, which was 0.2 mm in diameter as an early secondary


Histology_Ross

Histology_Ross. size of the secondary follicle and OMI concentration. The concentration is highest in small follicles and lowest in mature follicles. The follicle, which was 0.2 mm in diameter as an early secondary follicle when the fluid first appeared, continues to grow and reaches 10 mm or more in diameter.


Histology_Ross

Histology_Ross. Cells of the cumulus oophorus form a corona radiata around the secretory follicle oocyte. As the secondary follicle increases in size, the antrum, lined by several layers of granulosa cells, also enlarges (Fig. 23.7). The stratum granulosum has a relatively uniform thickness except for the region associated with the oocyte. Here the granulosa cells form a thickened mound, the cumulus oophorus, which projects into the antrum. The cells of the cumulus oophorus that immediately surround the oocyte and remain with it at ovulation are referred to as the corona radiata. The corona radiata is composed of cumulus cells that send penetrating microvilli throughout the zona pellucida to communicate via gap junctions with microvilli of the oocyte. During follicular maturation, the number of surface microvilli of


Histology_Ross

Histology_Ross. FIGURE 23.6 • Secondary follicle. a. Schematic drawing of a secondary follicle showing the fluid-filled antrum, which arises by the coalescence of small fluid-filled cavities among the granulosa cells. Note that this actively growing follicle has many dividing granulosa cells. Call-Exner bodies appear at this stage. The wedge-shaped enlargement of the shadowed area depicts the relationship of the granulosa cells, basal lamina, and the theca interna and theca externa. The theca interna cells differentiate into highly vascularized, steroid-producing cells. The theca interna is surrounded by an outer layer of stromal cells called the theca externa. The basal lamina separates the granulosa cells from the theca interna. b. Photomicrograph of a secondary follicle. The antrum (A), filled with follicular fluid, is visible within the stratum granulosum (GC). Multiple layers of theca interna cells (TI) and theca externa cells (TE) can be seen outside the basal lamina of the secondary follicle.


Histology_Ross

Histology_Ross. fluid, is visible within the stratum granulosum (GC). Multiple layers of theca interna cells (TI) and theca externa cells (TE) can be seen outside the basal lamina of the secondary follicle. 85.


Histology_Ross

Histology_Ross. FIGURE 23.7 • Secondary follicle in a late stage of development. a. Schematic drawing of a mature (Graafian) follicle with a large antrum containing an oocyte embedded within the cumulus oophorus. The cells of the cumulus oophorus immediately surrounding the oocyte remain with it after ovulation and are referred to as the corona radiata. b. Photomicrograph of a mature secondary follicle. Note the large fluid-filled antrum (A) and the cumulus oophorus (CO) containing the oocyte. The remaining cells that surround the lumen of the antrum make up the membrana granulosa (stratum granulosum, SG). The surface of the ovary is visible on the right. Note the presence of two primary follicles (upper right). TI, theca interna. 45.


Histology_Ross

Histology_Ross. granulosa cells increases and is correlated with an increased number of LH receptors on the free antral surface. Extracellular, densely staining, PAS-positive material called Call-Exner bodies (see Fig. 23.6a) may be seen between the granulosa cells. These bodies are secreted by granulosa cells and contain hyaluronan and proteoglycans. The mature or Graafian follicle contains the mature secondary oocyte.


Histology_Ross

Histology_Ross. The mature or Graafian follicle contains the mature secondary oocyte. The mature follicle, also known as a Graafan follicle, has a diameter of 10 mm or more. Because of its large size, it extends through the full thickness of the ovarian cortex and causes a bulge on the surface of the ovary. As the follicle nears its maximum size, the mitotic activity of the granulosa cells decreases. The stratum granulosum appears to become thinner as the antrum increases in size. As the spaces between the granulosa cells continue to enlarge, the oocyte and cumulus cells are gradually loosened from the rest of the granulosa cells in preparation for ovulation. The cumulus cells immediately surrounding the oocyte now form a single layer of cells of the corona radiata. These cells and loosely attached cumulus cells remain with the oocyte at ovulation.


Histology_Ross

Histology_Ross. During this period of follicle maturation, the thecal layers become more prominent. Lipid droplets appear in the cytoplasm of the theca interna cells, and the cells demonstrate ultrastructural features associated with steroid-producing cells. In humans, LH stimulates the cells of the theca interna to secrete androgens, which serve as estrogen precursors. Some androgens are transported to the smooth-surfaced endoplasmic reticulum (sER) in the granulosa cells. In response to FSH, the granulosa cells catalyze the conversion of androgens to estrogens, which in turn stimulate the granulosa cells to proliferate and thereby increase the size of the follicle. Increased estrogen levels from both follicular and systemic sources are correlated with increased sensitization of gonadotropes to gonadotropin-releasing hormone. A surge in the release of FSH or LH is induced in the adenohypophysis approximately 24 hours before ovulation. In response to the LH surge, LH receptors on granulosa cells are


Histology_Ross

Histology_Ross. hormone. A surge in the release of FSH or LH is induced in the adenohypophysis approximately 24 hours before ovulation. In response to the LH surge, LH receptors on granulosa cells are downregulated (desensitized), and granulosa cells no longer produce estrogens in response to LH. Triggered by this surge, the first meiotic division of the primary oocyte resumes. This event occurs between 12 and 24 hours after the LH surge, resulting in the formation of the secondary oocyte and the first polar body. The granulosa and thecal cells then undergo luteinization and produce progesterone (see page 839, section on the corpus luteum).


Histology_Ross

Histology_Ross. Ovulation is a hormone-mediated process resulting in the release of the secondary oocyte. Ovulation is the process by which a secondary oocyte is released from the Graafian follicle. The follicle destined to ovulate in any menstrual cycle is recruited from a cohort of several primary follicles in the first few days of the cycle. During ovulation, the oocyte traverses the entire follicular wall, including the germinal epithelium.


Histology_Ross

Histology_Ross. A combination of hormonal changes and enzymatic effects is responsible for the actual release of the secondary oocyte in the middle of the menstrual cycle (i.e., on the 14th day of a 28-day cycle). These factors include:  Increase in the volume and pressure of the follicular fluid  Enzymatic proteolysis of the follicular wall by activated plasminogen Hormonally directed deposition of glycosaminoglycans between the oocyte–cumulus complex and the stratum granulosum Contraction of the smooth muscle fibers in the theca externa layer, triggered by prostaglandins


Histology_Ross

Histology_Ross. Just before ovulation, blood flow stops in a small area of the ovarian surface overlying the bulging follicle. This area of the germinal epithelium, known as the macula pellucida or follicular stigma, becomes elevated and then ruptures (Fig. 23.8a). The oocyte, surrounded by the corona radiata and cells of the cumulus oophorus, is released from the ruptured follicle. At the time of ovulation, the fimbriae of the uterine tube become closely apposed to the surface of the ovary, and the cumulus mass containing oocyte is then gently swept by the fimbriae into the abdominal ostium of the uterine tube. The cumulus mass firmly adheres to the fimbriae and is actively transported by the ciliated cells lining the uterine tube, preventing its passage into the peritoneal cavity. Recently, nonsurgical ultrasound technology is being used to monitor ovarian follicle development. Transvaginal ultrasound examination can provide detailed information about


Histology_Ross

Histology_Ross. FIGURE 23.8 • Endoscopic and ultrasound examination of the ovary. a. This photograph shows a view of the human ovary during the endoscopic oocyte harvest surgery. The ovary is in stage just before ovulation. Note the area of bulging follicle with follicular stigma that is clearly visible. The germinal epithelium covering the tunica albuginea is ruptured in the area of imminent ovulation. b. Development of nonsurgical techniques such as ultrasound imaging helps in monitoring of follicular growth and is useful as a method for determining the time for harvesting preovulatory oocytes. (Courtesy Dr. Charles C. Coddington, III. Mayo Clinic.) the number and size of developing follicles (Fig 23.8b). After ovulation, the secondary oocyte remains viable for approximately 24 hours. If fertilization does not occur during this period, the secondary oocyte degenerates as it passes through the uterine tube.


Histology_Ross

Histology_Ross. Oocytes that fail to enter the uterine tube usually degenerate in the peritoneal cavity. Occasionally, however, one may be fertilized and implant in the peritoneal cavity on the surface of the ovary or intestine or inside the rectouterine (Douglas) pouch. Such ectopic implantations usually do not develop beyond early fetal stages but may have to be removed surgically. Ectopic pregnancy that develops at any site other than the endometrium of the uterine cavity continues to be the most common cause of death in the first half of pregnancy.


Histology_Ross

Histology_Ross. Normally, only one follicle completes maturation in each cycle and ruptures to release its secondary oocyte. Rarely, oocytes are released from other follicles that have reached full maturity during the same cycle, leading to the possibility of multiple zygotes. Drugs such as clomiphene citrate (Serophene) or human menopausal gonadotropins that stimulate ovarian activity greatly increase the possibility of multiple births by causing simultaneous maturation of several follicles. The primary oocyte is arrested for 12 to 50 years in the diplotene stage of prophase of the first meiotic division.


Histology_Ross

Histology_Ross. The primary oocyte is arrested for 12 to 50 years in the diplotene stage of prophase of the first meiotic division. The primary oocytes within the primordial follicles begin the first meiotic division in the embryo, but the process is arrested at the diplotene stage of meiotic prophase (see the section on meiosis in Chapter 3). The first meiotic prophase is not completed until just before ovulation. Therefore, primary oocytes remain arrested in the first meiotic prophase for 12 to 50 years. This long period of meiotic arrest exposes the primary oocyte to adverse environmental inﬂuences and may contribute to errors in meiotic division such as nondisjunction. Such errors result in anomalies such as trisomy of chromosome 21 (Down syndrome).


Histology_Ross

Histology_Ross. As the first meiotic division (reduction division) is completed in the mature follicle (Fig. 23.9), each daughter cell of the primary oocyte receives an equal share of chromatin, but one daughter cell receives most of the cytoplasm and becomes the secondary oocyte. It measures 150 m in diameter. The other daughter cell receives a minimal amount of cytoplasm and becomes the frst polar body. The secondary oocyte is arrested at metaphase in the second meiotic division just before ovulation.


Histology_Ross

Histology_Ross. As soon as the first meiotic division is completed, the secondary oocyte begins the second meiotic division. As the secondary oocyte surrounded by the cells of the corona radiata leaves the follicle at ovulation, the second meiotic division (equatorial division) is in progress. This division is arrested at metaphase and completed only if the secondary oocyte is penetrated by a spermatozoon. If fertilization occurs, the secondary oocyte completes the second meiotic division and forms a mature ovum with the maternal pronucleus containing a set of 23 chromosomes. The other cell produced at this division is a second polar body. In humans, the first polar body persists for more than 20 hours after ovulation and does not divide; therefore, the fertilized egg can be recognized by the presence of two polar bodies (diploid first polar body and haploid second polar body). In some mammals, the first polar body can divide, so the final outcome of meiosis consists of one oocyte and three haploid


Histology_Ross

Histology_Ross. two polar bodies (diploid first polar body and haploid second polar body). In some mammals, the first polar body can divide, so the final outcome of meiosis consists of one oocyte and three haploid polar bodies (see Fig. 23.9). The polar bodies, which are not capable of further development, undergo apoptosis.


Histology_Ross

Histology_Ross. Polycystic ovarian disease is characterized by bilaterally enlarged ovaries with numerous follicular cysts. When asso-ciated with oligomenorrhea, scanty menstruation, the clinical term Stein-Leventhal syndrome is used. The individual is infertile because of lack of ovulation. Morphologically, the ovaries resemble a small, white balloon filled with tightly packed marbles. Affected ovaries, often called oyster ovaries, have a smooth, pearl-white surface but do not show surface scarring because no ovulations have occurred. The condition is attributable to the large number of fluid-filled fol-licular cysts and atrophic secondary follicles that lie beneath an unusually thick tunica albuginea. The pathogenesis is not clear but seems to be related to a defect in the regulation of androgen biosynthesis that causes production of excessive amounts of androgens that are converted to estrogens. The selection process of the follicles that undergo maturation also seems to be disturbed. The


Histology_Ross

Histology_Ross. biosynthesis that causes production of excessive amounts of androgens that are converted to estrogens. The selection process of the follicles that undergo maturation also seems to be disturbed. The individual has an anovula-tory cycle characterized by only estrogenic stimulation of the endometrium because of the inhibition of progesterone pro-duction. Progesterone inhibition is caused by failure of the Graafian follicle to transform into a progesterone-producing corpus luteum. The treatment of choice is hormonal to stabi-lize and reconstruct the estrogen-to-progesterone ratio, but in some cases, surgical intervention is necessary. A wedge-shaped incision is made into the ovary to expose the cortex, thus allowing the ova, after hormonal treatment, to leave the ovary without physical restrictions created by the preexisting thickened tunica albuginea (Fig. F23.1.1).


Histology_Ross

Histology_Ross.  FOLDER 23.1 Clinical Correlation: Polycystic Ovarian Disease TATATATATA FIGURE F23.1.1 • Polycystic ovarian disease. This photo-micrograph shows a section through the cortex of the ovary from an individual with polycystic ovarian disease. Note the unusually thick tunica albuginea (TA) that overlies numerous follicles. The thickness of the tunica albuginea prevents ovulation of the mature (Graafian) follicles. Note that one of the follicles has developed to the primary follicle stage. 45. The collapsed follicle undergoes reorganization into the corpus luteum after ovulation.


Histology_Ross

Histology_Ross. At ovulation, the follicular wall, composed of the remaining granulosa and thecal cells, is thrown into deep folds as the follicle collapses and is transformed into the corpus luteum (yellow body), or luteal gland (Fig. 23.10a and Plate 94, page 876). At first, bleeding from the capillaries in the theca interna into the follicular lumen leads to formation of the corpus hemorrhagicum with a central clot. Connective tissue from the stroma then invades the former follicular cavity. Cells of the granulosa and theca interna layers then differentiate into granulosa luteal and theca luteal cells in the process called luteinization. These luteal cells undergo dramatic morphologic changes, increasing in size and filling with lipid droplets (Fig. 23.10b). A lipid-soluble pigment, lipochrome, in the cytoplasm of the cells gives them a yellow appearance in fresh preparations. At the ultrastructural level, the cells demonstrate features associated with steroid-secreting cells, namely, abundant sER


Histology_Ross

Histology_Ross. cytoplasm of the cells gives them a yellow appearance in fresh preparations. At the ultrastructural level, the cells demonstrate features associated with steroid-secreting cells, namely, abundant sER and mitochondria with tubular cristae (Fig. 23.11).


Histology_Ross

Histology_Ross. Two types of luteal cells are identified:  Granulosa lutein cells are large (about 30 m in diame ter), centrally located cells derived from the granulosa cells. Theca lutein cells are smaller (about 15 m), more deeply staining, and peripherally located cells derived from the cells of the theca interna layer (Plate 94, page 876) As the corpus luteum begins to form, blood and lymphatic vessels from the theca interna rapidly grow into the granulosa layer. A rich vascular network is established within the corpus luteum. This highly vascularized structure located in the cortex of the ovary secretes progesterone and estrogens. These hormones stimulate the growth and secretory activity of the lining of the uterus, the endometrium, to prepare it for the implantation of the developing zygote in the event that fertilization occurs. The corpus luteum of menstruation is formed in the absence of fertilization.


Histology_Ross

Histology_Ross. The corpus luteum of menstruation is formed in the absence of fertilization. If fertilization and implantation do not occur, the corpus luteum remains active only for 14 days; in this case it is called the corpus luteum of menstruation. In the absence of formation of centrosome of spermatozoon unpacked nucleus of spermatozoon formation of second polar body human chorionic gonadotropin (hCG) and other luteotropins, the rate of secretion of progestogens and estrogens declines, and the corpus luteum begins to degenerate about 10 to 12 days after ovulation.


Histology_Ross

Histology_Ross. The corpus luteum degenerates and undergoes a slow involution after pregnancy or menstruation. The cells become loaded with lipid, decrease in size, and undergo autolysis. A white scar, the corpus albicans, is formed as intercellular hyaline material accumulates among the degenerating cells of the former corpus luteum (Fig. 23.12). The corpus albicans sinks deeper into the ovarian cortex as it slowly disappears over a period of several months. During capacitation, the mature spermatozoa acquire the ability to fertilize the oocyte.


Histology_Ross

Histology_Ross. During capacitation, the mature spermatozoa acquire the ability to fertilize the oocyte. Following their maturation in the epididymis, spermatozoa must be activated within the female reproductive tract. During this activation process, called capacitation, structural and functional changes take place in the spermatozoon that result in its increased affinity to bind to zona pellucida receptors. Successful capacitation is confirmed by hyperactivation of the spermatozoa, which manifests as a vigorous, whiplash-like beating pattern of their flagella.


Histology_Ross

Histology_Ross. Capacitation involves several biochemical changes and modifications to the spermatozoon and its plasma membrane. They include:  Increased activity of adenylyl cyclase leading to increasing levels of cAMP  Increased rate of tyrosine phosphorylation (measurement of tyrosine phosphorylation is used clinically as a biochemical marker of capacitation)  Activation of Ca2 channels resulting in increased intracellular Ca2 levels  Release of seminal fluid glycoconjugates from the surface of the head of the spermatozoon. These surface glycosides (also called decapacitation factors) added during sperm maturation in the epididymis inhibit binding to the zona pellucida receptors  Extensive modification of the plasma membrane by removal of cholesterol, the predominant inhibitor of capacitation, and redistribution of phospholipids and carbohydrate moieties


Histology_Ross

Histology_Ross. FIGURE 23.9 • Diagram illustrating changes that occur during growth, maturation, and fertilization of the oocyte. The primary oocyte remains arrested in prophase I of meiosis. The first meiotic or reductional division is completed only after the oocyte progresses to ovulation. The second meiotic or equatorial division is not completed unless the secondary oocyte is impregnated by a spermatozoon. Note the formation of first and second polar bodies. In some mammals, the first polar body divides (as shown on this drawing) so that there are four total meiotic products. However, in humans, the first polar body does not divide but persists for about 20 hours; therefore, the fertilized egg can be recognized by the presence of two polar bodies. migration of nucleus to cell surface hyperactivation of spermatozoa impregnation of oocyte and resumption of second meiotic division alignment of male and female pronuclei


Histology_Ross

Histology_Ross. migration of nucleus to cell surface hyperactivation of spermatozoa impregnation of oocyte and resumption of second meiotic division alignment of male and female pronuclei FIGURE 23.10 • Photomicrograph of human corpus luteum. a. The corpus luteum is formed from the collapsed follicle wall that contains the granulosa and theca cells. The granulosa lutein cells form a thick, folded layer around the former follicular cavity (Cav). Within the folds are cells of the theca interna (arrows). 12. b. This photomicrograph shows the wall of the corpus luteum at higher magnification. The main cell mass is composed of granulosa lutein cells (GLC). These cells have a large spherical nucleus and a large amount of cytoplasm. The theca lutein cells (TLC) also have a spherical nucleus, but the cells are considerably smaller than the granulosa lutein cells. 240. Fertilization normally occurs in the ampulla of the uterine tube.


Histology_Ross

Histology_Ross. Fertilization normally occurs in the ampulla of the uterine tube. Usually, only a few hundred of the millions of spermatozoa in an ejaculate reach the site of fertilization, typically the ampulla of the uterine tube. On arrival, spermatozoa are confronted with the secondary oocyte surrounded by the corona radiata. Spermatozoa must penetrate the corona radiata to gain access to the zona pellucida. Although several spermatozoa may penetrate the zona pellucida, only one spermatozoon completes the fertilization process. Capacitation is complete when spermatozoa are able to bind to the zona pellucida receptors. Binding to the ZP-3 receptors on the zona pellucida triggers the acrosome reaction in which enzymes (mainly hyaluronidases) released from the acrosome enable a single spermatozoon to penetrate the zona pellucida. Penetration is accomplished by limited proteolysis of the zona pellucida in front of the advancing hypermotile spermatozoon.


Histology_Ross

Histology_Ross. After penetrating the zona pellucida, the spermatozoon enters the perivitelline space between the zona pellucida and the oocyte plasma membrane (or oolemma). Here the spermatozoon plasma membrane fuses with the oolemma, and the nucleus of the sperm head is finally incorporated into the oocyte. It forms the male pronucleus containing 23 paternal chromosomes. After the alignment and dissolution of nuclear membranes of the two pronuclei, the resulting zygote, with its diploid (2n) complement of 46 chromosomes, undergoes a mitotic division or first cleavage. This two-cell stage marks the beginning of embryonic development. Before spermatozoa can fertilize the secondary oocyte, they must acquire more thrust to penetrate the corona radiata and zona pellucida.


Histology_Ross

Histology_Ross. Before spermatozoa can fertilize the secondary oocyte, they must acquire more thrust to penetrate the corona radiata and zona pellucida. When approaching a secondary oocyte, a spermatozoon becomes hyperactivated: It swims faster, and its tail movements become more forceful and erratic. Recent studies indicate that this hyperactivation reaction is caused by a sudden influx of Ca2 into the tails of spermatozoa. The plasma membrane of the sperm tail contains large numbers of transmembrane Ca2 FIGURE 23.12 • Photomicrograph of the corpus albicans of a human ovary. Large amounts of hyaline material can be seen among the degenerating cells of the former corpus luteum. The corpus albicans is surrounded by ovarian stroma. 125.


Histology_Ross

Histology_Ross. FIGURE 23.11 • Electron micrograph of theca lutein cells from the corpus luteum of a monkey. At this early implantation stage (day 10.5 of gestation), membrane-bounded dense bodies are clustered near the Golgi apparatus (G); most of the cytoplasm is packed with tubules of smooth endoplasmic reticulum (sER), lipid droplets (L), and mitochondria (M). Note the capillary (Cap) and the closely apposed cell membranes of the theca lutein cells (arrows). 10,000. (Courtesy of Dr. Carolynn B. Booher.) channel proteins called CatSpers (cation channels of sperm). CatSper proteins are expressed exclusively in membranes of the tail. Influx of Ca2 causes the tail to be more active and bend more forcefully, resulting in faster sperm movement through the viscous environment of the uterine tube. Together with limited proteolysis of the zona pellucida, hyperactivation is responsible for the physical penetration of the oocyte.


Histology_Ross

Histology_Ross. Sperm hyperactivity is necessary for breaking physical barriers that protect the secondary oocyte from fertilization. Thus, activation of CatSpers is required for male fertility. Impregnation of the oocyte allows structures lying inside the spermatozoon to enter the cytoplasm of the oocyte. After penetrating the zona pellucida, the spermatozoon enters the perivitelline space between the zona pellucida and the oolemma (oocyte’s plasma membrane). Here, after docking to the oolemma, the spermatozoon plasma membrane fuses with the oolemma. This process, called the impregnation of the oocyte, allows the nucleus of the sperm (containing highly concentrated DNA), the centrosome, the midpiece with the mitochondria, and the kinocilium to be incorporated into the cytoplasm of the oocyte. The tail plasma membrane remains as an appendage to the oolemma.


Histology_Ross

Histology_Ross. An impregnating spermatozoon generates a molecular signal for resumption and termination of the second meiotic division. This division transforms the secondary oocyte into a mature oocyte and triggers the expulsion of the second polar body into the perivitelline space.


Histology_Ross

Histology_Ross. The male genetic material lying within the nucleus of incorporated sperm head is unpacked and used for building the male pronucleus, which contains 23 paternal chromosomes. Nuclear membranes of both female and male pronuclei dissolve (without fusion), and the chromosomes align themselves within the common mitotic spindle. The resulting zygote contains a diploid (2n) complement of 46 chromosomes and later undergoes the first mitotic division or cleavage. The male centrosome is essential for the alignment of the mitotic spindle that divides chromosomes into the first two cells of the embryo. Only centrosomes from the father are used in building first and subsequent mitotic spindles. The incorporated kinocilium is finally dissolved, and all sperm mitochondria are eliminated from the cytoplasm of the oocyte. Note that all mitochondria in human cells normally derive from the mother, but all centrosomes originate from the father’s sperm cell.


Histology_Ross

Histology_Ross. Several spermatozoa may penetrate the zona pellucida, but only one spermatozoon completes the fertilization process. As the fertilizing spermatozoon penetrates the ooplasm, at least three types of postfusion reactions occur to prevent other spermatozoa from entering the secondary oocyte (polyspermy). These events include the following.  Fast block to polyspermy. A large and long-lasting (up to 1 minute) depolarization of the oolemma creates a transient electrical block to polyspermy.  Cortical reaction. Changes in the polarity of the oolemma then trigger release of Ca2 from the ooplasmic stores. The Ca2 propagates a cortical reaction wave in which cortical granules move to the surface and fuse with the oolemma, leading to a transient increase in surface area of the ovum and reorganization of the membrane. The contents of the cortical granules are released into the perivitelline space.


Histology_Ross

Histology_Ross.  Zona reaction. The released enzymes (proteases) of the cortical granules not only degrade the glycoprotein oocyte plasma membrane receptors for sperm binding but also form the perivitelline barrier by cross-linking proteins on the surface of the zona pellucida. This event creates the final and permanent block to polyspermy. The corpus luteum of pregnancy is formed after fertilization and implantation. If fertilization and implantation occur, the corpus luteum increases in size to form the corpus luteum of pregnancy. The existence and function of the corpus luteum depends on a combination of paracrine and endocrine secretions, collectively described as luteotropins. Paracrine luteotropins are locally produced by the ovary. They include:


Histology_Ross

Histology_Ross. Paracrine luteotropins are locally produced by the ovary. They include: Endocrine luteotropins are produced at a distance from their target organ, the corpus luteum. They include:  hCG, a 37-kilodalton glycoprotein secreted by the trophoblast of the chorion, which stimulates LH receptors on the corpus luteum and prevents its degeneration (page 840)  LH and prolactin, both secreted by the pituitary gland  Insulin, produced by the pancreas


Histology_Ross

Histology_Ross. High levels of progesterone, produced from cholesterol by the corpus luteum, block the cyclic development of ovarian follicles. In early pregnancy, the corpus luteum measures 2 cm to 3 cm, thus filling most of the ovary. Its function begins to decline gradually after 8 weeks of pregnancy, although it persists throughout pregnancy. Although the corpus luteum remains active, the placenta produces sufficient amounts of estrogens and progestogens from maternal and fetal precursors to take over the function of the corpus luteum after 6 weeks of pregnancy. Human chorionic gonadotropin (hCG) can be detected in the serum as early as 6 days after conception and in the urine as early as 10 to 14 days of pregnancy. Detection of hCG in the urine by specific antibodies forms the basis of most over-the-counter pregnancy tests. In addition, the rapid increase in circulating level of hGC in early pregnancy is responsible for “morning sickness,” a condition characterized by nausea and vomiting. These


Histology_Ross

Histology_Ross. pregnancy tests. In addition, the rapid increase in circulating level of hGC in early pregnancy is responsible for “morning sickness,” a condition characterized by nausea and vomiting. These symptoms usually occur in the early hours of the morning are often among the first signs of pregnancy.


Histology_Ross

Histology_Ross. Most ovarian follicles are lost by atresia mediated by apoptosis of granulosa cells. As stated, very few of the ovarian follicles that begin their differentiation in the embryonic ovary are destined to complete their maturation. Most of the follicles degenerate and disappear through a process called ovarian follicular atresia. Atresia is mediated by apoptosis of granulosa cells. Large numbers of follicles undergo atresia during fetal development, early postnatal life, and puberty. After puberty, groups of follicles begin to mature during each menstrual cycle; normally, only one follicle completes its maturation. Atresia is now thought to be a mechanism whereby a few follicles are stimulated to maintain their development through the programmed death of the other follicles. Thus, at any stage of its maturation a follicle may undergo atresia. The process becomes more complex as the follicle progresses toward maturation.


Histology_Ross

Histology_Ross. In atresia of primordial and small, growing follicles, the immature oocyte becomes smaller and degenerates; similar changes occur in the granulosa cells. Atretic follicles shrink and eventually disappear from the stroma of the ovary as a result of repeated apoptosis and phagocytosis by granulosa cells (Plate 93, page 874). As the cells are reabsorbed and disappear, the surrounding stromal cells migrate into the space previously occupied by the follicle, leaving no trace of its existence.


Histology_Ross

Histology_Ross. In atresia of large, growing follicles, the degeneration of the mature oocyte is delayed and appears to occur secondary to degenerative changes in the follicular wall (Plate 93, page 874). This delay indicates that once the oocyte has achieved its maturity and competence, it is no longer sensitive to the same stimuli that initiate the atresia in granulosa cells. The follicular changes include the following sequential events:  Initiation of apoptosis within the granulosa cells, indicated by cessation of mitosis and expression of endonucleases and other hydrolytic enzymes within the granulosa cells  Invasion of the granulosa layer by neutrophils and macrophages  Invasion of the granulosa layer by strands of vascularized connective tissue  Sloughing of the granulosa cells into the antrum of the follicle  Hypertrophy of the theca interna cells  Collapse of the follicle as degeneration continues Invasion of connective tissue into the cavity of the follicle


Histology_Ross

Histology_Ross. Recent studies indicate that several gene products regulate the process of follicular atresia. One of these products is the


Histology_Ross

Histology_Ross. There are several indications for in vitro fertilization (IVF), but the primary one is infertility as a result of surgically un-correctable damage to, or absence of, the uterine tubes. To induce multiple follicle development and maturation, women selected for an IVF procedure undergo controlled hyper-stimulation of the ovaries. Hyperstimulation is achieved by different hormonal therapies using human menopausal go-nadotropins and clomiphene citrate (Serophene), with or without FSH. Mature preovulatory oocytes are collected from the Graafian follicles by either laparoscopic or ultrasound-guided percutaneous aspiration or transvaginal aspiration. Before insemination, the oocytes are preincubated in a specialized medium with serum complements for a time determined by their stage of maturity. The collected semen is placed in a special medium. The oocytes are then added to the medium containing the col-lected semen for fertilization. Twelve to 16 hours later, the oocytes are examined with


Histology_Ross

Histology_Ross. The collected semen is placed in a special medium. The oocytes are then added to the medium containing the col-lected semen for fertilization. Twelve to 16 hours later, the oocytes are examined with the differential interference con-trast microscope to determine the presence of female and male pronuclei, the indication of successful fertilization (Fig. F23.2.1a). At this stage, the fertilized oocyte may be frozen for future IVF transfers. Generally, 80% of mature oocytes cultured in vitro are fertilized. At this point, the embryo is transferred to a special growth medium for 24 to 48 hours, where it is allowed to grow to the stage of four to six cells (Fig. F23.2.1b). Several embryos are then trans-ferred into the uterus via the vagina and cervical canal on the third or fourth day after the initial aspiration of the oocyte. Before embryo transfer, the uterus has been pre-pared to receive the embryo by administration of appropri-ate hormones. Embryos are therefore placed into a


Histology_Ross

Histology_Ross. after the initial aspiration of the oocyte. Before embryo transfer, the uterus has been pre-pared to receive the embryo by administration of appropri-ate hormones. Embryos are therefore placed into a hormonally prepared uterus under conditions equivalent to those in normal implantation (see page 852). Intensive pro-gesterone treatment is usually begun just after the transfer to mimic the function of the corpus luteum of pregnancy. In recent years, existing treatment protocols have been optimized to such an extent that success rates of pregnancy and delivery with IVF programs have reached greater than 30% per embryo transfer. Further improvements in preg-nancy rates may be achieved by the introduction of new drugs, such as recombinant FSH or gonadotropin-releasing hormone (GnRH) antagonists that provide individualized hormonal treatment. Additionally, the occurrence of multiple pregnancies, which is the main complication of IVF, may be limited by reducing the number of transferred


Histology_Ross

Histology_Ross. that provide individualized hormonal treatment. Additionally, the occurrence of multiple pregnancies, which is the main complication of IVF, may be limited by reducing the number of transferred embryos.


Histology_Ross

Histology_Ross.  FOLDER 23.2 Clinical Correlation: In Vitro Fertilization aaba b FIGURE F23.2.1 • Early developmental stages of the human embryo. a. This image, obtained with an interference contrast microscope equipped with Nomarski optics, shows a human fertilized oocyte with two pronuclei. The zygote develops after alignment and dissolution of nuclear membranes of both female and male pronuclei. The resulting cell will contain a diploid complement of 46 chromosomes. 400. b. This image shows a 48-hour-old human embryo growing in a special growth medium. At this stage, the embryo consists of four cells. In IVF procedures, it is at this stage that the embryo is usually transferred into the uterine cavity. 400. (Courtesy of Dr. Peter Fehr.) gonadotropin-induced neural apoptosis inhibitory protein (NAIP), which inhibits and delays apoptotic changes in the granulosa cell. NAIP gene expression is present in all stages of the growing follicle but absent in follicles undergoing atresia. A high level of


Histology_Ross

Histology_Ross. which inhibits and delays apoptotic changes in the granulosa cell. NAIP gene expression is present in all stages of the growing follicle but absent in follicles undergoing atresia. A high level of gonadotropins inhibits apoptosis in ovarian follicles by increasing the expression of NAIP in the ovaries.


Histology_Ross

Histology_Ross. The oocyte undergoes typical changes associated with degeneration and autolysis, and the remnants are phagocytosed by invading macrophages. The zona pellucida, which is resistant to the autolytic changes occurring in the cells associated with it, becomes folded and collapses as it is slowly broken down within the cavity of the follicle. Macrophages in the connective tissue are involved in the phagocytosis of the zona pellucida and the remnants of the degenerating cells. The basement membrane between the follicle cells from the theca interna may separate from the follicle cells and increase in thickness, forming a wavy hyaline layer called the glassy membrane. This structure is characteristic of follicles in late stages of atresia.


Histology_Ross

Histology_Ross. Enlargement of the cells of the theca interna occurs in some atretic follicles. These cells are similar to theca lutein cells and become organized into radially arranged strands separated by connective tissue. A rich capillary network develops in the connective tissue. These atretic follicles, which resemble an old corpus luteum, are called corpora lutea atretica. The interstitial gland arises from the theca interna of the atretic follicle.


Histology_Ross

Histology_Ross. The interstitial gland arises from the theca interna of the atretic follicle. As atretic follicles continue to degenerate, a scar with hyaline streaks develops in the center of the cell mass, giving it the appearance of a small corpus albicans. This structure eventually disappears as the ovarian stroma invades the degenerating follicle. In the ovaries of a number of mammals, the strands of luteal cells do not degenerate immediately but become broken up and scattered in the stroma. These cords of cells contribute to the interstitial gland of the ovary and produce steroid hormones. The development of the interstitial gland is most extensive in animal species that have large litters.


Histology_Ross

Histology_Ross. In the human ovary, there are relatively few interstitial cells. They occur in the largest numbers in the first year of life and during the early phases of puberty, corresponding to times of increased follicular atresia. At menarche, involution of the interstitial cells occurs; therefore, few are present during the reproductive life span and menopause. It has been suggested that in humans the interstitial cells are an important source of the estrogens that influence growth and development of the secondary sex organs during the early phases of puberty. In other species, the interstitial cells have been shown to produce progesterone.


Histology_Ross

Histology_Ross. In humans, cells called ovarian hilar cells are found in the hilum of the ovary in association with vascular spaces and nonmyelinated nerve fibers. These cells, which appear to be structurally related to the interstitial cells of the testis, contain Reinke crystalloids. The hilar cells appear to respond to hormonal changes during pregnancy and at the onset of menopause. Research suggests that the hilar cells secrete androgens; hyperplasia or tumors associated with these cells usually lead to masculinization. Blood supply to the ovaries comes from two different sources: Ovarian and uterine arteries.


Histology_Ross

Histology_Ross. Blood supply to the ovaries comes from two different sources: Ovarian and uterine arteries. The ovarian arteries are the branches of the abdominal aorta that pass to the ovaries through the suspensory ligaments and provide the principal arterial supply to the ovaries and uterine tubes. These arteries anastomose with the second blood source to the ovary, the ovarian branches of the uterine arteries, which arise from the internal iliac arteries. Relatively large vessels arising from this region of anastomosis pass through the mesovarium and enter the hilum of the ovary. These large arteries are called spiral arteries because they branch and become highly coiled as they pass into the ovarian medulla (see Fig. 23.2). Veins accompany the arteries and form a plexus called the pampiniform plexus as they emerge from the hilum. The ovarian vein is formed from the plexus.


Histology_Ross

Histology_Ross. Veins accompany the arteries and form a plexus called the pampiniform plexus as they emerge from the hilum. The ovarian vein is formed from the plexus. In the cortical region of the ovary, networks of lymphatic vessels in the thecal layers surround the large developing and atretic follicles and corpora lutea. The lymphatic vessels follow the course of the ovarian arteries as they ascend to paraaortic lymph nodes in the lumbar region. Ovaries are innervated by the autonomic ovarian plexus.


Histology_Ross

Histology_Ross. Ovaries are innervated by the autonomic ovarian plexus. Autonomic nerve fibers that supply the ovary are conveyed mainly by the ovarian plexus. Although it is clear that the ovary receives both sympathetic and parasympathetic fibers, little is known about their actual distribution. Groups of parasympathetic ganglion cells are scattered in the medulla. Nerve fibers follow the arteries, supplying the smooth muscle in the walls of these vessels, as they pass into the medulla and cortex of the ovary. Nerve fibers associated with the follicles do not penetrate the basal lamina. Sensory nerve endings are scattered in the stroma. The sensory fibers convey impulses via the ovarian plexus and reach the dorsal root ganglia of the first lumbar spinal nerves. Therefore, ovarian pain is referred over the cutaneous distribution of these spinal nerves.


Histology_Ross

Histology_Ross. At ovulation, about 45% of women experience midcycle pain (“mittelschmerz”). It is usually described as a sharp, lower abdominal pain that lasts from a few minutes to as long as 24 hours and is frequently accompanied by a small amount of bleeding from the uterus. It is believed that this pain is related to smooth muscle cell contraction in the ovary as well as in its ligaments. These contractions are in response to an increased level of prostaglandin F2 mediated by the surge of LH.


Histology_Ross

Histology_Ross. The uterine tubes are paired tubes that extend bilaterally from the uterus toward the ovaries (see Fig. 23.1). Also commonly referred to as the Fallopian tubes, the uterine tubes transport the ovum from the ovary to the uterus and provide the necessary environment for fertilization and initial development of the zygote to the morula stage. One end of 846 changes that involve two phases:  Follicular phase  Luteal phase Ovulation occurs between the two phases (Fig. F23.3.1). The follicular phase begins with the development of a small number of primary follicles (10 to 20) under the influ-ence of FSH and LH. Selection of dominant follicles occurs by days 5 to 7 of the menstrual cycle. During the first 8 to 10 days of the cycle, FSH is the principal hormone influenc-ing the growth of the follicles. It stimulates the granulosa and thecal cells, which begin to secrete steroid hormones, principally estrogens, into the follicular lumen. As estrogen production from the dominant follicle


Histology_Ross

Histology_Ross. follicles. It stimulates the granulosa and thecal cells, which begin to secrete steroid hormones, principally estrogens, into the follicular lumen. As estrogen production from the dominant follicle increases, FSH is in-hibited by a negative feedback loop from the pituitary gland. Estrogens continue to accumulate in the follicular lumen, fi-nally reaching a level that makes the follicle independent of FSH for its continued growth and development. Late in the follicular phase, before ovulation, progesterone levels begin to rise under the influence of LH. The amount of estrogens in the circulating blood inhibits further production of FSH by the adenohypophysis. Ovulation is induced by a surge in the in the FSH level. It occurs approximately 34 to 36 hours after the start of the LH surge or about 10 to 12 hours after the peak of the LH surge. The luteal phase begins immediately after ovulation as the granulosa and thecal cells of the ruptured follicle undergo rapid morphologic


Histology_Ross

Histology_Ross. surge or about 10 to 12 hours after the peak of the LH surge. The luteal phase begins immediately after ovulation as the granulosa and thecal cells of the ruptured follicle undergo rapid morphologic transformation to form the cor-pus luteum. Estrogens and large amounts of progesterone are secreted by the corpus luteum. Under the influence of both hormones, but primarily progesterone, the en-dometrium begins its secretory phase, which is essential for the preparation of the uterus for implantation in the event that the egg is fertilized. LH appears to be responsi-ble for the development and maintenance of the corpus lu-teum during the menstrual cycle. If fertilization does not occur, the corpus luteum degenerates within a few days as the hormonal levels drop. If fertilization does occur, the corpus luteum is maintained and continues to secrete pro-gesterone and estrogens. hCG, which is initially produced by the embryo and later by the placenta, stimulates the corpus luteum and is


Histology_Ross

Histology_Ross. the corpus luteum is maintained and continues to secrete pro-gesterone and estrogens. hCG, which is initially produced by the embryo and later by the placenta, stimulates the corpus luteum and is responsible for its maintenance dur-ing pregnancy. menstrual phase proliferative phase secretory phase 0 5 10 14 20 25 28 0 5 10 15 20 0 10 20 30 40 50 menstrual cycle ovarian hormones (in blood) estrogen progesterone ovarian cycle pituitary hormones (in blood) LH FSH FIGURE F23.3.1 • Relationship of morphologic and physiologic events that occur in the men -strual cycle. This diagram illustrates the relation of the morphologic changes in the endo metrium and ovary to the pituitary and ovarian blood hormone levels that occur during the menstrual cycle. The pituitary and ovarian hormones and their plasma con centrations are indicated in arbitrary units. LH, luteinizing hormone; FSH, follicle-stimulating hormone.


Histology_Ross

Histology_Ross.  FOLDER 23.3 Functional Considerations: Summary of Hormonal Regulation of the Ovarian Cycle During each menstrual cycle, the ovary undergoes cyclic LH level, which occurs concomitantly with a smaller increase the tube is adjacent to the ovary and opens into the peritoneal cavity; the other end communicates with the uterine cavity. Each uterine tube is approximately 10 cm to 12 cm long and can be divided into four segments by gross inspection:  The infundibulum is the funnel-shaped segment of the tube adjacent to the ovary. At the distal end, it opens into the peritoneal cavity. The proximal end communicates with the ampulla. Fringed extensions, or fmbriae, extend from the mouth of the infundibulum toward the ovary.  The ampulla is the longest segment of the tube, constituting about two thirds of the total length, and is the site of fertilization.  The isthmus is the narrow, medial segment of the uterine tube adjacent to the uterus.


Histology_Ross

Histology_Ross.  The isthmus is the narrow, medial segment of the uterine tube adjacent to the uterus.  The uterine or intramural part, measuring about 1 cm in length, lies within the uterine wall and opens into the cavity of the uterus. The wall of the uterine tube is composed of three layers. The uterine tube wall resembles the wall of other hollow viscera, consisting of an external serosal layer, an intermediate muscular layer, and an internal mucosal layer. However, there is no submucosa.  The serosa or peritoneum is the outermost layer of the uterine tube and is composed of mesothelium and a thin layer of connective tissue.  The muscularis, throughout most of its length, is organized into an inner, relatively thick circular layer and an outer, thinner longitudinal layer. The boundary between these layers is often indistinct.


Histology_Ross

Histology_Ross.  The mucosa, the inner lining of the uterine tube, exhibits relatively thin longitudinal folds that project into the lumen of the uterine tube throughout its length. The folds are most numerous and complex in the ampulla (Fig. 23.13 and Plate 95, page 878) and become smaller in the isthmus. The mucosal lining is simple columnar epithelium composed of two kinds of cells—ciliated and nonciliated (Fig. 23.13b). They represent different functional states of a single cell type.  Ciliated cells are most numerous in the infundibulum and ampulla. The wave of the cilia is directed toward the uterus.


Histology_Ross

Histology_Ross.  Ciliated cells are most numerous in the infundibulum and ampulla. The wave of the cilia is directed toward the uterus. FIGURE 23.13 • Photomicrograph of a human uterine tube. a. This cross section is near the ampulla region of the uterine tube. The mucosa is thrown into extensive folds that project into the lumen of the tube. The muscularis is composed of a thick inner layer of circularly arranged fibers and an outer layer of longitudinal fibers. Note several branches of the uterine and ovarian arteries (BV ) that travel along the uterine tube. 16. b. The lumen of the tube is lined by a simple columnar epithelium composed of ciliated cells (above the point of the arrow) and nonciliated cells (below the point of the arrow). 640.  Nonciliated, peg cells are secretory cells that produce the fluid that provides nutritive material for the ovum.


Histology_Ross

Histology_Ross.  Nonciliated, peg cells are secretory cells that produce the fluid that provides nutritive material for the ovum. The epithelial cells undergo cyclic hypertrophy during the follicular phase and atrophy during the luteal phase in response to changes in hormonal levels, particularly estrogens. Also, the ratio of ciliated to nonciliated cells changes during the hormonal cycle. Estrogen stimulates ciliogenesis, and progesterone increases the number of secretory cells. At about the time of ovulation, the epithelium reaches a height of about 30 m and is then reduced to about one-half that height just before the onset of menstruation. Bidirectional transport occurs in the uterine tube.


Histology_Ross

Histology_Ross. The uterine tube demonstrates active movements just before ovulation as the fimbriae become closely apposed to the ovary and localize over the region of the ovarian surface where rupture will occur. As the oocyte is released, the ciliated cells in the infundibulum sweep it toward the opening of the uterine tube and thus prevent it from entering the peritoneal cavity. The oocyte is transported along the uterine tube by peristaltic contractions. The mechanisms by which spermatozoa and the oocyte are transported from opposite ends of the uterine tube are not fully understood. Research suggests that both ciliary movements and peristaltic muscular activity are involved in the movements of the oocyte. The movement of the spermatozoa is much too rapid, however, to be accounted for by intrinsic motility. Fertilization usually occurs in the ampulla, near its junction with the isthmus. The ovum remains in the uterine tube for about 3 days before it enters the uterine cavity.


Histology_Ross

Histology_Ross. Several conditions that may alter the integrity of the tubal transport system (e.g., inﬂammation, use of intrauterine devices, surgical manipulation, tubal ligation) may cause ectopic pregnancy. The majority of ectopic pregnancies, 98% occur in the uterine tube (tubal pregnancies); remaining sites for the implantation of the blastocyst in ectopic pregnancies are the peritoneal cavity, ovaries, and cervix.


Histology_Ross

Histology_Ross. The uterus receives the rapidly developing morula from the uterine tube. All subsequent embryonic and fetal development occurs within the uterus, which undergoes dramatic increases in size and development. The human uterus is a hollow, pear-shaped organ located in the pelvis between the bladder and rectum. In a nulliparous woman, it weighs 30 g to 40 g and measures 7.5 cm in length, 5 cm in width at its superior aspect, and 2.5 cm in thickness. Its lumen, which is also flattened, is continuous with the uterine tubes and the vagina. Anatomically, the uterus is divided into two regions:  The body is the large upper portion of the uterus. The an terior surface is almost flat; the posterior surface is convex.


Histology_Ross

Histology_Ross. The upper, rounded part of the body that expands above the attachment of the uterine tubes is termed the fundus.  The cervix is the lower, barrel-shaped part of the uterus separated from the body by the isthmus (see Fig. 23.1). The lumen of the cervix, the cervical canal, has a constricted opening at each end. The internal os communicates with the cavity of the uterus; the external os with the vagina. FIGURE 23.14 • Photomicrograph of a sagittal section of a human uterus. This section shows the three layers of the uterine wall: the endometrium, the innermost layer that lines the uterine cavity; the myometrium, the middle layer of smooth muscle; and the perimetrium, the very thin layer of peritoneum that covers the exterior surface of the uterus. The deep portion of the myometrium contains the larger blood vessels (BV ) that supply the uterus. 8. The uterine wall is composed of three layers (Fig. 23.14).


Histology_Ross

Histology_Ross. The uterine wall is composed of three layers (Fig. 23.14). From the lumen outward they are as follows.  The endometrium is the mucosa of the uterus.  The myometrium is the thick muscular layer. It is contin uous with the muscle layer of the uterine tube and vagina. The smooth muscle fibers also extend into the ligaments connected to the uterus.  The perimetrium, the outer serous layer or visceral peritoneal covering of the uterus, is continuous with the pelvic and abdominal peritoneum and consists of a mesothelium and a thin layer of loose connective tissue. Beneath the mesothelium, a layer of elastic tissue is usually prominent. The perimetrium covers the entire posterior surface of the uterus but only part of the anterior surface. The remaining part of the anterior surface consists of connective tissue or adventitia.


Histology_Ross

Histology_Ross. The perimetrium covers the entire posterior surface of the uterus but only part of the anterior surface. The remaining part of the anterior surface consists of connective tissue or adventitia. Both myometrium and endometrium undergo cyclic changes each month to prepare the uterus for implantation of an embryo. These changes constitute the menstrual cycle. If an embryo implants, the cycle stops, and both layers undergo considerable growth and differentiation during pregnancy (described in the next section). The myometrium forms a structural and functional syncytium. The myometrium is the thickest layer of the uterine wall. It is composed of three indistinctly defined layers of smooth muscle:  The middle muscle layer contains numerous large blood vessels (venous plexuses) and lymphatics and is called the stratum vasculare. It is the thickest layer and has interlaced smooth muscle bundles oriented in a circular or spiral pattern.


Histology_Ross

Histology_Ross.  The smooth muscle bundles in the inner and outer layers are predominantly oriented parallel to the long axis of activity of the endometrium during the cycle are correlated with the maturation of the ovarian follicles (see Folder 23.3). The end of each cycle is characterized by the partial destruction and sloughing of the endometrium, accompanied by bleeding from the mucosal vessels. The discharge of tissue and blood from the vagina, which usually continues for 3 to 5 days, is referred to as menstruation or menstrual fow. The menstrual cycle is defined as beginning on the day when menstrual flow begins. During reproductive life, the endometrium consists of two layers or zones that differ in structure and function (Fig. 23.15 and Plate 96, page 880): contraction, all three layers of the myometrium work together as a functional syncytium expelling the contents of the lumen through a narrow orifice.


Histology_Ross

Histology_Ross. In the nonpregnant uterus, the smooth muscle cells are about 50 m long. During pregnancy, the uterus undergoes enormous enlargement. The growth is primarily owing to the hypertrophy of existing smooth muscle cells, which may reach more than 500 m in length, and secondarily at tributable to the development of new fibers through the division of existing muscle cells and the differentiation of undifferentiated mesenchymal cells. The amount of connective tissue also increases. As pregnancy proceeds, the uterine wall becomes progressively thinner as it stretches because of the growth of the fetus. After parturition, the uterus returns straight artery to almost its original size. Some muscle fibers degenerate, but most return to their original size. The collagen pro duced during pregnancy to strengthen the myometrium is then enzymatically degraded by the cells that secreted it. The uterine cavity remains larger and the muscular wall remains thicker than before pregnancy.


Histology_Ross

Histology_Ross. Compared with the body of the uterus, the cervix has more connective tissue and less smooth muscle. Elastic fibers are abundant in the cervix but are found in appreciable quantities only in the outer layer of the myometrium of the body of the uterus. The endometrium proliferates and then degenerates during a menstrual cycle. Throughout the reproductive lifespan, the endometrium undergoes cyclic changes each month that prepare it for the implantation of the embryo and the subsequent events of embryonic and fetal development. Changes in the secretory


Histology_Ross

Histology_Ross. FIGURE 23.15 • Schematic diagram illustrating arterial blood supply to the endometrium of the uterus. The two layers of the endometrium, the stratum basale and stratum functionale, are supplied by branches of the uterine artery. The spiral arteries located at the interface between these two layers degenerate and regenerate during the menstrual cycle under the influence of estrogens and progesterone. (Based on Weiss L, ed. Cell and Tissue Biology: A Textbook of Histology, 6th ed. Baltimore: Urban & Schwarzenberg, 1988.)  The stratum functionale or functional layer is the thick part of the endometrium, which is sloughed off at men struation.  The stratum basale or basal layer is retained during menstruation and serves as the source for the regeneration of the stratum functionale. The stratum functionale is the layer that proliferates and degenerates during the menstrual cycle.


Histology_Ross

Histology_Ross. The stratum functionale is the layer that proliferates and degenerates during the menstrual cycle. During the phases of the menstrual cycle, the endometrium varies from 1 mm to 6 mm in thickness. It is lined by a simple columnar epithelium with a mixture of secretory and ciliated cells. The surface epithelium invaginates into the underlying lamina propria, the endometrial stroma, forming the uterine glands. These simple tubular glands, containing fewer ciliated cells, occasionally branch in the deeper aspect of the endometrium. The endometrial stroma, which resembles mesenchyme, is highly cellular and contains abundant inter-cellular ground substance. As in the uterine tube, no submucosa separates the endometrium from the myometrium. The vasculature of the endometrium also proliferates and degenerates during each menstrual cycle.


Histology_Ross

Histology_Ross. The endometrium contains a unique system of blood vessels (see Fig. 23.15). The uterine artery gives off 6 to 10 arcuate arteries that anastomose in the myometrium. Branches from these arteries, the radial arteries, enter the basal layer of the endometrium where they give off small straight arteries that supply this region of the endometrium. The main branch of the radial artery continues upward and becomes highly coiled; it is therefore called the spiral artery. Spiral arteries give off numerous arterioles that often anastomose as they supply a rich capillary bed. The capillary bed includes thin-walled dilated segments called lacunae. Lacunae may also occur in the venous system that drains the endometrium. The straight arteries and the proximal part of the spiral arteries do not change during the menstrual cycle. The distal portion of the spiral arteries, under the influence of estrogens and progesterone, undergoes degeneration and regeneration with each menstrual cycle.


Histology_Ross

Histology_Ross. Cyclic Changes During the Menstrual Cycle Cyclic changes of the endometrium during the menstrual cycle are represented by the proliferative, secretory, and menstrual phases. The menstrual cycle is a continuum of developmental stages in the functional layer of the endometrium. It is ultimately controlled by gonadotropins secreted by the pars distalis of the pituitary gland that regulate the steroid secretions of the ovary. The cycle normally repeats every 28 days, during which the endometrium passes through a sequence of morphologic and functional changes. It is convenient to describe the cycle as having three successive phases:  The proliferative phase occurs concurrently with follicular maturation and is influenced by ovarian estrogen secretion.  The secretory phase coincides with the functional activ ity of the corpus luteum and is primarily influenced by progesterone secretion.


Histology_Ross

Histology_Ross.  The menstrual phase commences as hormone produc tion by the ovary declines with the degeneration of the cor pus luteum (see Folder 23.3). The phases are part of a continuous process; there is no abrupt change from one to the next. The proliferative phase of the menstrual cycle is regulated by estrogens.


Histology_Ross

Histology_Ross. The proliferative phase of the menstrual cycle is regulated by estrogens. At the end of the menstrual phase, the endometrium consists of a thin band of connective tissue, about 1 mm thick, containing the basal portions of the uterine glands and the lower portions of the spiral arteries (see Fig. 23.15). This layer is the stratum basale; the layer that was sloughed off was the stratum functionale. Under the infuence of estrogens, the proliferative phase is initiated. Stromal, endothelial, and epithelial cells in the stratum basale proliferate rapidly, and the following changes can be seen:  Epithelial cells in the basal portion of the glands reconstitute the glands and migrate to cover the denuded endometrial surface.  Stromal cells proliferate and secrete collagen and ground substance.  Spiral arteries lengthen as the endometrium is reestablished; these arteries are only slightly coiled and do not extend into the upper third of the endometrium.


Histology_Ross

Histology_Ross. The proliferative phase continues until 1 day after ovulation, which occurs at about day 14 of a 28-day cycle. At the end of this phase, the endometrium has reached a thickness of about 3 mm. The glands have narrow lumina and are relatively straight but have a slightly wavy appearance (Fig. 23.16a). Accumulations of glycogen are present in the basal portions of the epithelial cells. In routine histologic preparations, extraction of the glycogen gives an empty appearance to the basal cytoplasm. The secretory phase of the menstrual cycle is regulated by progesterone.


Histology_Ross

Histology_Ross. The secretory phase of the menstrual cycle is regulated by progesterone. Under the infuence of progesterone, dramatic changes occur in the stratum functionale, beginning a day or two after ovulation. The endometrium becomes edematous and may eventually reach a thickness of 5 mm to 6 mm. The glands enlarge and become corkscrew shaped, and their lumina become sacculated as they fill with secretory products (Fig. 23.16b). The mucoid fluid produced by the gland epithelium is rich in nutrients, particularly glycogen, required to support development if implantation occurs. Mitoses are now rare. The growth seen at this stage results from hypertrophy of the epithelial cells, an increase in vascularity, and edema of the endometrium. The spiral arteries, however, lengthen and become more coiled. They extend nearly to the surface of the endometrium (Plate 97, page 882).


Histology_Ross

Histology_Ross. The sequential influence of estrogens and progesterone on the stromal cells enables their transformation into decidual cells. The stimulus for transformation is the implantation of the blastocyst. Large, pale cells rich in glycogen result from this transformation. Although the precise function of these cells is not known, it is clear that they provide a favorable environment for the nourishment of the embryo and that they create a FIGURE 23.16 • Photomicrographs of the uterine lining in proliferative, secretory, and menstrual phases of the menstrual cycle.


Histology_Ross

Histology_Ross. a. The upper panel shows the endometrium at the proliferative phase of the cycle. During this phase, the stratum functionale (separated by the dashed line from the stratum basale) greatly thickens. 15. The lower panel shows at higher magnification the endometrial glands that extend from the stratum basale to the surface. 55. b. The upper panel shows the endometrium at the secretory phase of the cycle. The glands have acquired a corkscrew shape as the endometrium increases further in thickness. The stratum basale (below the dashed line) exhibits less dramatic changes in morphology. 20. The lower panel shows uterine glands that have been cut in a plane that is close to their long axes. Note the pronounced corkscrew shape of the glands and mucous secretion (arrows). 60. c. The upper panel shows the stratum functionale (above the dashed line). Much of the stratum functionale has degenerated and sloughed away. 15. The lower panel shows the extravasated blood and necrosis of the stratum


Histology_Ross

Histology_Ross. shows the stratum functionale (above the dashed line). Much of the stratum functionale has degenerated and sloughed away. 15. The lower panel shows the extravasated blood and necrosis of the stratum functionale. 55.


Histology_Ross

Histology_Ross. specialized layer that facilitates the separation of the placenta The corpus luteum actively produces hormones for about from the uterine wall at the termination of pregnancy. 10 days if fertilization does not occur. As hormone levels rapidly decline, changes occur in the blood supply to the stra-The menstrual phase results from a decline in the ovarian tum functionale. Initially, periodic contractions of the walls of secretion of progesterone and estrogen. the spiral arteries, lasting for several hours, cause the stratum functionale to become ischemic. The glands stop secreting, and the endometrium shrinks in height as the stroma becomes less edematous. After about 2 days, extended periods of arterial contraction, with only brief periods of blood flow, cause disruption of the surface epithelium and rupture of the blood vessels. When the spiral arteries close off, blood flows into the stratum basale but not into the stratum functionale. Blood, uterine fluid, and sloughing stromal and


Histology_Ross

Histology_Ross. and rupture of the blood vessels. When the spiral arteries close off, blood flows into the stratum basale but not into the stratum functionale. Blood, uterine fluid, and sloughing stromal and epithelial cells from the stratum functionale constitute the vaginal discharge. As patches of tissue separate from the endometrium, the torn ends of veins, arteries, and glands are exposed (Fig. 23.16c). The desquamation continues until only the stratum basale remains. Clotting of blood is inhibited during this period of menstrual flow. Arterial blood flow is restricted except for the brief periods of relaxation of the walls of the spiral arteries. Blood continually seeps from the open ends of the veins. The period of menstrual fow normally lasts about 5 days. The average blood loss in the menstrual phase is 35 ml to 50 ml. Blood flow through the straight arteries maintains the stratum basale.


Histology_Ross

Histology_Ross. As noted, this process is cyclic. Figure F23.2.1 in Folder 23.3 shows a single cycle of the endometrium and then demonstrates a gravid state as it is established at the end of a secretory phase. In the absence of fertilization, cessation of bleeding would accompany the growth and maturation of new ovarian follicles. The epithelial cells would rapidly proliferate and migrate to restore the surface epithelium as the proliferative phase of the next cycle begins. In the absence of ovulation (a cycle referred to as an anovulatory cycle), a corpus luteum does not form, and progesterone is not produced. In the absence of progesterone, the endometrium does not enter the secretory phase and continues in the proliferative phase until menstruation. In cases of infertility, biopsies of the endometrium can be used to diagnose such anovulatory cycles as well as other disorders of the ovary and endometrium.


Histology_Ross

Histology_Ross. If fertilization and implantation occur, a gravid phase replaces the menstrual phase of the cycle. If fertilization and subsequent implantation occur, decline of the endometrium is delayed until after parturition. As the blastocyst becomes embedded in the uterine mucosa in the early part of the second week, cells in the chorion of the developing placenta begin to secrete hCG and other luteotropins. These hormones maintain the corpus luteum and stimulate it to continue the production of progesterone and estrogens. Thus, the decline of the endometrium is prevented, and the endometrium undergoes further development during the first few weeks of pregnancy. Implantation is the process by which the blastocyst settles into the endometrium.


Histology_Ross

Histology_Ross. Implantation is the process by which the blastocyst settles into the endometrium. The fertilized human ovum undergoes a series of changes as it passes through the uterine tube into the uterine cavity in preparation for becoming embedded in the uterine mucosa. The zygote undergoes cleavage, followed by a series of mitotic divisions without cell growth, resulting in a rapid increase in the number of cells in the embryo. Initially, the embryo is under the control of maternal informational macromolecules that have accumulated in the cytoplasm of the ovum during oogenesis. Later development depends on activation of the embryonic genome, which encodes various growth factors, cell junction components, and other macromolecules required for normal progression to the blastocyst stage.