Introduction and Key Concepts for the Female Reproductive System

The female reproductive system comprises the ovaries, oviducts, uterus, vagina, external genitalia, and mammary glands. The external genitalia (vulva) includes the labia minora, labia majora, mons pubis, clitoris, and vestibule. Female secondary sex characteristics appear at puberty, along with the monthly menstrual cycle. This cycle of changes in the reproductive system is influenced by interactions among the hypothalamus, pituitary gland, ovaries, and uterus; related events occur periodically during each menstrual cycle (Fig. 19-8). The menstrual cycle is influenced by hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, and progesterone. These hormones cause changes in the female reproductive organs and their functions, promote development of follicles and oocytes, and produce an ideal environment for fertilization, implantation, and fetal growth. The female reproductive system plays an important role in the production and regulation of female hormones (estrogen and progesterone) and in the development and maintenance of female sex characteristics.

Ovaries

The ovaries are paired, almond-shaped structures located in the upper part of the pelvic cavity. Their size and position vary depending on the age and reproductive state of the individual. The ovaries are suspended by the mesovarium of the broad ligament and are attached to the uterus by the ligament of the ovary (Fig. 19-1). Each ovary has a cortex and medulla. The cortex contains numerous developing follicles in various stages as well as postovulatory structures, a corpus luteum, and several corpora albicans. Each developing follicle contains an oocyte. The medulla is composed of loose connective tissue and blood vessels, nerve fibers, and lymphatic vessels (Fig. 19-3A).

1.Primordial follicles: In the earliest stage of follicular development, primordial follicles rest at the periphery of the

cortex. Each primordial follicle consists of a primary oocyte surrounded by a single layer of squamous supporting cells called follicular cells (Fig. 19-4A,B). The oocyte is small (about 20–30 μm) and is in prophase (dictyotene) of meiosis I. The nucleus of the oocyte has a pale appearance and contains decondensed chromatin.

2.Primary follicles: At puberty, the primordial follicles begin to grow, the oocyte increases its size, and the supporting follicle cells also increase in size and become cuboidal cells. These follicle cells are now called granulosa cells. When the oocyte of the primary follicle is surrounded by a single layer of granulosa cells, the follicle is called a unilaminar primary follicle. As the oocyte increases in size, the granulosa cells build up more layers, and the follicle is called a multilaminar primary follicle (Fig. 19-5A,B). The zona pellucida, a gel-like layer between the oocyte and the granulosa cells, first appears in the multilaminar primary follicle (Fig. 19-5B).

3.Secondary follicles: As granulosa cells continue to proliferate, the follicle size increases, and spaces filled with follicular fluid (liquor folliculi) develop among the cells. These spaces merge to become a single large space called the antrum. The stromal cells that cover the follicle develop into a layer called the theca folliculi. The theca folliculi is well developed in the secondary follicle, and it includes the theca interna and theca externa (Fig. 19-6A).

4.Graafian (preovulatory) follicle: In its final stage, the follicle reaches a maximum size of up to 25 mm (2.5 cm). This follicle has a large antrum filled with liquor folliculi. It has reached its mature stage and is ready to release the oocyte (ovulation). The oocyte has reached its maximum size, and is embedded in a mound of granulosa cells that protrude into the antrum (Fig. 19-6B). The granulosa cells that are in immediate contact with the oocyte are called the corona radiata and remain with the oocyte at ovulation. The graafian follicle bulges from the surface of the ovary. In response to a sharp increase in the level of LH (LH surge), the oocyte resumes meiotic division, becomes arrested as a secondary oocyte, and ovulation then occurs.

5.Postovulatory structures: After ovulation, the remainder of the graafian follicle develops into the corpus luteum (Fig. 19-7A) and continues to produce steroid hormones. If fertilization and implantation occur, the corpus luteum will remain active and continue to produce progesterone during the first 6 months of pregnancy. If fertilization does not occur, the corpus luteum degenerates after 10 to 14 days and becomes the corpus albicans (Fig. 19-7B).

Oviducts (Fallopian Tubes)

The oviducts are paired, muscular, open-ended tubes that receive the ovum and provide an ideal environment for fertilization. Each oviduct has four regions: the infundibulum, ampulla, isthmus, and intramural portion (Fig. 19-1). Fertilization usually occurs in the ampulla of the oviduct. The oviduct wall has a mucosa containing ciliated cells and secretory (peg) cells in its epithelium, a muscularis layer, and a serosa outer covering (Fig. 19-9A,B).

Uterus

The uterus is a pear-shaped muscular organ that connects to the two oviducts and to the vagina via the cervix. It is the site for implantation and placentation. Implantation is the attachment of the blastocyst to the uterine wall; placentation is the establishment of a placenta that nourishes the developing embryo and fetus via the umbilical cord. The uterus has a thick wall, which consists of endometrium (mucosa), myometrium (muscularis), and serosa. The uterus can be divided into three regions: the fundus, body, and cervix (Fig. 19-1). The endometrium undergoes the following morphological and functional changes during the menstrual cycle.

1.Menstrual phase: This is the initial stage (from days 1 to 4 of the cycle). The functional layer (functionalis) of the endometrium sloughs off and bleeds about 2 weeks after ovulation if fertilization does not occur (Fig. 19-10A).

2.Proliferative phase: Following the menstrual phase (days 5–14 of the cycle), the functionalis of the endometrium recovers and rebuilds itself. Its glands appear straight, and its surface is smooth (Fig. 19-10B).

3.Secretory phase: At this phase (days 15–28 of the cycle), the endometrium becomes ready for implantation. The endometrium thickens, and the glands appear coiled with large lumens and a sawtooth appearance. These changes are mainly influenced by progesterone (Fig. 19-10C). If a blastocyst becomes embedded in the endometrium (implantation), the development of the placenta takes place within a short time (Fig. 19-11A).

Vagina

The vagina is a muscular tube that connects the cervix to the external genitalia. It consists of mucosa, muscularis, and adventitia (Fig. 19-14B) and functions as a copulatory organ and birth passage.

Mammary Glands

The mammary glands are paired exocrine glands located beneath the skin on the chest. These glands can be classified as compound tubuloalveolar glands. In the female, the mammary glands undergo morphological and functional changes in response to female hormones (estrogen, progesterone). In later pregnancy, the mammary glands prepare to produce milk (lactation) for the newborn infant (Figs. 19-15A–C and 19-16A).

A

Primary follicle (multilaminar)

B

Mitochondria of

follicle cells

Junction between follicular cells

Follicular

cells

Nucleus of primary oocyte

Basal lamina of follicle

Nucleus of primary oocyte Mitochondria of primary oocyte Granules in oocyte

Nucleus of follicular cell

Nucleus of stromal cell

B

Zona pellucida

Granulosa cells

Microvilli

Theca folliculi

A

Granulosa Secondary cells follicle

Antrum

Theca Primary interna oocyte

Theca externa

Zona pellucida

Figure 19-6A. Secondary follicles, ovary. H&E,

108; inset 211

The secondary follicle develops from the continued growth of the multilaminar primary follicle. Spaces filled with follicular fluid (liquor folliculi) appear among the granulosa cells within the secondary follicle. These spaces gradually merge to form a single large space called the antrum. The zona pellucida is distinct, and the theca folliculi (surrounding the follicle) develops into the theca interna and theca externa. The theca interna is the inner vascular layer containing cuboidal (steroid-producing) secretory cells. These cells secrete androgens, which diffuse into the granulosa cells where they are converted into estrogens in response to FSH. The theca externa is an outer connective tissue layer containing mainly collagen and some small squamous cells mixed with a few smooth muscle cells.

B

Theca interna

Theca interna

Cytoplasm of granulosa lutein cells

Figure 19-7A. Corpus luteum, ovary. H&E, 36; insets 363

After ovulation, the remaining portion (wall) of the graafian follicle transforms into the corpus luteum (yellow body). The wall of the corpus luteum is folded and contains granulosa lutein cells (derived from granulosa cells) and theca lutein cells (from the theca interna). The granulosa lutein cells are large and have pale cytoplasm; these cells have features of steroid hormone–producing cells, and they produce primarily progesterone. The theca lutein cells are smaller but also have features of steroid hormone–secreting cells; these cells secrete primarily progesterone and androgens.

B

Blood vessels

Corpus albicans

Corpus albicans

Figure 19-7B. Corpus albicans, ovary. H&E, 34

In the absence of fertilization, the corpus luteum is active only for a short period of time (10–14 days). The corpus luteum degenerates, decreases in size, and forms a structure called the corpus albicans. The corpus albicans consists of dense connective tissue that appears as a white scar; it gradually decreases in size and remains in the ovary for months to years. However, if fertilization and implantation occur, the corpus luteum is rescued from degeneration by human chorionic gonadotropin (hCG) hormone from the placenta. During pregnancy, the corpus luteum will remain active for the first 6 months of gestation, after which it degenerates, and the corpus albicans is formed. Formation of the corpus luteum is stimulated by the LH surge.

C

Granulosa cell tumor with neoplastic cells arranged in cords

Figure 19-7C. Granulosa Cell Tumor. H&E, 52

Granulosa cell tumor of the ovary is a neoplasm composed of ovarian granulosa and, occasionally, theca cells. Granulosa cell tumors may arise at any age and are divided into juvenile and adult types. These tumors may produce excess estrogen, the result of which may cause precocious puberty, endometrial hyperplasia, and endometrial cancer. Symptoms may include abdominal pain, hemoperitoneum with hypotension, and mimicking an ectopic pregnancy in younger patients because of rupture of the tumor. Histologically, the tumor cells are small and cuboidal, and may be arranged in a variety of patterns including solid, trabecular, and cordlike. The tumor cells often contain a groove resembling a coffee bean. Small follicle-like structures named Call-Exner bodies may be visible in well-differentiated tumors. The behavior of granulosa cell tumors is variable and may take an aggressive course in some patients. A total abdominal hysterectomy and bilateral salpingo-oophorec- tomy are the treatments of choice in the early stage.

Hormone concentration in plasma

B

Cilia

Microvilli

Basal bodies

Nucleus of ciliated cell

Figure 19-9B. Epithelial cells lining the oviduct. EM, 8,900

The simple columnar epithelium that lines the oviduct is composed of two cell types (ciliated cells and peg cells); only ciliated cells are shown here. These ciliated cells function, along with smooth muscle of the muscularis, in mixing the contents (gametes) of the lumen and in transporting the oocyte and zygote at a precisely controlled rate along the length of the lumen of the oviduct. The number and activity of cilia change in response to changes in the levels of steroid hormones throughout the reproductive cycle, reaching a peak at the time of ovulation when estrogens dominate. Note that these cells also bear numerous microvilli, suggesting an additional absorptive function.

Uterine

glands

Functionalis

Figure 19-10A. Menstrual phase of the endometrium, uterus (days 1–4 of the cycle). H&E, 13; insets 93

The wall of the uterus includes the endometrium, the myometrium, and serosa. The endometrium, the mucosa of the uterus, is composed of a surface epithelium and simple tubular uterine glands within a stroma of connective tissue. The endometrium consists of the basalis (basal layer) and the functionalis (functional layer). The functionalis is near the lumen and undergoes changes during the menstrual cycle. During the menstrual phase, the functionalis sloughs off as a result of ischemia and necrosis caused by contraction of the coiled arteries. This occurs when fertilization does not take place and the corpus luteum atrophies, causing the levels of estrogen and progesterone to fall. The menstrual phase is the initial stage of the menstrual cycle; the endometrium will begin to recover at the end of the menstrual phase.

Luminal surface

Figure 19-10B. Proliferative phase of the endometrium, uterus (days 5–14 of the cycle). H&E, 18; inset (upper) 68; inset (lower) 293

The proliferative phase follows the menstrual phase. The epithelium, uterine glands, and connective tissue of the functionalis are rebuilt by proliferation and differentiation of cells that remained in the basalis. At this stage, the uterine glands are straight and have narrow lumens as shown here; the surface of the endometrium is smooth. The epithelial lining of the uterine glands commonly appears as pseudostratified columnar epithelium because of proliferation of the lining cells. Mitotic figures are occasionally seen (inset). The glands open onto the luminal surface of the uterus. During the proliferative phase, the changes in the endometrium are driven by estrogens that are produced by the granulosa cells of the developing follicles.

Uterine

glands

Functionalis

Stroma

Endometrium

Coiled arteries

C

Figure 19-10C. Secretory phase of the endometrium, uterus (days 15–28 of the cycle). H&E, 14; insets 89

The secretory phase begins shortly after ovulation occurs. It is influenced by progesterone produced by the corpus luteum. At this stage, the endometrium becomes thickest (6–7 mm), and the uterine glands are coiled and have large sacculated lumens. The upper inset shows tortuous glands with large, irregular, sawtooth-shaped lumens. The lower inset shows coiled arteries found in the endometrial stroma. These coiled arteries are also called spiral arteries and extend transiently from the basalis into the functionalis of the endometrium. The coiled arteries arise from arcuate arteries of the myometrium. During the secretory phase, these spiral arteries become elongated and highly coiled and extend into the functionalis of the endometrium. The arcuate arteries also give rise to straight arteries that permanently supply the basalis.

B

C

A

Cervix

EndocervixEndocervix

Stratified squamous

Cervical stroma epithelium (ectocervix)

Simple columnar epithelium

(endocervix)

Figure 19-12A. Cervix. H&E, 17; inset 350

The inferior part of the uterus forms the cervical canal, which bulges into the vagina. The internal os is the opening from the endocervical canal to the uterus; the external os is the opening to the vaginal canal. The surface of the endocervix is lined by simple columnar epithelium, which consists of mucus-secreting cells (inset); the ectocervix is lined by stratified squamous epithelium. The cervix contains long branched mucous glands known as cervical glands; when these glands become obstructed they form cervical cysts (nabothian cysts). The secretion of the cervix changes depending on the stage of the menstrual cycle; however, the mucosa of the cervix does not slough off as does the endometrium of the uterus. The cervical stroma is composed of dense connective tissue mixed with a small amount (about 15%) of smooth muscle. Usually, the cervix has a narrow canal; however, during delivery, dilation of the cervix allows the baby to pass through the canal.

The cervical transformation (transition) zone is the area of the cervical mucosa between the original squamocolumnar junction and the restored or new squamocolumnar junction that is formed through the processes of squamous metaplasia and squamous epithelialization. The majority of cervical carcinomas arise in this zone, and it is important that this area be sampled during screening with a Papanicolaou smear.

B

Squamous

epithelium

Squamous cell carcinoma

Figure 19-12B. Cervical Cancer. H&E (upper left), 20; (lower right), 115

Cervical cancer is a malignant neoplasm of the uterine cervix, the majority of which are squamous cell carcinomas. Risk factors include the early onset of sexual activity, multiple sexual partners, and exposure to human papillomavirus (HPV). Invasive squamous cell carcinoma is preceded by precursor lesions called cervical intraepithelial neoplasia, in which dysplastic epithelial changes are present. The majority of intraepithelial lesions are related to infection by HPV. The introduction of screening using the Papanicolaou smear, or “Pap” smear, has dramatically reduced the incidence of invasive cervical lesions. Symptoms of cervical cancer include abnormal vaginal bleeding, postcoital bleeding, and vaginal discharge. Histologically, the cancer typically arises in the cervical transformation zone and may show superficial ulceration with endophytic or exophytic growth patterns. The cancer can spread by direct invasion to nearby tissues and organs or metastasize through hematogenous or lymphatic routes. Gardasil, a vaccine against certain HPV types, is used in young women to prevent infection by the virus. Treatment options include surgical removal of the uterus (hysterectomy), radiation therapy, and chemotherapy.

A

Anchoring

villus

A

Umbilical

arteries

Mucous connective tissue (Wharton jelly)

Umbilical

vein

Figure 19-14A. Umbilical cord. H&E, 12; inset 79

The umbilical cord is a ropelike structure that connects the developing fetus to the placenta. It contains two umbilical arteries and one umbilical vein. These vessels carry oxygen and nutrients from the mother to the fetus and waste products away from the fetus. The blood vessels are surrounded by a mucous connective tissue (Wharton jelly). The umbilical arteries carry deoxygenated fetal blood to the placenta by way of the chorionic arteries and the chorionic villi. After gas and nutrient exchange with the maternal blood, the oxygenated blood is transported from chorionic veins to the umbilical vein, which returns blood to the fetus.

Funisitis is inflammation of the umbilical cord that often accompanies chorioamnionitis (inflammation of the fetal membranes). Funisitis typically occurs after 20 weeks of gestation, often because of a bacterial infection. Neutrophils migrate through the umbilical vessels and may enter the Wharton jelly. Another possible complication in pregnancy is an umbilical knot. In severe cases, obstruction of blood supply can result in the fetal death.

A

Lobe of mammary gland

Lobule of mammary gland

Interlobular

duct

Nipple

Openings

Lactiferous

duct

Lactiferous

sinus

Skin

Figure 19-15A. Overview of the mammary gland.

B

Adipose tissue

Lobules of

gland

Myoepithelial cell

Cuboidal epithelial cell

Figure 19-15B. Inactive (resting) mammary gland.

H&E, 41; inset 359

An example of a resting mammary gland shows a large amount of dense irregular connective tissue and adipose tissue with small mammary gland lobules. The glandular tissue contains mainly intralobular ducts, which are lined by cuboidal epithelial cells and underlying myoepithelial cells (inset). The resting mammary gland has only a few secretory alveoli, some undeveloped intralobular ducts, interlobular ducts, lactiferous sinuses, and lactiferous ducts.

C

Intralobular

ducts

Interlobular

duct

Alveolus

Lobule of

gland

Alveoli

Figure 19-15C. Active (during pregnancy) mammary gland. H&E, 41

An example of a mammary gland during pregnancy shows large lobules and a relatively small amount of interlobular connective tissue. The glandular tissue contains many proliferated alveoli and intralobular ducts. A large interlobular duct is located within the connective tissue shown here. When the mammary glands begin to secrete milk (lactation), the lumina of the alveoli and the ducts are dilated and filled with milk. The milk contains many lipid droplets and proteins (caseins, lactalbumin, and immunoglobulin A) as well as lactose, ions, vitamins, and water. Secretion of milk is initiated by hormonal changes: decrease of estrogen and progesterone and increase of prolactin after delivery and the loss of the placenta. The milk is released by the milk ejection reflex when stimulated by suckling (Fig. 19-16A).

Figure 19-16A. Nipple, mammary gland. H&E, 11; left inset

146; right inset 136

The nipple is a small projection at the center of the breast. It contains 15 to 25 openings of lactiferous ducts within its connective tissue and smooth muscle bundles. It is covered by thin skin and surrounded by the areola (pigmented skin). The nipple has many sensory nerve endings that receive stimulation during suckling. This stimulation results in release of oxytocin from the pars nervosa of the pituitary; the oxytocin stimulates contraction of the myoepithelial cells in the mammary gland. The contraction of the myoepithelial cells pushes milk out of the alveoli and ducts and through the lactiferous ducts to the surface of the nipple. This process is called the milk ejection reflex. The lactiferous ducts shown here are from the proximal portion of the ducts near the lactiferous sinuses.

CLINICAL CORRELATION

Infiltrating duct carcinoma of the breast

B

Figure 19-16B. Adenocarcinoma of the Breast (Breast Cancer).

H&E, left (lower) 44; right (upper) 71

Infiltrating duct carcinoma, or invasive ductal carcinoma, is the most common adenocarcinoma of the breast (breast cancer); it contains no features to further classify it into special types of breast carcinoma, such as lobular, tubular, and mucinous carcinomas. Risk factors for the development of breast cancer include female gender, increasing age, family history, long reproductive life, nulliparity, and the presence of proliferative breast lesions or ductal hyperplasia. Approximately 5% of breast cancers are related to specific gene mutations, including BRCA1 and BRCA2. Common signs and symptoms include a palpable breast mass, bloody discharge from the nipple, change in size or shape of a breast, skin dimpling, inverted nipple, peeling of the nipple skin, and redness or pitting of the skin over the breast. Mammograms and breast exams are used to screen for breast cancer. Biopsy is performed on suspicious lesions to determine a tissue diagnosis. Histologically, breast cancer varies from well-formed glandular structures to sheets of poorly differentiated cells. Histologic grading of breast cancer is based on tubule formation, nuclear pleomorphism, and the mitotic rate. Treatment includes surgical removal of a tumor (lumpectomy), removal of the entire breast (mastectomy) and lymph nodes, radiation therapy, chemotherapy, and hormone therapy.