OBJECTIVES

This chapter should help you to:

· Name the internal organs and external genitalia of the female reproductive system and give the structure, function, and location of each.
· Trace the entire life cycle of the female gametes (oval beginning with their embryonic origin, continuing with the changes they undergo during oogenesis, and ending with ovulation and the path they follow to the uterus.
· Describe the structural changes at each stage of ovarian follicle maturation, including primordial through mature follicles, atretic follicles, corpus luteum, and corpus albicans; describe the role of FSH and LH in follicular development and ovulation.
· Name the cells that produce estrogen and progesterone, describe the conditions under which they are produced, and describe their effects on FSH and LH production by the pituitary.
· Identify the following in a slide or photomicrograph of a section through an ovary: germinal epithelium; tunica albuginea; cortex; medulla; primordial, primary, secondary, mature, and atretic follicles; oocytes; granulosa cells; theca interna and externa; antrum; cumulus oophorus; corona radiata; zona pellucida; corpus luteum; corpus albicans; and granulosa lutein, theca lutein, and interstitial cells.
· Describe the endometrium in terms of location, structure, blood supply, and the changes that accompany the phases of the menstrual cycle; correlate the changes in the endometrium with events occurring in the ovary and with changing levels of pituitary and ovarian hormones.
· Identify the following in a slide or photomicrograph of a section through the fundus or body of the uterus: the phase of the menstrual cycle, the endometrium, myometrium, serosa or adventitia, functionalis, basalis, endometrial glands, and straight and coiled arteries.
· Identify the cervical glands, epithelial transition, internal and external os, and cervical canal in a slide or photomicrograph of a section through the uterine cervix.
· Describe the changes in the conceptus' structure and location and the usual amount of time elapsed between fertilization and implantation.
· Describe implantation in terms of the structural changes in the blastocyst and endometrium.
· Describe the placenta in terms of the fetal and maternal contributions, the steps in the development of the chorionic villi, and the layers of the placental barrier.
· Identify the following in a slide or photomicrograph of an implanted blastocyst or early embryo: chorion, syncytiotrophoblast, cytotrophoblast, extraembryonic mesenchyme, inner cell mass, decidual capsularis and basalis, uterine glands, maternal lacunae, and primary, secondary, and terti- ary chorionic villi.
· Describe the vaginal wall in terms of the structure of its 3 layers, the effect of estrogen on the lining epithelium, and its innervation; from a slide or photomicrograph, distinguish the structure of the vaginal wall from that of the esophagus in terms of mucosal glands and the orientation of the smooth muscle.
· Describe the vulva in terms of the structure and innervation of its components.
· Describe and identify, in a slide or photomicrograph, the histologic structure of the mammary gland in the prepubertal, resting adult, pregnant, and lactating states and identify the secretory cells, alveoli, lactiferous ducts and sinuses, connective tissue, adipocytes, and plasma cells.
· Describe the synthesis and secretion of milk by the mammary gland alveolar cpithelial cells and name the hormones responsible for breast growth, activation and maintenance of lactation, and milk ejection.

SYNOPSIS

I. GENERAL FEATURES OF THE FEMALE REPRODUCTIVE SYSTEM

A. Components of the System. The female reproductive system includes the ovaries, uterine tubes (oviducts), uterus, vagina, and external genitalia (Fig 23 i).

1. Ovaries are the female gonads. They contain the ovarian follicles, which harbor and promote the development of the ova (eggs), and produce estrogen. After ovulation, the remnants of the follicle form a corpus luteum, which produces estrogen and progesterone.
2. Uterine tubes (oviducts) capture the released ovum, serve as the primary site of fertilization, and convey the ovum (fertilized or not) to the uterus.
3. Uterus, This hollow muscular organ is lined by a mucosa (endometrium) that undergoes cyclic changes controlled by ovarian hormones. The changes prepare the uterus for the implantation and nourishment of the fertilized ovum.
4. Vagina. This tubelike organ helps to direct the spermatozoa through the narrow opening in the base of the uterus. Vaginal fluid increases sperm motility. Estrogen causes the vaginal epithelium to thicken and its cells to accumulate the glycogen that is released into the lumen during exfoliation.
5. External genitalia. These include the clitoris, and labia minora and majora; they contain numerous nerve endings, which play a role in sexual arousal.

B. Cyclic Changes: Between menarcbe (first menses) and menopause, cyclic changes occur, roughly every 28 days, in the structure and activity of each organ, especially the ovaries and uterus. The synchronization of these changes, crucial to normal reproductive function, is controlled mainly by the pituitary gonadotropins FSH and LH. These hormones directly affect the ovaries, modulating follicle growth and development as well as ovarian hormone production. Ovarian hormones (estrogen and progesterone) control the menstrual cycle tie, the cyclic changes in the uterine lining) and influence pituitary gonadotropin production through negative feedback.

C. Early Embryonic Development: Selected aspects of early development are described in this chapter as they relate to the structure and function of the female reproductive system. These include fertilization, preimplantation embryonic development, implantation, and the forma tion and functions of the placenta.

D. Mammary Glands: Mammary glands also undergo histologic changes related to the menstrual cycle, pregnancy, and pituitary and ovarian hormones.

II. OVARIES

A. General Organization: Lying in the pelvic cavity, the ovaries are paired, almond-shaped organs (3 x 1.5 x 1 cm). Their outermost covering, the germinal epithelium, does not form oocytes as the name suggests. It is a simple cuboidal epithelium derived from the peritoneum. The inner covering, the tnnica albuginea, is a dense connective tissue capsule between the germinal epithelium and ovarian cortex. Each ovary (Fig 23-2) has a peripheral cortex and a central medulla, The cortex harbors most of the oocyte-containing ovarian folliclcs embedded in connective tissue (stroma), The medulla consists of stroma containing a rich vascular bed.

B. Ovarian Follicles: Each follicle consists of a single oocyte surrounded by one or more layers of follicle (granulosa) cells. The cortex contains follicles at various stages of development.


1. Primordial follicles, The earliest stage of follicle development, these inactive follicles are the only ones present prior to puberty and constitute the majority thereafter. Each consists of a primary oocyte (most in the diplotene stage of meiosis I prophase) surrounded by one layer of squamous follicle cells.
2. Growing follicles, Follicle growth is stimulated by pituitary FSH. The oocyte enlarges to a diameter of 125-150 CLm. The follicle epithelium becomes cuboidal and proliferates to become stratified (multilaminar). The stromal connective tissue immediately surrounding the follicle differentiates into the steroid hormone-producing theca folliculi, a. Primary follicles consist of a primary oocyte surrounded by single or multiple layers of cuboidal follicle cells. They have no antrum. Unilaminar primary follicles consist of a single layer of cuboidal follicle cells surrounding an oocyte. At this stage, the glycoprotein-rich zona pellucida begins to form between the oocyte and the follicle cells. Multilaminar primary follicles have multiple layers of follicle cells surrounding an oocyte. During this stage, the zona pellucida thickens and the theca folliculi begins to form. b, Secondary follicles, During this stage, cavities filled with fluid (liquor folliculi) appear between the follicle cells, gradually coalescing to form one large cavity, or antrum, The theca folliculi forms 2 layers: the theca interna, containing a rich vascular network and steroid-secreting cuboidal cells with abundant SER, and the theca externa, consisting mainly of vascular connective tissue.
3. Mature (Graafian) follicles (Fig 23-3) are distinguished from late secondary follicles mainly by their large size (2.5 cm in diameter). In this stage, which immediately precedes ovulation, the antrum increases greatly in size. The oocyte is displaced to one side of the follicle, is surrounded by a few layers of follicle cells (corona radiata), and rests on a pedestal of follicle cells (cumulus oophorus),
4. Atretic follicles. Although about 400,000 follicles are normally present at birth, only about 450 develop to maturity. More than 99% become atretic tie, they degenerate by autolysis) at various stages of development. Atresia of the primordial follicles leaves a space that is filled by stroma; as a result, no vestiges of atretic primordial follicles are seen in adult ovaries. Autolytic remnants of larger primary and secondary follicles are removed by macrophages and replaced, by the stromal cells, with a wavy collagenous scar. The scar is gradually removed and remodeled into normal stromal tissue. Some thecal cells from the atretic follicles may remain, becoming interstitial cells that actively secrete steroids, especially androgens.

C. Origin and Maturation of Oocytes: Yolk sac endoderm gives rise to primordial germ cells, which migrate to the genital ridges, in the posterior wall of the abdominal cavity, from which the ovaries develop. The germ cells are surrounded by the flattened follicle cells of primordial follicles; they enter the first meiotic division and arrest in prophase. At this point, they are primary oocytes (comparable to primary spermatocytes; 22.II.C.2.b). The first meiotic division is completed just before ovulation and involves equal division of the chromatin but unequal division of the cytoplasm between the resulting secondary oocytes. The secondary oocyte that retains almost all the cytoplasm is the ovum; the other is termed the first polar body. Once formed, but still prior to ovulation, the ovum begins the second meiotic division, which halts in metaphase until fertilization occurs. At fertilization, the second meiotic division is completed and the second polar body is formed. The fertilized ovum is called the zygote.

D. Ovulation: Normally occurring about day 14 of an idealized 28-day cycle, ovulation involves the rupture of a mature follicle and the release of the ovum. It is preceded and stimulated by a surge in pituitary LH production. As the amount of liquor folliculi in the antrum increases, the ovum and its surrounding zona pellucida and corona radiata detach from the cumulus oophorus and float in the antrum. Perhaps owing to collagenase activity, the stroma thins and becomes ischemic between the preovulatory follicle and the ovary surface, indicating the site of imminent rupture, or stigma. Upon rupture, the ovum, with its corona intact, is expelled by the ovary and captured by the uterine tube. If it is not fertilized within 24 hours, the ovum degenerates.

E. Corpus Luteum: This temporary endocrine gland is formed by the remnants of the follicle after ovulation. After ovulation, the follicle collapses and the granulosal lining is thrown into folds. Cells in the granulosa layer and theca interna enlarge and begin secreting steroids. The granulosa lutein cells are large, pale-staining, progesterone-secreting cells derived from the granulosa cells. The theca lutein cells, which secrete estrogen, are smaller, darker-staining cells derived from the cells of the theca interna.

1. Corpus luteum of menstruation. If fertilization does not occur, the corpus luteum degenerates after about 14 days.
2. Corpus luteum of pregnancy. If fertilization does occur, the corpus luteum enlarges. It is maintained for 6 months; although it gradually declines thereafter, it persists until the end of pregnancy. In addition to estrogen and progesterone, it produces relaxin, a polypeptide hormone that loosens the fibrocartilage attachment of the symphysis pubis, allowing the pelvic opening to enlarge during parturition.
3. Corpus albicans. This dense connective tissue scar that replaces a degenerated corpus luteum is larger for a corpus luteum of pregnancy than for that of menstruation. Like atretic follicles, it is eventually removed by macrophages.

F. Hormones and Ovarian Function: Pituitary FSH stimulates follicle growth during the first half of the menstrual cycle. The growing follicles produce estrogen, whose high midcycle level exerts negative feedback on FSH production. This stimulates the LH surge, which controls the final maturation of the follicle, stimulates ovulation, and controls the formation and maintenance of the corpus luteum. The corpus luteum produces both estrogen and progesterone. Progesterone inhibits LH production, causing the corpus luteum to degenerate after about 14 days unless fertilization occurs. If the ovum is fertilized and implants in the uterus, cborionic gonadotropin produced by the developing placenta maintains the corpus luteum in the absence of LH.

III. UTERINE TUBES (OVIDUCTS, FALLOPIAN TUBES)

These are paired 12-cm-long muscular tubes whose lumens are continuous proximally with the uterine cavity (Fig 23-1). The distal end of each tube opens into the peritoneal cavity near the ovary.

A. Function: The uterine tube moves close to the ovary before ovulation and captures the ovulated ovum. It provides a suitable environment for, and is the most common site of, fertiliza tion and transports the zygote to the uterus.

B. Uterine Tube Segments: Each uterine tube has 4 named segments (Fig 23-1). The pars interstitialis (intramural portion) penetrates the uterine wall. It contains the fewest mucosal folds, and the myometrium contributes to its muscularis. The isthmus, the narrow segment adjacent to the uterine wall, contains few mucosal folds. The ampulla, the wide middle seg ment, contains extensive branched mucosal folds and is the most common site of fertilization. The infundibulum, the funnel-shaped distal segment, opens near the ovary. Fingerlike exten sions of its mucosal folds, the fimbriae, project from the opening toward the ovary.

C. Wall Structure: The wall of the uterine tube has 3 layers: mucosa, muscularis, and serosa. There is no definitive submucosa. The mucosa includes the lamina propria and the lining epithelium. The mucosal folds are largest and most numerous in the ampulla, decreasing in size and number toward the uterus. The lining is simple columnar epithelium with 2 main cell types. The cilia on the surface of the abundant ciliated columnar cells beat in waves. Most beat toward the uterus and thus aid in egg transport. Shorter, mucus-secreting peg cells are interspersed among the ciliated cells. The film they produce is propelled toward the uterus by cilia, helping transport the ovum and hindering bacterial access to the peritoneal cavity. The muscularis has inner circular and outer longitudinal smooth muscle layers. Its wavelike contractions move the ovum toward the uterus. The outer covering of the tubes is a serosa of visceral peritoneum.

IV. UTERUS

A pear-shaped muscular organ in the pelvic cavity, the uterus (womb) is the site of implantation and development of the embryo. It is grossly divided into 3 regions. The body, or corpus, is its large, round middle region. The fundus is the extension of the body above the point of entry of the uterine tubes. The neck, or cervix, is the narrow, downward extension of the uterus into the vagina. In the fundus and body, the uterine wall consists of 3 layers: the endometrium, myometrium, and serosa or adventitia.

A. Endometrium: The uterine mucosa, this layer consists of simple columnar epithelium sup ported by a lamina propria. Simple tubular glands extend from the luminal surface into the lamina propria; their lining is continuous with the surface. The endometrium receives a double blood supply and is divisible into 2 regions.

1. Stratum functionale (pars functionalis), This is the temporary layer at the luminal surface. It responds to ovarian hormones by undergoing cyclic thickening and shedding. It is further subdivided by some based on the density of the lamina propria into a zona compacta near the lumen and a deeper zona spongiosa,
2. Stratum basale (pars basalis), This thinner, deeper, permanent layer contains the basal portions of the endometrial glands and is retained during menstruation. The epithelial cells lining these glands divide and cover the raw surface exposed during menstruation.
3. Blood supply. Paired uterine arteries branch to form the arcuate arteries in the middle of the myometrium. The arcuates give rise to 2 sets of arteries: straight arteries to the stratum basale and coiled arteries to the functionalis. The double supply to the endometrium is important in the cyclic shedding of the functionalis, when the coiled arteries are lost and the straight arteries are retained.

B. Myometrium: The muscularis of the uterus, this is its thickest tunic, consisting of 4 poorly defined smooth muscle layers. The middle layers contain the abundant arcuate arteries. During pregnancy, the myometrium grows extensively by both hypertrophy and hyperplasia. At birth, a surge of pituitary oxytocin induces the forceful myometrial contractions that expel the fetus.

C. Serosa or Adventitia: The uterus has 2 types of outer coverings. The fundus is covered by a cap of serosa, and the body is surrounded by an adventitia of loose connective tissue.

D. Menstrual Cycle: The endometrium undergoes cyclic changes controlled by the ovarian hormones estrogen and progesterone. Ovarian hormone production is in turn controlled by the pituitary hormones FSH and LH and is related to follicle growth, to ovulation, and to the formation and degeneration of the corpus luteum. The menstrual cycle is divided into 3 phases based on structural and functional changes in the endometrium: the menstrual phase, the proliferative (or follicular) phase, and the secretory (or luteal) phase. Table 23-1 describes an idealized 28-day menstrual cycle in terms of its 3 main phases, the part of the cycle they occupy, the endometrial changes during each phase, and the correlated changes in ovarian function.

E. Uterine Cervix: The external surface of the cervix (neck) of the uterus bulges into the vaginal canal. Its wall consists mainly of dense connective tissue, with a small amount of smooth muscle. The mucosa has a tall simple columnar epithelium and branched cervical glands lining the cervical canal. Stratified squamous epithelium covers its external (vaginal) surface. The switch in epithelial type occurs just inside the opening of the cervical canal into the vagina (external os of the cervix), the most common site of cervical cancer. The cervical mucosa is not shed during menstruation, but cyclic changes do occur in the amount and viscosity of the cervical secretions. At ovulation, for example, watery secretions permit penetration by sperm; in the luteal phase and during pregnancy, the secretions are abundant and more viscous. Cervical dilation preceding parturition is due to intense collagenase activity in the cervical wall.

V. FERTILIZATION & PREIMPLANTATION DEVELOPMENT

Fertilization occurs at the ampullaristhmic junction in the uterine tube. Sperm penetrate the corona radiata and then the zona pellucida. Only one sperm head fuses with the plasma membrane of the ovum (oolemma). Fertilization stimulates the completion of the second meiotic division of the ovum, and the second polar body is formed. Finally, the haploid male and female pronuclei fuse to form the diploid nucleus of the zygote. The zygote undergoes several rounds of mitosis, with little or no cell growth between divisions, to become a solid ball of smaller cells, or morula, as it moves along the oviduct toward the uterus. As mitosis continues, a cavity forms at the center of the embryo, which is now called a hlastocyst, By this stage (day 4 after fertilization), the embryo has entered the uterus. The blastomeres--the cells of the blastocyst--form 2 layers: a peripheral trophoblast, which will form the fetal part of the placenta, and a disk of cells (the inner cell mass), which will form the embryo, bulging into the cavity. Once in the uterus, the blastocyst floats free for 2-3 days before implantation. The zona pellucida dissipates at this time, allowing the trophoblast cells to contact the endometrium directly.

VI. IMPLANTATION

This is the penetration of the uterine epithelium by the blastocyst. It is the first step in placentation and involves important activities in the blastocyst itself and in the uterine lining tie, the decidual reaction).

A. Blastocyst Activity:

1. Trophoblast, The trophoblast cells attach to the endometrium, divide rapidly, and differenti ate into 2 layers. The syncytiotrophoblast, the highly invasive outer layer, consists of multiple nuclei in a single large cytoplasm. It is formed by fusion of mononucleated cells from the underlying layer, the cytotrophoblast. The trophoblast erodes the uterine epi thelium, allowing the embryo to invade the stroma. By day 9 after fertilization, the embryo is completely embedded in the endometrium and is surrounded by a trophoblastic shell. Im plantation in which the embryo becomes completely embedded in the endometrium is termed interstitial implantation.
2. Inner cell mass. The inner cell mass forms a bilaminar disk (blastodisc), which becomes the embryo itself, and a shell of extraembryonic mesoderm that lines the inner surface of the cytotrophoblast. The blastodisc is separated from the extraembryonic mesoderm by a cavity, the extraembryonic coelom, The future embryo is thus separated from the endometrium by a 3-layered shell or chorion.
3. Chorion, The chorion includes derivatives of both the trophoblast (syncytiotrophoblast and cytotrophoblast) and the inner cell mass (extraembryonic mesoderm). It has 2 named re gions. The chorion frondosum is the portion that lies adjacent to the decidua basalis (VI.B), and forms the fetal part of the placenta. The chorion laeve is the portion adjacent to the decidua capsularis (VI.B). Midway through pregnancy, this layer fuses with the decidua parietalis (VI.B) on the opposite side of the uterus, obliterating the uterine cavity.

B. Decidual Reaction: Upon implantation, the endometrium undergoes changes referred to as the decidual reaction (the pregnant endometrium is now termed the decidua). During this reaction, the endometrium thickens and its stromal cells enlarge to become decidual cells, which secrete prolactin. The decidual reaction helps prevent invasion of the trophoblast beyond the endometrium (a condition termed decidua increta or decidua percreta). The decidua has 3 named parts. The decidua basalis is the portion underlying the implantation site; it forms the maternal part of the placenta. The decidua capsularis is the portion overlying the implanted embryo and separating it from the uterine cavity. The decidua parietalis is the remainder of the endometrium, ie, the portion not in direct contact with the embryo.

VII. PLACENTA

This is a temporary organ whose formation begins during implantation. It has both embryonic (chorion frondosum) and maternal (decidua basalis) components. The placenta transfers maternal nutrients and oxygen to the embryo, cleanses the fetal blood, and secretes hormones.

A. Steps in Placental Development (Placentation): The invading syncytiotrophoblast sur rounds and delineates small islands of endometrium containing blood vessels. Enzymes secreted by the syncytiotrophoblast lyse the maternal tissue, leaving spaces, or lacunae, and rupturing blood vessels. The ruptured vessels fill the syncytiotrophoblast-lined lacunae with maternal blood. Solid cords of chorionic tissue (chorionic villi) grow into these lacunae and develop, through a series of steps, both to bring the blood in the fetal vessels close enough to the maternal blood in the lacunae for exchange to occur and to form a selectively permeable placental barrier (VII.B; Fig 23-4). Primary villi are tongues of syncytiotrophoblast and cytotrophoblast. The underlying extraembryonic mesenchyme invades the primary villi to form secondary villi, composed of syncytiotrophoblast, cytotrophoblast, and a core of extra embryonic mesenchyme. The extraembryonic mesenchyme differentiates into blood vessels that later establish connections with the umbilical vessels of the fetus. Tertiary villi are thus com posed of syncytiotrophoblast, cytotrophoblast, and extraembryonic mesenchyme with blood vessels in their cores. In later stages, the cytotrophoblast disappears as all its cells fuse with the syncytiotrophoblast.

B. Placental Functions:

1. Transfer of nutrients and wastes. By day 23 of gestation, the fetal blood is circulating through the tertiary villi. Nutrients from the maternal blood in the lacunae reach the fetal circulation by passing successively through (I)the syncytiotrophoblast; (2) the cytotropho blast, which later disappears; (3) the basal lamina of the trophoblast; (4) the extraembryonic mesenchyme; (5) the basal lamina of the vessels in the tertiary villi; and (6) the fetal vascular endothelial cells. These 6 layers constitute the placental barrier (Pig 23-4), which restricts the substances that cross between the maternal and fetal circulations. The maternal-fetal boundary is further marked by fibrinoid, a layer of the products of necrosis that may form a nonantigenic barrier and explain maternal tolerance of fetal antigens.
2, Placental hormones, Many hormones are secreted by the syncytiotrophoblast of the chorion, and a few additional hormones are produced by the decidual cells. Placental hor mones include chorionic gonadotropin, chorionic thyrotropin, chorionic corticotropin, es trogens, progesterone, prolactin, and placental lactogen.

VIII. VAGINA

This muscular tube extends from the cervix to the external genitalia. Its walls lack glands, and vaginal lubrication involves secretions produced by the cervical and Bartholin's glands and smaller mucous glands in the vestibule. The vaginal walls have 3 layers: mucosa, muscularis, and adventitia.

A. Mucosa: The vaginal mucosa is a stratified squamous epithelium, rich in glycogen and sup ported by an elastic fiber-rich lamina propria. Bacterial metabolism of glycogen from the lining cells sloughed into the lumen results in lactic acid accumulation and the vagina's low pH. The extensive capillary plexus in the lamina propria provides much of the fluid that seeps into the lumen during sexual arousal. The vaginal mucosa contains few sensory nerve endings.

B. Muscularis: The vaginal muscularis consists mainly of longitudinal smooth muscle, but includes some circular fibers near the mucosa.

C, Adventitia: The vagina is surrounded by a sheath of dense connective tissue rich in elastic fibers. It contains an extensive venous plexus, bundles of nerve fibers, and clusters of neurons.

IX. EXTERNAL GENITALIA (VULVA)

This area is richly innervated with Meissner's and pacinian corpuscles along with free nerve endings.

A. Clitoris: A homologue of the dorsal part of the penis, this consists of 2 small erectile corpora cavernosa that end in a glans clitoridis. It is surrounded by a prepuce and covered by stratified squamous epithelium.

B. Vestibule: This is the area that receives the openings of the vagina and the urethra. It is covered by stratified squamous epithelium and includes 2 types of glands. Bartholin's glands (glandulae vestibulares majores) are 2 large, tubuloalveolar mucous glands on opposite sides of the vestibule. They are analogous to the bulbourethral (Cowper's) glands in males. The vestibular glands (glandulae vestibulares minores) are smaller and more numerous mucous glands scattered around the vestibule. Most lie near the urethra and clitoris. These are analogous to the glands of Littre in males.

C. Labia Minora: These are skin folds with a core of spongy (erectile) connective tissue, analogous to the male corpus spongiosum, covered by stratified squamous epithelium. They have a thin keratinized layer on their surfaces, and, although they contain sweat and sebaceous glands on both their surfaces, there are no hairs.

D. Labia Majora: These folds of skin have a core of subcutaneous fat and a thin layer of muscle. The inner surface of each is similar to that of the labia minora; the outer surface has more keratin and contains coarse hairs. Both surfaces contain numerous sebaceous and sweat glands. Their developmental analogue in males is the scrotum.

X. MAMMARY GLANDS

These accessory glands of the skin are specialized to secrete milk. Each of these compound tubuloalveolar glands contains 15-25 lobes, separated by both adipose tissue and bands of dense connective tissue. Each lobe empties through a lactiferous duct, which exhibits a terminal expansion, or lactiferous sinus, before opening independently on the surface of the richly innervated nipple (papilla), These glands undergo extensive changes correlated with age and the functional state of the reproductive system.

A. Embryonic Development: Paired ventral epidermal thickenings running from forelimb to hindlimb, the milk lines, appear at 6 weeks. Their caudal portions regress early. In the second trimester, 15-25 epithelial invaginations develop along these lines on each side of the thorax. These are the future lactiferous ducts. The rest of the milk lines normally degenerate. Mammary secretion in newborns (under the influence of placental and maternal hormones) is common.

B. Prepubertal Mammary Gland: The nonfunctional gland is composed of lactiferous ducts and sinuses. The small nipple is surrounded by a lightly pigmented areola.

C. Changes During Puberty: The female breasts enlarge as a result of the accumulation of adipose tissue and collagenous connective tissue, and the nipples enlarge and become more prominent. Increased production of ovarian estrogen stimulates fat deposition and the proliferation-increased length, diameter, and branching--of the lactiferous ducts.

D. Resting Adult Gland: The basic subunits of the gland, the lobules, develop as a result of growth during puberty. The lobules are separated by loose connective tissue, and few secretory alveoli are present. Most of the lobules consist of several blind-ended intralobular ducts; these are lined by cuboidal epithelium that rest on a basal lamina and are surrounded by a discon tinuous layer of myoepithelial cells. All the intralobular ducts from one lobule empty into a single terminal interlobular duct, which leads to a larger lactiferous duct. The lactiferous ducts are lined by cuboidal to columnar epithelium, overlying a layer of densely packed, spindle-shaped, longitudinally oriented myoepithelial cells that separates the epithelium from its basal lamina. The lactiferous ducts empty through the stratified squamous-lined lactiferous sinuses. Minor changes occur during the menstrual cycle. The estrogen peak at ovulation induces further proliferation of the ducts, which can cause premenstrual breast enlargement, attended by transient edema and tenderness.

E. Pregnant Adult Gland: The influence of several hormones, including estrogen, pro gesterone, prolactin, and human placental lactogen causes intense proliferation of the ducts and growth of alveoli at their ends, enlarging the breasts. The terminal epithelium of the intralobular ducts proliferates and differentiates into milk-secreting cells, resulting in the formation of numerous secretory alveoli within the lobules. In pregnancy, the mammary alveolar cells are characterized by basal nuclei that are surrounded by a supranuclear Golgi complex, scattered mitochondria, lysosomes, milk protein-containing secretory vesicles, and a few apical fat drop lets. Myoepithelial cells intervene between the alveolar cells and their basal lamina. Late in pregnancy, the number of plasma cells in the interlobular connective tissue increases. These cells add secretory IgA to the mammary secretions (especially colostrum) and confer passive immunity on the newborn. Although the glands are well developed during pregnancy, secretions are not found in their lumens until late in pregnancy, when they contain colostrum (protein-rich first milk), or during lactation, when they contain the actual lipid-rich milk.

F. Lactating Adult Gland: With the loss of the placenta at birth, estrogen and progesterone decrease and prolactin increases. The major change in histologic appearance from pregnant glands is the accumulation of milk in the alveolar lumens and their accompanying dilation. The secretory cells reduce in height from low columnar to low cuboidal, and there are numerous fat droplets containing neutral triglycerides in their cytoplasm. During secretion, the fat droplets acquire a membrane from the cell apex (apocrine secretion). Increased numbers of secretory vesicles containing milk proteins appear in the cytoplasm and are released via merocrine secre tion.

1. Milk composition. Milk typically contains 4% lipids, 1.5% proteins (caseins, lactalbumin, IgA), 7% lactose (disaccharide of glucose and galactose), and 87.5% water.
2. Maintaining lactation. The sensory stimuli of suckling inhibits dopamine (or prolactin inhibiting hormone) secretion by the hypothalamus. This increases the release of prolactin from the anterior pituitary, which in turn stimulates milk production. With weaning--the cessation of suckling--prolactin levels fall and the alveoli degenerate. 3. Milk ejection reflex. The sensory stimulus of suckling also causes oxytocin synthesis in the hypothalamus. The release of oxytocin by the posterior pituitary stimulates myoepithelial cell contraction, ejecting milk from the alveoli into the lactiferous ducts.

G. Senile Involution: After menopause, the secretory portions, ducts, and adipose and inter lobular connective tissues in the breasts atrophy.

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