Female reproductive system:

1. Internal genitalia. These are located in the pelvis, and include the ovaries, oviducts, uterus and vagina.

2. External genitalia. These are situated in the anterior part of the perineum, and include the mons pubis, labia majora, labia minora, clitoris, vestibule, opening of the vagina, and external urethral orifice.

3. Accessory organs: mammary glands and placenta.

1. Internal genitalia:

• Ovaries, which produce ova.
• Oviducts, which provide a suitable environment for fertilization and direct the fertilized ovum into the uterus.
• Uterus, which provides nutrients for the embryo until the time of parturition.
• Vagina, which joins the uterus to the exterior of the body.

2. External genitalia:

• Mons pubis
• Labia majora
• Labia minora
• Clitoris
• Vestibule
• Opening of the vagina
• External urethral orifice

Ovaries

Paired, almond-shaped and almond-sized. They have a hilum on one side where blood vessels, lymphatics, and nerves enter and exit. They are attached to the posterior surface of the broad ligament by a peritoneal fold, the mesovarium. The superior 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 pole is attached to the uterus by the ovarian ligament. This ligament is a remnant of the gubernaculum, the ligament that attaches the developing gonad to the floor of the pelvis.

General Structure of the ovary

Surface structure. The surface of the ovary is covered by a simple squamous or cuboidal epithelium, mistakenly termed germinal epithelium. It was incorrectly thought to be the site of germ cell formation. In fact, the primordial germ cells of both sexes are of extragonadal origin.

Stroma of the ovary. The stroma consists of dense cellular connective tissue with layers of collagen. Below the surface epithelium, the connective tissue in the cortex is less cellular and more compact, forming the tunica albuginea. The ovary contains two regions:

• Cortex, which is the peripheral region of the ovary, and is formed from rich cellular connective tissue with fine collagenous fibers. Different sizes of ovarian follicles are embedded in the cortex.
• Medulla, which is the central region of the ovary; it is formed from loose connective tissue and contains blood vessels, lymphatic vessels, and nerves.
  

During the first embryonic month, the primordial germ cells (oogonia) will form in the yolk sac. They migrate and divide mitotically and populate the cortex of the future ovary. Generally, only one ovum becomes mature and is liberated from the ovaries in each menstrual cycle (average duration 28 days). The reproductive life of a woman lasts about 30-40 years. Therefore, only about 300-400 ova are liberated. All the other follicles become atretic and degenerate.

1. Primordial follicles

During the third embryonic month, some of the oogonia enter prophase of the first meiotic division and become primary oocytes. A primary oocyte becomes surrounded by one layer of flattened cells, forming a primordial follicle. Primary oocytes become arrested at the diplotene stage of prophase 1, and remain in this stage until further follicular development during the menstrual cycle. Therefore, in women approaching menopause, the oocytes have been in this state for 40-45 years before continuing on with division. It is thought that this may be responsible for the increased frequency of nondisjunction of chromosomes (which can result in Down’s syndrome) observed with increased age.

2. Primary follicles

Primordial follicles develop into primary follicles. Changes occur in the oocyte, follicular cells, and adjacent connective tissue of the cortex. Hormonal stimulation of some of the primary oocytes causes them to enlarge and produce a thick glycoprotein membrane between the oocyte and adjacent follicular cells. As the oocyte grows, the flattened follicular cells of the primordial follicles become cuboidal or columnar in shape and proliferate to form several layers. These cells increase their number of FSH receptors and begin to produce estrogen. These cells now are called granulosa cells, and the layer is called stratum granulosum. The stratum granulosum is avascular. Cytoplasmic processes from the granulosa cells penetrate the zona pellucida in order to communicate with processes from the oocyte via gap junctions. While these changes are occuring in the oocyte and follicular cells, the adjacent stroma becomes organized into a sheath, the theca folliculi. The theca folliculi is separated from the stratum granulosum by a distinct basement membrane. The theca folliculi differentiate into an inner secretory layer, the theca interna, and an outer fibrous layer, the theca externa.These two layers are vascularized.

Secondary follicle

This structure contains a primary oocyte surrounded by 8-12 layers of granulosa cells (stratum granulosum). Small spaces filled with liquid appear between the granulosa cells. The fluid increases in amount, and the spaces fuse to form a single cavity called the follicular antrum. The follicle is now a secondary or antral follicle. The oocyte has reached its full size and undergoes no further growth. At this point, it is still a primary oocyte.

Graafian follicle

The oocyte is eccentrically placed in the follicle, surrounded by a mass of granulosa cells that project into the fluid-filled antrum, forming a hillock called the cumulus oophorus. The cells of the cumulus are continuous with those lining the antral cavity. The cloud of granulosa cells surrounding the oocyte is called the corona radiata, which is anchored to the zona pelucida by cytoplasmic processes. The corona radiata remains with the oocyte at the time of ovulation and stays until fertilization. The theca layers become more prominent. The theca interna cells stimulated by LH secrete androgens; these serve as precursors for estrogens. Some of the androgens are transported to the granulosa cells. In response to FSH, the granulosa cells convert the androgens to estrogen, which, in turn, stimulates the granulosa cells to proliferate and thereby increase the size of the follicle. A surge in the release of FSH and/or LH is induced in the adenohypophysis approximately 24 hours before ovulation. In response to the LH surge, the LH receptors on granulosa cells no longer produce estrogens in response to LH. Triggered by this surge, the meiotic division of the primary oocytes resumes, resulting in the formation of the secondary oocyte and first polar body.

At the middle of the menstrual cycle (on 14th day of a 28 day cycle), when the levels of FSH and LH peak, ovulation occurs and a secondary oocyte is released. There is an increase in follicular fluid, and in the enzymes which degrade the basement membrane and the wall of the ovary. There is a decrease in blood flow to tissue between the follicle and the outer surface of the ovary. This thin and translucent area is called the stigma, or macula pellucida. Collagenase produced by the granulosa cells adjacent to the tunica albuginea appears to be responsible for the breakdown of collagen fibers at the site of the stigma.

At the time of ovulation, the fimbriae of the oviduct becomes closely apposed to the surface of the ovary, directing the oocyte into the oviduct.
Meiosis II begins, but stops at metaphase II and will only continue after fertilization to produce the 2nd polar body and mature ovum. After ovulation, the oocyte is viable for approximately 24 hours. If fertilization fails, the secondary oocyte degenerates as it passes through the oviduct. Normally, only one follicle completes maturation in each cycle and ruptures to release its secondary oocyte.

Corpus luteum

• The corpus luteum produces both estrogen and progesterone.
• Granulosa cells increase greatly in size, smooth endoplasmic reticulum (sER) becomes abundant, and mitochondria show tubular cristae. These granulosa cells are now called granulosa lutein cells.
• The cells of the theca interna also enlarge and become epithelioid in character to form theca lutein cells.
• The granulosa cells and theca cells are invaded by blood vessels, while the antrum is eventually invaded by fibroblasts.
• The corpus luteum produces the progesterone necessary to prepare the endometrium for a fertilized ovum.
• If the ovum is not fertilized, the corpus luteum persists for about 14 days as a corpus leuteum of menstruation, which gradually degenerates. If pregnancy occurs, then it is called the corpus luteum of pregnancy.

If pregnancy take place, the corpus luteum enlarges and occupies most of the ovarian space, and is called the corpus luteum of pregnancy. It is maintained beyond the two weeks by human chorionic gonadotropin, a hormone synthesized by trophoblast cells. The corpus luteum of pregnancy produces the progesterone needed to maintain the pregnancy until placental membranes are adequate to do it by themselves (usually weeks 9-10).

Ovarian function

• Production of gametes
• Production of steroid hormones (estrogen and progesterone).

Maturation of ovarian follicles, their endocrine function, and ovulation, are regulated by follicle stimulating hormone (FSH) and luteinizing hormone (LH). These two hormones are called gonadotropin hormones (GTH), and are secreted by the anterior pituitary gland. During each menstrual cycle, the ovaries undergo cyclic changes that involves two phases:

• Follicular phase
• Luteal phase

FSH secreted by the pituitary causes maturation of the follicle and induces secretion of estrogen by granulosa cells. LH, together with FSH, cause ripening of the follicle and ovulation. LH alone causes corpus luteum formation. The corpus luteum secretes estrogen and progesterone. The cyclic nature of follicle formation and ovulation is the result of reciprocal interaction between the pituitary and gonadotropins and ovarian hormones. As production of estrogen by granulosa cells increases, release of FSH from the pituitary is inhibited, and the level of FSH falls below what is needed for maturation of a new follicle. However, high levels of estrogen cause an increase in secretion of LH, resulting in ovulation and formation of a corpus luteum. The corpus luteum secretes high levels of estrogen and progesterone. The increase in progesterone inhibits LH secretion, and when level of LH decrease, the corpus luteum is no longer maintained, estrogen diminishes, the pituitary no longer is inhibited from secreting FSH, and a new cycle of follicle formation begins.

The oviduct delivers the ovulated ovum and provides an environment for fertilization. The oviduct is divided into four segments:

• Infundibulum
• Ampulla
• Isthmus
• Intramural

The oviduct consist of 3 layers: Internal mucosa, intermediate muscularis, and external serosa.

1. The internal mucosa consists of a single layer of cuboidal to low columnar epithelium which is secretory, with some cilia. The lamina propria is a rich cellular connective tissue that contain reticular fibers and fibroblasts. The number of ciliated cells decreases from fimbrae to intramural region. The epithelium shows cyclic changes associated with ovarian cycles. During the luteal phase, the secretory cells are highly active. During the follicular phase, the number and height of ciliated cells will increase. Estrogen appears to be responsible for the appearance and maintenance of cilia, and progesterone increases the number of the secretory cells. The mucosa of the oviduct has a series of longitudinal folds called plicae. In the ampulla, the plicae are long and branched. In the isthmus, the plicae are shorter with little branching, and in the intramural part are very short.

2. The intermediate muscularis contains:

• An inner circular layer
• An outer longitudinal layer

3. The external serosa contains:

• A mesothelium plus a thin layer of connective tissue that covers the oviduct.

The uterus is located in the pelvic cavity between the bladder and rectum. The non-pregnant uterus is 7cm in length, 3-5cm at its widest (upper) part, and 2.5-3cm thick. The uterus receives the fertilized ovum and nourishes the embryo and fetus until birth. Anatomically it is divided into two regions:

• Body, which is the large upper portion. The rounded upper part of the body is called the fundus.
• Cervix, which is the narrow lower portion of the uterus. The lumen of the cervix, called the cervical canal, has a constricted opening or os at each end. The internal os communicates with the cavity of the uterus, the external os with the vagina.

The wall of the uterus consists of :

• Tunica mucosa (endometrium)
• Tunica musculosa (myometrium)
• Tunica adventitia (perimetrium).

The tunica mucosa (endometrium) consists of a simple columnar epithelium and a thick lamina propria (endometrial stroma). The lamina propria is a dense connective tissue with a high number of lymphocytes. The epithelium dips into the stroma to form numerous uterine glands. These glands are simple tubular glands with some basal branching. Their major secretion is glycogen. The endometrium can be divided into 3 basic layers:

• Stratum compactum
• Stratum spongiosum
• Stratum basalis

Together, the stratum compactum and stratum spongiosum form the stratum functionalis; this layer undergoes major cyclic changes and is shed during menstruation

Blood supply of the endometrium

Branches of the uterine artery penetrate the middle layer of the myometrium and run cicumferentially as arcuate arteries. One set of branches from these arteries supplies the superficial layer of the myometrium and endometrium. The radial branches provide a dual circulation to the endometrium. Straight arteries supply the basal layer, while the functional layer is supplied by highly coiled spiral arteries.

The menstrual cycle consists of five phases (during 28 days):

• Menstrual phase (days 1-5)
• Reparative phase (days 5-6)
• Proliferative phase (days 7-14)
• Secretory phase (days 15-27)
• Ischemic phase (day 28)

The myometrium has three muscular layers:

• inner longitudinal
• middle circular
• outer longitudinal

The perimetrium is the serosal or peritoneal layer that covers the body of the uterus posteriorly and anteriorly, except the supra-vaginal part of the cervix anteriorly.

Cervix

The cervical epithelium is not lost during menstruation. The epithelium is simple columnar. Cysts can form in mucous glands (nabothian cysts).

Secretions of the cervix change duing the menstrual cycle:

• Under estrogen stimulation
• Under progestrone stimulation
• During pregnancy
• Near parturition

Vagina

• Tunica mucosa; its epithelium is non-keratinized stratified squamous with no glands. This epithelium does show cyclic changes.
• Tunica muscularis, consisting of an inner circular and and an outer longitudinal muscle layer.
• Tunica adventitia, consisting of irregularly arranged, very vascular fibrous connective tissue.

Implantation.

After a few divisions, the fertilized ovum will form the blastocyst. The blastocyst implants in the body of the uterus.

The blastocyst is composed of an inner cell mass, which forms the embryo proper, and an outer cell mass, which forms the trophoblast and, later, the placenta.

The trophoblast differentiates into the syncytiotrophoblast and cytotrophoblast.

Decidualization involves changes of the endometrium of the uterus after it comes into close contact with the trophoblast. The portion of the endometrium that undergoes morphological changes and sheds after parturition is called the decidua graviditas. As the growing fetus fills the uterine lumen, three different regions of the decidua are identified by their relationship to the site of the implantation:

• Decidua basalis
• Decidua capsularis
• Decidua parietalis

The chorion consists of :

• Syncytiotrophoblast
• Cytotrophoblast
• Extraembryonic somatic mesoderm

The placenta is formed from a fetal part, the chorion, and a maternal part, the decidua basalis.

The uteroplacental circulatory system develops by anastomosis of the trophoblastic lacunae (which are formed within the syncytiotrophoblast) and maternal sinusoids (which are formed from capillaries of the maternal side).

Proliferation of the cytotrophoblast, growth of chorionic mesoderm, and blood vessel development give rise to the:

• Primary chorionic villi: a cord or mass of cells extending into the blood-filled trophoblastic lacunae in the syncytiotrophoblast.
• Secondary chorionic villi: The primary villi branch and the chorionic mesoderm cells invade their bases, forming a central core of loose connective tissue.
• Tertiary chorionic villi: blood vessels will form in the cores.

Placental barrier.

Exchange of substances between the maternal and fetal circulation take place through the placental barrier, which is composed of the following:

• Syncytiotrophoblast of the placenta.
• Discontinuous inner cytotrophoblast layer.
• Basal membrane of the trophoblast.
• Fetal loose connective tissue of the villus.
• Basal membrane of endothelium of fetal capillaries.
• Endothelium of the fetal placental capillary in the tertiary villus.

The placenta produces both steroid and protein hormones.

Steroid hormones include:

• Estrogen
• Progesterone

Peptide hormones include:

• Human chorionic gonadotropin (hCG)
• Endothelial growth factor (EGF)
• Insulin-like growth factor I and II (IGF I and IGF II)
• Relaxin

External genitalia:

• Clitoris, an incomplete counterpart of the penis. It lacks the corpus spongiosum and the urethra.
• Glands of Bartholin, which are mucous tubuloalveolar glands.
• Labia minora, a thin fold of mucous membrane that forms the lateral walls of the vestibulum.
• Labia majora, a thick fold of skin that covers the labia minora.

Objectives for female reproductive histology

• Briefly describe the major hormones related to the menstrual cycle and relate them to the steps in follicle development and endometrium morphology.
• Describe the general structure of the ovary.
• Describe the steps in oogenesis and follicle development including those following ovulation.
• Describe the organization of the oviduct and name the regions.
• Describe the layers of the uterus.
• Describe the endometrial changes that occur during the menstrual cycle.
• Describe the changes in the cervical secretions that occur during the menstrual cycle.
• Describe the organization of the vagina.
• Describe the accessory organs and external genitalia, i.e., clitoris, labia minora, labia majora, and glands of Bartholin.
• Name the components of the placental barrier.

Each mammary gland consists of 15-25 lobes of the compound tubuloalveolar type whose function is to secret milk to nourish newborns. Each lobe is separated from the others by dense connective tissue and adipose tissue and is really a gland in itself with its own excretory lactiferous duct. The lactiferous ducts open independently in the nipple. The histology of the mammary gland varies according to sex, age, and physiologic status of the person.

The mammary glands appear in a 6-week-old human embryo as a pair of thickenings of the epidermis. In the thoracic region of a second-trimester fetus, 15-25 ingrowths of the epithelium penetrate the underlying connective tissue and give rise to the future lactiferous ducts.

Breast enlargment during puberty in the female (due to an increase in ovarian estrogen) is the result of the accumulation of adipose tissue and collagenous connective tissue, with increased branching of lactiferous ducts playing a minor role. Lactiferous ducts close to the nipple dilate to form the lactiferous sinuses.

In the adult female breast, lobules will form. A lobule consists of several intralobular ducts that empty into one terminal interlobular duct. Dense, less-cellular interlobular connective tissue separates the lobules.

The nipple has a conical shape; its color may be pink, light brown, or dark brown. It is covered by keratinized stratified squamous epithelium. The epithelium of the nipple rests on a layer of connective tissue rich in smooth muscle fibers. The nipple is abundantly supplied with sensory nerve endings.

Near the opening of the nipple, the lactiferous ducts dilate to form the lactiferous sinuses. The lactiferous sinuses are lined by stratified squamous epithelium at their external openings. Very quickly, this epithelium changes to stratified columnar or cuboidal epithelium. The epithelial cells are joined by tight junctions and desmosomes. The terminal interlobular ducts consist of simple cuboidal epithelium resting on basal lamina and a discontinuous layer of myoepithelial cells. Lymphocytes and plasma cells are present in the intralobular connective tissue surrounding the alveoli. At the end of pregnancy, the plasma cells population increases significantly and is responsible for the secretion of immunoglobulines (secretory IgA) that confer passive immunity on the newborn. During the menstrual cycle, the cells of the ducts proliferate at the time of ovulation (when the amount of estrogen is high). Greater hydration of connective tissue in the premenstrual phase produces breast enlargment.

Breast during pregnancy.

The alveoli at the end of terminal intralobular ducts within the lobules proliferate. Alveoli are spherical collections of epithelial cells that become the active milk-secreting structures in lactations. A few fat droplets, not surrounded by a membrane, can be seen in the apical cytoplasm of alveolar cells, along with membrane-delimited secretory vacuoles containing milk proteins. The number of secretory vacuoles and fat droplets greatly increases in lactation. Myoepithelial cells are found between the alveolar epithelial cells and the basal lamina. The amount of adipose tissue and connective tissue decreases. Growth of the mammary glands during pregnancy occurs as a result of the synergistic action of several hormones, mainly estrogen, progesterone, prolactin, and human placental lactogen. These hormones stimulate the growth of the alveoli. The amount of estrogen during pregnancy increases since this hormone is also produced by the placenta. The amount of progesterone also increases . This hormone is produced first by the corpus luteum, and later by the placenta.

During lactation, milk is produced by the epithelial cells of the alveoli into their lumen and inside of the lactiferous ducts. Secretion of fat droplet is by apocrine secretion. Milk protein like caseins, lactalbumin, and immunoglobulin A, are released by exocytosis.