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Home , Cervical canal, Corpus albicans, Corpus luteum, Cumulus oophorus, Ovary, Theca

HISTOLOGY OF THE FEMALE

Learning Objectives 1. Describe the various ovarian follicles, correlating their growth and endocrine activity with the appropriate days and stage of the ovarian cycle. 2. Describe the and its formation, correlating its endocrine activity with the appropriate days and stage of the ovarian cycle. 3. Describe the histology of the , , uterine and and correlate changes in the histology or these subdivisions/organs with changes in secretion of ovarian . 4. Describe the histology of the during various stages of the uterine and correlate these changes with changes in secretion of ovarian hormones.

Although true of all systems, it is especially important, when studying the female reproductive system, to keep an overview of the entire system in mind and not to isolate any one . The ovarian hormones dictate the histology and physiology of the other organs in the female reproductive system. Therefore, it is essential to correlate the stages and hormones of the ovarian cycle and the peak activity of the other organs.

I. Components

A. Paired

1. Produces female germ cells, ova (sing., ovum) 2. Produces female hormones, and

B. Paired or Fallopian tubes

1. Provides site of fertilization 2. Transports female germ cells, and

C. Uterus

1. Houses and nourishes conceptus during 2. Forms maternal portion of the 3. Expels at

D. Vagina

1. Forms birth canal 2. Receives sperm

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OVARY

I. General organization

A. Flattened, ovoid, paired glands

1. Exocrine function – maturation and release of , the developing female germ cells.

2. Endocrine function – secretion of estrogen and progesterone

B. Two major subdivisions

1. Cortex

a. Covered with a serosa

i. Germinal - simple cuboidal epithelium ()

ii. Tunica albuginea - underlying, dense connective

b. Contents - exact contents vary with age of the and stage of ovarian cycle

i. Follicles - spheres of epithelial cells surrounding an . Multiple follicles progress through a series of stages until a single follicle ruptures to release the oocyte at . Follicles secrete estrogen during the first half of the ovarian cycle.

ii. Corpus luteum - formed from the wall of the ovulating follicle after the oocyte is ovulated. The corpus luteum secretes progesterone and estrogen and is present during the second half of the ovarian cycle. 2

iii. Atretic follicles - degenerating follicles that are not ovulated

iv. - degenerating corpus luteum

2. Medulla - inner region composed of , blood vessels and

III. Follicles – spherical bodies housing oocytes; active during Days 1-14 of ovarian cycle

A. A primordial follicle:

1. Contains a primary oocyte (see description next section)

2. Follicular cells form a simple squamous epithelium around the oocyte.

3. Is the only follicle present until

B. Primary follicles

1. A primary unilaminar follicle

a. Contains a primary oocyte.

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b. Follicular cells form a simple cuboidal or columnar epithelium around the oocyte.

2. A primary multilaminar follicle

a. Contains a primary oocyte

b. Follicular cells form a stratified epithelium around the oocyte.

c. , formed by both the oocyte and adjacent follicular cells, is a thick band surrounding the oocyte.

d. folliculi, a layer located outside the basement membrane of the follicular cells, is formed by the differentiation of the multipotential stromal cells.

C. Secondary follicle

1. Contains a primary oocyte.

2. Follicle cells increase in size and number and produce a follicular liquid.

3. Follicular liquid accumulates in antral spaces between follicular cells. Multiple antral spaces eventually coalesce to form a single antrum.

4. The granulosa layer (granulosa cells or ) are follicular cells surrounding the antrum. These cells convert , produced in , into estrogen.

5. The is a hillock of granulosa cells in which the primary oocyte is embedded. The innermost layer of cumulus cells, immediately surrounding the oocyte, forms the corona radiata.

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6. Theca folliculi develops into:

a. Theca interna, located outside the basement membrane of the follicular cells, is composed of cells that secrete the , .

b. , composed of multipotential connective tissue cells, resembles a layer of flattened . The theca externa serves as a reserve cell source for the theca interna.

7. Usually only a single secondary follicle progresses to the mature follicle stage.

D. Mature (Graafian) follicle - the follicle that will rupture, ovulating a secondary oocyte. Present only during the day preceding ovulation. Changes occurring during the time it is present include:

1. Increase in follicular liquid that greatly increases antral and follicle size; follicle will reach a diameter of ~2.0 cm.

2. Granulosa and theca interna cells begin formation of corpus luteum.

3. Enlarged follicle bulges from the ovarian surface, thinning the ovarian tissue covering the follicle and forming a stigma.

4. Oocyte and surrounding cumulus oophorus detach from the granulosa layer and lie free in the antral space.

5. I is completed with the formation of a secondary oocyte and first . Meiosis II arrests in metaphase. (see description next section)

5 E. Follicular growth and maturation of secondary and Graafian follicles are influenced by follicle stimulating hormone (FSH), secreted by the , acting on the granulosa cells. (LH), secreted by the pituitary gland, influences theca interna cells to secrete androgens, which are aromatized to estrogen by granulosa cells.

F. Ovulation - Day 14 of ovarian cycle

1. The Graafian follicle ruptures at the stigma, releasing the haploid secondary oocyte, cumulus oophorus, follicular liquid and blood.

2. Oocyte and the surrounding cumulus are transported through the oviduct to the ampulla to await fertilization. Fertilization triggers the completion of meiosis II and the formation of an ovum. (see description next section)

3. The follicle wall continues its conversion to a corpus luteum.

4. Ovulation is stimulated by a surge of luteinizing hormone (LH) from the pituitary gland.

G. Atretic follicles – degenerating stage of follicles

1. The process of oocyte/ begins before birth, so that only about 450,000 oocytes remain in the ovaries at puberty. A will ovulate about 450 of those oocytes during her reproductive years; the remainder will degenerate, thereby producing more atretic than “normal” follicles.

2. Atresia can occur at any stage of follicular development and will begin in different layers of the follicle or oocyte depending on the follicle’s stage of development. Therefore, many varieties of atretic follicles can be seen.

6 IV. Corpus luteum

A. The corpus luteum is a large, spherical, infolded body functional during the second half of the ovarian cycle.

B. Functional stage

1. The corpus luteum is formed by differentiation of the granulosa and theca interna cells in the Graafian follicle before and after ovulation.

2. Its formation is stimulated by luteinizing hormone (LH) secreted by the pituitary gland.

3. The life span of the corpus luteum is finite, lasting about 12 days during the average cycle, during days 14-26.

4. The corpus luteum is composed of:

a. Granulosa lutein cells - form from cells in the granulosa layer; typical steroid-secreting cells; major component of the corpus luteum

b. Theca lutein cells - form from theca interna cells; typical steroid-secreting cells but smaller than granulosa lutein cells; remain at the outer boundary of the corpus luteum surrounding the granulosa lutein cells, where they form a peripheral layer and the infoldings of the corpus luteum

5. Both cell types secrete progesterone; as in the follicle, theca lutein cells produce androgens which is converted to estrogen by granulose lutein cells.

6. If pregnancy occurs, placental hormones maintain the corpus luteum, and it is known as the corpus luteum of pregnancy. This structure is functional for the first trimester of pregnancy.

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C. Degenerating stage - corpus albicans

1. Consists of a white mass of scar tissue composed of much collagenous material and scattered fibroblasts. Size diminishes with age.

2. Results from the degeneration of the corpus luteum.

V. Ovarian cycle – based on an average 28-day cycle

A. (days 1-13) - follicles are differentiating and secreting estrogen. Follicles begin to develop while (days 1-4) is occurring.

B. Ovulation (day 14) - Graafian follicle ruptures, releasing secondary oocyte.

C. (days 15-28) - corpus luteum is the functional ovarian structure, secreting progesterone and estrogen. Hormone secretion diminishes after day 26.

VI.

A. The process by which a diploid , an , in the fetal ovary becomes a haploid ovum in the adult after fertilization occurs.

8 B. Stages

1. Oogonia migrate from the sac to the fetal ovary where further mitotic divisions occur.

2. Oogonia begin meiosis I (reductional division) to form diploid, primary oocytes that are located in primordial follicles. These primary oocytes arrest in prophase and are the only follicles present from birth until puberty, when selected follicles under go a series of changes during each ovarian cycle, resulting in ovulation.

3. Each month a cohort of primordial follicles is recruited into the ovarian cycle. These follicles pass through primary and secondary follicles stages and a single secondary follicle continues as the mature or Graafian follicle which is ovulated. Primary and secondary follicles contain primary oocytes.

4. A secondary oocyte is formed during the day preceding ovulation in each ovarian cycle. Stimulated by the LH surge, a primary oocyte in the Graafian follicle completes meiosis I to form a haploid, secondary oocyte. This secondary oocyte begins meiosis II but arrests in metaphase; this is the oocyte that is ovulated.

5. An ovum, a mature, haploid germ cell, is formed in the oviduct (completion of meiosis II) only after fertilization occurs.

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OVIDUCT

I. Overview

A. 12 cm long tube interconnecting ovary and uterus; suspended by a ; one end opens into adjacent to ovary, the other joins the .

B. Subdivisions

1. Infundibulum - funnel-shaped free end with finger-like embracing the ovary

2. Ampulla - thin walled, lateral 2/3; fertilization occurs here near its junction with the isthmus

3. Isthmus - thicker walled, narrower, medial 1/3

4. Intramural (interstitial) - within uterine wall; lumen is continuous with uterine lumen

II. Microanatomy shows gradations from infundibulum segment to intramural segment

A. Mucosa

1. Exhibits complex mucosal folds that are most elaborate in infundibulum and are sparse in the intramural part

2. Epithelium: simple columnar with: 10

a. Ciliated cells (CC) - most abundant in infundibulum

b. Secretory cells - most abundant in interstitial portion

3. Muscularis mucosae is lacking

B. Submucosa is continuous with propria, forming a continuous connective tissue layer.

C. Muscularis externa

1. Poorly-defined inner circular and outer longitudinal layers

2. Thinnest in infundibulum, thickest in intramural portion.

D. Serosa is present except on intramural portion

III. Histophysiology

A. Function of oviducts

1. Transport sperm and oocytes to site of fertilization; transport embryo to uterus following fertilization.

2. Serve as the site of fertilization

3. Provide secretory products to oocyte, sperm, and embryo

B. Oviducts reach maximal development around ovulation (day 14), as estrogen favors development and maintenance of ciliated cells and secretory cells. Progesterone inhibits effect of estrogen on these cells and stimulates muscle contraction.

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11 UTERUS

I. Gross

A. Pear shaped and pear sized;

B. Subdivisions

1. Fundus - domed portion above entrance of oviducts

2. Corpus or body – major portion

3. Isthmus - constricted portion at junction of cervix and body

4. Cervix - located above and within the vagina, defining supravaginal and vaginal portions

II. General histological organization of the body and fundus

A. - outermost layer of serosa, covering the upper and posterior regions only; an adventitia surrounds the remaining portions that lie adjacent to the

B. = muscularis externa

1. A thick, well vascularized band of arranged in ill-defined layers. The myometrium forms the major portion of the uterus

2. The myometrium undergoes both hypertrophy (cell growth) and hyperplasia (cell proliferation) during pregnancy.

C. Endometrium = mucosa

1. Components

a. Epithelium - simple columnar, some ciliated

b. (endometrial stroma) contains multipotential (stromal) cells and abundant ground substance

c. Simple tubular glands

2. Zonation

a. Functional zone (stratum functionalis) - luminal two thirds that is sloughed during menstruation

b. Basal zone (stratum basalis) – firmly attached to the myometrium and retained during menstruation. Cell growth from this zone restores functional zone following menstruation. 12

III. Arterial supply to endometrium arises from branches of uterine in the myometrium

A. Basal (straight) arteries - remain in and supply stratum basalis

B. Spiral arteries

a. Coiled portions are located at the junction of the basal and functional zones

b. Extend into and supply the functional zone and a:

c. Capillary plexus beneath the surface epithelium.

IV. Endometrial changes in the body and fundus during menstrual cycle

A. Coordinated with ovarian cycle and controlled by its hormones; approximately 28 days long

B. Phases of uterine menstrual cycle

1. Menstrual phase - days 1-4, the clinical beginning of the cycle; however, this phase actually marks the end of the cycle. At the end of menstruation the functional zone has been sloughed and only the basal zone remains.

2. Proliferative phase - days 5-14

13 a. Ovarian follicles are growing and secreting estrogen.

b. The functional zone proliferates and regenerates from the basal zone.

i. Rapid proliferation of epithelial and stromal cells thickens the endometrium to about 3-4 mm.

ii. Glands are initially straight but become slightly wavy toward end of the phase.

iii. Spiral arteries grow with endometrium but are difficult to see because they are not yet coiled, i.e., are straight.

3. Secretory phase - 15-26 days

a. Corpus luteum is present and functional.

b. Uterine glands are actively secreting glycogen and by day 20 or 21 when implantation could occur.

c. Endometrial changes leading up to day of implantation

i. Thickness increases to 5-6 mm due to continue growth and fluid accumulation.

ii. Glands enlarge, become tortuous, coiled, and filled with secretory products.

iii. Spiral arteries lengthen, are highly coiled and readily visible. iv. Stromal cells become (pre)decidual cells (about day 24)

1. Large, pale cells, filled with glycogen and , located under surface epithelium and around spiral arteries

2. If pregnancy occurs, these cells are called decidual cells and form the maternal placenta ()

3. If pregnancy does not occur, these same cells are called predecidual cells which are sloughed with menses

5. Pre-menstrual phase (ischemic portion of secretory phase) - days 26-28

a. Estrogen and progesterone production from corpus luteum decreases.

b. Compression of the endometrium, resulting from lack of hormones from the corpus luteum, causes the:

14 i. Constriction of the spiral arteries, which results in ischemia in the overlying tissue in the functional zone.

ii. The ischemia causes the endometrium to become necrotic and disrupted. iii. Spiral arteries reopen and blood flows into the ischemic tissue, resulting in from the spiral arteries into the stroma.

iv. Cycles of compression and reopening of the arteries leads to degeneration of the functional zone and menstruation.

6. Menstrual phase - days 1-4

a. Pre-menstrual phase activities continue.

b. The functional zone becomes necrotic and is sloughed as menses.

c. Menstrual flow contains blood, tissue fragments and uterine fluids.

d. Only the basal zone remains, from which the functional zone will be regenerated.

15 C. Endometrium following fertilization:

1. implants about day 20-21 when the endometrium is thickest, glands are secretory and spiral arteries well developed.

2. The blastocyst secretes a hormone (HCG, human chorionic gonadotrophin) that stimulates and maintains the corpus luteum, thus continuing progesterone and estrogen secretion and prohibiting pre-menstrual and menstrual phases.

V. Cervix - begins above and extends into the vagina

A. The cervix is the lowest portion of the uterus, beginning above and extending into the vagina

B. Endocervix – surrounds the (endo)

1. Histology

a. Mucosa

i. Simple columnar epithelium with cilia and many -secreting cells

ii. Lamina propria is filled with epithelial folds, the plica palmatae, that are lined with mucus-secreting cells.

iii. Nabothian cysts occur when a fold becomes occluded.

b. Remainder consists mainly of connective tissue with some smooth muscle

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2. Cyclic changes and functions of the cervix

a. Mucosa - not sloughed with menstrual cycle; spiral arteries are absent.

b. Cyclic changes in the cervical mucus:

i. At mid-cycle, secretions are abundant and the molecules are linearly arranged, facilitating the movement of sperm through the cervix and/or into the plica palmatae for storage. The alkalinity of the cervical mucus neutralizes the low vaginal pH, providing a more favorable environment for spermatozoa.

ii. At other times during the cycle, cervical mucus is more viscous, scanty and arranged in a meshwork, making sperm penetration difficult.

B. Ectocervix

1. Free portion of cervix that protrudes into the vagina

a. Covered by moist stratified squamous epithelium that is identical to and continuous with the .

b. The junction of this epithelium with the simple columnar epithelium of the endocervical canal is abrupt and is called the external os.

VAGINA

I. Histology

A. Mucosa

1. Epithelium - stratified squamous non-keratinized that accumulates glycogen; no glands are present.

2. Lamina propria - rich with numerous blood vessels and abundant elastic fibers.

3. Muscularis mucosae is lacking

4. Rugae (folds) allow for expansion.

5. Lubrication is primarily by cervical mucus

B. Submucosa – continuous with the lamina propria, forming a single connective tissue layer.

17 C. Muscularis

1. Inner circular and outer longitudinal smooth muscle intermingle.

2. Skeletal muscle surrounds vaginal orifice.

D. Adventitia of loose connective tissue

II. Cyclic changes

A. The epithelium synthesizes and accumulates glycogen, becoming thick and proliferative by midcycle under the influence of estrogen.

C. Glycogen use by bacteria produces lactic acid generated by the breakdown of the glycogen. The lactic acid creates an acidic environment, particularly near ovulation when the glycogen is most abundant.

III. Functions

A. Sperm deposition

B. Portion of birth canal

Correlations between hormonal, ovarian and uterine cycles

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Virtual slide links: Ovary Secretory uterus

Structures identified in this section Ovary Antral spaces Antrum Atretic follicles Corpus albicans Corpus luteum Cortex Cumulus oophorus Follicles Follicular cells Germinal epithelium Granulosa lutein cells Granulosal layer Medulla Primary multilaminar follicle Primary oocytes Primary unilaminar follicle Primordial follicle Secondary follicle Stromal cells Theca externa Theca folliculi Theca interna Theca lutein cells Tunica albuginea Zona pellucida Oviduct Cilia Secretory cells Simple columnar epithelium Uterus Basal zone Cervix Ectocervix Endocervical canal Endometrium Functional zone Menstrual stage

20 Mucous secretions Myometrium Plicae palmatae Predecidual cells Pre-menstrual stage Proliferative stage Secretory stage Uterine glands Spiral Vagina Glycogen Stratified squamous moist epithelium

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