ANATOMY AND PHYSIOLOGY OF THE REPRODUCTIVE SYSTEM

I. Overview

The reproductive system is a system of sex organs within an organism which

work together for the purpose of sexual production. In addition, the female

reproductive organs contribute to sustaining the growth of embyos and foetuses.

II. Structures (Female Reproductive System)

The organs of the female reproductive system include the ovaries, fallopian tubes,

uterus, vagina and external organs which are collectively called as vulva.

1. Ovaries

- These are paired glands which resemble an almond as to size and shape. It is

responsible in the production of (1) gametes (secondary oocytes that develop into

mature eggs) after fertilization and (2) hormones including progesterone,

estrogen, inhibin and relaxin.

2. Fallopian Tubes

- These are two uterine tubes which extend laterally from the uterus. The tube

measure about 10 cm. they provide a route for sperm to reach the ovum and

transport secondary oocytes and fertilized ova from the ovaries to the uterus. It

has segments namely:

a. Fimbrae – fingerlike projections which is attached to the ovary.

b. Infundibulum – segment preceding the fimbrae.

c. Ampulla – uterine tube’s widest and longest portion.

d. Isthmus – more medial, short, narrow, thick-walled

3. Vagina
 - It is the receptacle for the penis during sexual intercourse, the outlet of menstrual

flow, and the passageway for childbirth. Situated between the urinary bladder and

the rectum

4. Vulva – composed of the mons pubis, labia majora, labia minora, clitoris, vestibule ,

vaginal orifice, urethral orifice, bartholin’s glands.

5. Uterus

- It is the site of implantation of a fertilized ovum, development of the fetus during

pregnancy. During reproductive cycle, when fertilization does not occur, it is the

source of menstrual flow.

a. Anatomy

Situated between the urinary bladder and the rectum, the uterus is the size

and shape of an inverted pear. Anatomical subdivisions of the uterus include:

a.1. Fundus – dome-shaped portion superior to the fallopian tubes.

a.2. Body – Central portion.

a.3. Cervix – An inferior narrow portion that opens into the vagina.

a.4. Isthmus – Between the body of the uterus and the cervix

a.5. Uterine cavity – the interior of the body

a.6. Cervical canal – the interior of the cervix. It opens into the uterine

cavity at the internal os and into the vagina at the external os

b. Histology

The uterus is composed of three layers of tissue namely:

 b.1. Perimetrium – outer layer; composed of simple squamous epithelium and

areolar connective tissue.

b.2. Myometrium – middle layer; consists of three layers of smooth muscle

fibers that are thickest in the fundus and thinnest in the cervix.

b.3. Endometrium – inner layer; highly vascularized

b.3.1. Components

 Simple columnar epithelium (ciliated and secretory cells) –

innermost; lines the lumen

 Endometrial stroma – very thick region of lamina propia (areolar

connective tissue)

 Endometrial (uterine) glands – invaginations of luminal epithelium

and extend almost to the myometrium

b.3.2. Layers

 Stratum functionalis (functional layer)- lines the uterine cavity and

sloughs off during menstruation

 Stratum basalis (basal layer) – gives rise to new stratum

functionalis after menstruation

b.3.3. Cervical Mucus

The secretory cells of the mucosa of the cervix produce a secretion

called the cervical mucus. It is a mixture of water, glycoproteins, lipids, enzymes

and inorganic salts. Cervical mucus supplements the energy needs of the sperm
 and both cervix and cervical mucus protects the sperm from phagocytes and

hostile environment in the vagina and uterus.

III. Hormones

Estrogen Progesterone Relaxin Inhibin

 Promotes  Works with  Inhibits  Inhibits the

development and estrogens to contractions of release of FSH

maintenance of prepare uterine smooth and to a lesser

female endometrium muscles extent, LH

reproductive for implantation  During labor,

structures,  Prepares increases

feminine mammary flexibility of

secondary sex glands to secrete pubic

characteristics milk symphysis and

and breasts  Inhibits the dilates the

 Increase protein release of uterine cervix

anabolism GnRH and LH

 Lowers blood

cholesterol

 Moderate levels

inhibit release of

GnRH, FSH and

LH
IV. Menstrual Cycle

MENSTRUAL PHASE (5 days)

Events in the Ovaries Events in the Uterus

 Under FSH influence, several primordial  Menstrual discharge occurs

follicles develop into primary follicle and because of declining levels of

then into secondary follicles estrogen and progesterone

stimulate release of prostaglandin

causing uterine spiral arterioles to

constrict

 Cells deprived of oxygen begin to

die

 Stratum functionalis slough off

(stratum basalis remains)

PRE-OVULATORY PHASE (day 6-13)

Events in the Ovaries Events in the Uterus (proliferative phase)

 Secondary follicles begin to secrete  Estrogen stimulate the repair of

estrogens and inhibin endometrium

 One dominant follicle outgrow others  Cells of stratum basalis undergo

 Estrogen and inhibin of dominant follicle mitosis to form new stratum

decrease FSH causing other follicles to functionalis

stop growing  Thickness of endometrium

 Dominant follicle become the mature doubles

(graffian) follicle
 OVULATION (day 14)

Events in the Ovaries Events in the Uterus

 Rupture of mature (graffian) follicle and

release of secondary oocyte

 High levels of estrogen during the last part

of preovulatory phase exert a positive

feedback effect on cells secreting LH and

GnRH

POST-OVULATORY PHASE (day 15-28)

Events in the Ovaries (Luteal phase) Events in the Uterus (secretory phase)

 Mature follicle collapses to form corpus  Progesterone and estrogen

luteum under the influence of LH produced by corpus luteum

 Corpus luteum under the influence of LH promote growth of endometrium

secretes progesterone, estrogen, relaxin

and inhibin

If fertilization does not occur… If fertilization does not occur…

 Corpus luteum degenerates and become  Levels of progesterone and

corpus albicans estrogen decline due to the

 As levels of progesterone, estrogens and degeneration of corpus luteum

inhibin decrease, release of GnRH, FSH  Withdrawal of estrogen and

and LH rise due to loss negative feedback progesterone causes menstruation

suppression by the ovarian hormone

  Follicular growth resume as new ovarian

cycle begins

If fertilization occurs…

 Human chorionic gonadotrophin (hCG)

produced by chorion of embryo about 8

days after fertilization stimulates the

secretory activity of the corpus luteum.

V. Fertilization

The union of an ovum and a sperm. This usually occurs in the ampulla of the

fallopian tube. As the ovum is extruded from the graffian follicle of an ovary with

ovulation, it is surrounded by a ring of mucopolysaccharide fluid (zona pellucida) and

a circle of cells (corona radiata). the is extruded from the gaafian follicle of an ovary

of ovulation, it is surrounded by a ring of mucopolysaccharide fluid (the zona

pellucida) and a circle of cells. (the corona radiata). The ovum and these surrounding

cells are propelled into a nearby fallopian tube by currents initiated by the fimbriae.

At the time of ovulation, there is a reduction in the viscosity (thickness) of the

woman’s cervical mucus, which makes it easy for spermatozoa to penetrate it.

Spermatozoa moves through the cervix and the body of the uterus and into the

fallopian tube, toward a waiting ovum by the combination of movement by their

flagella (tails) and uterine contractions. All of the spermatozoa that reach the ovum

cluster around its protective layer of corona cells. Hyaluronidase (a proteolytic

enzyme) is released by the spermatozoa and dissolves the layer of cells protecting the

ovum.

Once it penetrates the cell, the cell membrane changes composition to become

impervious to other spermatozoa. Immediately after penetration of the ovum, the

chromosomal material of the ovum and spermatozoon fuse to form a zygote.

Out of this single-cell fertilized ovum (zygote), the future child and also the

accessory structures needed for support during intrauterine life (placenta, fetal

membranes, amniotic fluid, and umbilical cord) will form.

Once fertilization is complete, a zygote migrates over the next 3 to 4 days

toward the body of the uterus, aided by the currents initiated by the muscular

contractions of the fallopian tubes.

Implantation or contract between the growing structure and uterine

endometrium, occurs approximately 8 to 10 days after fertilization. About 8 days

after ovulation, the blastocyst sheds the last residues of the corona and zona pellucida,

brushes against the rich uterine endometrium and settles down into its soft folds.

Once implanted, the zygote is called an embryo and continue to develop.

PATHOPHYSIOLOGY

I. BRIEF DESCRIPTION

Cancer is a group of heterogenous diseases that share common biologic

response all caused by an accumulation of genetic alterations.

Diagnosis: G2p2 (2002) cervical adenocarcinoma ST IV; Anemia very severe

1. Cervical – cancer at the uterine cervix

2. Adenocarcinoma – cancer that arise from ductal and glandular epithelium.

3. Stage IV-A – the carcinoma has extended beyond the pelvis or has clinically

involved the mucosa of the bladder or rectum. “A” means it has already spread to

adjacent organs.

4. Anemia – decrease in Red Blood Cell (RBC) mass

II. RISK FACTORS

1. Family history of cancer

Cancer is caused by certain changes to genes that control the way cells function,

especially how they grow and divide. These changes include mutations in the DNA that

makes up the genes. Genetic changes that increase cancer risk can be inherited from

parents if the changes are present in germ cells (egg cells and sperm cells). Such changes,

called germ line changes are found in every cell of the offspring. Types of defective

genes include:

a. Proto-oncogenes (mutated)/Oncogenes – oncogenes normally promote growth

through direct synthesis of proteins that accelerate proliferation; once mutated and

become abnormal, it promotes uncontrolled cell proliferation/growth.

 b. Tumor Supressor Genes (mutated) - normally encode proteins which negatively

regulate/stop proliferation; once inactivated, there will be continuous cell

proliferation

c. Mismatch Repair Gene (mutated) – normally encode proteins that are involved in

repairing the DNA (errors in DNA replication, mutations caused by ultraviolet

rays, mutations from drugs and chemicals); once mutated, defective DNA tend to

divide and cause cancer.

d. Apoptosis Genes (mutated) – normally responsible for programmed cell death;

mutation of this gene results to continuous growth of cells.

2. Human Papilloma Virus (HPV) Infection

Virus-linked cancer account for about 80% of cancer of the cervix. Virtually, all

human cervical cancer is due to infection with specific subtypes of HPV. HPV infects

basal skin cells and many subtypes cause warts. It is spread primarily through sexual

contact. HPV causes cancer when the viral DNA becomes accidentally integrated into the

infected cervical basal cell chromosome and directs the production of viral oncogenes.

3. Immune system deficiencies

Cancer cells express tumor-associated antigens (TAA) that are not normally found

in normal cells. This TAA is recognized by the immune system as foreign, thus, it

destroys these cancer cells and prevents it from developing into a clinically detectable

tumors. However, some cancer cells are capable of bypassing this surveillance through

various factors namely:

a. Tumor cell camouflage – some cancer cells can mimic the normal cells because

they are coated with fibrin which gives them protection from the immune system
 b. Antigen modulation – some cancer cells have the ability to modulate this TAA in

response to recognition by the immune system

c. Overwhelming antigen exposure – cancer cells grow at a rate more rapid than the

immune cells can destroy them

d. Blocking agents – some cancer cells produce fibrin blocking them against

antibodies

4. Chronic inflammation (most common is chlamydia infection)

a. After injury, inflammatory cells release factors which stimulate cell proliferation.

In chronic inflammation, these factors combine to promote continuous

proliferation.

b. In addition, inflammatory cells release compounds such as reactive oxygen

species and other reactive molecules that can both promote mutations and block

the cellular response to DNA damage.

c. Also, cancer cells and macrophages may secrete inflammatory mediators such as

interleukin-8 that stimulate immune and other cells to increase vascular

permeability and angiogenesis which favours tumour growth.

5. Age

Generally, the incidence of cancer increases dramatically with advancing age and

is related to the accumulation of genetic mutations over time.

6. Smoking and exposure to second hand smoke

Smoking is a well-established human papillomavirus (HPV) cofactor for the

development of cervical cancer. This is primarily because carcinogenic substances from

cigarettes are inhaled and absorbed in the lungs and carried through the bloodstream.
 However, the molecular mechanisms by which it increases the risk of cervical cancer

remain unknown. There are two possible explanations but still under active investigation

(Division of Cancer Epidemiology and Genetics, National Cancer Institute):

a. Smoking inhibits the immune response to HPV

b. There were instances that tobacco substances are found in the cervix of a

woman who smokes and researchers believe that these carcinogens damage

the DNA of cervical cells.

7. Sexual activity (multiple sex partners, sex with uncircumcised males, sexual contact with

males whose partners have had cervical cancer) – higher risk in acquiring HPV infection

or other sexually transmitted infections.

8. Early childbearing and high parity

Women who have had 3 or more pregnancies and got pregnant at an early age

have an increased risk in developing cervical cancer. It is still under study however, it is

pointed out to hormonal changes during pregnancy as possibly making women more

susceptible to HPV infection or cancer growth. Another though is that pregnant women

might have weaker immune system allowing HPV infection and cancer growth

9. Increased exposure to Estrogen

Estrogen is known to have a direct carcinogenic effect on the occurrence of

vaginal and cervical cell carcinomas. It stimulates proliferation and may increase the risk

of mutation at the same time stimulate the replication of the mutated cell.

a. DES (Diethylstilbetrol) in utero - DES is a hormonal drug that was given to

some women between 1940 and 1971 to prevent miscarriage. Women whose
 mothers took DES when pregnant with them are at risk in developing clear-

cell adenocarcinoma of the cervix.

b. Prolonged use of birth control pills – birth control pills’ main ingredient is

estrogen. Thus taking oral contraceptives increases the risk of cervical cancer.

10. Low socioeconomic status

Many low-income women do not have easy access to adequate health care

services, including Pap tests. This means they may not get screened or treated for

cervical pre-cancers.

12. Overweight status

Adipose tissue is an active endocrine and metabolic tissue. In response to

endocrine and metabolic signals from other organs, adipose tissue responds by increasing

or decreasing the release of free fatty acids (fuel for skeletal muscles and other tissues),

peptide hormones leptin, resistin, tumor necrosis factor-y and reduce adiponectin

(important for energy balance and lipid metabolism). Increased release of free fatty acids,

resistin and TNF-y and reduced release of adiponectin give rise to insulin resistance (a

state characterized by reduced metabolic response to insulin by the tissues) resulting to a

chronic hyperinsulinemia. Increased insulin levels ultimately lead to decreased liver

synthesis and blood levels of Insulin-like Growth Factor-Binding Protein (IGFP). IGFP

functions to stabilize large pool of IGF-1 in the circulation. Thus, a decrease of such leads

to an increase in the circulating IGF-1.

An increased insulin and IGF-1 in the blood signal insulin receptors and

IGF-1 receptors to stimulate cell proliferation and inhibit apoptosis. These events

promote tumor development.

III. CARCINOGENESIS

The process begins with a single cell that has sustained genetic change.

Carcinogenesis is a multistep process and involves a number of genetic mutations that cause

progressive transformation of normal cells into highly malignant derivatives. Cancer

development is categorized into four stages namely: (1) Initiation, (2) Latency/Promotion,

(3) Progression and (4) Invasion.

Initiation Stage. In the first stage, cells are exposed to an initiating agent or

carcinogen that makes them susceptible to malignant transformation. An initiating agent is a

chemical, biologic or physical agent capable of producing an irreversible damage in the

DNA of a cell. Viral, environmental or lifestyle and genetic factors have all been identified

as initiators of carcinogenesis.

Latency/Promotion Stage. In the second stage, repeated exposure to the promoting

agents causes expression of abnormal genetic information resulting to further cellular

growth and dysfunction.

Progression Stage. In the third stage, the tumor cells acquire malignant

characteristics that include:

a. Anaplasia – marked change in the structure and orientation of cells completely not in

resemblance to the original cell. Cancer cells have an evident increase in size with

ongoing proliferation. They are variable in size and shape. In response to anaplasia,

the cancer cells loss differentiation and develop cellular heterogeneity.

Undifferentiated cells has all the ability to replicate frequently.

b. Loss of contact inhibition – cancer cells also loss respect for boundaries.
 c. Loss of cellular cohesiveness – cancer cells do not stick together therefore, they can

easily detach to primary tumor and spread

d. Secretion of enzymes – cancer cells secrete hyaluronidase which enables them to

destroy intracellular cementing substances which facilitates their spread

e. Tumor angiogenesis – cancer cells stimulate the formation of a vascular supply which

is essential for continued tumor growth and metastasis. Tumor cells produce

angiogenic factors such as vascular endothelial growth factor (VEGF) to stimulate

blood vessel growth.

Invasion Stage. Tumor spread can occur by direct extension or local invasion of

adjacent organs, metastases by implantation and metastases to distant organs by lymph or

circulatory system. The process of metastasis is a cascade of linked sequential steps.

Multistep Nature of Metastasis:

1. Growth and progression of the primary tumor – the first requirement for metastasis is

rapid growth of the primary tumor. Most tumours must reach 1 billion cells or 1 cm in

size before metastasis is possible.

2. Angiogenesis at the primary site – extensive angiogenesis is necessary for the tumor

to exceed 1 mm in diameter. The release of angiogenic factors by tumor cells is

necessary to stimulate new capillary formation

3. Local invasion – Several factors are involved in tumor cell invasion. First, rapid

tumor growth creates a mechanical pressure that forces finger-like projections of

cancer cells into the adjacent tissue. Second, increased cell motility can contribute to

tumor cell invasion. The lack of adhesion among tumor cells increases their ability to
 escape and invade. Third, tumor cells secrete enzymes (hyaluronidase) that are

capable of destroying the basement membrane. With these events, tumor cells then

break down the tissue stroma and basement membrane of adjacent tissue to reach

blood vessels or lymphatic system.

4. Detachment and embolization – once in the circulation, tumor cells are vulnerable to

destruction by the host cells. Therefore, as a protection, they cluster with blood cells

primarily platelets and for a fibrin-platelet emboli. This protects the tumor cells and

promotes metastasis by enhancing their ability to adhere to the capillary walls of the

target organ.

5. Arrest in distant organ capillary beds – The most frequent location of metastases is

the first capillary bed or lymphatic tissue in an organ adjacent to the primary site.

Factors that may influence certain tumors to metastasize to specific sites include

patterns of blood flow or tumor-cell expression of preferred specific organ

6. Extravasation – After the tumor cells have firmly attached themselves to the

endothelial cells of a vessel, the tumor cells must penetrate through the vessel wall to

grow into the extravascular tissue. Once tumor cells escape the vessel wall, it invades

the organ tissue.

7. Proliferation – Once tumor cells arrive in the extravascular tissue, a blood supply and

nutrients must be acquired for continued growth

IV. Manifestations classified as to causative factors

A. Tumor irritate the nerve endings and press on adjacent structures

- Pain during sex

- Pelvic pain
 - Anorexia and weight loss related to the pain which supresses appetite

B. Growing tumor causes rupture of minute blood vessels along the affected area

- Post-coital bleeding

- bleeding after menoupause

- bleeding and spotting between periods

- menstrual periods that are longer and heavier than usual

- anemia secondary to chronic blood loss

C. Tumor causes inflammation

- Foul and abnormal vaginal discharge

- Pain

- Fever

D. Penetration of tumor to adjacent structures

- Colorectal – creation of rectovaginal fistula manifested by passage of gas,

stool or pus in the vagina, foul smelling vaginal discharge, irritation or pain,

pain during sexual intercourse and possible infection.

- Genitourinary - Vaginal leakage of urine which is caused by penetration of

the tumour to the bladder wall.