The Uterus
The uterus is a muscular pear-shaped organ of reproduction in the female. It is specialized for containing and nourishing a developing embryo from implantation to paturition (birth). The epithelial lining of the uterus undergoes cyclic changes that make it hospitable for the early embryo if fertilization has occurred. The muscular and elastic elements are specialized for expansion with the growing baby and for the expulsion of the baby at birth.
Structure
The never pregnant (nulliparous) uterus is a 7-8 cm long to 4-5 cm wide, muscular pear-shaped organ lying in the pelvic cavity on the superior surface of the bladder. The uterus weighs under 50 grams and is divided into the broad-ended fundus, body and thin isthmus that ends in the uterine cervix. The cervix is made mostly of dense connective tissue, about 2.5 cm in length and is covered interiorly by a mucous secreting ciliated epithelium at the upper regions and by stratified squamous epithelium at the vaginal end. The opening of the cervix into the vagina is almost at a right angle to the long axis of the vagina. The uterine cavity has a triangular shape that is widest at the fundus and flattened in sagittal section (sliced through, front-to-back). Uterine (Fallopian) tubes enter the uterus as the fundus and are supported by the broad ligaments as they span the distance from the ovary to the uterus.
When the bladder is empty the uterus angles forward over the bladder. As the bladder fills the uterus is lifted dorsally and may become retroflexed pressing against the rectum. Uterine blood supply is via the uterine and ovarian arteries with venous return traveling via the uterine veins. The hypogastric and ovarian nerve plexuses supply sympathetic and parasympathetic fibers as well as carry uterine afferent sensory fibers on their way to the spinal cord (T11 & 12).
Histologically, the uterus is composed of three layers: 1) an outer perimetrium composed of connective tissue, 2) a thick smooth muscle and elastic tissue, myometrium, and 3) a mucosal epithelial lining called the endometrium. The myometrium consists of roughly four layers of smooth muscle. The tubular glands of the endothelium can be seen near the myometrium near their beginning in the lamina propria. The epithelium contains simple columnar and ciliated cells. The lamina propria is made of extracellular matrix, many fibroblasts and mostly reticular fibers. Blood supply to the uterus is carried by the arcuate arteries that branch to supply the endometrium in the form of straight arteries to endometrial epithelium and coiled arteries to the menstrual epithelium.
Function
Functionally the endometrium can be divided into two zones: 1) the functionalis, which is built up and sloughed monthly during menstruation, and 2) the basalis, the epithelium and glandular elements that remain and supply the replicative cells to generate the next month's functionalis.
The Menstrual Cycle
The average menstrual cycle is 28 days, however only a very small percentage of cycles are exactly 28 days, most cycles range from 25-36 days. Menstrual cycles usually start between the ages of 12 and 15 and continue to about the age ot 45-50 when menopause occurs.
Females have four major hormones involved in the menstrual cycle: follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (estradiol) and progesterone. FSH and LH are protein hormones produced by cells of the anterior pituitary within the brain, in response to small peptide hormones from the hypothalamus (hypothalamic releasing factors). These pituitary hormones travel in the blood to the ovary where they stimulate the development of one or more eggs, each within a follicle. A follicle consists of an ovum surrounded by cells responsible for the growth and nurturing of the ovum. As the cycle progresses, one follicle becomes dominant and all others regress.
The menstrual cycle can be divided into three phases: the follicular (proliferative) phase, the ovulatory phase, and the luteal (secretory) phase. The follicular phase begins with the first day of menses (menstrual flow) and continues to approximately day 13 or 14 when ovulation takes place. During the follicular phase, FSH and LH are slowly rising in preparation for the LH surge (very high level of LH) at the time of ovulation. FSH is stimulating the growth of follicles in the ovary. Estrogen and progesterone are relatively low throughout this time but slowly begin to rise toward the end of this phase. Estrogen, and progesterone to a lesser degree, are steroid hormones produced by cells of the developing ovarian follicle. Estrogen causes the endometrium to increase in thickness and vascularization (i.e.blood supply). At the end of the proliferative (follicular) phase, the endometrium is 2-3 mm thick and the glands are straight tubules with narrow lumens.
LH surges and peaks during the ovulatory phase (around day 14) and estrogen peaks at the same time. These peaks trigger ovulation. The ovum lives about 72 hours after ovulation, but it is fertilizable for only about 36 hours. Just before ovulation, progesterone levels begin to rise rapidly. Changes in cervical mucous accompany ovulation. The amount of mucous increases and it becomes clear and thin. This facilitates conception by aiding the passage of sperm through the cervical canal. Sperm can live for up to 72 hours in the female reproductive system. Therefore, the fertile period during a 28-day cycle is only about 4-5 days.
After ovulation (at the midpoint of the cycle), under the influence of LH, the ovarian follicular cells shift to the production of progesterone becoming a yellowish structure called the corpus luteum (luteal phase). The corpus luteum remains intact for the remainder of the cycle. Progesterone causes the endometrial lining to become secretory and nutritive in anticipation of implantation of a fertilized egg. The uterine glands become very coiled and the endometrial lining reaches maximum thickness of about 5 mm during the luteal (secretory phase). Progesterone also inhibits the contractions of smooth muscle cells of the myometrium. The breast swelling, tenderness and pain experience by some women is most likely due to the effects of progesterone on breast tissue.
In the luteal phase progesterone levels are very high--progesterone is important during this phase because if the egg is fertilized, and implanted in the uterus, progesterone keeps the uterus intact so that the pregnancy is maintained. The continued health of the corpus luteum (progesterone secretion) is assured by the production of human chorionic gonadotropin (hCG) by the implanted embryo, until the placenta develops and can take over. The detection of hCG in urine is the basis of laboratory and home pregnancy tests.
If fertilization and implantation have occurred, than the corpus luteum will be stimulated by hCG to continue its production of estrogen and progesterone to maintain the pregnancy. This is important because the corpus luteum dies 14-22 days after ovulation if fertilization and implantation do not occur. At the end of the secretory (luteal) phase, blood levels of estrogen and progesterone drop rapidly. The coiled arteries serving the endometrial lining contract, causing ischemia leading to tissue death in the functionalis. The blood vessels above the vasoconstriction rupture and bleeding begins resulting in the monthly menstrual flow that normally lasts about 5 days.
Pathology
Endometriosis
Endometriosis is the abnormal location of endometrial tissue that can occur within the myometrium or at external sites such as the outer surface of the uterus, Fallopian tubes, ovaries, bladder, appendix or bowel. This aberrant tissue responds to ovarian hormones as normal endometrial tissue would thus causing the site dependent symptoms. The most common symptom is low abdominal or pelvic pain associated with onset of menstruation. Pain during sexual intercourse indicates uterine involvement and pain during urination reflects bladder involvement. No laboratory test is available. Physical examination and exploratory surgery may be necessary to identify the lesion. Symptoms are generally handled with analgesics in women of childbearing years where the symptoms are not severe. Hormone therapy that prevents ovulation may be helpful. When the endometriosis is embedded within the myometrium, hysterectomy is indicated to prevent the symptoms of painful intercourse, severe cramps and pelvic discomfort.
Premenstrual Syndrome (PMS)
PMS is the name given to the common symptoms that accompany the onset of the monthly period. Symptoms include headache, mood changes, breast tenderness, bloating, edema, weight gain, backache, irritability, depression, and anxiety. Treatment is symptomatic and includes analgesics, diuretics, tranquilizers and sedatives.
Dysmenorrhea
More commonly referred to as cramps, dysmenorrhea is painful menstruation caused by abnormal uterine contractility that effects some 50% of menstruating women. Primary dysmenorrhea is that which is not related to an obvious physical cause. Sharp cramps are experienced the first couple days of the menses. Headache, nausea, vomiting, diarrhea and fatigue also may be symptoms of dysmenorrhea and are thought to be caused by the liberation of prostaglandins in the endometrium. Treatments include analgesics, antiprostaglandins and hormones. Non-steroidal anti-inflammatory drugs, such as aspirin, indomethacin, and ibuprofen inhibit prostaglandin synthesis and act as analgesics. In severe cases, hormone therapy is initiated to prevent ovulation as anovulatory cycles are usually painless.
Dysmenorrheic women produce more prostaglandins in the endometrium and menstrual fluids than those without dysmenorrhea. Dysmenorrheic women also have been reported to have lower progesterone levels than normal women creating a dominance of estrogen in the endometrium which favors prostaglandin synthesis. At the end of an ovulatory cycle progesterone declines leading to a cascade of enzymatic events that lead to the production of prostaglandins. These prostaglandins cause uterine hypercontractility, decreased blood flow and ischemia, and uterine hypoxia that causes pain. Cyclooxygenase inhibitors such as aspirin, naproxen or ibuprofen prevent the formation of prostaglandins and relieve the symptoms of dysmenorrhea. Oral contraceptives inhibit ovulation (prevent formation of corpus luteum and decrease the thickness of the endometrial lining) and therefore prevent the environment necessary for increased prostaglandin production.
Amenorrhea
Physiologic amenorrhea, or the cessation of menstrual periods, normally occurs in pregnancy, lactation, adolescence, and menopause. Pathologic amenorrhea may be caused by endocrine disorders such as dysfunction of the hypothalamus, pituitary, ovary, thyroid or adrenal glands. Metabolic and psychogenic causes include malnutriton, obesity, chronic stress, drug addiction, diabetes, anorexia nervosa and anemia. Removal of the underlying cause will usually result in the resumption of normal periods. If hormone deficiencies are found, substitutional therapy is recommended.
Primary amenorrhea is hypogonadotropic and hypogonadal, meaning that blood levels of the gonadotropins and gonadal steroids are abnormally low. Release of LH and FSH are inhibited by endorphins at the level of the hypothalamus where they inhibit GnRH release. Without the gonadotropins the ovaries do not make gonadal steroids. Stress of many difererent kinds causes the synthesis of an ACTH precursor molecule in the hypothalamus that contains the sequence for endorphin and enkephalin. The cells making and processing the precursor are in direct contact with cells that make GnRH.
A shift in body composition or weight loss as in anorexia nervosa, ballet dancers, long-distance runners or malnutrition can cause amenorrhea. There seems to be a body fat threshold for the maintenance of normal cycles that is in the neighborhood of 18%. In many of these cases, if the patient gains weight normal cycles will resume. In obesity, weight loss and the concomitant decrease in stress on the body will enable a resumption of normal function. Amenorrhea may also result from psychogenic causes such as depression or chronic emotional stress.
Infections
The female reproductive tract is subject to bacterial, fungal, protozoal and viral infections. Many of these, such as trichomonas, gonorrhea, genital herpes and syphilis affect the vagina and external genitalia. Those that are sexually transmitted are covered at i-STD.com. Infections of the upper reproductive tract (above the cervix) are lumped together under the heading of pelvic inflammatory disease. Common causes of pelvic inflammatory disease include Gonococcus, Staphylococcus, Streptococcus and Chlamydia. It is associated with IUD use, abortion and post delivery. Symptoms include severe pelvic pain, chills, fever, nausea, vomiting, and a heavy odorous vaginal discharge. Treatment depends on the cause and extent of the infection but may include hospitalization, antibiotics, and analgesics. Inadequately treated pelvic inflammatory disease may result in infertility or sterility.
Tumors
Uterine Fibroids
Uterine fibroids, masses of muscle and connective tissue that are stimulated by estrogen, occur in some 20 to 50 percent of women between the ages of 30 and 50. Fibroids are more often seen in African-American women. Diagnosis is made by physical exam, ultrasound or x-rays. The size of these benign tumors varies from pea size up to that of a tennis or softball. These smooth, firm, rounded tumors are usually asymptomatic. However, large tumors can cause excessive menstrual bleeding, menstrual cramps, urinary frequency, constipation, low abdominal pain, and infertility. Tumors that distort the uterine cavity or endometrium can cause infertilty or spontaneous abortion. Treatment is dependent on age, symptoms, parity and patient condition. No treatment is required for asymptomatic persons. For women approaching menopause the withdrawal of estrogen causes a stasis or regression of the fibroids. Hysterectomy may be necessary in women with excessive bleeding.
Endometrial Cancer
Endometrial cancer affects mostly postmenopausal women and is the third most prevalent cancer in women. Exogenous estrogens may contribute to the development of endometrial cancer. Obesity, diabetes, hypertension, family history, and upper socioeconomic levels are also associated with a higher incidence of these slow growing tumors. Endometrial cancer spreads first to the cervix and myometrium followed by the vagina, pelvis and lungs. Abnormal uterine bleeding is often the first sign. Other signs include cramping, bleeding after intercourse, or swollen lymph nodes. Diagnosis is by dialation of the cervix and scraping the endometrial lining for microscopic study. Early stages of endometrial cancer are curable by hysterectomy and radiation.
Cervical Cancer
Early onset of sexual intercourse, low socioeconomic status, race, promiscuity, and multiparity are all risk factors for the development of cervical cancer. Cervical cancer is seen most frequently in the 30-50 year old woman who began intercourse prior to the age of 20. There are profound differences in the incidence and death rate associated with race (e.g., African-Americans, Hispanics and American Indians have higher death rates than the national average). Race and age are risk factors that obviously cannot be controlled. The age of onset of sexual relations and promiscuity are, however, matters of personal choice. Frequent unprotected sex with multiple partners is a definite risk factor for the development of cervical cancer. A link to genital herpes and other sexually transmitted disease has been found.
As the carcinoma progresses it may metastasize to the bladder, rectum, lymph nodes, lungs, bones and liver. Early cervical cancer is asymptomatic making early diagnosis key. Routine (yearly) Pap smears are and excellent diagnostic tool. Treatment is by laser surgery, electrocautery or cryosurgery to remove the lesion early. In advanced or recurrent cases, hysterectomy and radiation therapy may be indicated.
