The major components of the upper female reproductive tract are shown in Figure 9-7. The ovaries normally release a single oocyte (ovum or egg) into the reproductive tract, which occurs approximately once per month. The oocyte travels along a fallopian tube to a hollow muscular organ, the uterus. The fallopian tube is the normal site where fertilization of the ovum by a single sperm cell occurs; the uterus is the site of implantation and development of the embryo.
Female internal reproductive organs. The ovaries are placed laterally in the pelvis. Oocytes are released into the peritoneal cavity and caught by fimbria at the distal end of the fallopian tubes, which conduct the oocyte to the cavity of the uterus. The uterus communicates with the vagina via the cervix.
The lower reproductive tract consists of the vagina and the vulva (external genitalia). The functions of the vagina are to receive the penis during intercourse and to temporarily retain semen. The vagina and vulva also comprise the lowest part of the birth canal.
The Ovaries and the Fallopian Tubes
The paired ovaries are the female gonads. There is one ovary located laterally on each side of the pelvis. The ovary is the site of gametogenesis (oogenesis) and the major source of the sex steroids. The histologic appearance of the ovary varies throughout the ovarian cycle; oocytes in various stages of development within follicles, as well as a temporary endocrine gland, the corpus luteum, may be seen (Figure 9-8).
Microscopic appearance of the ovary. (Note: the structures shown are not all present at the same time). In the first half of the menstrual cycle, several oocytes begin to develop as a cohort of follicles. A single dominant follicle is visible about midcycle and has differentiated into a large graafian follicle. Ovulation occurs by forceful rupture of the graafian follicle. After ovulation, the graafian follicle transforms into the corpus luteum.
The fallopian tubes transport the ovum and sperm to the site of fertilization, and transport the zygote to the site of implantation in the uterus. There is one fallopian tube associated with each ovary and each one has four areas (Figure 9-7):
The most distal part of a fallopian tube is funnel-shaped and bears finger-like projections called fimbria, which receive the ovum when it is released from the ovary at ovulation. A ciliated epithelial lining propels the ovum along the fallopian tube toward the uterus.
The usual site of fertilization of the oocyte is a dilated area called the ampulla.
A narrow portion, called the isthmus, helps to retain the early embryo within the tube for 2–3 days after fertilization. During this time, there is final maturation of the endometrium (lining of the uterus) to facilitate implantation of the embryo.
Each fallopian tube has an intramural portion, where it joins the hollow uterus. The point of entry of the fallopian tube is called the cornua of the uterus.
Pelvic inflammatory disease (PID) is caused by an ascending sexually transmitted disease. PID is most commonly due to chlamydia and gonorrhea, and ascends from the cervix to the endometrium, to the fallopian tubes, and to the pelvic cavity. As a complication, the fallopian tubes can become scarred, increasing the risk of an ectopic tubal pregnancy, which is a potentially fatal condition! The most common site of implantation of an ectopic pregnancy is the ampulla of the fallopian tube.
The uterus is a pear-shaped muscular organ within the pelvis, located between the bladder and rectum. The function of the uterus is to support the growing fetus during pregnancy. There is dramatic growth of the uterus during pregnancy, occurring by a process of both muscle cell hyperplasia and production of new muscle cells from the resident stem cells. During parturition (childbirth), the uterine smooth muscle contracts powerfully to expel the fetus. The uterus is supported in position by several connective tissue ligaments. Damage to the uterine ligaments (e.g., during childbirth) may result in prolapse of the uterus downward into the vagina.
Pelvic relaxation most commonly results from mechanical trauma related to childbirth. Complications of pelvic relaxation include uterine prolapse, cystocele (bulging of the anterior vaginal wall and bladder into the vagina), rectocele (bulging of the posterior vaginal wall and rectum into the vagina), enterocele (herniation of the pouch of Douglas containing small intestine into the vagina), and urinary stress incontinence (leakage of urine during coughing, sneezing, or laughing).
The structure of the uterus includes three areas:
The fundus is the area above the openings of the fallopian tubes.
The corpus is the main body of the uterus. The lower third of the corpus is called the lower uterine segment. Contraction of this area draws the dilated cervix (lowest part of the uterus) upward during labor.
The cervix is about 4-cm long and is mainly composed of connective tissue; this contrasts with the corpus, which is mainly composed of smooth muscle. Approximately half of the cervix protrudes into the upper vagina. The cervical canal joins the vaginal lumen and uterine cavity, and is lined by a mucous-secreting epithelium. The properties of cervical mucus change significantly during the menstrual cycle. About the time of ovulation at midcycle, under the influence of high estrogen and low progesterone, the mucus is thin and readily allows passage of sperm. A sample of cervical mucus placed on a microscope slide at this time dries in a fern-like pattern, hence the term ferning of cervical mucus. Later in the menstrual cycle, high concentrations of progesterone promote the secretion of thicker mucus, which resists the passage of sperm.
Cervical cancer most commonly occurs at the squamocolumnar junction, which is the transition zone between vaginal epithelium and cervical epithelium. The most effective screening tool for the detection of cervical cancer was developed by George Papanicolaou and is known as the Pap smear. Cells collected from the cervical squamocolumnar junction are stained with the multichromatic Papanicolaou's stain and examined under the microscope for signs of dysplasia. Infection with human papillomavirus (HPV), including types 16 and 18, plays an important etiologic role in the development of cervical cancer. HPV viral proteins have the capacity to inactivate tumor-suppressor genes, which may explain the carcinogenic effects of the virus. The recent development of an HPV vaccine (Gardasil) protects women from persistent infection with the virus and may significantly alter the epidemiology of cervical cancer in the future.
The endometrium is the epithelial lining of the uterus and undergoes dramatic changes during the monthly cycle. There are three phases of the monthly menstrual cycle:
The proliferative phase occurs in the first half of the cycle prior to ovulation and is under the influence of high estrogen levels. During this time, there is marked thickening of the endometrium, growth of the endometrial glands, and the appearance of spiral arteries.
The secretory phase occurs after ovulation, during the second half of the monthly cycle when there is progesterone dominance. There is copious secretion of progesterone from the endometrial glands in preparation for implantation of an embryo at this time.
The menstrual phase occurs if implantation of an embryo does not occur; progesterone levels decrease toward the end of the cycle, causing the uterine spiral arteries to spasm. Tissue necrosis and bleeding (menses) occurs, usually over a period of 4–5 days, as the endometrial lining sloughs off.
The vagina is a tube that extends from the vaginal opening (introitus) to the cervix. Many mucus-secreting glands line the introitus and are stimulated during intercourse to provide lubrication. The largest and most important of these glands is Bartholin's gland, which is located posterolaterally. The vulva is the collective name for the female external genitalia and comprises the lower third of the vagina, the labia, and the clitoris (Figure 9-9). The clitoris is the female homologue of the penis and consists of erectile tissue of the paired corpora cavernosa, ending in the highly sensitive glans clitoris. The urethral opening lies between the clitoris and the introitus.
Female external genitalia.
Condyloma acuminatum (or genital warts) can occur in men or women. HPV types 6 and 11 have been associated with this contagious venereal disease.
Oogenesis is the process through which the mature female gamete is formed. Oogenesis begins in fetal life but is not completed until the time of fertilization. The proliferation of oogonia by mitosis ends midway through fetal life, at which time oocytes are arrested in the first meiotic division. Thereafter, the number of oocytes gradually declines with age; there are about 1–2 million oocytes at birth and about 100,000 at puberty. Oocytes may be stimulated to develop for release at ovulation, or they will die through a process called atresia.
Oogenesis occurs in the ovary within structures called follicles. Each unstimulated follicle contains a single primary oocyte surrounded by a single layer of granulosa cells, which in turn are associated with thecal cells. With each monthly menstrual cycle, several follicles are stimulated to develop, but only one will become the dominant follicle that continues to ovulation.
The oocyte and granulosa cells in developing follicles enlarge.
A clear gelatinous ring of extracellular matrix appears around the oocyte, called the zona pellucida.
The dominant follicle becomes a graafian follicle (Figure 9-10). After the LH surge, the oocyte within a graafian follicle completes the first meiotic division to become a secondary oocyte.
Rupture of the graafian follicle at ovulation expels the oocyte into the peritoneal space near the fimbria of the fallopian tube.
The ruptured follicle collapses and granulosa cells proliferate to fill the space. Under the influence of LH, structural transformation to the corpus luteum occurs.
A graafian follicle. The oocyte is surrounded by a gelatinous ring (the zona pellucida) by the granulosa cells of the cumulus oophorus and by the follicular fluid (the antrum). Thinning of the outer follicular wall of thecal cells occurs just prior to ovulation. Rupture of the follicle at ovulation ejects the oocyte-cumulus complex.
Trisomy (e.g., trisomy 21, also known as Down syndrome) is associated with increased maternal age. The mechanism that causes trisomy is thought to be related to prolonged arrest of the first meiotic division and age-dependent degradation of the meiotic proteins in the primary oocyte. The first meiotic division is arrested during fetal life and is not completed until that particular oocyte is “chosen” to become the dominant follicle for ovulation.
The Menstrual (Ovarian) Cycle
The cyclic activity of the hypothalamic-pituitary-ovarian axis results in ovulation and the simultaneous development of a uterine environment that is capable of supporting pregnancy, should fertilization occur. The terms menstrual cycle and ovarian cycle are both used to describe a sequence of events that recurs approximately every 28 days. The first day of menstrual bleeding defines day 1 of a menstrual cycle. From the perspective of events taking place in the ovary, the cycle is divided into three phases (Figure 9-11):
The follicular phase (days 1–14). The follicular phase is the first half of the menstrual cycle. Toward the end of the previous cycle, the corpus luteum dies, resulting in a sharp decrease in the blood levels of progesterone, estrogen, and inhibin. The loss of negative feedback inhibition of FSH secretion allows plasma FSH concentration to increase. Under the influence of FSH, a cohort of primary follicles develops (a process that begins in the final 2–3 days of the previous cycle).
Granulosa cells secrete estrogen and inhibin under the influence of FSH, accounting for the increase in plasma concentration of these hormones during the follicular phase (Figure 9-11). Granulosa cells rely on a supply of androgens from thecal cells as a substrate for estrogen production. By the midfollicular phase, FSH secretion is suppressed, preventing the recruitment of more follicles.
A dominant follicle emerges, which has high sensitivity to FSH, and continues to develop and to secrete estrogen, despite the now low levels of circulating FSH. The less dominant follicles undergo atresia and die, leaving a single oocyte for release at ovulation.
The ovulatory phase (days 13–15). Ovulation occurs at the midpoint of a normal menstrual cycle. It is triggered by an LH surge and occurs about 12 hours after the peak LH concentration (Figure 9-11). The dominant follicle signals its maturity to the pituitary gland by a rapid increase in estrogen secretion, which exerts positive feedback on the anterior pituitary by sensitizing it to GnRH.
When the LH surge occurs, the primary oocyte completes the first meiotic division to form a larger secondary oocyte, which stops in the second meiotic division until fertilization.
Ovulation occurs due to thinning and rupture of the dominant follicle, under the influence of LH, progesterone, and locally released prostaglandins.
The released oocyte is surrounded by the zona pellucida and granulosa cells. The oocyte is guided into the fallopian tube by fimbria and is propelled toward the uterus by the ciliated epithelial lining cells of the fallopian tube.
The luteal phase (days 15–28). After ovulation, the corpus luteum is formed, under the influence of LH by differentiation of both theca and granulosa cells, into theca-lutein and granulosa-lutein cells, respectively. Progesterone is the major secretory product of these cells, although both estrogen and inhibin are also secreted. During the luteal phase, high levels of estrogen are unable to induce another LH surge in the presence of high progesterone levels.
If pregnancy does not occur, the corpus luteum spontaneously degenerates. Continued progesterone secretion by the corpus luteum is essential to early pregnancy. If implantation of an embryo occurs, the trophoblast cells of the developing placenta secrete the LH analogue hCG, which supports the corpus luteum until the developing placenta assumes the production of progesterone.
Ovarian, hormonal, and uterine events that occur during the menstrual cycle. LH, luteinizing hormone; FSH, follicle-stimulating hormone.
Menopause is a normal stage of life—the physiologic effects of menopause can be viewed as a syndrome of “ovarian failure.” Cessation of menstruation is a universal feature of menopause. Withdrawal of estrogen is particularly important in accounting for the symptoms of menopause, which include insomnia, hot flushes, variable degrees of vaginal atrophy, and decreased breast size. Estrogen deficiency causes bone loss and increases the risk of osteoporosis.
During menopause, there is marked reduction of estrogen and progesterone concentrations. The loss of ovarian function removes negative feedback on GnRH, producing high serum concentrations of FSH and LH. FSH levels are particularly high in postmenopausal women because inhibins, which exert selective negative feedback on FSH secretion, are no longer produced by the ovary.
Despite the proposed cardioprotective effects of estrogen, the leading causes of death are similar in men and women: (1) cardiovascular disease, (2) cancer, and (3) stroke. The Women's Health Initiative studied the effects of hormone replacement therapy (combined use of estrogen and progestin, known as HRT) on postmenopausal women. The results showed that, compared to women in the placebo group, women on HRT had higher rates of breast cancer, coronary heart disease, stroke, and pulmonary embolism. The only benefits noted were reduced rates of hip fracture and colon cancer. These findings from the Women's Health Initiative have contributed to the controversy surrounding the use of combined estrogen and progestin.
Endometrial cancer is the most common malignant tumor of the female genital tract. It is primarily a disease of postmenopausal women and typically presents clinically as postmenopausal vaginal bleeding. Exposure to unopposed estrogen plays a critical etiologic role. Risk factors include obesity, nulliparity (no pregnancies), late menopause, chronic anovulation (e.g., polycystic ovarian syndrome), and use of estrogen replacement therapy.
Andropause occurs in men; there is reduced testosterone secretion, but the effects of andropause are usually mild compared to the effects of menopause in most women.