Download Disorders of the Female Reproductive System

CHAPTER
Disorders of the Female
Reproductive System
47
Patricia McCowen Mehring
DISORDERS OF THE EXTERNAL GENITALIA
AND VAGINA
Disorders of the External Genitalia
Vulvitis and Folliculitis
Bartholin’s Gland Cyst and Abscess
Epidermal Cysts
Nevi
Nonneoplastic Epithelial Disorders
Vulvodynia
Cancer of the Vulva
Disorders of the Vagina
Vaginitis
Cancer of the Vagina
DISORDERS OF THE CERVIX AND UTERUS
Disorders of the Uterine Cervix
Cervicitis and Cervical Polyps
Cancer of the Cervix
Disorders of the Uterus
Endometritis
Endometriosis
Adenomyosis
Endometrial Cancer
Leiomyomas
DISORDERS OF THE FALLOPIAN TUBES
AND OVARIES
Pelvic Inflammatory Disease
Clinical Course
Ectopic Pregnancy
Clinical Course
Cancer of the Fallopian Tube
Benign Ovarian Cysts and Tumors
Ovarian Cysts
Benign and Functioning Ovarian Tumors
Ovarian Cancer
DISORDERS OF PELVIC SUPPORT AND
UTERINE POSITION
Disorders of Pelvic Support
Cystocele
Rectocele and Enterocele
Uterine Prolapse
Treatment of Pelvic Support Disorders
Variations in Uterine Position
MENSTRUAL DISORDERS
Dysfunctional Menstrual Cycles
Amenorrhea
Dysmenorrhea
Premenstrual Syndrome
DISORDERS OF THE BREAST
Galactorrhea
Mastitis
Ductal Disorders
Fibroadenoma and Fibrocystic Disease
Breast Cancer
Detection
Diagnosis and Classification
Treatment
Paget Disease
INFERTILITY
Male Factors
Female Factors
Ovulatory Dysfunction
Cervical Mucus Problems
Uterine Cavity Abnormalities
Tubal Factors
Assisted Reproductive Technologies
D
isorders of the female genitourinary system have widespread effects on physical and psychological function,
affecting sexuality and reproductive function. The
reproductive structures are located close to other pelvic
structures, particularly those of the urinary system, and
disorders of the reproductive system may affect urinary
function. This chapter focuses on infection and inflammation, benign conditions, and neoplasms of the female reproductive structures; disorders of pelvic support and uterine position; and alterations in menstruation. An overview
of infertility also is included.
1065
1066
UNIT XI
Genitourinary and Reproductive Function
Disorders of the External Genitalia
and Vagina
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Compare the abnormalities associated with vulvitis,
Bartholin’s cyst, epidermal cysts, nevi, nonneoplastic
epithelial disorders, vulvodynia, and cancer of the vulva
✦ State the role of Döderlein’s bacilli in maintaining the
normal ecology of the vagina
✦ Describe the conditions that predispose to vaginal infections and the methods used to prevent and treat
these infections
✦ Cite the association between diethylstilbestrol and
adenocarcinoma of the vagina
DISORDERS OF THE EXTERNAL GENITALIA
quently recur (Fig. 47-1). Abscesses can be extremely tender and painful.
Asymptomatic cysts require no treatment. The treatment of symptomatic cysts consists of the administration
of appropriate antibiotics, local application of moist heat,
and incision and drainage. Cysts that frequently are abscessed or are large enough to cause blockage of the introitus may require surgical intervention (i.e., marsupialization,
a procedure that involves removal of a wedge of vulvar skin
and the cyst wall).1
Epidermal Cysts
Epidermal cysts (i.e., sebaceous or inclusion cysts) are
common semisolid tumors of the vulva. These small nodules are lined with stratified squamous epithelium and
contain cellular debris with a sebaceous appearance and
odor. Epidermal cysts may be solitary or multiple and have
a yellow appearance when stretched or compressed. They
usually resolve spontaneously, and treatment is unnecessary unless they become infected or significantly enlarged.
Vulvitis and Folliculitis
Vulvitis is characterized by inflammation and pruritus
(itching) of the vulva. It is not considered a specific disease
but typically accompanies other local and systemic disorders. The cause often is an irritating vaginal discharge.
Candida albicans, a yeast, is the most common cause of
chronic vulvar pruritus, particularly in women with diabetes mellitus. Vulvitis also may be a component of sexually transmitted diseases (STDs) such as herpes genitalis
and human papillomavirus (HPV) infection (i.e., condyloma). Local dermatologic reactions to chemical irritants,
such as laundry products, perfumed soaps or sprays, and
spermicides, or to allergens such as poison ivy, also can
cause inflammation. Vulvar itching also may be caused by
atrophy that is part of the normal aging process.
Management of vulvitis focuses on appropriate treatment of underlying causes and comfort measures to relieve the irritation. These include keeping the area clean
and dry; using warm sitz baths with baking soda, wet
dressings, or Burow’s solution soaks (a mild astringent); or
applying a mild hydrocortisone cream for the immediate
relief of symptoms.
Folliculitis is an infection that involves the hair follicles of the mons or labia majora. The infection, characterized by small red papules or pustules surrounding the hair
shaft, is relatively common because of the density of bacteria in this area and the occlusive nature of clothing covering the genitalia. Treatment includes thorough cleaning
of the area with germicidal soap, followed by the application of a mild antibacterial ointment (e.g., Neosporin or
Polysporin).
Nevi
Nevi (moles) occur on the vulva as elsewhere on the body.
They can be singular or multiple, flat or raised, and may
vary in degree of pigmentation from flesh colored to dark
brown or black. Nevi are asymptomatic but should be observed for changes that could indicate cancer. Nevi may resemble melanomas or basal cell carcinomas, and excisional
biopsy is recommended when doubt exists (see Chapter 61).
Nonneoplastic Epithelial Disorders
Nonneoplastic epithelial disorders of the vulva (formerly
vulvar dystrophy) are characterized by white lesions of the
Bartholin’s Gland Cyst and Abscess
Bartholin’s cyst is a fluid-filled sac that results from the occlusion of the duct system in Bartholin’s gland. When the
cyst becomes infected, the contents become purulent; if
the infection goes untreated, an abscess can result. The
obstruction that causes cyst and abscess formation most
commonly follows a bacterial, chlamydial, or gonococcal
infection. Cysts can attain the size of an orange and fre-
FIGURE 47-1 Bartholin’s gland cyst. The 4-cm lesion is located to the
right of and posterior to the vaginal introitus. (Rubin E., Farber J.L.
[1999]. Pathology [3rd ed., p. 970]. Philadelphia: Lippincott-Raven)
CHAPTER 47
vulva accompanied by itching or irritation. The lesions can
be further categorized as lichen sclerosus, squamous cell
hyperplasia, or other dermatoses, depending on clinical
and histologic characteristics.
Lichen sclerosus patches are hypopigmented, plaquelike areas that may progress to parchment-thin epithelium
with focal areas of ecchymosis and superficial ulceration
secondary to scratching. Atrophy and agglutination of the
labia minora with eventual stenosis of the introitus is common when this condition becomes chronic. Perirectal involvement is not uncommon.2
Squamous cell hyperplasia presents as thickened, graywhite plaques with an irregular surface. Presumed to be a
response of the genital skin to some type of irritant, this
diagnosis is used only when HPV, fungal infections, or
other known causative conditions have been excluded.3
Pruritus is the most common presenting complaint, but unlike lichen sclerosus, hyperplasia is generally not symmetric and often presents as a focal area involving the labia
majora.
Current treatment of lichen sclerosus favors the use of
potent topical corticosteroids (clobetasol or halobetasol).3
Hyperplastic areas respond well to a combination corticosteroid (e.g., betamethasone valerate) and antipruritic
cream (e.g., crotamiton) and to the removal of any irritants
(e.g., detergents, perfumes). Lichen sclerosus frequently recurs, and lifetime maintenance therapy may be required.
Hyperplastic areas that occur in the field of lichen sclerosus may be sites of malignant change and warrant close
follow-up and possible biopsy.
Vulvodynia
Vulvodynia is a syndrome of unexplained vulvar pain, also
referred to as vulvar pain syndrome or burning vulva syndrome.
It is a chronic disorder characterized by burning, stinging,
irritation, and rawness. Several forms or subsets of vulvodynia have been identified, including cyclic vulvaginitis,
vulvar dermatoses, vulvar vestibular syndrome, and vulvar
dysesthesia. Because vulvodynia is a multifaceted condition, certain subsets may coexist with others.
Cyclic vulvodynia demonstrates episodic flares that
occur only before menses or after coitus. Vulvar dermatoses
are manifested by pruritus, and in some cases, pain develops progressively during the perimenopausal or postmenopausal period. Vulvar dermatoses include thick and
scaly (e.g., papulosquamous) lesions. Erosions may occur
from excessive scratching.
Vulvar vestibulitis syndrome (VVS) is characterized by
pain at onset of intercourse (i.e., insertional dyspareunia),
localized point tenderness near the vaginal opening, and
sensitivity to tampon placement, tight-fitting pants, bicycling, or prolonged sitting. It is the leading cause of dyspareunia in women younger than 50 years of age. VVS can
be primary (present from first contact) or secondary (developing after a period of comfortable sexual relations). Etiology is unknown but VVS can evolve from chronic vulvar
inflammation or trauma. Nerve fibers to the vestibular epithelium become highly sensitized, causing neurons in the
dorsal horn to respond abnormally, which transforms the
sensation of touch in the vestibule into pain (allodynia).4
Disorders of the Female Reproductive System
1067
Surgical vestibulectomy can become necessary for symptom relief when medical management fails.
Vulvar dysesthesia, also known as idiopathic or essential vulvodynia, involves severe, constant, widespread burning that interferes with daily activities. No abnormalities
are found on examination, but there is diffuse and variable hypersensitivity and altered sensation to light touch.
The quality of pain shares many of the features of neuropathic pain, particularly complex regional pain syndrome
(see Chapter 50) or pudendal neuralgia. Although the
cause of the neuropathic pain is unknown, it has been
suggested that it may result from myofascial restrictions
affecting sacral and pelvic floor nerves. Surface electromyography-assisted pelvic floor muscle rehabilitation has
been shown to be an effective and long-term cure for
dysesthetic vulvodynia.5
Possible causes for other forms of vulvodynia include
candidal hypersensitivity related to chronic recurrent yeast
infections; chemical irritation or drug effects, especially prolonged use of topical steroid creams; the irritating effects of
elevated urinary levels of calcium oxalate; immunoglobulin
A deficiency; and dermatoses such as lichen sclerosus, lichen
planus, or squamous cell hyperplasia. Herpes simplex virus
may be related to episodic vulvodynia, and long-term viral
suppressive therapy may be of benefit to women with known
herpes simplex virus infection who experience multiple outbreaks each year. Previous links to HPV infection have not
been supported by studies, and the finding of subclinical
HPV infection in women with vulvodynia now is thought
to be a secondary or unrelated phenomenon.
Treatment of this chronic, often debilitating problem
is aimed at symptom relief and elimination of suspected
underlying problems. Careful history taking and physical
assessment are essential for the differential diagnosis and
treatment. Regimens can include long-term vaginal or oral
antifungal therapy, avoidance of potential irritants, cleaning with water only or a gentle soap, sitz baths with baking soda, emollients such as vitamin E or vegetable oil for
lubrication, low-oxalate diet plus calcium citrate supplements (calcium binds oxalate in the bowel, and citrate inhibits the formation of oxalate crystals), topical anesthetic
or steroid ointments, physical therapy, and surgery. The
tricyclic antidepressants are often used to treat the neuropathic pain associated with vulvar dysesthesia. Psychosocial support often is needed because this condition can
cause strain in sexual, family, and work relationships. Vulvodynia often needs to be managed from a multidimensional, chronic pain perspective.5
Cancer of the Vulva
Carcinoma of the vulva accounts for approximately 4% of
all cancers of the female genitourinary system. This translates to approximately 4000 U.S. cases of vulvar cancer in
2003, resulting in 800 deaths.6 Vulvar cancer appears to
exist as two separate diseases affecting different age groups.
Invasive carcinoma occurs most frequently in women who
are 60 years of age or older, and its incidence has remained
relatively stable since the early 1980s. The mean age for carcinoma in situ is 20 years younger than for invasive carcinoma (45 to 50 years), and the incidence of vulvar cancer
1068
UNIT XI
Genitourinary and Reproductive Function
in women younger than 50 years of age has increased from
2% to 21% during the past 20 years.7
Approximately 90% of vulvar malignancies are squamous cell carcinomas. Less common types of cancer found
on the vulva include adenocarcinoma in the form of extramammary Paget disease (intraepithelial or invasive) or carcinoma of Bartholin’s gland, basal cell carcinoma, and
malignant melanoma.6
Vulvar intraepithelial neoplasia (VIN), which is a precursor lesion of squamous cell carcinoma, represents a
spectrum of neoplastic changes that range from minimal
cellular atypia to invasive cancer. VIN appears to be caused
by the oncogenic (cancer-promoting) potential of certain
strains of HPV (subtypes 16 and 18) that are sexually transmitted and is associated with the type of vulvar cancer
found in younger women.7 VIN lesions may take many
forms. The lesions may be singular or multicentric, macular, papular, or plaquelike. VIN frequently is multicentric,
and approximately 50% are associated with squamous neoplasms in the vagina and cervix.2 Microscopically, VIN presents as a proliferative process characterized by cells with
abnormal epithelial maturation, nuclear enlargement, and
nuclear atypia. The same system that is used for grading
cervical cancer is used for vulvar cancer.2,3 The extent of replacement of epithelial cells by abnormal cells determines
the grade of involvement (VIN I, II, or III). Full-thickness
replacement, VIN III, is synonymous with carcinoma in
situ. Spontaneous resolution of VIN lesions has occurred.
The risk for progression to invasive cancer increases in
older women and in immunosuppressed women.
A second form of vulvar cancer, which is seen more
often in older women, is generally preceded by vulvar nonneoplastic epithelial disorders (VNED) such as chronic vulvar irritation or lichen sclerosus. The pruritus associated
with VNED causes an itch–scratch cycle that can lead to
squamous cell hyperplasia. If left untreated, the hyperplasia progresses to atypia (differentiated VIN), and many of
these women develop invasive cell carcinoma after 6 to 7
GYNECOLOGIC CANCERS
➤ Cancers of the vulva, cervix, endometrium, and ovaries represent a spectrum of malignancies.
➤ Cancers of the vulva and cervix are mainly squamous cell
carcinomas. Certain types of sexually transmitted human
papillomaviruses are risk factors for cervical intraepithelial
neoplasia, which can be a precursor lesion of invasive
carcinoma.
➤ Endometrial cancers, which are seen most frequently in
women 55 to 65 years of age, are strongly associated with
conditions that produce excessive estrogen stimulation
and endometrial hyperplasia.
➤ Ovarian cancer is the second most common female cancer
and the most lethal. The most significant risk factors for
ovarian cancers are the length of time that a woman’s
ovarian cycles are not suppressed by pregnancy, lactation,
or oral contraceptive use, and family history.
years.7 The etiology of this type of VIN is infrequently associated with HPV.
The initial lesion of squamous cell vulvar carcinoma
may appear as an inconspicuous thickening of the skin, a
small raised area or lump, or an ulceration that fails to
heal. It may be single or multiple and vary in color from
white to velvety red or black. The lesions may resemble
eczema or dermatitis and may produce few symptoms,
other than pruritus, local discomfort, and exudation. A recurrent, persistent, pruritic vulvitis may be the only complaint. The symptoms frequently are treated with various
home remedies before medical treatment is sought. The lesion may become secondarily infected, causing pain and
discomfort. The malignant lesion gradually spreads superficially or as a deep furrow involving all of one labial side.
Because there are many lymph channels around the vulva,
the cancer metastasizes freely to the regional lymph nodes.
The most common extension is to the superficial inguinal,
deep femoral, and external iliac lymph nodes. Overall incidence of lymph node metastasis is approximately 30%.7
Early diagnosis is important in the treatment of vulvar
carcinoma. Because malignant lesions can vary in appearance and commonly are mistaken for other conditions,
biopsy and treatment often are delayed. Any vulvar lesion
that is increasing in size or has an unusual warty appearance should be biopsied.7 Treatment is primarily wide surgical excision of the lesion for noninvasive cancer and
radical excision or vulvectomy with node resection for invasive cancer. Postoperative groin and pelvic radiation is
recommended when groin lymph nodes are involved. Nonsurgical treatment options such as photodynamic therapy
or topical immunotherapy are currently under investigation for patients with early-stage vulvar cancer.8
The 5-year survival rate for women with lesions less
than 3 cm in diameter and minimal node involvement is
approximately 90% after surgical treatment. Follow-up visits every 3 months for the first 2 years after surgery and
every 6 months thereafter are important to detect recurrent
disease or a second primary cancer. The 5-year survival rate
for patients who have larger lesions in conjunction with
pelvic lymphadenopathy drops to 30% to 55% after surgical
treatment. Outlook for survival diminishes with increasing
nodal involvement.6
DISORDERS OF THE VAGINA
The normal vaginal ecology depends on the delicate balance of hormones and bacterial flora. Normal estrogen levels maintain a thick, protective squamous epithelium that
contains glycogen. Döderlein’s bacilli, part of the normal
vaginal flora, metabolize glycogen, and in the process produce the lactic acid that normally maintains the vaginal
pH below 4.5. Disruptions in these normal environmental
conditions predispose to infection.
Vaginitis
Vaginitis is inflammation of the vagina; it is characterized
by vaginal discharge and burning, itching, redness, and
swelling of vaginal tissues. Pain often occurs with urination
and sexual intercourse. Vaginitis may be caused by chemi-
CHAPTER 47
cal irritants, foreign bodies, or infectious agents. The causes
of vaginitis differ in various age groups. In premenarchal
girls, most vaginal infections have nonspecific causes, such
as poor hygiene, intestinal parasites, or the presence of foreign bodies. C. albicans, Trichomonas vaginalis, and bacterial vaginosis are the most common causes of vaginitis in
the childbearing years, and some of these organisms can
be transmitted sexually2,3,9 (see Chapter 48). In postmenopausal women, atrophic vaginitis is the most common form.
Atrophic vaginitis is an inflammation of the vagina
that occurs after menopause or removal of the ovaries
and their estrogen supply. Estrogen deficiency results in
a lack of regenerative growth of the vaginal epithelium,
rendering these tissues more susceptible to infection and
irritation. Döderlein’s bacilli disappear, and the vaginal
secretions become less acidic. The symptoms of atrophic
vaginitis include itching, burning, and painful intercourse.
These symptoms usually can be reversed by local application of estrogen.2,3
Every woman has a normal vaginal discharge during
the menstrual cycle, but it should not cause burning or itching or have an unpleasant odor. These symptoms suggest
inflammation or infection. Because these symptoms are
common to the different types of vaginitis, precise identification of the organism is essential for proper treatment. A
careful history should include information about systemic
disease conditions, the use of drugs such as antibiotics that
foster the growth of yeast, dietary habits, stress, and other
factors that alter the resistance of vaginal tissue to infections.
A physical examination usually is done to evaluate the nature of the discharge and its effects on the genital structures.
Microscopic examination of a saline wet-mount smear
(prepared by placing a sample of vaginal mucus in one to
two drops of normal saline) is the primary means of identifying the organism responsible for the infection. A small
amount of 10% potassium hydroxide (KOH) is added to a
second specimen on the slide to aid in the identification
of C. albicans. KOH destroys the cellular material, causing
the epithelial cells to become increasingly transparent so
that the hyphae and buds that are characteristic of Candida become much easier to see. Culture methods may be
needed when the organism is not apparent on the wetmount preparation.3
The prevention and treatment of vaginal infections depend on proper hygiene habits and accurate diagnosis and
treatment of ongoing infections. Measures to prevent infection include development of daily hygiene habits that
keep the genital area clean and dry, maintenance of normal vaginal flora and healthy vaginal mucosa, and avoidance of contact with organisms known to cause vaginal
infections. Perfumed products, such as feminine deodorant
sprays, douches, bath powders, soaps, and even toilet paper, can be irritating and may alter the normal vaginal
flora. Tight clothing prevents the dissipation of body heat
and evaporation of skin moisture and promotes favorable
conditions for irritation and the growth of pathogens.
Nylon and other synthetic undergarments, pantyhose, and
swimsuits hold body moisture next to the skin and harbor
infectious organisms, even after they have been washed.
Cotton undergarments that withstand hot water and
Disorders of the Female Reproductive System
1069
bleach (i.e., a fungicide) may be preferable for women to
prevent such infections. Swimsuits and other garments
that cannot withstand hot water or bleaching should be
hung in the sunlight to dry. Women should be taught to
wipe the perineal area from front to back to avoid bringing
rectal contamination into the vagina. Avoiding sexual contact whenever an infection is known to exist or suspected
should limit that route of transmission.
Cancer of the Vagina
Primary cancers of the vagina are extremely rare. They account for approximately 3% of all cancers of the female reproductive system. Like vulvar carcinoma, carcinoma of
the vagina is largely a disease of older women. Approximately half of women are 60 years of age or older at the
time of diagnosis. The exception to that is the clear cell
adenocarcinoma associated with diethylstilbestrol (DES)
exposure in utero, which is associated with an average age
at diagnosis of 19 years. Vaginal cancers may result from
local extension of cervical cancer, from exposure to sexually transmitted HPV, or rarely from local irritation such
as occurs with prolonged use of a pessary.10
Approximately 85% to 90% of vaginal cancers are
squamous cell carcinomas, with other common types being
adenocarcinomas (5% to 10%), sarcomas (2% to 3%), and
melanomas (2% to 3%).10 Squamous cell carcinomas begin
in the epithelium and progress over many years from precancerous changes called vaginal intraepithelial neoplasia
(VAIN). Maternal ingestion of DES in early pregnancy has
been associated with the development of clear cell adenocarcinoma in female offspring who were exposed in utero.
Between 1938 and 1971, DES, a nonsteroidal synthetic estrogen, commonly was prescribed to prevent miscarriage.11
The incidence of clear cell adenocarcinoma of the vagina
is low, approximately 0.1%, in young women who were
exposed to DES in utero. Although only a small percentage of girls exposed to estrogen actually develop clear cell
adenocarcinoma, 75% to 90% of them develop benign
adenosis (i.e., ectopic extension of cervical columnar epithelium into the vagina, which normally is stratified squamous epithelium), which may predispose to cancer. Most
DES-exposed daughters are now between 40 and 60 years
of age, so they are just entering the postmenopausal period
when this malignancy develops in women who were not
exposed to DES. Because the upper age limit for this type
of cancer is unknown, there is no age at which a DESexposed daughter can be considered risk free.12
The most common symptom of vaginal carcinoma is
abnormal bleeding. Other signs or symptoms include an abnormal vaginal discharge, a palpable mass, or pain during
intercourse. Ten to twenty percent of women are asymptomatic, with the cancer being discovered during a routine
pelvic examination. The anatomic proximity of the vagina
to other pelvic structures (e.g., urethra, bladder, rectum) permits early spread to these areas. Pelvic pain, dysuria, and
constipation can be associated symptoms. Vaginal squamous cell carcinoma most often is detected in the upper posterior one third of the vagina, with adenocarcinoma more
often found on the lower anterior and lateral vaginal vault.
Women should continue to have vaginal cytology studies
1070
UNIT XI
Genitourinary and Reproductive Function
(Papanicolaou’s test [Pap smear]) every 3 to 5 years after hysterectomy to exclude development of vaginal cancer if the
hysterectomy was performed for a reproductive cancer. Diagnosis requires biopsy of suspicious lesions or areas.
Treatment of vaginal cancer must take into consideration the type of cancer; the size, location, and spread of
the lesion; and the woman’s age. Local excision, laser vaporization, or a loop electrode excision procedure (LEEP)
can be considered with stage 0 squamous cell cancer. Radical surgery and radiation therapy are both curative with
more advanced cancers. When there is upper vaginal involvement, radical surgery may be required. This includes
a total hysterectomy, pelvic lymph node dissection, partial
vaginectomy, and placement of a graft from the buttock to
the area from which the vagina was excised. Vaginal reconstruction often is possible to allow for sexual intercourse. The ovaries usually are preserved unless they are
diseased. Extensive lesions and those located in the middle or lower vaginal area usually are treated by radiation
therapy, which can be intracavitary, interstitial, or external beam. The prognosis depends on the stage of the disease, the involvement of lymph nodes, and the degree of
mitotic activity of the tumor. With appropriate treatment
and follow-up, the 5-year survival rate for squamous cell
and adenocarcinoma ranges from 96% for stage 0 and 73%
when confined to the vagina (stage I), to 36% for those
with extensive spread (stages III and IV).10
In summary, the surface of the vulva is affected by disorders
that affect skin on other parts of the body. These disorders include inflammation (i.e., vulvitis and folliculitis), epidermal
cysts, and nevi. Although these disorders are not serious, they
can be distressing because they produce severe discomfort
and itching. Bartholin’s cysts are the result of occluded ducts
in Bartholin’s glands. They often are painful and can become
infected. Nonneoplastic epithelial disorders are characterized
by thinning or hyperplastic thickening of vulvar tissues. Vulvodynia is a chronic vulvar pain syndrome with several classifications and variable treatment results. Cancer of the vulva,
which accounts for 4% of all female genitourinary cancers, is
associated with HPV infections in younger women and lichen
sclerosus in older women.
The normal vaginal ecology depends on the delicate balance of hormones and bacterial flora. Normal estrogen levels
maintain a thick protective squamous epithelium that contains
glycogen. Döderlein’s bacilli, which are part of the normal vaginal flora, metabolize glycogen and, in the process, produce
the lactic acid that normally maintains the vaginal pH below
4.5. Disruptions in these normal environmental conditions
predispose to vaginal infections. Vaginitis or inflammation of
the vagina is characterized by vaginal discharge and burning,
itching, redness, and swelling of vaginal tissues. It may be
caused by chemical irritants, foreign bodies, or infectious
agents. Primary cancers of the vagina are relatively uncommon, accounting for 3% of all cancers of the female reproductive system. Daughters of women treated with DES to
prevent miscarriage are at increased risk for development of
adenocarcinoma of the vagina.
Disorders of the Cervix and Uterus
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Describe the importance of the cervical transformation
zone in the development of cervical cancer
✦ Compare the lesions associated with nabothian cysts and
cervical polyps
✦ List the complications of untreated cervicitis
✦ Compare the age distribution and risk factors for cervical
and endometrial cancer
✦ Characterize the development of cervical cancer, from
✦
✦
✦
✦
✦
the appearance of atypical cells to the development of
invasive cervical cancer
Relate the importance of Papanicolaou’s test in early
detection and decreased incidence of deaths from
cervical cancer
Describe the methods used in the treatment of cervical
cancer
Compare the pathology and manifestations of
endometriosis and adenomyosis
Cite the major early symptom of endometrial cancer
Compare intramural and subserosal leiomyomas
DISORDERS OF THE UTERINE CERVIX
The cervix is composed of two distinct types of tissue. The
exocervix, or visible portion, is covered with stratified
squamous epithelium, which also lines the vagina. The
endocervical canal is lined with columnar epithelium. The
junction of these two tissue types (i.e., squamocolumnar
junction) appears at various locations on the cervix at different points in a woman’s life (Fig. 47-2). During periods
of high estrogen production, particularly fetal existence,
menarche, and the first pregnancy, the cervix everts or
turns outward, exposing the columnar epithelium to the
vaginal environment. The combination of estrogen and
low vaginal pH leads to a gradual transformation from
columnar to squamous epithelium—a process called metaplasia (see Chapter 5). The dynamic area of change where
metaplasia takes place is called the transformation zone. The
process of transformation is increased by trauma and infections occurring during the reproductive years.2,12 As the
squamous epithelium expands and obliterates the surface
columnar papillae, it covers and obstructs crypt openings,
with trapping of mucus in the deeper crypts (glands) to
form retention cysts, called nabothian cysts. These are benign cysts that require no treatment unless they become
so numerous that they cause cervical enlargement. The
nabothian cyst farthest away from the external cervical os
indicates the outer aspect of the transformation zone.
The transformation zone is a critical area for the development of cervical cancer. During metaplasia, the newly
developed squamous epithelial cells are vulnerable to development of dysplasia and genetic change if exposed to
carcinogenic agents (i.e., cancer-producing substances). Dysplasia means disordered growth or development. Although
initially a reversible cell change, untreated dysplasia can
CHAPTER 47
Disorders of the Female Reproductive System
1071
Columnar
epithelium
Functional
squamocolumnar
junction
Squamous
epithelium
Ectropion
Original
squamocolumnar
junction
Transformation zone
FIGURE 47-2 The transformation zone of the cervix. (Rubin E., Farber J.L. [1999]. Pathology [3rd. ed.,
p. 978]. Philadelphia: Lippincott-Raven)
develop into carcinoma. The transformation zone is the
area of the cervix that must be sampled to have an adequate Pap smear and the area most carefully examined
during colposcopy.
Cervicitis and Cervical Polyps
Cervicitis is an acute or chronic inflammation of the cervix.
Acute cervicitis may result from the direct infection of the
cervix or may be secondary to a vaginal or uterine infection.
It may be caused by a variety of infective agents, including
C. albicans, T. vaginalis, Neisseria gonorrhoeae, Gardnerella
vaginalis, Chlamydia trachomatis, Ureaplasma urealyticum,
and herpes simplex virus. C. trachomatis is the organism
most commonly associated with mucopurulent cervicitis.
Chronic cervicitis represents a low-grade inflammatory
process. It is common in parous women and may be a sequela to minute lacerations that occur during childbirth,
instrumentation, or other trauma. The organisms usually
are of a nonspecific type, often staphylococcal, streptococcal, or coliform bacteria.
With acute cervicitis, the cervix becomes reddened
and edematous. Irritation from the infection results in copious mucopurulent drainage and leukorrhea. The symptoms of chronic cervicitis are less well defined: the cervix
may be ulcerated or normal in appearance; it may contain
nabothian cysts; the cervical os may be distorted by old lacerations or everted to expose areas of columnar epithelium;
and a mucopurulent drainage may be present.
Untreated cervicitis may extend to include the development of pelvic cellulitis, low back pain, painful intercourse, cervical stenosis, dysmenorrhea, and further infection of the uterus or fallopian tubes. Depending on the
causative agent, acute cervicitis is treated with appropriate
antibiotic therapy. Diagnosis of chronic cervicitis is based
on vaginal examination, colposcopy, cytologic (Pap) smears,
and occasionally biopsy to exclude malignant changes.
The treatment usually involves cryosurgery or cauterization, which causes the tissues to slough and leads to eradication of the infection. Colposcopically guided laser vaporization of abnormal epithelium is the newest but most
expensive treatment for cervicitis.
Polyps are the most common lesions of the cervix.
They can be found in women of all ages, but their incidence
is higher during the reproductive years. Polyps are soft, velvety red lesions; they usually are pedunculated and often
are found protruding through the cervical os. They usually
develop as a result of inflammatory hyperplasia of the endocervical mucosa. Polyps typically are asymptomatic but
may have associated postcoital bleeding. Most are benign,
but they should be removed and examined by a pathologist
to exclude the possibility of malignant change.
Cancer of the Cervix
Cervical cancer is readily detected and, if detected early, is
the most easily cured of all the cancers of the female reproductive system. According to the American Cancer
Society, an estimated 12,200 cases of invasive cervical cancer were diagnosed in 2003, with approximately 4100 deaths
from cervical cancer during the same period.13 By comparison, there were four times as many new cases of cervical
carcinoma in situ (i.e., precancerous lesion) diagnosed, indicating that a large number of potentially invasive cancers are cured by early detection and effective treatment.
The death rate has steadily declined over the past 50 years
with the introduction of more sensitive and readily available screening methods (e.g., Pap smear, colposcopy, cervicography), consistent use of a standardized grading
system that guides treatment, and more effective treatment methods. However, the mortality rate is more than
twice as high for black women as for white women. The
5-year survival rate for all patients with cervical cancer is
71%. For women with localized disease, the 5-year survival
rate is 92%, but only 56% of cancers are discovered at that
stage in white women and 46% in African Americans.13
Risk Factors and Pathogenesis. Carcinoma of the cervix is
considered an STD. It is rare among celibate women. Risk
factors include early age at first intercourse, multiple sexual
partners, a promiscuous male partner, smoking, and a history of STDs.13–15 A preponderance of evidence suggests a
causal link between HPV infection and cervical cancer. Certain strains of HPV have been identified in invasive carcinoma of the cervix, whereas others are associated more
often with dysplasia or carcinoma in situ. The strongest link
is with HPV types 16, 18, 31, 33, 35, 39, 45, 52, 56, 58, and
59.1,2 Because these viruses are spread by sexual contact,
1072
UNIT XI
Genitourinary and Reproductive Function
their association with cervical cancer provides a tempting
hypothesis to explain the relation between sexual practices
and cervical cancer. HPV is discussed further in Chapter 48.
Other factors such as smoking, nutrition, and coexisting
sexual infections such as C. trachomatis, herpes simplex
virus type 2 (HSV-2), and human immunodeficiency virus
(HIV) may play a contributing role in determining whether
a woman with HPV infection develops cervical cancer.2,14
One of the most important advances in the early diagnosis and treatment of cancer of the cervix was made
possible by the observation that this cancer arises from
precursor lesions, which begin with the development of
atypical cervical cells. These atypical cells gradually progress to carcinoma in situ and to invasive cancer of the
cervix. Atypical cells differ from normal cervical squamous
epithelium. There are changes in the nuclear and cytoplasmic parts of the cell and more variation in cell size and
shape (i.e., dysplasia). Carcinoma in situ is localized to the
epithelial layer, whereas invasive cancer of the cervix
spreads to deeper layers.2
A system of grading devised to describe the dysplastic
changes of cancer precursors uses the term cervical intraepithelial neoplasia (CIN). This histologic terminology system
divides the precursors according to the extent of involvement of the epithelial thickness of the cervix. (Table 47-1).
It was presumed that CIN represented a single, progressive
disease process. Current understanding of the pathogenesis of cervical cancer precursors now suggests two distinct
biologic entities: a productive viral infection (HPV), which
can regress spontaneously (mild dysplasia or CIN 1), and a
true neoplastic process confined to the epithelium (CIN 2
or 3). CIN histologic terminology has been largely replaced
with cytopathology terms for these two biologic entities:
low-grade squamous intraepithelial lesion (LSIL) and highgrade squamous intraepithelial lesion (HSIL).2
The precursor lesions can exist in a reversible form,
which may regress spontaneously, persist, or progress and
undergo malignant change. Studies of the natural history
of these precursor lesions have yielded variable rates of
progression and regression. Generally, only a small percentage of lesions progress to invasive carcinoma. HSIL has
TABLE 47-1
a much greater potential for progressing than does LSIL. De
novo development of HSIL has also been demonstrated,
challenging the concept that LSIL is always a precursor to
HSIL. Cancers of the cervix have a long latent period; untreated dysplasia gradually progresses to carcinoma in situ,
which may remain static for 7 to 10 years before it becomes
invasive. After the preinvasive period, growth may be rapid, and survival rates decline significantly depending on
the extent of disease at the time of diagnosis.2
The atypical cellular changes that precede frank neoplastic changes consistent with cancer of the cervix can be
recognized by a number of direct and microscopic techniques, including Pap smear, colposcopy, and cervicography. Currently, Pap smears are used for cervical cancer
screening. The purpose of the Pap smear is to detect the
presence of abnormal cells on the surface of the cervix or
in the endocervix. Following an extensive review of the literature, the American Cancer Society (ACS) in late 2002 released revised guidelines for cervical cancer screening16
(Chart 47-1). The U.S. Preventive Services Task Force (USPSTF) screening guidelines were also updated in 2002.17
Although many clinicians and women themselves are reluctant to move away from yearly Pap smears, the evidence
about the natural progression of cervical cancer supports
the position that this is the more cost-effective approach
to screening.
It has been estimated that approximately 20% of
women with intraepithelial lesions have normal Pap smear
results.16 Care must be taken to obtain an adequate smear
from the transformation zone that includes endocervical
cells and to ensure that the cytologic examination is done
by a competent laboratory. New techniques of specimen
collection, slide preparation and processing, and computerassisted evaluation of Pap smears are being evaluated and
offer hope of improved accuracy in diagnosis of precancerous cervical changes.
The presence of normal endometrial cells in a cervical
cytologic sample during the luteal phase of the menstrual
cycle or during the postmenopausal period has been associated with endometrial disease and warrants further evaluation with endometrial biopsy. This demonstrates that
Classification Systems for Papanicolaou Smears
Dysplasia/Neoplasia
CIN
Bethesda System
Benign
Benign with inflammation
Mild dysplasia
Moderate dysplasia
Severe dysplasia and
carcinoma in situ
Invasive cancer
Benign
Benign with inflammation
CIN 1
CIN 2
CIN 3
Negative for intraepithelial lesion or malignancy
Negative for intraepithelial lesion or malignancy, ASC-US
Low-grade SIL, ASC-H
High-grade SIL
Invasive cancer
Invasive cancer
CIN, cervical intraepithelial neoplasia; SIL, squamous intraepithelial lesion; ASC-US, atypical squamous cells of
undetermined significance; ASC-H, cannot rule out high-grade SIL.
Adapted from information in Rubin E., Farber J.L. (1999). Pathology (3rd ed., p 982). Philadelphia: Lippincott-Raven;
Solomon D., Davey D., Kurman R., et al., Forum Group Members and Bethesda 2001 Workshop. (2002). The 2001
Bethesda System. Journal of the American Medical Association 287(16), 2114–2119.
CHAPTER 47
CHART 47-1
Guidelines for Cervical Cancer Screening Using
the Papanicolaou (Pap) Smear
• Screening should begin 3 years after first vaginal
intercourse or after age 21, whichever comes first.
• Women 30 years of age and older may be screened
at longer intervals after three consecutive normal/
negative cytology results.
• Screening may be discontinued in women aged
65 years and older if they had adequate screening
with normal Pap smears and are not otherwise at
increased risk for cervical cancer.
• Women who have had a total hysterectomy with
removal of the cervix do not need screening unless
the surgery was performed to treat cervical cancer
or a precancerous condition.
• If a woman has risk factors, such as HPV infection,
DES exposure in utero, or strong family history of
cervical cancer, more frequent Pap smears may be
recommended.
Adapted from Smith R.A., Cokkinides V., von Eschenbach A.C.,
et al. (2002). American Cancer Society guideline for early
detection of cervical neoplasia and cancer. CA: A Cancer Journal
for Clinicians 52(1), 8–22; U.S. Preventive Services Task Force.
(2002). Recommendations for Screening for Cervical Cancer.
[On-line]. Available: http://www.AHRQ.gov.
shedding of even normal cells at an inappropriate time
may indicate disease. Because adenocarcinoma of the cervix is being detected more frequently, especially in women
younger than 35 years of age, a Pap smear result of atypical glandular cells (AGCs) warrants further evaluation by
endocervical or endometrial curettage, hysteroscopy, or,
ultimately, a cone biopsy if the abnormality cannot be
located or identified through other means.2,3
The accepted format for reporting cervical and vaginal cytologic diagnoses, called The Bethesda System
(TBS), was developed during a National Cancer Institute
Workshop in 1989 and updated in 1991 and 2001 (see
Table 47-1).18 TBS 2001 Terminology includes the following components: specimen type (conventional vs. liquid
based); specimen adequacy (satisfactory or unsatisfactory
for evaluation); general categorization (negative for intraepithelial lesion or malignancy versus epithelial cell
abnormality); and interpretation/result (negative for intraepithelial lesion or malignancy: includes the presence of
organisms and other nonneoplastic findings, versus epithelial cell abnormalities: squamous cell or glandular
cell).18 In 2002, a task force composed of Bethesda 2001
group members and representatives of the American Society of Colposcopy and Cervical Pathology (ASCCP) provided additional guidance regarding Pap specimen adequacy and management.19 The minimally abnormal Pap
smear (i.e., atypical squamous cells [ASC], or low-grade
squamous intraepithelial lesion [LSIL]) presents the greatest challenge to clinicians.
Disorders of the Female Reproductive System
1073
Current guidelines indicate that the management of
women with atypical squamous cells (ASC) depends on
whether the Pap test is subcategorized as “of undetermined significance” (ASC-US) or as “cannot exclude highgrade squamous intraepithelial lesion [HSIL]” (ASC-H).
The uncertain significance of ASC-US often is related to inflammation, atrophy, or other temporary or reversible processes. Even squamous intraepithelial lesions (SILs) regress
spontaneously in approximately 60% of patients, and costly
evaluation or aggressive treatment may not be warranted.
Follow-up with repeat Pap smears at 4- to 6-month intervals for a total of three tests is the preferred conservative
approach for women with ASC-US. Referral for colposcopy
is generally recommended for women with ASC-H, LSIL,
or HSIL or if compliance with follow-up observation is uncertain; women who have had suspicious findings on
exam, previous abnormal Pap results, history of STDs or
high-risk sexual behaviors; and women who are long-term
or heavy smokers or are immunocompromised. Colposcopy, with endocervical curettage, or directed biopsy
may be used to confirm the presence of a lesion so that
treatment can be selected.2,3,14,15
DNA testing for high-risk strains of HPV provides an
additional means of determining which women may be
acceptable candidates for conservative management and
those who may be at greatest risk for developing cervical
cancer. Adjunct HPV DNA testing is an acceptable tool to
determine which women with ASC-US may benefit from
immediate referral for colposcopy. Research is ongoing in
this area, but at this time, HPV DNA typing is not recommended for primary screening.14–17,19 A vaccine to prevent
infection with the HPV subtype 16 has shown promising
results in preliminary trials and offers hope that we may
someday have the means to prevent cervical cancer.14
Clinical Course. Diagnosis of cervical cancer requires pathologic confirmation. Pap smear results demonstrating SIL
often require further evaluation by colposcopy. This is a
vaginal examination that is done using a colposcope, an instrument that affords a well-lit and magnified stereoscopic
view of the cervix. During colposcopy, the cervical tissue
may be stained with an iodine solution (i.e., Schiller’s test)
or acetic acid solution to accentuate topographic or vascular changes that can differentiate normal from abnormal
tissue. A biopsy sample may be obtained from suspect areas
and examined microscopically.
An alternate diagnostic tool in areas where colposcopy is not readily available is cervicography, a noninvasive photographic technique that provides permanent
objective documentation of normal and abnormal cervical patterns. Acetic acid (5%) is applied to the cervix, a
cervicography camera is used to take photographs, and
the projected cervicogram (i.e., slide after film developing) can be sent for expert evaluation. In one study, the
cervicogram was found to give a greater yield of CIN than
Pap smear alone in patients with previous abnormal pap
smears.20
Before the availability of colposcopy, many women
with abnormal Pap smears required surgical cone biopsy
for further evaluation. Cone biopsy involves the removal
1074
UNIT XI
Genitourinary and Reproductive Function
of a cone-shaped wedge of cervix, including the entire
transformation zone and at least 50% of the endocervical
canal. Postoperative hemorrhage, infection, cervical stenosis, infertility, and incompetent cervix are possible sequelae that warrant avoidance of this procedure unless it
is truly necessary. Diagnostic conization still is indicated
when a lesion is partly or completely beyond colposcopic
view or when colposcopically directed biopsy fails to explain the cytologic findings.
The LEEP or large loop excision of the transformation
zone (LLETZ), a refinement of loop diathermy techniques
dating back to the 1940s, is quickly becoming the first-line
management tool for SIL. This outpatient procedure allows for the simultaneous diagnosis and treatment of dysplastic lesions found on colposcopy. It uses a thin, rigid,
wire loop electrode attached to a generator that blends
high-frequency, low-voltage current for cutting and a modulated higher voltage for coagulation. In skilled hands, this
wire can remove the entire transformation zone, providing adequate treatment for the lesion while obtaining a
specimen for further histologic evaluation. The width and
depth of the tissue excised are controlled by the size and
shape of the loop and the speed and pressure that is applied
during the procedure. This can help avoid the problems
that can occur after surgical cone biopsy (e.g., stenosis, incompetent cervix). Bleeding can be minimized by fulguration of the base with electrocoagulation or by applying a
thin layer of Monsel’s gel (i.e., chemical cautery). Although
long-term results are not available, this procedure, which
requires only local anesthesia, appears to provide a lowercost, office-based alternative to cone biopsy.
Early treatment of cervical cancer involves removal of
the lesion by one of various techniques. Biopsy or local
cautery may be therapeutic in and of itself. Electrocautery,
cryosurgery, or carbon dioxide laser therapy may be used
to treat moderate to severe dysplasia that is limited to the
exocervix (i.e., squamocolumnar junction clearly visible).
Therapeutic conization becomes necessary if the lesion extends into the endocervical canal and can be done surgically or with LEEP in the physician’s office.3
Depending on the stage of involvement of the cervix,
invasive cancer is treated with radiation therapy, surgery,
or both. External beam irradiation and intracavitary cesium irradiation (i.e., insertion of a closed metal cylinder
containing cesium) can be used in the treatment of cervical cancer. Intracavitary radiation provides direct access to
the central lesion and increases the tolerance of the cervix
and surrounding tissues, permitting curative levels of radiation to be used. External beam radiation eliminates
metastatic disease in pelvic lymph nodes and other structures and shrinks the cervical lesion to optimize the effects
of intracavitary radiation. Surgery can include extended
hysterectomy (i.e., removal of the uterus, fallopian tubes,
ovaries, and upper portion of the vagina) without pelvic
lymph node dissection, radical hysterectomy with pelvic
lymph node dissection, or pelvic exenteration (i.e., removal of all pelvic organs, including the bladder, rectum,
vulva, and vagina). The choice of treatment is influenced
by the stage of the disease as well as the woman’s age and
health.3
DISORDERS OF THE UTERUS
Endometritis
Inflammation or infection of the endometrium is an illdefined entity that produces variable symptoms. The presence of plasma cells is required for diagnosis. Endometritis
can occur as a postpartum or postabortal infection, with
gonococcal or chlamydial salpingitis, or after instrumentation or surgery, or it can be associated with an intrauterine device or tuberculosis.3 Causative organisms, in
addition to N. gonorrhoeae, Chlamydia, and Mycobacterium
tuberculosis, include Escherichia coli, Proteus, Pseudomonas,
Klebsiella, Bacteroides, and Mycoplasma species. Abnormal
vaginal bleeding, mild to severe uterine tenderness, fever,
malaise, and foul-smelling discharge have been associated
with endometritis, but the clinical picture is variable. Treatment involves oral or intravenous antibiotic therapy, depending on the severity of the condition.
Endometriosis
Endometriosis is the condition in which functional endometrial tissue is found in ectopic sites outside the uterus.
The site may be the ovaries, posterior broad ligaments,
uterosacral ligaments, pouch of Douglas (cul-de-sac), pelvis,
vagina, vulva, perineum, or intestines (Fig 47-3). Rarely,
endometrial implants have been found in the nostrils, umbilicus, lungs, and limbs.
The cause of endometriosis is unknown. There appears
to have been an increase in its incidence in the developed
Western countries during the past four to five decades. Approximately 10% to 15% of premenopausal women have
some degree of endometriosis. The incidence may be
higher in women with infertility (15% to 70%) or women
younger than 20 years of age with chronic pelvic pain
(47% to 73%).21 It is more common in women who have
postponed childbearing. Risk factors for endometriosis
may include early menarche; regular periods with shorter
cycles (<27 days), longer duration (>7 days), or heavier
flow; increased menstrual pain; and other first-degree relatives with the condition.
Several theories attempt to account for endometriosis.
One theory suggests that menstrual blood containing
fragments of endometrium is forced upward through the
fallopian tubes into the peritoneal cavity. Retrograde menstruation is not an uncommon phenomenon, and it is unknown why endometrial cells implant and grow in some
women but not in others. Another proposal is that dormant, immature cellular elements, spread over a wide area
during embryonic development, persist into adult life and
that the ensuing metaplasia accounts for the development
of ectopic endometrial tissue. Another theory suggests that
the endometrial tissue may metastasize through the lymphatics or vascular system. Altered cellular immunity and
genetic components also have been studied as contributing
factors to the development of endometriosis.2,3
The gross pathologic changes that occur in endometriosis differ with location and duration. In the ovary,
the endometrial tissue may form cysts (i.e., endometriomas
filled with old blood that resembles chocolate syrup [chocolate cysts]). Rupture of these cysts can cause peritonitis and
CHAPTER 47
Disorders of the Female Reproductive System
1075
Umbilicus
Ovary
Small bowel
Colon
Fallopian tube
Uterine serosa
Peritoneum
Rectovaginal septum
and uterosacral
ligaments
Bladder
Uterovesical fold
FIGURE 47-3 Common locations of
endometriosis within the pelvis and
abdomen.
adhesions. Elsewhere in the pelvis, the tissue may take
the form of small hemorrhagic lesions that may be black,
bluish, red, clear, or opaque. Some may be surrounded by
scar tissue. These ectopic implants respond to hormonal
stimulation in the same way normal endometrium does, becoming proliferative, then secretory, and finally undergoing menstrual breakdown. Bleeding into the surrounding
structures can cause pain and the development of significant pelvic adhesions. Extensive fibrotic tissue can develop
and occasionally causes bowel obstruction.
Endometriosis may be difficult to diagnose because its
symptoms mimic those of other pelvic disorders. The severity of the symptoms does not always reflect the extent of the
disease. The classic triad of dysmenorrhea, dyspareunia, and
infertility strongly suggests endometriosis. Accurate diagnosis can be accomplished only through laparoscopy. This
minimally invasive surgery allows direct visualization of
pelvic organs to determine the presence and extent of endometrial lesions. Imaging techniques including ultrasound
and magnetic resonance imaging (MRI) can be useful tools
in evaluating endometriomas. CA-125 is a serum marker
that may be elevated in the presence of endometriosis. It
has limitations as a screening tool but can be useful in monitoring response to therapy and recurrence.21
Treatment goals for endometriosis are pain management or restoration of fertility. Treatment modalities fall
into three categories: pain relief, endometrial suppression, and surgery. In young women, simple observation
and antiprostaglandin analgesics (i.e., nonsteroidal antiinflammatory drugs) may be sufficient treatment. The use
of hormones to induce physiologic amenorrhea is based
on the observation that pregnancy affords temporary relief by inducing atrophy of the endometrial tissue. This
can be accomplished through administration of progesterone, oral contraceptive pills, danazol (a synthetic androgen), or long-acting gonadotropin-releasing hormone
analogs that inhibit the pituitary gonadotropins and suppress ovulation.3,22
Surgery is the most definitive therapy for many women
with endometriosis. In the past, laparoscopic cautery was
limited to mild endometriosis without significant adhesions. More extensive treatment required laparotomy. With
the advent of carbon dioxide, potassium-titanyl-phosphate
(KTP), neodymium–yttrium-aluminum-garnet (Nd-YAG),
argon, and holmium-YAG lasers, in-depth treatment of
endometriosis or pelvic adhesions can be accomplished by
means of laparoscopy. Advantages of laser surgery include
better hemostasis, more precision in vaporizing lesions with
less damage to surrounding tissue, and better access to areas
that are not well visualized or would be difficult to reach
with cautery. Each type of laser has distinct properties that
allow it to be useful for tissue vaporization under different
conditions. The KTP laser is particularly useful for endometriosis because of its flexible fiberoptic delivery system,
which allows tissue incision and vaporization in addition to
photocoagulation, and its green beam, which makes visualization and fine focusing easier. Carbon dioxide permits the
operator to excise easily with extreme accuracy and control
and causes less peripheral tissue damage than other wavelengths. The Nd-YAG laser allows for a contact mode that
avoids direct application of laser energy to tissues. Lasers are
expensive instruments and require skill to use effectively.
Some hospitals and surgeons have turned to other therapies
in an effort to conserve financial resources. Electrosurgical,
thermal, and ultrasonic ablation techniques are under investigation.23 Radical treatment involves total hysterectomy
and bilateral salpingo-oophorectomy (i.e., removal of the
fallopian tubes and ovaries) when the symptoms are unbearable or the woman’s childbearing is completed.
Treatment offers relief but not cure. Recurrence of
endometriosis is not uncommon, regardless of the treatment (except for radical surgery). Recurrence rates appear
1076
UNIT XI
Genitourinary and Reproductive Function
to correlate with severity of disease. With medical treatment, recurrence rates after 7 years ranged from 34% in
women with mild disease to 74% in those with severe disease. Recurrence rates of 20% to 40% have been reported
within 5 years after surgery.24 Pregnancy may delay but
does not preclude recurrence.
Adenomyosis
Adenomyosis is the condition in which endometrial glands
and stroma are found within the myometrium, interspersed between the smooth muscle fibers. In contrast to
endometriosis, which usually is a problem of young, infertile women, adenomyosis typically is found in multiparous women in their late fourth or fifth decade. It is
thought that events associated with repeated pregnancies,
deliveries, and uterine involution may cause the endometrium to be displaced throughout the myometrium.
Adenomyosis frequently coexists with uterine myomas or
endometrial hyperplasia. The diagnosis of adenomyosis
often occurs as an incidental finding in a uterus removed
for symptoms suggestive of myoma or hyperplasia. Heavy,
painful periods with clots and painful intercourse are common complaints of women with adenomyosis. Although
in the past the diagnosis was made primarily through careful history and the pelvic examination findings of an enlarged, boggy uterus, magnetic resonance imaging is now
considered an excellent diagnostic tool for confirming this
condition. Color Doppler ultrasound can be used to distinguish vascular patterns that may differentiate adenomyosis from uterine fibroids.25 Adenomyosis resolves with
menopause. Conservative therapy using oral contraceptives or gonadotropin-releasing hormone (GnRH) agonists
is the first choice for treatment. Hysterectomy (with preservation of the ovaries in premenopausal women) is considered when this approach fails.
Endometrial Cancer
Endometrial cancer is the most common cancer found in
the female pelvis; it occurs more than twice as often as cervical cancer. In 2003, the American Cancer Society estimated that approximately 40,100 women were diagnosed
with endometrial cancer and 6800 died of the disorder.13
Endometrial cancer occurs more frequently in older women
(peak ages of 55 to 65 years), with only a 2% to 5% incidence among women younger than 40 years of age.
Prolonged estrogen stimulation with excessive growth
(i.e., hyperplasia) of endometrium has been identified as a
major risk factor for the development of type I (endometrioid) endometrial cancer. Obesity, anovulatory cycles, conditions that alter estrogen metabolism, estrogen-secreting
neoplasms, and unopposed estrogen therapy all increase the
risk for endometrial cancer.2,3,13
Estrogens are synthesized in body fats from adrenal
and ovarian androgen precursors. Endometrial hyperplasia and endometrial cancer appear to be related to obesity.
Ovulatory dysfunction that causes infertility at any age or
occurs with declining ovarian function in perimenopausal
women also can result in unopposed estrogen and increase the risk for endometrial cancer. Diabetes mellitus,
hypertension, and polycystic ovary syndrome are condi-
tions that alter estrogen metabolism and elevate estrogen
levels.
Endometrial cancer risk also is increased in women
with estrogen-secreting granulosa cell tumors and in those
receiving unopposed estrogen therapy. A sharp rise in endometrial cancer was seen in the 1970s among middle-aged
women who had received unopposed estrogen therapy
(i.e., estrogen therapy without progesterone) for menopausal symptoms. It was later determined that it was not
the estrogen exposure that increased the risk for cancer,
but that the hormone was administered without progesterone. It is the presence of progesterone in the second
half of the menstrual cycle that matures the endometrium
and the withdrawal of progesterone that ultimately results
in endometrial sloughing. Long-term unopposed estrogen
exposure without periodic addition of progesterone allows
for continued endometrial growth. Hyperplasia may develop, with or without the presence of atypical cells, and
can progress to carcinoma if left untreated. Hyperplasia
usually regresses after treatment with cyclic progesterone.
Sequential oral contraceptives (estrogen alone for 15 days
followed by 7 days of combined estrogen and progestin)
were withdrawn from the market in the 1970s because of
potential risk for endometrial hyperplasia. In contrast,
combination oral contraceptives (estrogen and progestin
in each pill) effectively prevent hyperplasia and decrease
the risk for cancer by 50%.3 Tamoxifen, a drug that blocks
estrogen receptor sites and is used in treatment of breast
cancer, exerts a weak estrogenic effect on the endometrium
and represents another exogenous risk factor for endometrial cancer.
A small subset of women in whom endometrial cancer develops do not exhibit increased estrogen levels or
preexisting hyperplasia (type II or serous carcinoma).
These women usually acquire the disease at an older age.
These tumors arise from clones of cancer-initiated mutant
cells and are more poorly differentiated. This type of endometrial cancer usually has a poorer prognosis than that
associated with prolonged estrogen stimulation and endometrial hyperplasia.2
Endometrial cancer is the most commonly inherited
gynecologic cancer. Women with a family history of hereditary nonpolyposis colon cancer (HNPCC) may have an
inherited mutation that has been identified as mismatch
repair genes. This autosomal dominant disease carries an
80% risk of developing cancer of some type for those who
inherit the mutation. In the normal population, the lifetime risk for developing endometrial cancer is 1.6%,
compared with 60% with the inherited mismatch repair
defect.3 A detailed family history for cancer can be the
best means of identifying those who would benefit from
genetic counseling.
Clinical Course. The major symptom of endometrial hyperplasia or overt endometrial cancer is abnormal, painless
bleeding. In menstruating women, this takes the form of
bleeding between periods or excessive, prolonged menstrual flow. In postmenopausal women, any bleeding is abnormal and warrants investigation. Abnormal bleeding is
an early warning sign of the disease, and because endo-
CHAPTER 47
metrial cancer tends to be slow growing in its early stages,
the chances of cure are good if prompt medical care is
sought. Later signs of uterine cancer may include cramping, pelvic discomfort, postcoital bleeding, lower abdominal pressure, and enlarged lymph nodes.
Although the Pap smear can identify a small percentage of endometrial cancers, it is not a good screening test
for this gynecologic cancer. Endometrial biopsy (i.e., tissue
sampling obtained in an office procedure by direct aspiration of the endometrial cavity) is far more accurate; 80% to
90% of endometrial cancers are identified if adequate tissue
is obtained. Dilatation and curettage (D & C), which consists of dilating the cervix and scraping the uterine cavity, is
the definitive procedure for diagnosis because it provides a
more thorough evaluation. Transvaginal ultrasonography
used to measure the endometrial thickness is being evaluated as an initial test for postmenopausal bleeding because
it is less invasive than endometrial biopsy and less costly
than D & C when biopsy is not possible.
The prognosis for endometrial cancer depends on the
clinical stage of the disease when it is discovered and its
histologic grade and type. Surgery and radiation therapy
are the most successful methods of treatment for endometrial cancer. When used alone, radiation therapy has a
20% lower cure rate than surgery for stage I disease. It may
be the best option, however, in women who are not good
surgical candidates. Total abdominal hysterectomy with bilateral salpingo-oophorectomy plus sampling of regional
lymph nodes and peritoneal washings for cytologic evaluation of occult disease is the treatment of choice whenever
possible. Postoperative radiation therapy may be added in
cases of advanced disease for more complete treatment
and to prevent recurrence or metastasis, although the benefits of this as adjuvant therapy are still controversial. The
5-year relative survival rates are 96%, 64%, and 26% if the
cancer is diagnosed at local, regional, and distant stages,
respectively.13
Leiomyomas
Leiomyomas are benign neoplasms of smooth muscle origin. They also are known as myomas and sometimes are
called fibroids. These are the most common form of pelvic
tumor and are believed to occur in one of every four or five
women older than 35 years of age. They are seen more
often and their rate of growth is more rapid in black women
than in white women. Leiomyomas usually develop in the
corpus of the uterus; they may be submucosal, subserosal,
or intramural (Fig. 47-4). Intramural fibroids are embedded
in the myometrium. They are the most common type of fibroid and present as a symmetric enlargement of the nonpregnant uterus. Subserosal tumors are located beneath the
perimetrium of the uterus. These tumors are recognized as
irregular projections on the uterine surface; they may become pedunculated, displacing or impinging on other genitourinary structures and causing hydroureter or bladder
problems. Submucosal fibroids displace endometrial tissue
and are more likely to cause bleeding, necrosis, and infection than either of the other types.
Leiomyomas are asymptomatic approximately half
of the time and may be discovered during a routine pelvic
Disorders of the Female Reproductive System
1077
Subserosal
Intramural
Submucosal
A
B
FIGURE 47-4 (A) Submucosal, intramural, and subserosal leiomyomas.
(A redrawn from Green T.H. [1977]. Gynecology: Essentials of clinical
practice [3rd ed.]. Boston: Little, Brown.) (B) A bisected uterus displays
a prominent, sharply circumscribed, fleshy tumor. (Rubin E., Farber
J.L. [1999]. Pathology [3rd ed., p. 999]. Philadelphia: Lippincott-Raven)
examination, or they may cause menorrhagia (excessive
menstrual bleeding), anemia, urinary frequency, rectal
pressure/constipation, abdominal distention, and infrequently pain. Their rate of growth is variable, but they may
increase in size during pregnancy or with exogenous estrogen stimulation (i.e., oral contraceptives or menopausal estrogen replacement therapy). Interference with pregnancy
is rare unless the tumor is submucosal and interferes with
implantation or obstructs the cervical outlet. These tumors may outgrow their blood supply, become infarcted,
and undergo degenerative changes. Most leiomyomas
regress with menopause, but if bleeding, pressure on the
bladder, pain, or other problems persist, hysterectomy may
1078
UNIT XI
Genitourinary and Reproductive Function
be required. Myomectomy (removal of just the tumors) can
be done to preserve the uterus for future childbearing. Cesarean section may be recommended if the uterine cavity
is entered during myomectomy. GnRH (e.g., leuprolide
[Lupron]) may be used to suppress leiomyoma growth before surgery. Uterine artery embolization done by an interventional radiologist is a nonsurgical therapy for management of heavy bleeding.26
In summary, disorders of the cervix and uterus include
inflammatory conditions (i.e., cervicitis and endometritis), cancer (i.e., cervical and endometrial cancer), endometriosis, and
leiomyomas. Cervicitis is an acute or chronic inflammation of
the cervix. Acute cervicitis may result from the direct infection
of the cervix or may be secondary to a vaginal or uterine infection. It may be caused by a variety of infective agents.
Chronic cervicitis represents a low-grade inflammatory process
resulting from trauma or nonspecific infectious agents. Cervical cancer is readily detected, and if detected early, it is the
most easily cured of all the cancers of the female reproductive
system. It arises from precursor lesions that can be detected on
a Pap smear; the condition can be cured if detected and
treated early.
Endometritis represents an ill-defined inflammation or infection of the endometrium that produces variable symptoms.
Endometriosis is the condition in which functional endometrial
tissue is found in ectopic sites outside the uterus such as the
ovaries, broad ligaments, pouch of Douglas (cul-de-sac), pelvis,
vagina, vulva, perineum, or intestines. It causes dysmenorrhea, dyspareunia, and infertility. Adenomyosis is the condition in which endometrial glands and stroma are found in the
myometrium, interspersed between the smooth muscle fibers.
Endometrial cancer is the most common cancer found in the
female pelvis; it occurs more than twice as often as cervical
cancer. Prolonged estrogen stimulation with hyperplasia of
the endometrium has been identified as a major risk factor for
endometrial cancer.
Leiomyomas are benign uterine wall neoplasms of smooth
muscle origin. They can develop in the corpus of the uterus
and can be submucosal, subserosal, or intramural. Submucosal fibroids displace endometrial tissue and are more likely to
cause bleeding, necrosis, and infection than either of the other
types.
Disorders of the Fallopian Tubes
and Ovaries
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ List the common causes and symptoms of pelvic
✦
✦
✦
✦
inflammatory disease
State the causative factors associated with tubal pregnancy
Describe the symptoms of a tubal pregnancy
State the underlying cause of ovarian cysts
Differentiate benign ovarian cyst and polycystic ovary
syndrome (previously called Stein-Leventhal syndrome)
✦ List the hormones produced by the three types of
functioning ovarian tumors
✦ State the reason that ovarian cancer may be difficult to
detect in an early stage
PELVIC INFLAMMATORY DISEASE
Pelvic inflammatory disease (PID) is an inflammation of
the upper reproductive tract that involves the uterus
(endometritis), fallopian tubes (salpingitis), or ovaries
(oophoritis). Most women with acute salpingitis have
N. gonorrhoeae or C. trachomatis identified in the reproductive tract. PID is a polymicrobial infection, and the cause
varies by geographic location and population. In addition
to the primary causative agents already mentioned, Mycoplasma hominis, Ureaplasma urealyticum, Bacteroides, Peptostreptococcus, E. coli, Haemophilus influenzae, and Streptococcus agalactiae may be involved.27 The organisms ascend
through the endocervical canal to the endometrial cavity,
and then to the tubes and ovaries. The endocervical canal
is slightly dilated during menstruation, allowing bacteria to
gain entrance to the uterus and other pelvic structures. After
entering the upper reproductive tract, the organisms multiply rapidly in the favorable environment of the sloughing
endometrium and ascend to the fallopian tube.
Factors that predispose women to the development of
PID include an age of 16 to 24 years, unmarried status, nulliparity, history of multiple sexual partners, and previous
history of PID. Although the use of an intrauterine contraceptive device (IUD) has been associated with a threefold to fivefold increased risk for development of PID,
studies have shown that women with only one sexual
partner who are at low risk for acquiring STDs have no significant risk for development of PID from using an IUD.
Clinical Course
The symptoms of PID include lower abdominal pain,
which may start just after a menstrual period; purulent
cervical discharge; adnexal tenderness; and an exquisitely
painful cervix. New-onset breakthrough bleeding on oral
contraceptives, Depo-Provera, or Norplant has recently
been associated with PID. Fever (>101°F), increased erythrocyte sedimentation rate, and an elevated white blood
cell count (>10,000 cells/mL) commonly are seen, even
though the woman may not appear acutely ill. A newer
test involves measurement of C-reactive protein in the
blood. Elevated C-reactive protein levels equate with inflammation. Laparoscopy is the gold standard for diagnosis of PID, but clinical criteria have a positive predictive
value of 65% to 90% compared with laparoscopy.27 Minimal criteria for a presumptive diagnosis of PID require only
the presence of lower abdominal, adnexal, and cervical
motion tenderness.
Treatment may involve hospitalization with intravenous administration of antibiotics. If the condition is
diagnosed early, outpatient antibiotic therapy may be sufficient. Antibiotic regimens should be selected according
to STD treatment guidelines, which are published every
4 years by the Centers for Disease Control and Prevention
(CDC).28 Treatment is aimed at preventing complications,
CHAPTER 47
which can include pelvic adhesions, infertility, ectopic
pregnancy, chronic abdominal pain, and tubo-ovarian
abscesses. Accurate diagnosis and appropriate antibiotic
therapy may decrease the severity and frequency of PID
sequelae. The CDC recommends empiric treatment with a
presumptive diagnosis of PID, while waiting for confirmation by culture or other definitive test results.
ECTOPIC PREGNANCY
Although pregnancy is not discussed in detail in this text, it
is reasonable to mention ectopic pregnancy because it represents a true gynecologic emergency and should be considered when a woman of reproductive age presents with
the complaint of pelvic pain. Ectopic pregnancy occurs
when a fertilized ovum implants outside the uterine cavity.
The most common site for ectopic pregnancy is the fallopian tube (Fig. 47-5). According to the CDC, between 1970
and 1992, the number of ectopic pregnancies increased
from 17,800 to 108,800, and the rate of occurrence among
women aged 15 to 44 years rose from 4.5 to 19.7 per 1000
reported pregnancies (i.e., live births, abortions, and ectopic
pregnancies).29 Although ectopic pregnancy is the leading
cause of maternal mortality in the first trimester and accounts for 9% of all maternal deaths in the United States,
the death rate has steadily declined as a result of improved
diagnostic methods. Earlier detection reduces the risk for
tubal rupture, which could result in intraabdominal hemorrhage, major complications, future infertility, or death.30
The cause of ectopic pregnancy is delayed ovum transport, which may result from decreased tubal motility or
distorted tubal anatomy (i.e., narrowed lumen, convolutions, or diverticula). Factors that may predispose to the
FIGURE 47-5 Ectopic pregnancy. An enlarged fallopian tube has
been opened to disclose a minute fetus. (Rubin E., Farber J.L. [1999].
Pathology [3rd ed., p. 1001]. Philadelphia: Lippincott-Raven)
Disorders of the Female Reproductive System
1079
development of an ectopic pregnancy include PID, therapeutic abortion, tubal ligation or tubal reversal, previous
ectopic pregnancy, intrauterine exposure to DES, infertility, and the use of fertility drugs to induce ovulation.
Contraceptive failure with progestin-only birth control
pills or the “morning-after pill” also has been associated
with ectopic pregnancy.
Clinical Course
The site of implantation in the tube (e.g., isthmus, ampulla) may determine the onset of symptoms and the timing of diagnosis. As the tubal pregnancy progresses, the
surrounding tissue is stretched. The pregnancy eventually
outgrows its blood supply, at which point the pregnancy
terminates or the tube itself ruptures because it can no
longer contain the growing pregnancy. Symptoms can include lower abdominal discomfort—diffuse or localized to
one side—which progresses to severe pain caused by rupture, spotting, syncope, referred shoulder pain from bleeding into the abdominal cavity, and amenorrhea.
Physical examination usually reveals adnexal tenderness; an adnexal mass is found in only 50% of cases.
Although rarely used today, culdocentesis (i.e., needle aspiration from the cul-de-sac) may reveal blood if rupture
has occurred. Quantitative β-human chorionic gonadotropin (hCG) pregnancy tests may detect lower-thannormal hCG production. Pelvic ultrasound studies after
5 weeks’ gestation may demonstrate an empty uterine cavity or presence of the gestational sac outside the uterus. In
a comparison of various protocols for diagnosing ectopic
pregnancy, ultrasound followed by serial hCG levels was
found to yield the best results.30 Definitive diagnosis may
require laparoscopy. Differential diagnosis for this type of
pelvic pain includes ruptured ovarian cyst, threatened or
incomplete abortion, PID, acute appendicitis, and degenerating fibroid.
Treatment usually is surgical: a laparoscopic salpingostomy to remove the ectopic pregnancy if the fallopian
tube has not ruptured or salpingectomy to remove the tube
if it has. In salpingostomy, a linear incision is made in the
tube and allowed to heal closed without suturing to decrease scar tissue formation; this procedure preserves fertility but requires careful surgical technique to minimize the
risk for recurrent ectopic pregnancies. Laparoscopic treatment of ectopic pregnancy is well tolerated and more cost
effective than laparotomy because of shorter convalescence and the reduced need for postoperative analgesia.
When possible, it is the preferred method of treatment. In
laparotomy, an open incision is made into the abdominopelvic cavity; this procedure becomes necessary when there
is uncontrolled internal bleeding, when the ectopic site cannot be visualized through the laparoscope, or when the surgeon is not trained in operative laparoscopy.
Methotrexate, a chemotherapeutic agent, has been
successfully used to eliminate residual ectopic pregnancy
tissue after laparoscopy, in cases in which the pregnancy
is diagnosed early and is unruptured, or in which surgery is
contraindicated. There are several methotrexate regimens
and no standardized protocol as yet. Overall success rate
for women treated with intramuscular methotrexate has
1080
UNIT XI
Genitourinary and Reproductive Function
been reported as 89%, with the multidose regimen being
most successful.31 The drug is given for 1 to 8 days and is
better tolerated when given orally or in a single injection.
Adverse effects can include oral lesions, transient elevation
of liver enzyme levels, and anemia. Close follow-up with
weekly monitoring of hCG levels is necessary until the
pregnancy is completely resolved.32
CANCER OF THE FALLOPIAN TUBE
Although a common site of metastases, primary cancer of
the fallopian tube is rare, accounting for less than 1% of
all female genital tract cancers. Fewer than 3000 cases have
been reported worldwide. Most primary tubal cancers are
papillary adenocarcinomas, and these tumors develop bilaterally in 30% of patients with advanced disease.
Symptoms are uncommon, but intermittent serosanguineous vaginal discharge, abnormal vaginal bleeding,
and colicky low abdominal pain have been reported. An
adnexal mass may be present; however, the preoperative
diagnosis in most cases is leiomyoma or ovarian tumor.
Management is similar to that for ovarian cancer and
usually includes total hysterectomy, bilateral salpingooophorectomy, and pelvic lymph node dissection. More
extensive procedures may be warranted, depending on
the stage of the disease. Two thirds of patients are diagnosed at stage I or II. The 5-year survival rate in these
cases is approximately 60%, but drops to 10% if metastasis has occurred.2
BENIGN OVARIAN CYSTS AND TUMORS
The ovaries have a dual function: they produce germ cells,
or ova, and they synthesize the female sex hormones. Disorders of the ovaries frequently cause menstrual and fertility problems. Benign conditions of the ovaries can present
as primary lesions of the ovarian structures or as secondary disorders related to hypothalamic, pituitary, or adrenal
dysfunction.
Ovarian Cysts
Cysts are the most common form of ovarian tumor. Many
are benign. A follicular cyst is one that results from occlusion of the duct of the follicle. Each month, several follicles begin to develop and are blighted at various stages of
development. These follicles form cavities that fill with
fluid, producing a cyst. The dominant follicle normally
ruptures to release the egg (i.e., ovulation) but occasionally
persists and continues growing. Likewise, a luteal cyst is a
persistent cystic enlargement of the corpus luteum that is
formed after ovulation and does not regress in the absence
of pregnancy. Functional cysts are asymptomatic unless
there is substantial enlargement or bleeding into the cyst.
This can cause considerable discomfort or a dull, aching
sensation on the affected side. The cyst may become twisted
or may rupture into the intraabdominal cavity (Fig. 47-6).
These cysts usually regress spontaneously.
Polycystic Ovary Syndrome. Ovarian dysfunction associated with infrequent or absent menses in obese, infer-
FIGURE 47-6 Follicle cyst of the ovary. The rupture of this thin-walled
cyst has been opened and the rupture site indicated with a dowel
stick. (Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1002].
Philadelphia: Lippincott-Raven)
tile women was first reported in the 1930s by Stein and
Leventhal, for whom the syndrome was originally named.
Polycystic ovary syndrome (PCOS) is characterized by numerous cystic follicles or follicular cysts. Once thought to
be relatively rare, it appears that this clinical entity is one
of the most common endocrine disorders among women
in the reproductive years.33–35
PCOS is characterized by varying degrees of hirsutism,
obesity, and infertility, and often is associated with hyperinsulinemia or insulin resistance. This syndrome has been
the subject of considerable research. Chronic anovulation,
causing amenorrhea or irregular menses, is now thought to
be the underlying cause of the bilaterally enlarged “polycystic” ovaries. Hence, the appearance of the ovary is a sign,
not the disease itself.33 The precise etiology of this condition is still being debated. A possible genetic basis has been
suggested with an autosomal dominant mode of inheritance and premature balding as the phenotype in males.34
Most women with PCOS have elevated luteinizing
hormone (LH) levels with normal estrogen and folliclestimulating hormone (FSH) production. Elevated levels of
testosterone, dehydroepiandrosterone sulfate (DHAS), or
androstenedione are not uncommon, and these women
occasionally have hyperprolactinemia or hypothyroidism.
Persistent anovulation results in an estrogen environment
that alters the hypothalamic release of GnRH. Increased
sensitivity of the pituitary to GnRH results in increased LH
secretion and suppression of FSH. This altered LH⬊FSH
ratio often is used as a diagnostic criterion for this condition, but it is not universally present. The presence of
some FSH allows for new follicular development; however,
full maturation is not attained, and ovulation does not
occur. The elevated LH level also results in increased an-
CHAPTER 47
drogen production, which in turn prevents normal follicular development and contributes to the vicious cycle of
anovulation.33 The association between hyperandrogenism
and insulin resistance is now well recognized. Evidence
suggests that the hyperinsulinemia may lead to the excess
androgen production, and several reports have shown that
normal ovulation and sometimes pregnancy have occurred when women with hyperandrogenism were treated
with insulin-sensitizing drugs.36,37
The diagnosis can be suspected from the clinical picture. Although there is no consensus about which laboratory tests should be used, laboratory evaluation to exclude
hyperprolactinemia, late-onset adrenal hyperplasia, and
adrenogenic-secreting tumors of the ovary and adrenal
gland is commonly done. Because insulin resistance is
common and may affect treatment, fasting blood glucose
and insulin levels are often measured to evaluate for hyperinsulinemia.34,35 Confirmation with ultrasonography or
laparoscopic visualization of the ovaries is not required.
The overall goal of treatment is to suppress insulinfacilitated, LH-driven androgen production. Although numerous medications and protocols are available, the choice
depends on the manifestations that are bothersome to the
woman and on her stage in reproductive life. If fertility is
not desired, oral contraceptives or cyclic progesterone can
induce regular menses and prevent the development of endometrial hyperplasia caused by unopposed estrogen.
Chronic anovulation can increase a woman’s risk for endometrial cancer, cardiovascular disease, and hyperinsulinemia, leading to diabetes mellitus. Treatment is essential
for anyone with this condition.
When fertility is desired, the condition usually is
treated by the administration of the hypothalamicpituitary–stimulating drug clomiphene citrate or injectable
gonadotropins to induce ovulation. These drugs must be
used carefully because they can induce extreme enlargement of the ovaries. Metformin, an insulin-sensitizing drug,
may be used before or concurrent with ovulation-inducing
medications.37 Use of this drug has been associated with reductions in androgen and LH levels. When medication is
ineffective, laser surgery to puncture the multiple follicles
may restore normal ovulatory function, although adhesion
formation is a potential problem. Weight loss also may be
beneficial in restoring normal ovulation when obesity is
present.
Benign and Functioning Ovarian Tumors
Serous cystadenoma and mucinous cystadenoma are the
most common benign ovarian neoplasms. Some of these
adenomas, however, are considered to have low malignant
potential. They are asymptomatic unless their size is sufficient to cause abdominal enlargement. Endometriomas
are the “chocolate cysts” that develop secondary to ovarian endometriosis (see the endometriosis section earlier in
this chapter). Ovarian fibromas are connective tissue tumors composed of fibrocytes and collagen. They range in
size from 6 to 20 cm. Cystic teratomas, or dermoid cysts,
are derived from primordial germ cells and are composed
of various combinations of well-differentiated ectodermal,
mesodermal, and endodermal elements. Not uncommonly,
they contain sebaceous material, hair, or teeth. Treatment
Disorders of the Female Reproductive System
1081
for all ovarian tumors is surgical excision. Ovarian tissue
that is not affected by the tumor can be left intact if frozensection analysis does not reveal malignancy. When ovarian tumors are very large, as is frequently the case with
serous or mucinous cystadenomas, the entire ovary must
be removed.
The three types of functioning ovarian tumors are estrogen secreting, androgen secreting, and mixed estrogenandrogen secreting. These tumors may be benign or cancerous. One such tumor, the granulosa cell tumor, is associated
with excess estrogen production. When it develops during
the reproductive period, the persistent and uncontrolled
production of estrogen interferes with the normal menstrual cycle, causing irregular and excessive bleeding,
endometrial hyperplasia, or amenorrhea and fertility problems. When it develops after menopause, it causes postmenopausal bleeding, stimulation of the glandular tissues
of the breast, and other signs of renewed estrogen production. Androgen-secreting tumors (i.e., Sertoli-Leydig cell
tumor or androblastoma) inhibit ovulation and estrogen
production. They tend to cause hirsutism and development
of masculine characteristics, such as baldness, acne, oily
skin, breast atrophy, and deepening of the voice. The treatment is surgical removal of the tumor.
Ovarian Cancer
Ovarian cancer is the second most common female genitourinary cancer and the most lethal. In 2003, 25,400 new
cases of ovarian cancer were reported in the United States,
two thirds of which were in advanced stages of the disease.
Most of these women die of the disease (14,300 women in
2003).13 The incidence of ovarian cancer increases with
age, being greatest between 65 and 84 years of age. Ovarian cancer is difficult to diagnose, and up to 75% of women
have metastatic disease before the time of discovery.
The most significant risk factor for ovarian cancer appears to be ovulatory age—the length of time during a
woman’s life when her ovarian cycle is not suppressed by
pregnancy, lactation, or oral contraceptive use. The incidence of ovarian cancer is much lower in countries where
women bear numerous children than in the United States.
Family history also is a significant risk factor for ovarian
cancer. Women with two or more first- or second-degree
relatives who have had site-specific ovarian cancer have up
to a 50% risk for development of the disease. There are
two other types of inherited risk for ovarian cancer: breastovarian cancer syndrome, in which both breast and ovarian
cancer occur among first- and second-degree relatives, and
family cancer syndrome or Lynch syndrome II (a subtype of
hereditary nonpolyposis colon cancer [HNPCC]), in which
male or female relatives have a history of colorectal, endometrial, ovarian, pancreatic, or other types of cancer.2,38,39
The breast cancer (BRCA) susceptibility genes, BRCA1 and
BRCA2, which are tumor suppressor genes (see Chapter 8),
are incriminated in approximately 10% of hereditary ovarian cancers despite being identified as “breast cancer genes.”
Susceptibility to ovarian cancer is transmitted as an autosomal dominant characteristic; therefore, a mutated gene
from either parent is sufficient to cause the problem. Most
men who pass on the BRCA mutations do not themselves
1082
UNIT XI
Genitourinary and Reproductive Function
manifest male breast cancer.40 A high-fat Western diet and
use of powders containing talc in the genital area are other
factors that have been linked to the development of ovarian cancer.
Chemoprevention strategies that have been suggested
include long-term oral contraceptive use, nonsteroidal
antiinflammatory drugs (NSAIDs), acetaminophen, or retinoids.41 Each of these agents acts in a slightly different
way. The NSAIDs are thought to exert their protective effects through growth inhibition and increased apoptosis
(programmed cell death) of ovarian cancer cell lines. The
structure of the acetaminophen bears a similarity to the sex
hormones, suggesting a potential sex steroid–antagonist
property. Support for the use of retinoids comes from experimental data in which retinoic acid was shown to induce
the differentiation of cultured ovarian cancer cells. Undoubtedly, continued laboratory studies and clinical trials
will provide further evidence of the effectiveness of these
chemoprevention agents. Surgical strategies that have reduced the risk for developing ovarian cancer include prophylactic removal of both tubes and ovaries (BSO) and
bilateral tubal ligation. These strategies have generally
been reserved for women at highest risk, and those who
undergo surgical intervention must be counseled that
there is still a small risk for developing peritoneal cancer.41
Cancer of the ovary is complex because of the diversity of tissue types that originate in the ovary. As a result
of this diversity, there are several types of ovarian cancers.
Malignant neoplasms of the ovary can be divided into
three categories: epithelial tumors, germ cell tumors, and
gonadal stromal tumors. Epithelial tumors account for approximately 90% of cases. These different cancers display
various degrees of virulence, depending on the type of
tumor and degree of differentiation involved. A welldifferentiated cancer of the ovary may have produced
symptoms for many months and may still be found operable at the time of surgery. A poorly differentiated tumor
may have been clinically evident for only a few days but
found to be widespread and inoperable. Often, no correlation exists between the duration of symptoms and the extent of the disease.
Clinical Course. Most cancers of the ovary produce no
symptoms, or the symptoms are so vague that the woman
seldom seeks medical care until the disease is far advanced.
These vague discomforts include abdominal distress, flatulence, and bloating, especially after ingesting food. These
gastrointestinal manifestations may precede other symptoms by months. Many women take antacids or bicarbonate of soda for a time before consulting a physician. The
physician also may dismiss the woman’s complaints as
being caused by other conditions, further delaying diagnosis and treatment. It is not fully understood why the
initial symptoms of ovarian cancer are manifested as
gastrointestinal disturbances. It is thought that biochemical changes in the peritoneal fluids may irritate the bowel
or that pain originating in the ovary may be referred to the
abdomen and be interpreted as a gastrointestinal disturbance. Clinically evident ascites (i.e., fluid in the peritoneal cavity) is seen in approximately one fourth of women
with malignant ovarian tumors and is associated with a
worse prognosis.
No good screening tests or other early methods of detection exist for ovarian cancer. The serum tumor marker
CA-125 is a cell surface antigen; its level is elevated in 80%
to 90% of women with stage II to IV nonmucinous ovarian epithelial cancers. The result is negative, however, for
as many as 50% of women with stage I disease. In a postmenopausal woman with a pelvic mass, an elevated CA-125
has a positive predictive value of greater than 70% for
cancer. It also can be used in monitoring therapy and recurrences when preoperative levels have been elevated.
Despite its role in diagnostic evaluation and follow-up,
CA-125 is not cancer or tissue specific for ovarian cancer.
Levels also are elevated in the presence of endometriosis,
uterine fibroids, pregnancy, liver disease, and other benign
conditions and with cancer of the endometrium, cervix,
fallopian tube, and pancreas. Because it lacks sensitivity
and specificity, CA-125 has limited value as a single screening test. Clinical trials to identify more sensitive and specific ovarian cancer tumor markers are under way.42
Transvaginal ultrasonography (TVS) has been used to
evaluate ovarian masses for malignant potential. As a screening test, it has demonstrated 80% to 90% sensitivity and
83% to 95% specificity. Because the lifetime risk for development of ovarian cancer is 1 in 70 women with family
history of the disease, the cost of universal screening for
ovarian cancer using the available technology has been
estimated at $2.7 million to diagnose one case of ovarian
cancer.39 The National Institutes of Health Consensus
Panel convened in 1995 recommended no widespread
screening of women for ovarian cancer. CA-125 with TVS
is suggested only for women who are part of a family with
hereditary ovarian cancer syndrome (i.e., two or more affected first-degree relatives), or less than 1% of all women.43
Several large national studies are under way to determine
the benefit of widespread population-based screening for
ovarian cancer.38,39 Molecular biologic studies have identified tumor suppressor genes that may play a role in the
cause of ovarian cancer. Further evaluation in this area is
ongoing and may eventually lead to identification of appropriate screening techniques for ovarian cancer.
When ovarian cancer is suspected, surgical evaluation
is required for diagnosis, complete and accurate staging,
and cytoreduction and debulking procedures to reduce the
size of the tumor. At the time of surgery, the uterus, fallopian tubes, ovaries, and omentum are removed; the liver,
diaphragm, retroperitoneal and aortic lymph nodes, and
peritoneal surface are examined and biopsies are taken as
needed. Cytologic washings are done to test for cancerous
cells in the peritoneal fluid. Recommendations regarding
treatment beyond surgery and prognosis depend on the
stage of the disease. Women with limited disease (i.e., welldifferentiated stage Ia or Ib) usually do not require adjuvant
treatment; women with intermediate disease (i.e., stage Ib
or II) or advanced disease (i.e., stage III or IV) can benefit
from chemotherapy with cisplatin and cyclophosphamide.
When this combination therapy fails, salvage chemotherapy with newer drugs such as paclitaxel (Taxol) may prolong survival. Irradiation no longer plays a major role in
CHAPTER 47
treatment of ovarian cancer because of the difficulty in irradiating the entire abdomen without causing life-threatening
damage to vital organs.
The lack of accurate screening tools and the resistant nature of ovarian cancers significantly affects success of treatment and survival. The 5-year survival rate is 80% to 90% for
women whose ovarian cancer is detected and treated early;
however, only 25% of all cases are detected at the localized
stage. Overall, the 5-year survival rate is 50.4%.44,45
In summary, PID is an inflammation of the upper reproductive tract that involves the uterus (endometritis), fallopian tubes
(salpingitis), or ovaries (oophoritis). It is most commonly caused
by N. gonorrhoeae or C. trachomatis. Accurate diagnosis and appropriate antibiotic therapy are aimed at preventing complications such as pelvic adhesions, infertility, ectopic pregnancy,
chronic abdominal pain, and tubo-ovarian abscesses.
Ectopic pregnancy occurs when a fertilized ovum implants
outside the uterine cavity; the common site is the fallopian
tube. Causes of ectopic pregnancy are delayed ovum transport
resulting from complications of PID, therapeutic abortion,
tubal ligation or tubal reversal, previous ectopic pregnancy, or
other conditions such as use of fertility drugs to induce ovulation. It represents a true gynecologic emergency, often necessitating surgical intervention. Cancer of the fallopian tube is
rare; the diagnosis is difficult, and the condition usually is well
advanced when diagnosed.
Disorders of the ovaries include benign cysts, functioning
ovarian tumors, and cancer of the ovary; they usually are
asymptomatic unless there is substantial enlargement or bleeding into the cyst, or the cyst becomes twisted or ruptures. Polycystic ovarian disease is characterized by numerous cystic
follicles or follicular cysts; it causes various degrees of hirsutism,
obesity, and infertility. Benign ovarian tumors consist of endometriomas, which are chocolate cysts that develop secondary to ovarian endometriosis; ovarian fibromas, which are
connective tissue tumors composed of fibrocytes and collagen;
and cystic teratomas or dermoid cysts, which are derived from
primordial germ cells and are composed of various combinations of well-differentiated ectodermal, mesodermal, and endodermal elements. Functioning ovarian tumors are of three
types: estrogen secreting, androgen secreting, and mixed
estrogen–androgen secreting, and may be benign or cancerous. Cancer of the ovary is the second most common female
genitourinary cancer and the most lethal. It can be divided into
three categories: epithelial tumors, germ cell tumors, and gonadal stromal tumors. There are no effective screening methods for ovarian cancer, and often the disease is well advanced
at the time of diagnosis.
Disorders of the Female Reproductive System
1083
the pelvic organs, including the uterus, bladder, and
rectum
✦ Describe the manifestations of cystocele, rectocele, and
enterocele
✦ Explain how uterine anteflexion, retroflexion, and
retroversion differ from normal uterine position
✦ Describe the cause and manifestations of uterine prolapse
DISORDERS OF PELVIC SUPPORT
The uterus and the pelvic structures are maintained in
proper position by the uterosacral ligaments, round ligaments, broad ligament, and cardinal ligaments. The two
cardinal ligaments maintain the cervix in its normal position. The uterosacral ligaments normally hold the uterus
in a forward position (Fig. 47-7). The broad ligament suspends the uterus, fallopian tubes, and ovaries in the pelvis.
Disorders of Pelvic Support
and Uterine Position
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Characterize the function of the supporting ligaments
and pelvic floor muscles in maintaining the position of
FIGURE 47-7 (A) Normal support of the uterus and vagina. (B) Relaxation of pelvic support structures with descent of the uterus as
well as formation of cystocele and rectocele. (Rock J.A., Thompson
J.D. [1992]. Te Linde’s operative gynecology [7th ed.]. Philadelphia:
J.B. Lippincott)
1084
UNIT XI
Genitourinary and Reproductive Function
The vagina is encased in the semirigid structure of the
strong supporting fascia. The muscular floor of the pelvis
is a strong, slinglike structure that supports the uterus,
vagina, urinary bladder, and rectum (Fig. 47-8). In the female anatomy, nature is faced with the problems of supporting the pelvic viscera against the force of gravity and
increases in intraabdominal pressure associated with coughing, sneezing, defecation, and laughing while at the same
time allowing for urination, defecation, and normal reproductive tract function, especially the delivery of an infant. Three supporting structures are provided for the
abdominal pelvic diaphragm. The bony pelvis provides
support and protection for parts of the digestive tract and
genitourinary structures, and the peritoneum holds the
pelvic viscera in place. The main support for the viscera,
however, is the pelvic diaphragm, made up of muscles and
connective tissue that stretch across the bones of the
pelvic outlet. The openings that must exist for the urethra,
rectum, and vagina cause an inherent weakness in the
pelvic diaphragm. Congenital or acquired weakness of
the pelvic diaphragm results in widening of these openings, particularly the vagina, with the possible herniation
of pelvic viscera through the pelvic floor (i.e., prolapse).
Relaxation of the pelvic outlet usually comes about
because of overstretching of the perineal supporting tissues during pregnancy and childbirth. Although the tissues are stretched only during these times, there may be
no difficulty until later in life, such as the fifth or sixth
decade, when further loss of elasticity and muscle tone
occurs. Even in a woman who has not borne children, the
combination of aging and postmenopausal changes may
give rise to problems related to relaxation of the pelvic
support structures. The three most common conditions asBulbocavernosus
sociated with this relaxation are cystocele, rectocele, and
uterine prolapse. These may occur separately or together.
Cystocele
Cystocele is a herniation of the bladder into the vagina. It
occurs when the normal muscle support for the bladder is
weakened, and the bladder sags below the uterus. The
vaginal wall stretches and bulges downward because of the
force of gravity and the pressure from coughing, lifting, or
straining at stool. The bladder herniates through the anterior vaginal wall, and a cystocele forms (see Fig. 47-7).
The symptoms include an annoying bearing-down
sensation, difficulty in emptying the bladder, frequency
and urgency of urination, and cystitis. Stress incontinence
may occur at times of increased abdominal pressure, such
as during squatting, straining, coughing, sneezing, laughing, or lifting.
Rectocele and Enterocele
Rectocele is the herniation of the rectum into the vagina.
It occurs when the posterior vaginal wall and underlying
rectum bulge forward, ultimately protruding through the
introitus as the pelvic floor and perineal muscles are weakened. The symptoms include discomfort because of the
protrusion of the rectum and difficulty in defecation (see
Fig. 47-7). Digital pressure (i.e., splinting) on the bulging
posterior wall of the vagina may become necessary for
defecation.
The area between the uterosacral ligaments just posterior to the cervix may weaken and form a hernial sac
into which the small bowel protrudes when the woman is
standing. This defect, called an enterocele, may extend into
the rectovaginal septum. It may be congenital or acquired
Ischiocavernosus
Pubis
Gluteus
maximus
Femur
Ischial
tuberosity
Transverse
perineal
Levator ani
Anus
External anal sphincter
FIGURE 47-8 Muscles of the pelvic floor
(female perineum).
CHAPTER 47
Disorders of the Female Reproductive System
through birth trauma. Enterocele can be asymptomatic or
cause a dull, dragging sensation and occasionally causes
low backache.
1085
Retroversion
Acute
anteflexion
Retroflexion
Uterine Prolapse
Uterine prolapse is the bulging of the uterus into the
vagina that occurs when the primary supportive ligaments
(i.e., cardinal ligaments) are stretched. Prolapse is ranked
as first, second, or third degree, depending on how far the
uterus protrudes through the introitus. First-degree prolapse shows some descent, but the cervix has not reached
the introitus. In second-degree prolapse, the cervix or part
of the uterus has passed through the introitus. The entire
uterus protrudes through the vaginal opening in thirddegree prolapse (i.e., procidentia).
The symptoms associated with uterine prolapse result
from irritation of the exposed mucous membranes of the
cervix and vagina and the discomfort of the protruding
mass. Prolapse often is accompanied by perineal relaxation,
cystocele, or rectocele. Like cystocele, rectocele, and enterocele, it occurs most commonly in multiparous women
because childbearing is accompanied by injuries to pelvic
structures and uterine ligaments. It also may result from
pelvic tumors and neurologic conditions, such as spina bifida and diabetic neuropathy, that interrupt the innervation of pelvic muscles. A pessary may be inserted to hold
the uterus in place and may stave off surgical intervention
in women who want to have children or in older women
for whom the surgery may pose a significant health risk.
Treatment of Pelvic Support Disorders
Most of the disorders of pelvic relaxation require surgical
correction. These are elective surgeries and usually are deferred until after the childbearing years. The symptoms
associated with the disorders often are not severe enough
to warrant surgical correction. In other cases, the stress of
surgery is contraindicated because of other physical disorders; this is particularly true of older women, in whom
many of these disorders occur.
There are a number of surgical procedures for the conditions that result from relaxation of pelvic support structures. Removal of the uterus through the vagina (vaginal
hysterectomy) with appropriate repair of the vaginal wall
(colporrhaphy) often is done when uterine prolapse is accompanied by cystocele or rectocele. A vesicourethral suspension may be done to alleviate the symptoms of stress
incontinence. Repair may involve abdominal hysterectomy along with anteroposterior repair. Kegel exercises,
which strengthen the pubococcygeus muscle, may be helpful in cases of mild cystocele or rectocele or after surgical
repair to help maintain the improved function.
Normal
FIGURE 47-9 Variations in uterine position.
The uterus usually is flexed approximately 45 degrees
anteriorly, with the cervix positioned posteriorly and
downward in the anteverted position. When the woman
is standing, the angle of the uterus is such that it lies practically horizontal, resting lightly on the bladder. Asymptomatic, normal variations in the axis of the uterus in
relation to the cervix (i.e., flexion) and physiologic displacements that arise after pregnancy or with pathology of
the cul-de-sac include anteflexion, retroflexion, and retroversion (Fig. 47-9). An anteflexed uterus is flexed forward
on itself. Retroflexion is flexion backward at the isthmus.
Retroversion describes the condition in which the uterus
inclines posteriorly while the cervix remains tilted forward. Simple retroversion of the uterus is the most common displacement, found in 30% of normal women. It
usually is a congenital condition caused by a short anterior
vaginal wall and relaxed uterosacral ligaments; together,
these force the uterus to fall back into the cul-de-sac. Retroversion also can follow certain diseases, such as endometriosis and PID, which produce fibrous tissue adherence
with retraction of the fundus posteriorly. Large leiomyomas also may cause the uterus to move into a posterior
position. Dyspareunia with deep penetration or low back
pain with menses can be associated with retroversion.
Most symptoms in these women are caused by the associated condition (e.g., adhesions, fibroids) rather than
congenital retroversion.
VARIATIONS IN UTERINE POSITION
Variations in the position of the uterus are common. Some
variations are innocuous; others, which may be the result
of weakness and relaxation of the perineum, give rise to
various problems that compromise the structural integrity
of the pelvic floor, particularly after childbirth.
In summary, alterations in pelvic support frequently occur
because of weaknesses and relaxation of the pelvic floor and
perineum. Cystocele and rectocele involve herniation of the
bladder or rectum into the vagina. Uterine prolapse occurs
when the uterus bulges into the vagina. Pelvic relaxation
1086
UNIT XI
Genitourinary and Reproductive Function
disorders typically result from overstretching of the perineal
supporting muscles during pregnancy and childbirth. The loss
of elasticity in these structures that is a normal accompaniment
of aging contributes to these problems. Variations in uterine
position are common; they include anteflexion, retroflexion,
and retroversion. These disorders, which often are innocuous,
can be the result of a congenital shortness of the vaginal wall,
development of fibrous adhesions secondary to endometriosis
or PID, or displacement caused by large uterine leiomyomas.
Menstrual Disorders
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Define the terms amenorrhea, hypomenorrhea,
oligomenorrhea, menorrhagia, metrorrhagia, and
menometrorrhagia
✦ State the function of alterations in estrogen and
progesterone levels as a cause of dysfunctional
menstrual cycles
✦ Differentiate between primary dysmenorrhea and
secondary dysmenorrhea
✦ Characterize the manifestations of the premenstrual
syndrome, its possible causes, and the methods of
treatment
DYSFUNCTIONAL MENSTRUAL CYCLES
Although unexplained uterine bleeding can occur for many
reasons, such as pregnancy, abortion, bleeding dyscrasias,
and neoplasms, the most frequent cause in the nonpregnant female is what is commonly called dysfunctional menstrual cycles or bleeding. Dysfunctional cycles may take the
form of amenorrhea (absence of menstruation), hypomenorrhea (scanty menstruation), oligomenorrhea (infrequent menstruation, periods more than 35 days apart), polymenorrhea
(frequent menstruation, periods less than 27 days apart),
menorrhagia (excessive menstruation), or metrorrhagia (bleeding between periods). Menometrorrhagia is heavy bleeding
during and between menstrual periods.
Dysfunctional menstrual cycles are related to alterations in the hormones that support normal cyclic endometrial changes. Estrogen deprivation causes retrogression
of a previously built-up endometrium and bleeding. Such
bleeding often is irregular in amount and duration, with
the flow varying with the time and degree of estrogen stimulation and with the degree of estrogen withdrawal. A lack
of progesterone can cause abnormal menstrual bleeding;
in its absence, estrogen induces development of a much
thicker endometrial layer with a richer blood supply. The
absence of progesterone results from the failure of any of
the developing ovarian follicles to mature to the point of
ovulation, with the subsequent formation of the corpus
luteum and production and secretion of progesterone.
Periodic bleeding episodes alternating with amenorrhea are caused by variations in the number of functioning
DYSFUNCTIONAL MENSTRUAL CYCLES
➤ The pattern of menstrual bleeding tends to be fairly consistent in most healthy women with regard to frequency,
duration, and amount of flow.
➤ Dysfunctional bleeding in postpubertal women can take
the form of absent or scanty periods, infrequent periods,
excessive and irregular periods, excessive bleeding during
periods, and bleeding between periods.
➤ When the basic pattern of bleeding is changed it is most
often due to a lack of ovulation and disturbances in the
pattern of hormone secretion.
➤ When the basic pattern is undisturbed and there are superimposed episodes of bleeding or spotting, the etiology is
more likely to be related to organic lesions or hematologic
disorders.
ovarian follicles present. If sufficient follicles are present
and active and if new follicles assume functional capacity,
high levels of estrogen develop, causing the endometrium
to proliferate for weeks or even months. In time, estrogen
withdrawal and bleeding develop. This can occur for two
reasons: an absolute estrogen deficiency may develop when
several follicles simultaneously degenerate, or a relative deficiency may develop as the needs of the enlarged endometrial tissue mass exceed the capabilities of the existing
follicles, even though estrogen levels remain constant. Estrogen and progesterone deficiency are associated with the
absence of ovulation, hence the term anovulatory bleeding.
Because the vasoconstriction and myometrial contractions
that normally accompany menstruation are caused by progesterone, anovulatory bleeding seldom is accompanied by
cramps, and the flow frequently is heavy. Anovulatory
cycles are common among adolescents during the first several years after menarche, when ovarian function is becoming established, and among perimenopausal women,
whose ovarian function is beginning to decline.
Dysfunctional menstrual cycles can originate as a primary disorder of the ovaries or as a secondary defect in
ovarian function related to hypothalamic-pituitary stimulation. The latter can be initiated by emotional stress,
marked variation in weight (i.e., sudden gain or loss), or
nonspecific endocrine or metabolic disturbances. Organic
causes of irregular menstrual bleeding include endometrial
polyps, submucosal myoma (i.e., fibroid), blood dyscrasia,
infection, endometrial cancer, polycystic ovarian disease,
and pregnancy.
The treatment of dysfunctional bleeding depends on
what is identified as the probable cause. The minimum
evaluation should include a detailed history with emphasis on bleeding pattern and a physical examination. Endocrine studies (FSH⬊LH ratio, prolactin, testosterone, DHAS),
β-hCG pregnancy test, ultrasound of the endometrium
with or without saline infusion, endometrial biopsy, D & C
with or without hysteroscopy, and progesterone withdrawal tests may be needed for diagnosis. Organic causes
CHAPTER 47
generally require surgical intervention. D & C can be therapeutic as well as diagnostic. Endometrial ablation (thinning or elimination of the basalis layer of the endometrium
from which the monthly buildup generates) has become a
primary management strategy for heavy bleeding and can
be accomplished with heat, cold, light, microwaves, chemicals, and radiofrequency as energy sources.46 Approximately
80% to 90% of women will have a significant reduction in
their menorrhagia, with 25% to 40% experiencing amenorrhea.3 If organic problems are excluded and alterations in
hormone levels are the primary cause, treatment may include the use of oral contraceptives, cyclic progesterone
therapy, or long-acting progesterone injections.
AMENORRHEA
There are two types of amenorrhea: primary and secondary. Primary amenorrhea is the failure to menstruate by
16 years of age, or by 14 years of age if failure to menstruate is accompanied by absence of secondary sex characteristics. Secondary amenorrhea is the cessation of menses for
at least 6 months in a woman who has established normal
menstrual cycles. Primary amenorrhea usually is caused by
gonadal dysgenesis, congenital mullerian agenesis, testicular feminization, or a hypothalamic-pituitary-ovarian axis
disorder. Causes of secondary amenorrhea include ovarian,
pituitary, or hypothalamic dysfunction; intrauterine adhesions (i.e., Asherman’s syndrome); infections (e.g., tuberculosis, schistosomiasis); pituitary tumor; anorexia nervosa;
or strenuous physical exercise, which can alter the critical
body fat–to-muscle ratio needed for menses to occur.47
Diagnostic evaluation resembles that for dysfunctional
uterine bleeding, with the possible addition of a computed
tomographic scan to exclude a pituitary tumor. Treatment is based on correcting the underlying cause and inducing menstruation with cyclic progesterone or combined
estrogen-progesterone regimens.
DYSMENORRHEA
Dysmenorrhea is pain or discomfort with menstruation.
Although not usually a serious medical problem, it causes
some degree of monthly disability for a significant number of women. There are two forms of dysmenorrhea: primary and secondary. Primary dysmenorrhea is menstrual
pain that is not associated with a physical abnormality or
pathology.48 It usually occurs with ovulatory menstruation
beginning 6 months to 2 years after menarche. Symptoms
may begin 1 to 2 days before menses, peak on the first day
of flow, and subside within several hours to several days.
Severe dysmenorrhea may be associated with systemic
symptoms such as headache, nausea, vomiting, diarrhea,
fatigue, irritability, dizziness, and syncope. The pain typically is described as dull, lower abdominal aching or cramping, spasmodic or colicky in nature, often radiating to the
lower back, labia majora, or upper thighs.
Secondary dysmenorrhea is menstrual pain caused by
specific organic conditions, such as endometriosis, uterine
fibroids, adenomyosis, pelvic adhesions, IUDs, or PID.
Disorders of the Female Reproductive System
1087
Laparoscopy often is required for diagnosis of secondary
dysmenorrhea if medication for primary dysmenorrhea is
ineffective.
Treatment of primary dysmenorrhea is directed at
symptom control. Although analgesic agents such as aspirin
and acetaminophen may relieve minor uterine cramping or
low back pain, prostaglandin synthetase inhibitors, such as
ibuprofen, naproxen, mefenamic acid, and indomethacin,
are more specific for dysmenorrhea and are the treatment
of choice if contraception is not desired. Several cyclooxygenase II (COX II) inhibitors (valdecoxib, celecoxib,
rofecoxib) also carry the indication for dysmenorrhea.
Ovulation suppression and symptomatic relief of dysmenorrhea can be instituted simultaneously with the use of oral
contraceptives. Relief of secondary dysmenorrhea depends
on identifying the cause of the problem. Medical or surgical intervention may be needed to eliminate the problem.
PREMENSTRUAL SYNDROME
The premenstrual syndrome (PMS) is a distinct clinical entity
characterized by a cluster of physical and psychological
symptoms limited to 3 to 14 days preceding menstruation and relieved by onset of the menses. According to
surveys, 80% of women experience premenstrual emotional
or physical changes, with 20% to 40% of the adult female
population in the United States indicating that these mild to
moderate monthly symptoms cause some difficulty; only
2% to 5% report extreme or severe symptoms that negatively affect their life.49 How many of these women have
symptoms that are severe enough to warrant treatment is
unknown. The incidence of PMS seems to increase with
age. It is less common in women in their teens and twenties, and most of the women seeking help for the problem
are in their mid-thirties. There is some dispute about
whether PMS occurs more frequently in women who have
not had children or in those who have had children. The
disorder is not culturally distinct; it affects non-Westerners
and Westerners.
The physical symptoms of PMS include painful and
swollen breasts, bloating, abdominal pain, headache, and
backache. Psychologically, there may be depression, anxiety, irritability, and behavioral changes. In some cases,
there are puzzling alterations in motor function, such as
clumsiness and altered handwriting. Women with PMS
may report one or several symptoms, with symptoms varying from woman to woman and from month to month in
the same patient. Signs and symptoms associated with this
disorder are summarized in Table 47-2. PMS can significantly affect a woman’s ability to perform at normal levels. She may lose time from or function ineffectively at
work. Family responsibilities and relationships may suffer.
Students have had lower grades during the premenstrual
period. More crimes are committed by females during the
premenstrual phase of the cycle, and more lives are lost to
suicide during this period. The term premenstrual dysphoric
disorder (PMDD) is a psychiatric diagnosis that has been
developed to distinguish those women whose symptoms
are severe enough to interfere significantly with activities
1088
UNIT XI
Genitourinary and Reproductive Function
TABLE 47-2
Symptoms of Premenstrual Syndrome (PMS) by System
Body System
Symptoms
Cerebral
Irritability, anxiety, nervousness, fatigue, and exhaustion;
increased physical and mental activity; lability; crying
spells; depressions; inability to concentrate
Craving for sweets or salts, lower abdominal pain, bloating,
nausea, vomiting, diarrhea, constipation
Headache, edema, weakness, or fainting
Swelling and tenderness of the breasts, pelvic congestion,
ovarian pain, altered libido
Trembling of the extremities, changes in coordination,
clumsiness, backache, leg aches
Weight gain, insomnia, dizziness, acne
Gastrointestinal
Vascular
Reproductive
Neuromuscular
General
of daily living. A minimum of 5 of the 11 symptom groups
described in the DSM-IV must be present to establish the
diagnosis of PMDD. Presence of a single symptom is sufficient for the diagnosis of PMS.48,50
Although the causes of PMS are poorly documented,
they probably are multifactorial. Like dysmenorrhea, it is
only recently that PMS has been recognized as a bona fide
disorder rather than merely a psychosomatic illness. There
has been a tendency to link the disorder with endocrine imbalances such as hyperprolactinemia, estrogen excess, and
alteration in the estrogen-to-progesterone ratio. Prolactin
concentration affects sodium and water retention, is higher
in the luteal phase than in the follicular phase, and can be
increased by estrogens, stress, hypoglycemia, pregnancy,
and oral contraceptives.51 Estrogens stimulate anxiety and
nervous tension, and increased progesterone levels may
produce depression. The role of hormonal factors in the
cause of PMS is supported by two well-established phenomena. First, women who have undergone a hysterectomy but not an oophorectomy may have cyclic symptoms
that resemble PMS. Second, PMS symptoms are rare in
postmenopausal women. Research has failed to confirm
these theories.
Other hypotheses suggest that increased aldosterone
may contribute to symptoms associated with fluid retention (e.g., headache, bloating, breast tenderness, weight
gain); that pyridoxine (vitamin B6) deficiency may lead to
estrogen excess or decreased production of the neurotransmitters dopamine and serotonin, which may contribute to PMS symptoms; or that decreased prostaglandin
E1 concentrations can lead to abnormal sensitivity to prolactin, with associated fluid retention, irritability, and depression. In addition, increased appetite, binge eating,
fatigue, and depression have been associated with altered
endorphin activity and subclinical hypoglycemia.51 There
also is evidence that learned beliefs about menstruation
can contribute to the production of PMS or at least affect
the woman’s response to the symptoms.
The most recent theory to emerge suggests a relationship between normal gonadal fluctuations and central
neurotransmitter activity, particularly serotonin. It is unclear whether decreased levels of serotonin are present
during the luteal phase and only susceptible women respond with varying degrees of premenstrual symptoms, or
whether women with PMDD have a neurotransmitter
abnormality.3,48,50
Diagnosis focuses on identification of the symptom
clusters by means of prospective charting for at least
3 months. Several validated tools are available for recording symptoms; however, any calendar used for this purpose
must include information regarding specific symptoms,
severity, timing in relation to the menstrual cycle, and
baseline level of symptoms in the follicular phase.3 A complete history and physical examination are necessary to exclude other physical causes of the symptoms. Depending
on the symptom pattern, blood studies, including thyroid
hormones, glucose, and prolactin assays, may be done.
Psychosocial evaluation is helpful to exclude emotional illness that is merely exacerbated premenstrually.
In the past, the treatment of PMS has been largely
symptomatic. Attempts have been made to effect weight
loss and reduce fluid retention through the use of diuretics.
Tranquilizer drugs were used to treat mood changes, and
pain was treated with mild analgesics. Treatment still is directed to some extent toward somatic complaints. Relief of
somatic pain does not, however, totally resolve PMS suffering. The latest approach is to recommend an integrated
program of personal assessment by diary, regular exercise,
avoidance of caffeine, and a diet low in simple sugars and
high in lean proteins. Additional therapeutic regimens include vitamin or mineral supplements (particularly pyridoxine, vitamin E, and magnesium), natural progesterone
supplements, low-dose monophasic oral contraceptives,
GnRH agonists, bromocriptine for prolactin suppression,
danazol (a synthetic androgen), spironolactone (an aldosterone antagonist and steroidogenesis inhibitor), evening
primrose oil (which contains linoleic acid, a precursor of
prostaglandin E1), and lithium for marked functional impairment from affective symptoms.49–51 Few treatments
have been adequately evaluated in randomized, controlled
trials. The use of selective serotonin reuptake inhibitors,
however, has demonstrated significant improvement in
overall symptoms compared with placebo, whether used
continuously or only in the luteal phase.52
CHAPTER 47
The daily use of prescribed relaxation techniques during the premenstrual period can improve physical and
emotional symptoms.51 Management of PMS/PMDD includes education and support directed toward lifestyle
changes. Drug therapy should be used cautiously until
well-controlled studies establish criteria for use and effective treatment results. The placebo effect may account for
symptom relief in a significant number of women. It is unlikely that a single cause or treatment for PMS will be
found. Evaluation and management should focus on identifying and controlling the individual symptom clusters
when possible.
In summary, menstrual disorders include dysfunctional menstrual cycles, dysmenorrhea, and PMS. Dysfunctional menstrual
cycles occur when the hormonal support of the endometrium
is altered. Estrogen deprivation causes retrogression of a previously built-up endometrium and bleeding. A lack of progesterone can cause abnormal menstrual bleeding; in its absence,
estrogen induces development of a much thicker endometrial
layer with a richer blood supply. The absence of progesterone
results from the failure of any of the developing ovarian follicles to mature to the point of ovulation, with the subsequent
formation of the corpus luteum and production and secretion
of progesterone. Dysfunctional menstrual cycles produce amenorrhea, oligomenorrhea, metrorrhagia, or menorrhagia. Dysmenorrhea is characterized by pain or discomfort during
menses. It can occur as a primary or secondary disorder.
Primary dysmenorrhea is not associated with other disorders
and begins soon after menarche. Secondary dysmenorrhea is
caused by a specific organic condition, such as endometriosis or
pelvic adhesions. It occurs in women with previously painless
menses. PMS represents a cluster of physical and psychological
symptoms that precede menstruation by 1 to 2 weeks. PMDD
describes the most severe, disabling form of PMS. The true incidence and nature of PMS has been recognized only recently,
and its cause and methods for treatment are still under study.
Disorders of the Breast
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Describe changes in breast function that occur with
galactorrhea, mastitis, and ductal ectasia
✦ Describe the manifestations of fibrocystic disease and
state why it is often referred to as a “catchall” for breast
irregularities
✦ Cite the risk factors for breast cancer, the importance of
breast self-examination, and recommendations for
mammography
✦ Describe the methods used in the diagnosis and
treatment of breast cancer
Most breast disease may be described as benign or cancerous. Breast tissue is never static; the breast is constantly
responding to changes in hormonal, nutritional, psycho-
Disorders of the Female Reproductive System
1089
logical, and environmental stimuli that cause continual
cellular changes. Benign breast conditions are nonprogressive; some forms of benign disease, however, increase the
risk for malignant disease. In light of this, strict adherence
to a dichotomy of benign versus malignant disease may
not always be appropriate. This dichotomy, however, is
useful for the sake of simplicity and clarity.
GALACTORRHEA
Galactorrhea is the secretion of breast milk in a nonlactating breast. Galactorrhea may result from vigorous nipple
stimulation during lovemaking, exogenous hormones, internal hormonal imbalance, or local chest infection or
trauma. A pituitary tumor may produce large amounts of
prolactin and cause galactorrhea. Galactorrhea occurs in
men and women and usually is benign. Observation may
be continued for several months before diagnostic hormonal screening.
MASTITIS
Mastitis is inflammation of the breast. It most frequently
occurs during lactation but may also result from other
conditions.
In the lactating woman, inflammation results from an
ascending infection that travels from the nipple to the ductile structures. The most common organisms isolated are
Staphylococcus and Streptococcus.3 The offending organisms
originate from the suckling infant’s nasopharynx or the
mother’s hands. During the early weeks of nursing, the
breast is particularly vulnerable to bacterial invasion because of minor cracks and fissures that occur with vigorous
suckling. Infection and inflammation cause obstruction of
the ductile system. The breast area becomes hard, inflamed,
and tender if not treated early. Without treatment, the area
becomes walled off and may abscess, requiring incision and
drainage. It is advisable for the mother to continue breastfeeding during antibiotic therapy to prevent this.
Mastitis is not confined to the postpartum period; it
can occur as a result of hormonal fluctuations, tumors,
trauma, or skin infection. Cyclic inflammation of the breast
occurs most frequently in adolescents, who commonly
have fluctuating hormone levels. Tumors may cause mastitis secondary to skin involvement or lymphatic obstruction. Local trauma or infection may develop into mastitis
because of ductal blockage of trapped blood, cellular debris, or the extension of superficial inflammation.
The treatment of mastitis symptoms may include application of heat or cold, excision, aspiration, mild analgesics, antibiotics, and a supportive brassiere or breast
binder.
DUCTAL DISORDERS
Ductal ectasia manifests in older women as a spontaneous, intermittent, usually unilateral, grayish-green nipple discharge. Palpation of the breast increases the discharge. Ectasia occurs during or after menopause and is
1090
UNIT XI
Genitourinary and Reproductive Function
symptomatically associated with burning, itching, pain,
and a pulling sensation of the nipple and areola. The disease results in inflammation of the ducts and subsequent
thickening. The treatment requires removal of the involved
ductal mass.
Intraductal papillomas are benign epithelial tissue
tumors that range in size from 2 mm to 5 cm. Papillomas
usually manifest with a bloody nipple discharge. The
tumor may be palpated in the areolar area. The papilloma
is probed through the nipple, and the involved duct is
removed.
FIBROADENOMA AND
FIBROCYSTIC DISEASE
Fibroadenoma is seen in premenopausal women, most
commonly in the third and fourth decade. The clinical
findings include a firm, rubbery, sharply defined round
mass. On palpation, the mass “slides” between the fingers
and is easily movable. These masses usually are singular;
only 15% are multiple or bilateral. Fibroadenoma is asymptomatic and usually found by accident. It is not thought to
be precancerous. Treatment involves simple excision.
The term fibrocystic breast disease is the most frequent
lesion of the breast. It is most common in women 30 to
50 years of age and is rare in postmenopausal women not
receiving hormone replacement.53 Fibrocystic disease usually presents as nodular (i.e., “shotty”), granular breast
masses that are more prominent and painful during the
luteal or progesterone-dominant portion of the menstrual
cycle. Discomfort ranges from heaviness to exquisite tenderness, depending on the degree of vascular engorgement
and cystic distention.
Fibrocystic disease encompasses a wide variety of lesions and breast changes. Microscopically, fibrocystic disease refers to a constellation of morphologic changes
manifested by (1) cystic dilation of terminal ducts, (2) relative increase in fibrous tissue, and (3) variable proliferation of terminal duct epithelial elements.54 Autopsy studies
have demonstrated some degree of fibrocystic change in
60% to 80% of adult women in the United States.54 Symptomatic fibrocystic disease, in which large, clinically detectable cysts are present, is much less common, occurring
in approximately 10% of adult women between 35 and
50 years of age.54 Although fibrocystic disease often has
been thought to increase the risk for breast cancer, only
certain variants in which proliferation of the epithelial
components is demonstrated represent a true risk. Fibrocystic disease with giant cysts and proliferative epithelial lesions with atypia are more common in women who are at
increased risk for developing breast cancer. The nonproliferative form of fibrocystic disease that does not carry an increased risk for development of cancer is more common.
Diagnosis of fibrocystic disease is made by physical examination, biopsy (i.e., aspiration or tissue sample), and
mammography. The presence of diffuse radiographic densities, lumpy breasts, or premenstrual breast pain correlate
poorly with the presence or degree of fibrocystic change.
Instead, a diagnosis of fibrocystic disease should be based
on the results of a microscopic examination of a biopsy
specimen. Fine-needle aspiration may be used, but if a suspect mass that was nonmalignant on cytologic examination does not resolve over several months, it should be
removed surgically. Any discrete mass or lump on the
breast should be viewed as possible carcinoma, and cancer
should be excluded before instituting the conservative
measures used to treat fibrocystic disease. The use of
mammography for diagnosis in high-risk groups younger
than 35 years of age on a routine basis is still controversial.
Mammography may be helpful in establishing the diagnosis, but increased breast tissue density in women with
fibrocystic disease may make an abnormal or cancerous
mass difficult to discern among the other structures.
Hand-held ultrasonography can be useful in clarifying inconclusive mammographic densities.
Treatment of fibrocystic breast disease usually is symptomatic. Aspirin, mild analgesics, and local application of
heat or cold may be recommended. Some physicians attempt to aspirate prominent or persistent cysts and send
any fluid obtained to the laboratory for cytologic analysis.
Women are advised to avoid foods that contain xanthines
(e.g., coffee, cola, chocolate, and tea) in their daily diets,
particularly premenstrually. Vitamin E may be helpful in
reducing mastalgia (breast pain), and women should be encouraged to wear a good supporting brassiere. Danazol can
be used for women with severe pain, although the potential for adverse effects warrants trying other methods first.3
BREAST CANCER
Cancer of the breast is the most common female cancer.
One in eight women in the United States will have breast
cancer in her lifetime. In 2003, breast cancer affected
211,300 American women and killed an estimated 40,200
women.13 Although the breast cancer mortality rate has
shown a slight decline, it is second only to lung cancer as
a cause of cancer-related deaths in women. An additional
400 deaths occurred from breast cancer in males.13 Incidence rates for carcinoma in situ have increased dramatically since the mid-1970s because of recommendations
regarding mammography screening. The decline in the
breast cancer mortality rate since 1989 is due to this earlier
diagnosis as well as improvements in cancer treatments.13
Risk factors for breast cancer include sex, increasing
age, personal or family history of breast cancer (i.e., at highest risk are those with multiple affected first-order relatives),
history of benign breast disease (i.e., primary “atypical”
hyperplasia), and hormonal influences that promote breast
maturation and may increase the chance of cell mutation
(i.e., early menarche, late menopause, and no term pregnancies or first child after 30 years of age).13 Most women
with breast cancer have no identifiable risk factors.
Approximately 10% of all breast cancers are hereditary, with genetic mutations causing up to 80% of breast
cancers in women younger than 50 years of age.55 Two
breast cancer susceptibility genes—BRCA1 on chromosome
17 and BRCA2 on chromosome 13—may account for most
inherited forms of breast cancer (see Chapter 8). BRCA1 is
known to be involved in tumor suppression. A woman
with known mutations in BRCA1 has a lifetime risk of 56%
CHAPTER 47
to 85% for breast cancer and an increased risk for ovarian
cancer. BRCA2 is another susceptibility gene that carries
an elevated cancer risk similar to that with BRCA1.48,55 A
task force organized by the National Institutes of Health
and the National Genome Research Institute has proposed
a set of provisional consensus recommendations for monitoring known carriers of BRCA1 and BRCA2 mutations.
The task force recommended that known carriers should
begin monthly breast self-examination (BSE) at 18 years of
age and begin having annual mammograms at 25 years of
age.55 Prophylactic surgery, in the form of bilateral mastectomy, bilateral oophorectomy, or both, may decrease
the risk for developing cancer. These controversial surgeries can have physical and psychological side effects that
warrant careful consideration before proceeding.55
Detection
Cancer of the breast may manifest clinically as a mass, a
puckering, nipple retraction, or unusual discharge. Many
cancers are found by women themselves through BSE—
sometimes when only a thickening or subtle change in
breast contour is noticed. The variety of symptoms and
potential for self-discovery underscore the need for regular, systematic self-examination. BSE should be done routinely by women older than 20 years of age. Premenopausal women should conduct the examination right after
menses. This time is most appropriate in relation to cyclic
breast changes that occur in response to fluctuations in
hormone levels. Postmenopausal women and women who
have had a hysterectomy should perform the examination
on the same day of every month. Examination should be
done in the shower or bath or at bedtime. The most important aspect of BSE is to devise a regular, systematic,
convenient, and consistent method of examination. As an
adjunct to BSE, women should have a clinical examination by a trained health professional at least every 3 years
between 20 and 40 years of age, and annually after 40 years
of age.
Mammography is the only effective screening technique for the early detection of clinically inapparent lesions. Although recent studies have brought into question
the value of mammography,56–58 in 2002, the United States
Preventive Services Task Force (USPSTF) issued new guidelines concluding that there were sufficient data to justify
recommending mammography every 1 to 2 years in
women older than 40 years.59 A generally slow-growing
form of cancer, breast cancer may have been present for 2 to
9 years before it reaches 1 cm, the smallest mass normally
detected by palpation. Mammography can disclose lesions
as small as 1 mm and the clustering of calcifications that
may warrant biopsy to exclude cancer. The American Cancer Society recommends annual evaluation for women
after 40 years of age.60 Mammography has a sensitivity of
80% to 85% for the detection of breast cancer even when
performed by the most capable institutions.61 Approximately 40% of breast cancers can be detected only by palpation and another 40% only by mammography.13 The
most comprehensive approach to screening is a combination of BSE, clinical evaluation by a health professional,
and mammography.
Disorders of the Female Reproductive System
1091
Diagnosis and Classification
Procedures used in the diagnosis of breast cancer include
physical examination, mammography, ultrasonography,
percutaneous needle aspiration, stereotactic needle biopsy
(i.e., core biopsy), and excisional biopsy. Figure 47-10 illustrates the appearance of breast cancer on mammography.
Breast cancer often manifests as a solitary, painless, firm,
fixed lesion with poorly defined borders. It can be found
anywhere in the breast but is most common in the upper
outer quadrant. Because of the variability in presentation,
any suspect change in breast tissue warrants further investigation. The diagnostic use of mammography enables additional definition of the clinically suspect area (e.g., appearance, character, calcification). Placement of a wire
marker under radiographic guidance can ensure accurate
surgical biopsy of nonpalpable suspect areas. Ultrasonography is useful as a diagnostic adjunct to differentiate cystic from solid tissue in women with nonspecific thickening.
Fine-needle aspiration is a simple in-office procedure
that can be performed repeatedly in multiple sites and with
minimal discomfort. It can be accomplished by stabilizing
a palpable mass between two fingers or in conjunction
with handheld sonography to define cystic masses or fibrocystic changes and to provide specimens for cytologic
examination. Fine-needle aspiration can identify the presence of malignant cells, but it cannot differentiate in situ
from infiltrating cancers. Stereotactic needle biopsy is an
outpatient procedure done with the guidance of a mammography machine. After the lesion is localized radiologically, a large-bore needle is mechanically thrust quickly
into the area, removing a core of tissue. Discomfort is similar to that with ear piercing, and even when multiple
cores are obtained, healing occurs quite rapidly. Cells are
available for histologic evaluation with 96% accuracy in
detecting cancer. This procedure is less costly than excisional biopsy. Excisional biopsy to remove the entire lump
provides the only definitive diagnosis of breast cancer and
often is therapeutic without additional surgery. Magnetic
resonance imaging (MRI) techniques, positron-emission
tomography, and computer-based or digital mammography are being evaluated as additional diagnostic modalities for breast cancer and may be recommended to supplement conventional mammography in women with a
strong family history of cancer or known carriers of BRCA1
or BRCA2.55
Tumors are classified histologically according to tissue
characteristics and staged clinically according to tumor size,
nodal involvement, and presence of metastasis. It is recommended that estrogen and progesterone receptor analysis
be performed on surgical specimens. Information about the
presence or absence of estrogen and progesterone receptors
can be used in predicting tumor responsiveness to hormonal manipulation. High levels of both receptors improve
the prognosis and increase the likelihood of remission.
Treatment
The treatment methods for breast cancer are controversial.
They may include surgery, chemotherapy, radiation therapy, and hormonal manipulation. Radical mastectomy
(i.e., removal of the entire breast, underlying muscles, and
1092
UNIT XI
A
Genitourinary and Reproductive Function
B
FIGURE 47-10 Carcinoma of the breast. (A) Mammogram. An irregularly shaped, dense mass (arrows) is
seen in this otherwise fatty breast. (B) Mastectomy specimen. The irregular white, firm mass in the center is surrounded by fatty tissue. (Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 1042]. Philadelphia:
Lippincott-Raven)
all axillary nodes) rarely is used today as a primary surgical
therapy unless breast cancer is advanced at the time of diagnosis. Modified surgical techniques (i.e., mastectomy
plus axillary dissection or lumpectomy for breast conservation) accompanied by chemotherapy or radiation therapy have achieved outcomes comparable with those obtained with radical surgical methods and constitute the
preferred treatment methods.
The prognosis is related more to the extent of nodal
involvement than to the extent of breast involvement.
Greater nodal involvement requires more aggressive postsurgical treatment, and many cancer specialists believe
that a diagnosis of breast cancer is not complete until dissection and testing of the axillary lymph nodes has been
accomplished. A newer technique for evaluating lymph
node involvement is a sentinel lymph node (SLN) biopsy.
A radioactive substance or dye is injected into the region
of the tumor. In theory, the dye is carried to the first (sentinel) node to receive lymph from the tumor.62 This would
therefore be the node most likely to contain cancer cells
if the cancer has spread. If the sentinel node biopsy is positive, more nodes are removed. If it is negative, further
lymph node evaluation may not be needed. Successful
identification of the SLN occurs 92% to 98% of the time,
and when blue dye and isotope are used together, SLN has
a positive predictive value approaching 100% and a negative predictive value near 95%.3
Adjuvant systemic therapy refers to the administration of chemotherapy or hormonal therapy to women
without detectable metastatic disease. The goal of this therapy depends on nodal involvement, menopausal status,
and hormone receptor status. Adjuvant systemic therapy
has been widely studied and has demonstrated benefits in
reducing rates of recurrence and death from breast cancer.3
Tamoxifen is a nonsteroidal antiestrogen that binds to
estrogen receptors and blocks the effects of estrogens on
the growth of malignant cells in the breast. Studies have
shown decreased cancer recurrence, decreased mortality
rates, and increased 5-year survival rates in women with estrogen receptor–positive tissue samples who have been
treated with the drug. Autologous bone marrow transplantation and peripheral stem cell transplantation are experimental therapies that may be used for treatment of
advanced disease or in women at increased risk for recurrence. Immunotherapy, using a drug called trastuzumab
(Herceptin), is used to stop the growth of breast tumors
that express the HER2/neu receptor on their cell surface.
The HER2/neu receptor binds an epidermal growth factor
that contributes to cancer cell growth. Trastuzumab is a recombinant DNA-derived monoclonal antibody that binds
to the HER2/neu receptor, thereby inhibiting proliferation
of tumor cells that overexpress the receptor gene.62
The 5-year survival rate for localized cancer is 97%;
with nodal involvement, it is approximately 78%; and it
CHAPTER 47
is approximately 23% with distant metastasis.13 Five-year
survival rates by age at diagnosis range from 81% for
women younger than 45 years to 87% for women older
than 65 years of age.12
Paget Disease
Paget disease accounts for 1% of all breast cancers. The disease presents as an eczemoid lesion of the nipple and areola (Fig. 47-11). Paget disease usually is associated with an
infiltrating, intraductal carcinoma. When the lesion is limited to the nipple only, the rate of axillary metastasis is approximately 5%. Complete examination is required and
includes a mammogram and biopsy. Treatment depends
on the extent of spread.
In summary, the breasts are subject to benign and malignant
disease. Mastitis is inflammation of the breast, occurring most
frequently during lactation. Galactorrhea is an abnormal secretion of milk that may occur as a symptom of increased prolactin secretion. Ductal ectasia and intraductal papilloma cause
abnormal drainage from the nipple. Fibroadenoma and fibrocystic disease are characterized by abnormal masses in the
breast that are benign. By far the most important disease of
the breast is breast cancer, which is a significant cause of death
in women. BSE and mammography afford a woman the best
protection against breast cancer. They provide the means for
early detection of breast cancer and, in many cases, allow
early treatment and cure.
Disorders of the Female Reproductive System
1093
Infertility
After completing this section of the chapter, you should be able to
meet the following objectives:
✦ Provide a definition of infertility
✦ List male and female factors that contribute to infertility
✦ Briefly describe methods used in the treatment of
infertility
Infertility is the inability to conceive a child after
1 year of unprotected intercourse. It affects approximately
15% of couples in the United States. Primary infertility
refers to situations in which there has been no prior conception. Secondary infertility is infertility that occurs after
one or more previous pregnancies. Sterility is the inability
to father a child or to become pregnant because of congenital anomalies, disease, or surgical intervention. Approximately 1% to 2% of U.S. couples are affected by sterility.
The complexity of the process that must occur to
achieve a pregnancy is taken for granted by most couples.
For some couples, pregnancy occurs far too easily, whereas
for others, no amount of money, hard work, love, patience,
or medical resources seems to be able to bring about this
amazing, desired event. Although a full discussion of the
diagnosis and treatment of infertility is beyond the scope
of this book, an overview of the areas in which problems
can occur is presented.
The causes of infertility are almost equally divided
among male factors (30% to 40%), female factors (30% to
40%), and combined factors (30% to 40%). In approximately 10% to 25% of infertile couples, the cause remains
unknown even after a full workup.
MALE FACTORS
FIGURE 47-11 Paget disease of the nipple. An erythematous, scaly,
and weeping “eczema” involves the nipple. (Rubin E., Farber J.L.
[1999]. Pathology [3rd ed., p. 1043]. Philadelphia: Lippincott-Raven)
For pregnancy to occur, the male must be able to provide
sperm in sufficient quantity, delivered to the upper end
of the vagina, with adequate motility to traverse the female reproductive tract. The male contribution to this process is assessed by means of a semen analysis, which
evaluates volume of semen (normally 2 to 5 mL), sperm
density (20 million/mL), motility (50% good progressive),
viability (50%), morphology (60% normal), and viscosity
(full liquefaction within 20 minutes). The specimen is
best collected by masturbation into a sterile container
after 3 days of abstinence. Because of variability in specimens, abnormal results should lead to a repeat test before the need for treatment is presumed.
Azoospermia is the absence of sperm; oligospermia refers
to decreased numbers of sperm; and asthenospermia refers
to poor motility of sperm. Tests of sperm function include
cervical mucus penetration tests (e.g., postcoital test, Penetrak), sperm penetration assay (i.e., Hamster Zona Free
Ovum test), and sperm antibody testing. None of these
tests are included in the routine infertility evaluation.
The causes of male infertility include varicocele, ejaculatory dysfunction, hyperprolactinemia, hypogonadotropic hypogonadism, infection, immunologic problems
1094
UNIT XI
Genitourinary and Reproductive Function
(i.e., antisperm antibodies), obstruction, and congenital
anomalies. Risk factors for sperm problems include a history of mumps orchitis, cryptorchidism (i.e., undescended
testes), testicular torsion, hypospadias, previous urologic
surgery, infection, and exposure to known gonadotoxins.48
Treatment depends on the cause and may include surgery,
medication, or the use of artificial insemination to deliver
a more concentrated specimen directly to the cervical canal
or uterine fundus. Artificial insemination with donor sperm
can be offered if the male is sterile and if this alternative is
acceptable to the husband and wife.
FEMALE FACTORS
The female contribution to pregnancy is more complex,
requiring production and release of a mature ovum capable of being fertilized; production of cervical mucus that
assists in sperm transport and maintains sperm viability
in the female reproductive tract; patent fallopian tubes
with the motility potential to pick up and transfer the
ovum to the uterine cavity; development of an endometrium that is suitable for the implantation and nourishment of a fertilized ovum; and a uterine cavity that allows
for growth and development of a fetus. Each of these factors is discussed briefly, along with an overview of diagnostic tests and treatment.
Ovulatory Dysfunction
In a normally menstruating female, ovulatory cycles begin
several months to a year after menarche. Release of FSH
from the pituitary causes the development of several primordial follicles in the ovary. At some point, a dominant
follicle is selected, and the remaining follicles undergo atresia. When the dominant follicle has become large enough
to contain a mature ovum (16 to 20 mm in diameter) and
is producing sufficient estradiol to ensure adequate proliferation of the endometrium, production of LH increases
(i.e., the LH surge), and the increased LH level induces release of the ovum from within the follicle (i.e., ovulation).
After ovulation, under the influence of LH, the former follicle luteinizes and begins producing progesterone in addition to estradiol. The progesterone stimulates
the development of secretory endometrium, which has
the capability to nourish a fertilized ovum if one should
implant.
The presence of progesterone after ovulation causes a
rise in the woman’s basal body temperature (BBT). This
thermogenic property of progesterone provides the basis
for the simplest, most inexpensive beginning test of ovulatory function—the measurement of BBT. Women should
be able to detect at least a 0.4°F rise in their BBT (at rest)
after ovulation that should be maintained throughout the
luteal phase. This biphasic temperature pattern demonstrates that ovulation has taken place, where in the cycle
it occurred, and the length of the luteal phase. BBT can be
influenced by many other factors, including restless sleep,
alcohol intake, drug use, fever due to illness, and change
in usual rising time. However, as an initial step in the infertility investigation, it can provide useful information to
direct other forms of testing.
Endometrial biopsy, the removal of a sample of the
endometrium during an office procedure, provides histologic evidence of secretory endometrium and the level of
maturation of the lining. In a normal cycle, the luteal
phase should be 14 days long. Without pregnancy and the
subsequent secretion of hCG, the corpus luteum begins to
degenerate 7 to 10 days after the LH surge. The luteal
phase of the cycle is so consistent that a pathologist can
tell by evaluating a section of endometrium that it is representative of a particular day of the luteal phase. The
pathologist’s assessment of maturation is compared with
the arrival of the next menses. If a discrepancy of more
than 2 days exists, the woman is said to have a luteal phase
defect (LPD). This diagnosis indicates that, although ovulation is occurring, endometrial development is insufficient and implantation may not be possible. Pregnancy
requires fertilization and implantation. LPD also can be
suggested by an abnormal serum progesterone level 7 days
after ovulation. It can be treated directly with supplemental progesterone after ovulation or with the use of clomiphene citrate to stimulate increased pituitary production
of FSH and LH.
Anovulation (no ovulation) and oligoovulation (irregular ovulation) are other forms of ovulatory dysfunction.
These problems can be identified by the tests for LPD previously described but are more often identified and treated
based on a history of menstrual irregularity. Ovulatory
problems can be primary problems of the ovary or secondary problems related to endocrine dysfunction. When
disturbances in ovulation are confirmed, it is reasonable
to evaluate other endocrine functions before initiating
treatment. If the results of tests for pituitary hormones
(e.g., FSH, LH, prolactin), thyroid studies, and tests of adrenal function (e.g., DHAS, androstenedione) are normal,
ovulatory dysfunction is primary and should respond to
treatment. Abnormalities in any of the other endocrine
areas should be further evaluated as needed and treated
appropriately. Hyperprolactinemia responds well to bromocriptine, but pituitary microadenoma may need to be
excluded first. Hypothyroidism requires thyroid replacement, and hyperthyroidism requires suppressive therapy
and, sometimes, surgical intervention with thyroid replacement later. Adrenal suppression can be instituted with
dexamethasone, a glucocorticoid analog. Normal ovulatory function may resume without further intervention; if
not, treatment can be concurrent with management of
other endocrine problems.
Cervical Mucus Problems
High preovulatory levels of estradiol stimulate the production of large amounts of clear, stretchy cervical mucus
that aids the transport of sperm into the uterine cavity and
helps to maintain an environment that keeps the sperm
viable for up to 72 hours. Insufficient estrogen production
(i.e., inherent or secondary to treatment with clomiphene
citrate, an antiestrogen), cervical abnormalities from disease or invasive procedures (e.g., DES exposure, stenosis,
conization), and cervical infection (e.g., chlamydial infection, mycoplasmal infection, gonorrhea) can adversely
affect the production of healthy cervical mucus.
CHAPTER 47
A postcoital test (Sims-Huhner) involves evaluation of
the cervical mucus 1 to 8 hours after intercourse within
the 48 hours before ovulation. A sample of cervical mucus
is obtained using a special syringe and evaluated grossly
for amount, clarity, and stretch (i.e., spinnbarkeit) and microscopically for cellularity, number and quality of motile
sperm, and the presence of ferning after the sample has
air-dried on the slide. To obtain good-quality mucus, it is
essential to obtain the sample within the 48 hours before
ovulation. Tests may have to be repeated in the same cycle
or in subsequent cycles to ensure appropriate timing. This
can be a source of stress and frustration, as well as added
cost to the couple. Intrauterine insemination (IUI) with
the husband’s sperm can bypass the cervical mucus and
may be offered empirically as an alternative to postcoital
testing.
If inadequate estrogen effect is seen (poor-quality
mucus), supplemental oral estrogen can be given in the
first 9 days of the next cycle, and the test can be repeated.
Administration of mucolytic expectorants (1 teaspoon four
times daily, starting on day 10 and continuing until ovulation is confirmed) also may improve the quality of the
mucus. If mucus is good but sperm are inadequate in number or motility, further evaluation of the male may be
needed. The man and woman can be tested for antisperm
antibodies when repeated postcoital tests reveal that the
sperm are all dead or agglutinated; however, IUI is the only
effective treatment for sperm antibodies and may be offered
without the need for further testing.
Cervical cultures for gonorrhea, chlamydial infection,
and mycoplasmal infection should be obtained and treatment instituted as needed. Prophylactic treatment with antibiotics can be provided before IUI or other procedures
that pass through the cervical canal as a more cost-effective
alternative to obtaining cervical cultures.
Uterine Cavity Abnormalities
Alterations in the uterine cavity can occur because of DES
exposure, submucosal fibroids, cervical polyps, bands of
scar tissue, or congenital anomalies (e.g., bicornuate septum, single horn). These defects may be suspected from the
patient’s history or pelvic examination but require hysterosalpingography (i.e., x-ray study in which dye is placed
through the cervix to outline the uterine cavity and demonstrate tubal patency) or hysteroscopy (i.e., study in which a
lighted fiberoptic endoscope placed through the cervix
under general anesthesia allows direct visualization of the
uterine cavity) for confirmation. Treatment is surgical when
possible.
Tubal Factors
Tubal patency is required for fertilization and can be disrupted secondary to PID, ectopic pregnancy (i.e., after
salpingectomy or salpingostomy), large myomas, endometriosis, pelvic adhesions, and previous tubal ligation.
Hysterosalpingography can reveal the location and type
of any blockage, such as fimbrial, cornual, or hydrosalpinx.
Microsurgical repair sometimes is possible.
Even when tubal patency is demonstrated, tubal disease may make ovum pickup impossible. Contrary to pop-
Disorders of the Female Reproductive System
1095
ular belief, the ovum is not extruded directly into the fallopian tube. The tube must be free to move to engulf the
ovum after release. Pelvic adhesions from previous infection, surgery, or endometriosis can interfere with the tube’s
mobility. Laparoscopic evaluation of the pelvis is needed
for diagnosis. Laser ablation or cautery can be used to lyse
adhesions and remove endometriosis through the laparoscope or, if severe, by means of laparotomy.
ASSISTED REPRODUCTIVE TECHNOLOGIES
In vitro fertilization (IVF) was developed in 1978 for
women with significantly damaged or absent tubes to provide them with an opportunity for pregnancy where none
normally existed. The ovaries are superstimulated to produce multiple follicles using clomiphene citrate, human
menopausal menotropins (e.g., Pergonal, Repronex), pure
FSH (e.g., Gonal-F, Follistim, Bravelle), or a combination of
these drugs. Follicular maturation is monitored by means
of ultrasonography and assay of serum estradiol levels.
When preovulatory criteria are met, an injection of hCG
is given to simulate an LH surge; 35 hours later, the follicles are aspirated laparoscopically or, more often, by the
ultrasound-guided transvaginal route. The follicular fluid
is evaluated microscopically for the presence of ova. When
found, they are removed and placed into culture media in
an incubator.
The eggs are inseminated with sperm from the husband that have been prepared by a washing technique that
removes the semen, begins the capacitation process, and
allows the strongest sperm to be used for fertilization.
When very low numbers of normal motile sperm are available, microsurgical techniques can be used to assist with
fertilization. Earlier procedures such as partial zona dissection (PZD), which involves the creation of a small opening
in the layer (i.e., zona pellucida) that surrounds the egg,
and subzonal insertion, whereby several sperm are inserted
into the space just beneath the protective layer, are rarely
used today. The most definitive form of micromanipulation is a procedure called intracytoplasmic sperm injection
(ICSI), whereby a single spermatozoa is injected directly
into the cytoplasm of the egg.
Between 12 and 24 hours after insemination, the ova
are evaluated for signs of fertilization. If signs are present,
the ova are returned to the incubator, and 48 to 72 hours
after egg retrieval, the fertilized eggs are placed back into the
woman’s uterus by means of a transcervical catheter. A procedure similar to PZD can be performed just before embryo
transfer to help the fertilized egg escape from the zona pellucida. This “assisted hatching” improves the chances of
implantation. In an effort to reduce the number of multiple
births resulting from this type of technology, the embryos
may be grown to the blastocyst stage and transferred back
to the uterus on the fifth day after fertilization. Because
many embryos will not advance to the blastocyst stage in
vitro, this therapy usually is limited to those women who
have produced a significant number of embryos.
Hormonal supplementation of the luteal phase often
is used to increase the possibility of implantation. The
1096
UNIT XI
Genitourinary and Reproductive Function
overall live delivery rate in 2000 for women using their
own eggs, as reported by the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine, was 31.6% per egg retrieval.63 Indications for IVF have been expanded to include male factors
(i.e., severe oligospermia or asthenospermia), immunologic infertility, severe endometriosis, and idiopathic infertility (i.e., infertility of unknown cause). The substantial
risk for multiple births with IVF procedures has been reduced with the availability of cryopreservation, which allows freezing of excess embryos and limits the number of
fresh embryos transferred. The live delivery rate in 2000
after frozen embryo transfer was 20.3%.63
An outgrowth of IVF technology is gamete intrafallopian transfer (GIFT), which uses similar ovarian stimulation
protocols and egg retrieval procedures but uses laparoscopy
to place ovum and sperm directly into the fallopian tube.
This procedure requires at least one patent fallopian tube
and was developed primarily to increase the pregnancy
rate in women with idiopathic infertility. The basic premises are that if a transportation problem is interfering
with ovum pickup, GIFT could solve that problem, and
that implantation may result more often if fertilization occurs in the body. Because of the added expense involving
laparoscopy and the limited indications, GIFT procedures
are used infrequently. In 2000, GIFT represented less than
1% of all ART procedures performed, and statistics were
not reported separately.63
Other ART include zygote intrafallopian transfer (ZIFT)
and tubal embryo transplant (TET). With ZIFT, the zygote
is placed laparoscopically into the fallopian tube after the
traditional IVF procedure. With TET, the embryos are transferred into the fallopian tubes transcervically using ultrasound guidance or by means of hysteroscopy. The theoretic advantages of these procedures involve tubal factors
that may facilitate implantation. As with GIFT, these procedures accounted for only 1% of all assisted reproductive
technology (ART) procedures performed in 2000 and statistics were not reported separately.63
By 2003, more than 1 million infants had been born
worldwide using some type of ART, with almost 100,000
births being made possible with the use of intracytoplasmic sperm injection. Future research will focus on understanding and improving the implantation process.
In summary, infertility is the inability to conceive a child after
1 year of unprotected intercourse. Male factors are related to
number and motility of sperm and their ability to penetrate the
cervical mucus and the ovum. Causes of male infertility include
varicocele, ejaculatory dysfunction, hyperprolactinemia, hypogonadotropic hypogonadism, infection, immunologic problems (i.e., antisperm antibodies), obstruction, and congenital
anomalies. Risk factors for sperm disorders include a history
of mumps orchitis, cryptorchidism (undescended testes), testicular torsion, hypospadias, previous urologic surgery, infection, and exposure to known gonadotoxins.
The female contribution to pregnancy is more complex,
requiring production and release of a mature ovum capable of
being fertilized; production of cervical mucus that assists in
sperm transport and maintains sperm viability in the female
reproductive tract; patent fallopian tubes with the mobility potential to pick up and transfer the ovum to the uterine cavity;
development of an endometrium that is suitable for the implantation and nourishment of a fertilized ovum; and a uterine cavity that allows for growth and development of a fetus.
Evaluation and treatment of infertility can be lengthy and
highly stressful for the couple. Options for therapy continue to
expand, but newer ART modalities are expensive, and financial resources can be strained while couples seek to fulfill their
sometimes elusive dream of having a child.
REVIEW EXERCISES
A 32-year-old woman has been told that the report of her
annual Pap test revealed the presence of mild dysplasia.
A. What questions should this woman ask as a means
of becoming informed about the significance of
these findings?
B. In obtaining additional information about the results
of her Pap test, the woman is informed that dysplastic changes are consistent with CIN 1 classification.
1. Does this mean that the woman has cervical
cancer?
2. How would these findings translate into the
Bethesda System for grading cervical cytology?
3. Cervical cancer is often referred to as a sexually
transmitted disease. Explain.
4. What type of follow-up care would be indicated?
A 30-year-old woman consults her gynecologist because
of amenorrhea, and she has been unable to become
pregnant. Her physical exam reveals an obese woman
with hirsutism. The physician tells the woman that she
might have a condition known as polycystic ovary disease and that further laboratory tests are indicated.
A. Among tests ordered are a fasting blood glucose, LH,
FSH, and dehydroepiandrosterone levels. What information can these tests provide that would help in establishing a diagnosis of polycystic ovarian syndrome?
B. What is the probable cause of this woman’s amenorrhea, hirsutism, and failure to become pregnant?
C. What type of treatment might be used to help this
woman become pregnant?
A 45-year-old woman makes an appointment to see her
physician because of a painless lump in her breast that
she discovered while doing her routine monthly breast
exam.
A. What tests should be done to confirm the presence
or absence of breast cancer?
B. During the removal of breast cancer, a sentinel node
biopsy is often done to determine whether the cancer has spread to the lymph nodes. Explain how this
procedure is done and its value in determining lymph
node spread.
CHAPTER 47
C. Following surgical removal of breast cancer, tamoxifen may used as an adjuvant systemic therapy for
women without detectable metastatic disease. The
presence or absence of estrogen receptors in the cytoplasm of tumor cells is important in determining
the selection of an agent for use in adjuvant therapy.
Explain.
References
1. Hill A.D., Lense J.J. (1998). Office management of Bartholin
gland cysts and abscesses. American Family Physician 57,
1611–1620.
2. Kurman R.J. (2002). Blaustein’s pathology of the female genital
tract (5th ed., pp. 53–55, 99, 109, 168, 216–222, 253–256, 327,
336, 746–749, 502–503, 637–639, 801, 802). New York:
Springer-Verlag.
3. Scott J.R., Gibbs R.S., Karlan B.Y., Haney A.F. (2003). Danforth’s
obstetrics and gynecology (9th ed., pp. 585, 586, 591, 606–608,
653–662, 713–720, 727, 839, 898, 899, 906, 913, 927, 941–949,
953–963). Philadelphia: Lippincott Williams & Wilkins.
4. Stewart E.G. (2003). Treatment options for vulvar vestibulitis.
Contemporary OB/GYN 1, 47–61.
5. Edwards L. (2003). New concepts in vulvodynia. American
Journal of Obstetrics and Gynecology 189(3, S-1): S24–30.
6. Cancer Reference Information. (2003). Vulvar cancer. The
American Cancer Society. [On-line]. Available: http:/www.
cancer.org/docroot/CRI. Accessed October 1, 2003.
7. Canavan T.P., Cohen D. (2002). Vulvar cancer. American Family Physician 66, 1269–1274.
8. Tyring S.K. (2003). Vulvar squamous cell carcinoma: guidelines for early diagnosis and treatment. American Journal of
Obstetrics and Gynecology 189(3, S-1), S17–23.
9. Sweet R.L., Gibbs R.S. (2002). Infectious diseases of the female
genital tract (4th ed., pp. 337–340). Philadelphia: Lippincott
Williams & Wilkins.
10. Cancer Reference Information. (2003). Vaginal cancer. The
American Cancer Society. [On-line]. Available: http:/www.
cancer.org/docroot/CRI. Accessed October 1, 2003.
11. Hammes B., Laitman C.J. (2003). Diethylstilbestrol (DES) update: Recommendations for the identification and management of DES-exposed individuals. Journal of Midwifery and
Women’s Health 48(1): 19–29.
12. Crum C.P., Lester S.C., Cotran R.S. (2003). The female genital
system and breast. In Kumar V., Cotran R.S., Robbins S.L.
(Eds.), Robbins basic pathology (7th ed., pp. 679–717).
Philadelphia: W.B. Saunders.
13. American Cancer Society. (2003). Cancer facts and figures
2003. New York: Author.
14. Snyder U. (2003). March/April 2003: A look at cervical cancer.
Medscape Ob/Gyn & Women’s Health 8(1); posted 4/25/2003.
[On-line.] Available: http://www.medscape.com/viewarticle/
452727. Accessed November 7, 2003.
15. Choma K.K. (2003). ASC-US HPV testing. American Journal of
Nursing 103(2):42–50.
16. Saslow D., Runowicz C.D., Solomon D., et al. (2002). American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA: A Cancer Journal for Clinicians
52(6), 342–362.
17. U.S. Preventive Services Task Force. (2003). Screening for cervical cancer: Recommendations and rationale. American Journal of Nursing 103(11), 101–109.
Disorders of the Female Reproductive System
1097
18. Solomon D., Davey D., Kurman R., et al., for the Forum
Group Members and the Bethesda 2001 Workshop. (2002).
The 2001 Bethesda System. Journal of the American Medical
Association 287(16), 2114–2119.
19. Wright T., Cox, T., Massad L.S., et al., for the 2001 ASCCPSponsored Consensus Conference. (2002). 2001 Consensus
guidelines for the management of women with cervical cytological abnormalities. Journal of the American Medical Association 287(16), 2120–2129.
20. Eskridge C., Begneaud W.P., Landwehr C. (1998). Cervicography combined with repeat Papanicolaou test as triage for
low grade cytologic abnormalities. Obstetrics and Gynecology
92, 351–355.
21. Spaczynski R.Z., Duleba A.J. (2003). Diagnosis of endometriosis. Seminars in Reproductive Medicine 21(2), 193–207.
22. Gambone J.C., Mittman B.S., Munro M.G., et al., for the
Chronic Pelvic Pain/Endometriosis Working Group. (2002).
Consensus statement for the management of chronic pelvic
pain and endometriosis: proceedings of an expert-panel consensus process. Fertility and Sterility 78(5), 961–972.
23. Feste J.R., Schattman G.L. (2000). Laparoscopy and endometriosis: Preventing complications and improving outcomes.
In Changing perspectives: A new outlook on gynecologic disorders.
Symposia proceedings 2000 (p. 40–42). Medical Education
Collaborative.
24. American College of Obstetricians and Gynecologists. (1999).
Medical management of endometriosis. ACOG Practice Bulletin no. 11. In 2001 Compendium of selected publications
(pp. 982, 986). Washington, DC: Author.
25. Johnson K. (2003). Differentiating adenomyosis and fibroids. Medscape OB/Gyn & Women’s Health 8(2). [On-line]
Available: https://www.medscape.com/viewarticle/459772.
Accessed November 20, 2003.
26. Pron G., Bennett J., Common A., et al., for the Ontario Uterine Fibroid Embolization Collaborative Group. (2003). The
Ontario Uterine Fibroid Embolization Trial. 2. Uterine fibroid
reduction and symptom relief after uterine artery embolization for fibroids. Fertility and Sterility 799(1), 120–127.
27. Mott A.M. (2000). Prevention and management of pelvic inflammatory disease by primary care providers. American Journal of Nurse Practitioners 8, 7–13.
28. Centers for Disease Control and Prevention. (2002). 2002
Guidelines for treatment of sexually transmitted diseases.
Morbidity and Mortality Weekly Report 51(RR06), 1–80.
29. Centers for Disease Control and Prevention. (1995). Current
trends for ectopic pregnancy—United States, 1990–1992.
Morbidity and Mortality Weekly Report 44(RR-3), 46–48.
30. Gracie C.R., Barnhart K.T. (2001). Diagnosing ectopic pregnancy: Decision analysis comparing six strategies. Obstetrics
& Gynecology 97(3), 464–470.
31. Barnhart K.T., Gosman G., Ashby R., Sammel M. (2003). The
medical management of ectopic pregnancy: a meta-analysis
comparing “single dose” and “multidose” regimens. Obstetrics & Gynecology 101(4), 778–784.
32. Tenore J.L. (2000). Ectopic pregnancy. American Family Physician 61, 1080–1088.
33. Speroff L., Glass R.H., Kase N.G. (1999). Clinical gynecologic
endocrinology and infertility (6th ed., pp. 497–503), Philadelphia:
Lippincott Williams & Wilkins.
34. Mark T.L., Menta A.E. (2003). Polycystic ovary syndrome:
Pathogenesis and treatment over the short and long term.
Cleveland Clinic Journal of Medicine 70(1), 31–45.
35. Richardson M.B. (2003). Current perspectives in polycystic
ovary syndrome. American Family Physician 68(4), 697–704.
36. Nestler J.E., Stovall D., Ahkter N., et al. (2002). Strategies for
the use of insulin-sensitizing drugs to treat infertility in
1098
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
UNIT XI
Genitourinary and Reproductive Function
women with polycystic ovary syndrome. Fertility and Sterility
17(2), 20915.
Costello M.F., Eden J.A., (2003). A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertility and Sterility 79(1), 1–13.
Harris L.L. (2002). Ovarian cancer: Screening for early detection. American Journal of Nursing 102(10), 46–52.
Rubin S.C., Sutton G.P. (2001). Ovarian cancer (2nd ed.,
pp. 167–177). Philadelphia: Lippincott Williams & Wilkins.
Frank T.S. (1998). Identifying women with inherited risk for
ovarian cancer: Who and why? Contemporary OB/Gyn 12,
27–50.
Barnes M.N., Grizzle W.E., Grubbs C.J, Partridge E.E. (2002).
Paradigms for primary prevention of ovarian carcinoma. CA:
A Cancer Journal for Clinicians 52(4), 216–225.
Petricoin E.F. III, Ardekani A.M., Hitt B.A., et al. (2002). Use
of proteomic patterns in serum to identify ovarian cancer.
Lancet 359, 572–577.
National Institutes of Health Consensus Development Panel
on Ovarian Cancer. (1995). Ovarian cancer: Screening and
follow-up. Journal of the American Medical Association 273,
491–497.
Cancer Reference Information. (2003). Ovarian cancer. The
American Cancer Society. [On-line.] Available: http://www.
cancer.org/docroot/CRI. Accessed December 6, 2003.
National Cancer Institute. (2000). SEER Cancer statistics review
1973–1997 (pp. 122, 370). [On-line]. Available: http://www.
seer.cancer.gov.
Feitozoa S.S., Gebhart J.B., Gostour B.S., et al. (2003). Efficacy
of thermal balloon ablation in patients with abnormal uterine bleeding. American Journal of Obstetrics and Gynecology
189, 453–457.
American College of Obstetricians and Gynecologists. (2000).
Management of anovulatory bleeding. ACOG Practice Bulletin no. 14. In 2001 Compendium of selected publications
(pp. 961–968). Washington, DC: Author.
Mishell D.R., Goodwin T.M., Brenner P.F. (2002). Management
of common problems in obstetrics and gynecology (4th ed., 236,
253, 260, 278, 395, 428, 431–435). Williston, VT: Blackwell
Science.
Hudson T. (2002). Premenstrual syndrome, part 1. Female
Patient 27, 38–40.
50. Kovacs P. (2002). Evaluation and recognition of premenstrual
dysphoric disorder. Clinical Advisor 5(4), 110–118.
51. Moline M.L., Zendell S.M. (2000). Evaluating and managing
premenstrual syndrome. Medscape Women’s Health 5(2).
[On-line]. Available: http://www.medscape.com/Medscape
WomensHealth/journal/2000/v05,n02.
52. Dimmock P.W., Wyatt K.M., Jones P.W., O’Brien P.M.S. (2000).
Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: A systemic review. Lancet 356, 1131–1136.
53. Giuliano A.E. (2001). Benign breast disorders. In Tierney L.M.,
McPhee S.J., Papadakis M.A. (Eds.), Current medical diagnosis
and treatment (40th ed., pp. 706–707). New York: Lange Medical Books/McGraw-Hill.
54. Rubin E., Farber J.L., (1999). Pathology (3rd ed., 1033–1035).
Philadelphia: Lippincott-Raven.
55. Zimmerman V.L. (2002). BRCA gene mutations and cancer.
American Journal of Nursing 102(8): 28–36.
56. Gotzsche P.C., Olsen O. (2000). Is screening for breast cancer
with mammography justifiable? Lancet 355, 129–134.
57. Olsen O., Gotzsche P.C. (2001). Cochrane review on screening
for breast cancer with mammography. Lancet 358, 1340–1342.
58. Miller A.B., To T., Baines C.J., Wall C. (2002). The Canadian
National Breast Screening Study. 1. Breast cancer mortality
after 11 to 16 years of follow-up. Annuals of Internal Medicine
137, 305–312.
59. Humphrey L.L., Helfand M, Chan B.K.S., Woolf S.H. (2002).
Breast cancer screening: A summary of the evidence for the
U.S. Preventive Service Task Force. Annals of Internal Medicine
137, 347–360.
60. Smith R.A., Saslow D, Sawyers K.A., et al. American Cancer
Society guidelines for breast cancer screening updated 2003.
CA: A Cancer Journal for Clinicians 53, 134–137.
61. Harvey S.C., Geller B., Oppenheimer R.G., et al. (2003). Increase in cancer detection and recall rates with independent
double interpretation of screening mammography. American
Journal of Roentgenology 180, 1461–1467.
62. Hortobagyi G.N. (1998). Treatment of breast cancer. New England Journal of Medicine 339, 974–984.
63. CDC’s Reproductive Health Information Source. (2003). 2000
Assisted reproductive technology success rates. Centers for Disease Control and Prevention. [On-line.] Available: http://
www.cdc.gov/reproductivehealth/ART. Accessed December 5,
2003.