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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. 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