14 - Alimentary Tract

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

> Table of Contents > 17 - Gynecology

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17

Gynecology

H. Trent MacKay MD, MPH

Abnormal Premenopausal Bleeding

Essentials of Diagnosis

  • Blood loss of over 80 mL per cycle.

  • Excessive bleeding, often with the passage of clots, may occur at regular menstrual intervals (menorrhagia) or irregular intervals (dysfunctional uterine bleeding).

  • Etiology most commonly dysfunctional uterine bleeding on a hormonal basis.

General Considerations

Normal menstrual bleeding lasts an average of 4 days (range, 2–7 days), with a mean blood loss of 40 mL. Blood loss of over 80 mL per cycle is abnormal and frequently produces anemia. Excessive bleeding, often with the passage of clots, may occur at regular menstrual intervals (menorrhagia) or irregular intervals (dysfunctional uterine bleeding). When there are fewer than 21 days between the onset of bleeding episodes, the cycles are likely to be anovular. Ovulation bleeding, a single episode of spotting between regular menses, is quite common. Heavier or irregular intermenstrual bleeding warrants investigation.

Dysfunctional uterine bleeding is usually caused by overgrowth of endometrium due to estrogen stimulation without adequate progesterone to stabilize growth; this occurs in anovular cycles. Anovulation commonly occurs in teenagers, in women aged late 30s to late 40s, and in extremely obese women or those with polycystic ovary syndrome.

Clinical Findings

A. Symptoms and Signs

The diagnosis of the disorders underlying the bleeding usually depends on the following: (1) A careful description of the duration and amount of flow, related pain, and relationship to the last menstrual period (LMP). The presence of blood clots or the degree of inconvenience caused by the bleeding may be more useful indicators. (2) A history of pertinent illnesses or weight change. (3) A history of all medications the patient has taken in the past month. (4) A history of coagulation disorders in the patient or family members. (5) A careful pelvic examination to look for pregnancy, uterine myomas, adnexal masses, or infection.

B. Laboratory Studies

Cervical smears should be obtained as needed for cytologic and culture studies. Blood studies should include a complete blood count, sedimentation rate, and glucose levels to rule out diabetes. Diabetes may occasionally initially present with abnormal bleeding. A test for pregnancy and studies of thyroid function and coagulation disorders should be considered in the clinical evaluation. Up to 18% of women with severe menorrhagia may have a coagulopathy. Tests for ovulation in cyclic menorrhagia include basal body temperature records, serum progesterone measured 1 week before the expected onset of menses, and analysis of an endometrial biopsy specimen for secretory activity shortly before the onset of menstruation.

C. Imaging

Ultrasound may be useful to evaluate endometrial thickness or to diagnose intrauterine or ectopic pregnancy or adnexal masses. Endovaginal ultrasound with saline infusion sonohysterography may be used to diagnose endometrial polyps or subserous myomas. MRI can definitively diagnose submucous myomas and adenomyosis.

D. Cervical Biopsy and Endometrial Curettage

Biopsy, curettage, or aspiration of the endometrium and curettage of the endocervix may be necessary to diagnose the cause of bleeding. These and other invasive gynecologic diagnostic procedures are described in Table 17-1. Polyps, endometrial hyperplasia, and submucous myomas are commonly identified in this way. If cancer of the cervix is suspected, colposcopically directed biopsies and endocervical curettage are indicated as first steps.

Table 17-1. Common gynecologic diagnostic procedures.

Colposcopy
   Visualization of cervical, vaginal, or vulvar epithelium under 5-50 × magnification with and without dilute acetic acid to identify abnormal areas requiring biopsy. An office procedure.
D&C
   Dilation of the cervix and curettage of the entire endometrial cavity, using a metal curette or suction cannula and often using forceps for the removal of endometrial polyps. Can usually be done in the office under local anesthesia.
Endometrial biopsy
   Removal of one or more areas of the endometrium by means of a curette or small aspiration device without cervical dilation. Diagnostic accuracy similar to D&C. An office procedure performed under local anesthesia.
Endocervical curettage
   Removal of endocervical epithelium with a small curette for diagnosis of cervical dysplasia and cancer. An office procedure performed under local anesthesia.
Hysteroscopy
   Visual examination of the uterine cavity with a small fiberoptic endoscope passed through the cervix. Biopsies, and excision of myomas can be performed. Can be done in the office under local anesthesia or in the operating room under general anesthesia.
Saline infusion sonohysterography
   Introduction of saline solution into endometrial cavity with catheter to visualize submucous myomas or endometrial polyps by transvaginal ultrasound. May be performed in the office with oral analgesia.
Hysterosalpingography
   Injection of radiopaque dye through the cervix to visualize the uterine cavity and oviducts. Mainly used in investigation of infertility.
Laparoscopy
   Visualization of the abdominal and pelvic cavity through a small fiberoptic endoscope passed through a subumbilical incision. Permits diagnosis, tubal sterilization, and treatment of many conditions previously requiring laparotomy. General anesthesia is usually used.

E. Hysteroscopy

Hysteroscopy can visualize endometrial polyps, submucous myomas, and exophytic endometrial cancers,

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and the procedure can be followed immediately by dilatation and curettage (D&C).

Treatment

Premenopausal patients with abnormal uterine bleeding include those with submucous myomas, infection, early abortion, or pelvic neoplasms. The history, physical examination, and laboratory findings should identify such patients, who require definitive therapy depending on the cause of the bleeding. A large group of patients remains, most of whom have dysfunctional uterine bleeding on a hormonal basis.

Dysfunctional uterine bleeding can usually be treated hormonally. Women over the age of 35 should have endometrial sampling to rule out endometrial hyperplasia or carcinoma prior to initiation of hormonal therapy. Progestins, which limit and stabilize endometrial growth, are generally effective. Medroxyprogesterone acetate, 10 mg/d, or norethindrone acetate, 5 mg/d, should be given for 10–14 days starting on day 15 of the cycle, following which withdrawal bleeding (so-called medical curettage) will occur. The treatment is repeated for several cycles; it can be reinstituted if amenorrhea or dysfunctional bleeding recurs. In women who are bleeding actively, any of the combination oral contraceptives can be given four times daily for 1 or 2 days followed by two pills daily through day 5 and then one pill daily through day 20; after withdrawal bleeding occurs, pills are taken in the usual dosage for three cycles. In cases of intractable heavy bleeding, danazol, 200 mg four times daily, is sometimes used to create an atrophic endometrium. Alternatively, a GnRH agonist such as depot leuprolide, 3.75 mg intramuscularly monthly, or nafarelin, 0.2–0.4 mg intranasally twice daily, can be used for up to 6 months to create a temporary cessation of menstruation by ovarian suppression.

In cases of heavy bleeding, intravenous conjugated estrogens, 25 mg every 4 hours for three or four doses, can be used, followed by oral conjugated estrogens, 2.5 mg daily, or ethinyl estradiol, 20 mcg daily, for 3 weeks, with the addition of medroxyprogesterone acetate, 10 mg daily for the last 10 days of treatment, or a combination oral contraceptive daily for 3 weeks. This will thicken the endometrium and control the bleeding. If the abnormal bleeding is not controlled by hormonal treatment, hysteroscopy, saline infusion sonohysterography, or a D&C is necessary to check for polyps, submucous myomas, or endometrial cancer.

Endometrial ablation through the hysteroscope with laser photocoagulation or electrocautery—or blindly with hyperthermia or cryotherapy—is an option; these techniques are designed to reduce or prevent any future menstrual flow.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen or mefenamic acid in the usual anti-inflammatory doses will often reduce blood loss in menorrhagia—even that associated with a copper intrauterine device (IUD). The levonorgestrel-releasing IUD will markedly reduce menstrual blood loss and may be a good alternative to other medical or surgical therapies.

Prolonged use of a progestin, as in a minipill, in injectable contraceptives, or in the therapy of endometriosis, can also lead to intermittent bleeding, sometimes severe. In this instance, the endometrium is atrophic and fragile. If bleeding occurs, it should be treated with estrogen as follows: ethinyl estradiol, 20 mcg/d for 7 days, or conjugated estrogens, 1.25 mg/d for 7 days.

It is useful for the patient and the clinician to discuss stressful situations or lifestyles that may contribute to anovulation and dysfunctional bleeding, such as prolonged emotional turmoil or excessive use of drugs or alcohol.

Albers JR et al: Abnormal uterine bleeding. Am Fam Physician 2004;69:1915.

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Hurskainen R et al: Levonorgestrel-releasing intrauterine system in the treatment of heavy menstrual bleeding. Curr Opin Obstet Gynecol 2004;16:487.

Postmenopausal Vaginal Bleeding

Essentials of Diagnosis

  • Vaginal bleeding that occurs 6 months or more following cessation of menstrual function.

  • Bleeding is usually painless.

  • Bleeding may be a single episode of spotting or profuse bleeding for days or months.

General Considerations

Vaginal bleeding that occurs 6 months or more following cessation of menstrual function should be investigated. The most common causes are atrophic endometrium, endometrial proliferation or hyperplasia, endometrial or cervical cancer, and administration of estrogens with or without added progestin. Other causes include atrophic vaginitis, trauma, endometrial polyps, friction ulcers of the cervix associated with prolapse of the uterus, and blood dyscrasias. Uterine bleeding is usually painless, but pain will be present if the cervix is stenotic, if bleeding is severe and rapid, or if infection or torsion or extrusion of a tumor is present. The patient may report a single episode of spotting or profuse bleeding for days or months.

Diagnosis

The vulva and vagina should be inspected for areas of bleeding, ulcers, or neoplasms. A cytologic smear of the cervix and vaginal pool should be taken. If available, transvaginal sonography (TVS) should be used to measure endometrial thickness. A measurement of 5 mm or less indicates a low likelihood of hyperplasia or endometrial cancer, although up to 4% of endometrial cancers may be missed with sonography. If the thickness is greater than 5 mm or there is a heterogeneous appearance to the endometrium, endocervical curettage and endometrial biopsy or D&C preferably with hysteroscopy should be performed.

Treatment

Endometrial biopsy or D&C may be curative. Simple endometrial hyperplasia calls for cyclic progestin therapy (medroxyprogesterone acetate, 10 mg/d, or norethindrone acetate, 5 mg/d) for 21 days of each month for 3 months. A repeat endometrial biopsy should be performed. If endometrial hyperplasia with atypical cells or carcinoma of the endometrium is found, hysterectomy is necessary.

Tabor A et al: Endometrial thickness as a test for endometrial cancer in women with postmenopausal vaginal bleeding. Obstet Gynecol 2002;99:663.

Premenstrual Syndrome (Premenstrual Tension)

The premenstrual syndrome is a recurrent, variable cluster of troublesome physical and emotional symptoms that develop during the 7–14 days before the onset of menses and subside when menstruation occurs. The syndrome intermittently affects about 40% of all premenopausal women, primarily those 25–40 years of age. In about 10–15% of affected women, the syndrome may be severe. Although not every woman experiences all the symptoms or signs at one time, many describe bloating, breast pain, ankle swelling, a sense of increased weight, skin disorders, irritability, aggressiveness, depression, inability to concentrate, libido change, lethargy, and food cravings. The pathogenesis of premenstrual syndrome is still uncertain. Psychosocial factors may play a role.

Current treatment methods are mainly empiric. The clinician should provide the best support possible for the patient's emotional and physical distress. This includes the following:

  • Careful evaluation of the patient, with understanding, explanation, and reassurance, is of first importance.

  • Advise the patient to keep a daily diary of all symptoms for 2–3 months, to help in evaluating the timing and characteristics of the syndrome. If her symptoms occur throughout the month rather than in the 2 weeks before menses, she may be depressed or may have other emotional problems in addition to premenstrual syndrome.

  • For mild to moderate symptoms, a program of aerobic exercise; reduction of caffeine, salt, and alcohol intake; and an increase in complex carbohydrates in the diet may be helpful.

  • When physical symptoms predominate, spironolactone, 100 mg daily during the luteal phase, is effective for reduction of bloating and breast tenderness. Oral contraceptives or injectable progestin medroxyprogesterone acetate (DMPA) will decrease breast pain and cramping. NSAIDs, such as 500 mg of mefenamic acid three times a day, will reduce a number of symptoms but not breast pain.

  • When mood disorders predominate, serotonin reuptake inhibitors such as 20 mg/d of fluoxetine, either daily or only on symptom days, are effective in relieving tension, irritability, and dysphoria with few side effects.

  • When the above regimens are not effective, ovarian function can be suppressed with continuous high-dose progestin (20–30 mg/d of oral medroxyprogesterone acetate [MPA] or 150 mg of DMPA every 3 months or GnRH agonist with add-back therapy if continued for more than 6 months).

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Johnson SR: Premenstrual syndrome, premenstrual dysphoric disorder, and beyond: a clinical primer for practitioners. Obstet Gynecol 2004;104:845.

Dysmenorrhea

1. Primary Dysmenorrhea

Primary dysmenorrhea is menstrual pain associated with ovulatory cycles in the absence of pathologic findings. The pain usually begins within 1–2 years after the menarche and may become more severe with time. The frequency of cases increases up to age 20 and then decreases with age and markedly with parity. Fifty to 75 percent of women are affected at some time and 5–6% have incapacitating pain.

Primary dysmenorrhea is low, midline, wave-like, cramping pelvic pain often radiating to the back or inner thighs. Cramps may last for 1 or more days and may be associated with nausea, diarrhea, headache, and flushing. The pain is produced by uterine vasoconstriction, anoxia, and sustained contractions mediated by prostaglandins.

Clinical Findings

The pelvic examination is normal between menses; examination during menses may produce discomfort, but there are no pathologic findings.

Treatment

NSAIDs (ibuprofen, ketoprofen, mefenamic acid, naproxen) are generally helpful. Drugs should be started at the onset of bleeding to avoid inadvertent drug use during early pregnancy. Medication should be continued on a regular basis for 2–3 days. Ovulation can be suppressed and dysmenorrhea usually prevented by oral contraceptives or depot-medroxyprogesterone acetate. For women who do not wish to use hormonal contraception, other therapies that have shown at least some benefit include local heat; thiamine, 100 mg/d orally; vitamin E, 200 units/d orally from 2 days prior to and for the first 3 days of menses; the Japanese herbal remedy toki-shakuyaku-san, 2.5 g 3 times daily; and high-frequency transcutaneous electrical nerve stimulation.

2. Secondary Dysmenorrhea

Secondary dysmenorrhea is menstrual pain for which an organic cause exists. It usually begins well after menarche, sometimes even as late as the third or fourth decade of life.

Clinical Findings

The history and physical examination commonly suggest endometriosis or pelvic inflammatory disease (PID). Other causes may be submucous myoma, IUD use, cervical stenosis with obstruction, or blind uterine horn (rare).

Diagnosis

Laparoscopy is often needed to differentiate endometriosis from PID. Submucous myomas can be detected most reliably by MRI but also by hysterogram, by hysteroscopy, or by passing a sound or curette over the uterine cavity during D&C. Cervical stenosis may result from induced abortion, creating crampy pain at the time of expected menses with no blood flow; this is easily cured by passing a sound into the uterine cavity after administering a paracervical block.

Treatment

A. Specific Measures

Periodic use of analgesics, including the NSAIDs given for primary dysmenorrhea, may be beneficial, and oral contraceptives may give relief, particularly in endometriosis. Danazol and GnRH agonists are effective in the treatment of endometriosis (see below).

B. Surgical Measures

If disability is marked or prolonged, laparoscopy or exploratory laparotomy is usually warranted. Definitive surgery depends on the degree of disability and the findings at operation.

French L: Dysmenorrhea. Am Fam Physician 2005;71:285.

Proctor M et al: Dysmenorrhea. Clin Evid 2004;12:2524.

Vaginitis

Essentials of Diagnosis

  • Vaginal irritation.

  • Pruritus.

  • Pain.

  • Unusual discharge.

General Considerations

Inflammation and infection of the vagina are common gynecologic problems, resulting from a variety of pathogens, allergic reactions to vaginal contraceptives or other products, or the friction of coitus. The normal vaginal pH is 4.5 or less, and Lactobacillus is the predominant organism. At the time of the midcycle estrogen surge, clear, elastic, mucoid secretions from the cervical os are often profuse. In the luteal phase and during pregnancy, vaginal secretions are thicker, white, and sometimes adherent to the vaginal walls. These normal secretions can be confused with vaginitis by concerned women.

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Clinical Findings

When the patient complains of vaginal irritation, pain, or unusual discharge, a careful history should be taken, noting the onset of the LMP; recent sexual activity; use of contraceptives, tampons, or douches; and the presence of vaginal burning, pain, pruritus, or unusually profuse or malodorous discharge. The physical examination should include careful inspection of the vulva and speculum examination of the vagina and cervix. The cervix is cultured for Gonococcus or Chlamydia if applicable. A specimen of vaginal discharge is examined under the microscope in a drop of 0.9% saline solution to look for trichomonads or clue cells and in a drop of 10% potassium hydroxide to search for Candida. The vaginal pH should be tested; it is frequently greater than 4.5 in infections due to trichomonads and bacterial vaginosis. A bimanual examination to look for evidence of pelvic infection should follow.

A. Vulvovaginal Candidiasis

Pregnancy, diabetes, and use of broad-spectrum antibiotics or corticosteroids predispose patients to Candida infections. Heat, moisture, and occlusive clothing also contribute to the risk. Pruritus, vulvovaginal erythema, and a white curd-like discharge that is not malodorous are found. Microscopic examination with 10% potassium hydroxide reveals filaments and spores. Cultures with Nickerson's medium may be used if Candida is suspected but not demonstrated.

B. Trichomonas vaginalis Vaginitis

This protozoal flagellate infects the vagina, Skene's ducts, and lower urinary tract in women and the lower genitourinary tract in men. It is transmitted through coitus. Pruritus and a malodorous frothy, yellow-green discharge occur, along with diffuse vaginal erythema and red macular lesions on the cervix in severe cases. Motile organisms with flagella are seen by microscopic examination of a wet mount with saline solution.

C. Bacterial Vaginosis

This condition is considered to be a polymicrobial disease that is not sexually transmitted. An overgrowth of Gardnerella and other anaerobes is often associated with increased malodorous discharge without obvious vulvitis or vaginitis. The discharge is grayish and sometimes frothy, with a pH of 5.0–5.5. An amine-like (“fishy”) odor is present if a drop of discharge is alkalinized with 10% potassium hydroxide. On wet mount in saline, epithelial cells are covered with bacteria to such an extent that cell borders are obscured (clue cells). Vaginal cultures are generally not useful in diagnosis.

D. Condylomata Acuminata (Genital Warts)

Warty growths on the vulva, perianal area, vaginal walls, or cervix are caused by various types of the human papillomavirus (HPV). They are sexually transmitted. Pregnancy and immunosuppression favor growth. Vulvar lesions may be obviously wart-like or may be diagnosed only after application of 4% acetic acid (vinegar) and colposcopy, when they appear whitish, with prominent papillae. Fissures may be present at the fourchette. Vaginal lesions may show diffuse hypertrophy or a cobblestone appearance. Cervical lesions may be visible only by colposcopy after pretreatment with 4% acetic acid. These lesions may be related to dysplasia and cervical cancer. Vulvar cancer is also currently considered to be associated with HPV infection.

Treatment

A. Vulvovaginal Candidiasis

A variety of regimens are available to treat vulvovaginal candidiasis. Women with uncomplicated vulvovaginal candidiasis will usually respond to a 1- to 3-day regimen of a topical azole. Women with complicated infection (including four or more episodes in 1 year, severe signs and symptoms, non-albicans species, uncontrolled diabetes, HIV infection, corticosteroid treatment, or pregnancy) should receive 7–14 days of a topical regimen or two doses of fluconazole 3 days apart. (Pregnant women should use only topical azoles.)

1. Single-dose regimens

Miconazole, 200-mg vaginal suppository; tioconazole, 6.5%, 5 g; or sustained-release butoconazole, 2% cream, 5 g.

2. Three-day regimens

Butoconazole (2% cream, 5 g once daily), clotrimazole (two 100-mg vaginal tablets once daily), teraconazole (0.8% cream, 5 g, or 80-mg suppository once daily), or miconazole (200 mg vaginal suppository once daily).

3. Seven-day regimens

The following regimens are given once daily: clotrimazole (1% cream or 100-mg vaginal tablet), miconazole (2% cream, 5 g, or 100-mg vaginal suppository), or teraconazole (0.4% cream, 5 g).

4. Fourteen-day regimen

Nystatin (100,000-unit vaginal tablet once daily).

5. Recurrent vulvovaginitis (maintenance therapy)

Clotrimazole (500-mg vaginal suppository once weekly or 200 mg cream twice weekly) or fluconazole (100, 150, or 200 mg orally once weekly) are effective regimens for maintenance therapy for up to 6 months.

B. Trichomonas vaginalis Vaginitis

Treatment of both partners simultaneously is recommended; metronidazole, 2 g orally as a single dose or 500 mg orally twice a day for 7 days, is usually used. In the case of treatment failure in the absence of reexposure, the patient should be re-treated with metronidazole, 500 mg orally twice a day for 7 days. If treatment failure occurs again, give metronidazole, 2 g orally once daily for 3–5 days. If this is not effective in eradicating the organisms, metronidazole susceptibility testing can be arranged with the CDC at 770–488-4115.

C. Bacterial Vaginosis

The recommended regimens are metronidazole, 500 mg orally twice daily for 7 days, clindamycin vaginal cream

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(2%, 5 g), once daily for 7 days, or metronidazole gel (0.75%, 5 g), twice daily for 5 days. Alternative regimens include metronidazole, 2 g orally as a single dose, clindamycin, 300 mg orally twice daily for 7 days, or clindamycin ovules, 100 g intravaginally at bedtime for 3 days.

D. Condylomata Acuminata

Recommended treatments for vulvar warts include podophyllum resin 10–25% in tincture of benzoin (do not use during pregnancy or on bleeding lesions) or 80–90% trichloroacetic or bichloroacetic acid, carefully applied to avoid the surrounding skin. The pain of bichloroacetic or trichloroacetic acid application can be lessened by a sodium bicarbonate paste applied immediately after treatment. Podophyllum resin must be washed off after 2–4 hours. Freezing with liquid nitrogen or a cryoprobe and electrocautery are also effective. Patient-applied regimens include podofilox 0.5% solution or gel and imiquimod 5% cream. Vaginal warts may be treated with cryotherapy with liquid nitrogen, trichloroacetic acid, or podophyllum resin. Extensive warts may require treatment with CO2 laser under local or general anesthesia. Interferon is not recommended for routine use because it is very expensive, associated with systemic side effects, and no more effective than other therapies. Routine examination of sex partners is not necessary for the management of genital warts since the risk of reinfection is probably minimal and curative therapy to prevent transmission is not available. However, partners may wish to be examined for detection and treatment of genital warts and other sexually transmitted diseases. While condom use does not appear to prevent HPV transmission, it may result in accelerated regression of associated lesions, including untreated cervical intraepithelial neoplasia (CIN) and in accelerated clearance of genital HPV infection in women.

Anderson MR et al: Evaluation of vaginal complaints. JAMA 2004;291:1368.

Holmes KK et al: Effectiveness of condoms in preventing sexually transmitted infections. Bull World Health Organ 2004;82: 454.

Sexually transmitted disease treatment guidelines 2006. Centers for Disease Control and Prevention. MMWR Recomm Rep 2006;55(RR11):1.

Cervicitis

Infection of the cervix must be distinguished from physiologic ectopy of columnar epithelium, which is common in young women. Mucopurulent cervicitis is characterized by a red edematous cervix with a purulent yellow discharge. The infection may result from a sexually transmitted pathogen such as Neisseria gonorrhoeae, Chlamydia, or herpesvirus (which presents with vesicles and ulcers on the cervix during a primary herpetic infection), although in most cases none of these organisms can be isolated.

Mucopurulent cervicitis is an insensitive predictor of either gonorrheal or chlamydial infection and in addition has a low positive predictive value. Treatment should be based on microbiologic testing. Presumptive antibiotic treatment of mucopurulent cervicitis is not indicated unless there is a high prevalence of either N gonorrhoeae or Chlamydia in the population or if the patient is unlikely to return for treatment. (See Chapter 33 for discussion.)

Cervical Polyps

Cervical polyps commonly occur after menarche and are occasionally noted in postmenopausal women. The cause is not known, but inflammation may play an etiologic role. The principal symptoms are discharge and abnormal vaginal bleeding. However, abnormal bleeding should not be ascribed to a cervical polyp without sampling the endocervix and endometrium. The polyps are visible in the cervical os on speculum examination.

Cervical polyps must be differentiated from polypoid neoplastic disease of the endometrium, small submucous pedunculated myomas, and endometrial polyps. Cervical polyps rarely contain malignant foci.

Treatment

Cervical polyps can generally be removed in the office by avulsion with a uterine packing forceps or ring forceps. If the cervix is soft, patulous, or definitely dilated and the polyp is large, surgical D&C is required (especially if the pedicle is not readily visible). Hysteroscopy may aid removal and lead to identification of concomitant endometrial disease. Because of the possibility of endometrial disease, cervical polypectomy should routinely be accompanied by endometrial sampling.

Spiewankiewicz B et al: Hysteroscopy in cases of endocervical polyps. Eur J Gynaecol Oncol 2003;24:67.

Cyst & Abscess of Bartholin'S Duct

Trauma or infection may involve Bartholin's duct, causing obstruction of the gland. Drainage of secretions is prevented, leading to pain, swelling, and abscess formation. The infection usually resolves and pain disappears, but stenosis of the duct outlet with distention often persists. Reinfection causes recurrent tenderness and further enlargement of the duct.

The principal symptoms are periodic painful swelling on either side of the introitus and dyspareunia. A fluctuant swelling 1–4 cm in diameter in the inferior portion of either labium minus is a sign of occlusion of Bartholin's duct. Tenderness is evidence of active infection.

Pus or secretions from the gland should be cultured for gonococci, chlamydiae, and other pathogens and treated accordingly (see Chapter 33); frequent warm soaks may be helpful. If an abscess develops, aspiration or incision and drainage are the simplest forms of therapy, but the problem may recur. Marsupialization (in the absence of an abscess), incision and drainage with

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the insertion of an indwelling Word catheter, or laser treatment will establish a new duct opening. Antibiotics are unnecessary unless cellulitis is present. An asymptomatic cyst does not require therapy.

Omole F et al: Management of Bartholin's duct cyst and gland abscess. Am Fam Physician 2003;68:135.

Effects of Exposure To Diethylstilbestrol In Utero

Between 1947 and 1971, diethylstilbestrol (DES) was widely used in the United States for diabetic women during pregnancy and to treat threatened abortion. It is estimated that at least 2–3 million fetuses were exposed. A relationship between fetal DES exposure and clear cell carcinoma of the vagina was later discovered, and a number of other related anomalies have since been noted. In one-third of all exposed women, there are changes in the vagina (adenosis, septa), cervix (deformities and hypoplasia of the vaginal portion of the cervix), or uterus (T-shaped cavity).

All women known to be exposed prenatally are advised to have an initial colposcopic examination to outline vaginal and cervical areas of abnormal epithelium, followed by cytologic examination of the vagina (all four quadrants of the upper half of the vagina) and cervix at yearly intervals. Lugol's iodine stain of the vagina and cervix will also outline areas of metaplastic squamous epithelium.

Many women are not aware of having been exposed to DES. Therefore, in the age groups at risk (35–59 years), examiners should pay attention to structural changes of the vagina and cervix that may signal the possibility of DES exposure and indicate the need for follow-up.

The incidence of clear cell carcinoma is approximately 1 in 1000 exposed women, and the incidence of cervical and vaginal intraepithelial neoplasia (dysplasia and carcinoma in situ) is twice as high as in unexposed women. DES daughters have more difficulty conceiving and have an increased incidence of early abortion, ectopic pregnancy, and premature births. In addition, mothers treated with DES in pregnancy appear to have a small increase in the incidence of breast cancer, beginning 20 years after exposure.

Schrager S et al: Diethylstilbesterol exposure. Am Fam Physician 2004;69:2395.

Cervical Intraepithelial Neoplasia (Dysplasia of The Cervix)

Essentials of Diagnosis

  • The presumptive diagnosis is made by an abnormal Pap smear of an asymptomatic woman with no grossly visible cervical changes.

  • Diagnose by colposcopically directed biopsy.

  • Increased in women with HIV.

General Considerations

The squamocolumnar junction of the cervix is an area of active squamous cell proliferation. In childhood, this junction is located on the exposed vaginal portion of the cervix. At puberty, because of hormonal influence and possibly because of changes in the vaginal pH, the squamous margin begins to encroach on the single-layered, mucus-secreting epithelium, creating an area of metaplasia (transformation zone). Factors associated with coitus (see Prevention, below) may lead to cellular abnormalities, which over a period of time can result in the development of squamous cell dysplasia or cancer. There are varying degrees of dysplasia (Table 17-2), defined by the degree of cellular atypia; all types must be observed and treated if they persist or become more severe.

Clinical Findings

There are no specific symptoms or signs of CIN. The presumptive diagnosis is made by cytologic screening of an asymptomatic population with no grossly visible cervical changes. All visibly abnormal cervical lesions should be biopsied.

Diagnosis

A. Cytologic Examination (Papanicolaou Smear)

Screening should begin within 3 years of the onset of sexually activity or at age 21. Testing should be done annually

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for 3 years and then at least every 3 years if no abnormality is detected. After age 65 or 70, if there have been no abnormalities on the last 3 cytologic tests, screening may be discontinued. With liquid-based cytology (LCB), the initial interval may be increased to every 2 years. Specimens should be taken from a nonmenstruating patient, spread on a single slide, and fixed or rinsed directly into preservative solution if LCB is to be used. A specimen should be obtained from the squamocolumnar junction with a wooden or plastic spatula and from the endocervix with a cotton swab or nylon brush.

Table 17-2. Classification systems for Papanicolaou smears.

Numerical Dysplasia CIN Bethesda System
1 Benign Benign Normal
2 Benign with inflammation Benign with inflammation Normal, ASC-US
3 Mild dysplasia CIN I Low-grade SIL
3 Moderate dysplasia CIN II High-grade SIL
3 Severe dysplasia CIN III
4 Carcinoma in situ
5 Invasive cancer Invasive cancer Invasive cancer
CIN = cervical intraepithelial neoplasia; ASC-US = atypical squamous cells of undetermined significance; SIL = squamous intraepithelial lesion.

Cytologic reports from the laboratory may describe findings in one of several ways (see Table 17-2). While use of class 1–5 is now rare, the CIN classification continues to be used along with a description of abnormal cells, including evidence of HPV. The Bethesda System uses the terminology “squamous intraepithelial lesions (SIL),” low-grade or high-grade. Cytopathologists consider a Pap smear to be a medical consultation and will recommend further diagnostic procedures, treatment for infection, and comments on factors preventing adequate evaluation of the specimen. Reflex testing for high-risk HPV types with thin layer cytologic smears is useful for triage of atypia (atypical squamous cells of unknown significance; ASC-US). The routine use of combined cytologic screening and high-risk HPV testing is appropriate in women over the age of 30 who are being screened no more frequently than every 3 years. Women who have undergone hysterectomy for benign disease do not need to be screened.

B. Colposcopy

Women with ASC-US and a negative HPV screening may be followed-up in 1 year. If the HPV screen is positive, colposcopy should be performed. If HPV screening is unavailable, repeat cytology may be done at 4- to 6-month intervals until two consecutive normal results, or the patient may be referred directly for colposcopy. All patients with SIL or atypical glandular cells should undergo colposcopy. Viewing the cervix with 10–20× magnification allows for assessment of the size and margins of an abnormal transformation zone and determination of extension into the endocervical canal. The application of 3–5% acetic acid (vinegar) dissolves mucus, and the acid's desiccating action sharpens the contrast between normal and actively proliferating squamous epithelium. Abnormal changes include white patches and vascular atypia, which indicate areas of greatest cellular activity. Paint the cervix with Lugol's solution (strong iodine solution [Schiller's test]). Normal squamous epithelium will take the stain; nonstaining squamous epithelium should be biopsied. (The single-layered, mucus-secreting endocervical tissue will not stain either but can readily be distinguished by its darker pink, shinier appearance.)

C. Biopsy

Colposcopically directed punch biopsy and endocervical curettage are office procedures. If colposcopy is not available, the normal-appearing cervix shedding atypical cells can be evaluated by endocervical curettage and multiple punch biopsies of nonstaining squamous epithelium or biopsies from each quadrant of the cervix. Data from both cervical biopsy and endocervical curettage are important in deciding on treatment.

Prevention

Cervical infection with the HPV is associated with a high percentage of all cervical dysplasias and cancers. There are over 70 recognized HPV subtypes, of which types 6 and 11 tend to cause genital warts and mild dysplasia, while types 16, 18, 31, and others cause higher-grade cellular changes. In 2006, the FDA approved a vaccine to prevent cervical cancer and vaginal and vulvar pre-cancers caused by HPV types 16 and 18, and to protect against low-grade and pre-cancerous lesions and genital warts caused by HPV types 6, 11, 16, and 18. The vaccine, Gardisil, is recommended for all girls and women aged 11 to 26. Girls as young as nine should receive the vaccine at the judgement of the practitioner. A therapeutic vaccine to treat existing HPV infections is in earlier stages of development.

Cervical cancer is epidemiologically related to the number of sexual partners a woman has had and the number of other female partners a male partner has had. Use of the diaphragm or condom has some protective effect. Long-term oral contraceptive users develop more dysplasias and cancers of the cervix than users of other forms of birth control, and smokers, as well as women exposed to second-hand smoke, are also at increased risk. Preventive measures include regular cytologic screening to detect abnormalities, limiting the number of sexual partners, using a diaphragm or condom for coitus, and stopping smoking or exposure to second-hand smoke.

Women with HIV infection appear to be at increased risk for the disease and of recurrent disease after treatment. Women with HIV infection should receive regular cytologic screening and should be followed closely after treatment for CIN.

Treatment

Treatment varies depending on the degree and extent of CIN. Biopsies should always precede treatment.

A. Cauterization or Cryosurgery

The use of either hot cauterization or freezing (cryosurgery) is effective for noninvasive small lesions visible on the cervix without endocervical extension.

B. CO2 Laser

This well-controlled method minimizes tissue destruction. It is colposcopically directed and requires special training. It may be used with large visible lesions. In current practice, it involves the vaporization of the transformation zone on the cervix and the distal 5–7 mm of endocervical canal.

C. Loop Resection

When the CIN is clearly visible in its entirety, a wire loop can be used for excisional biopsy. Cutting and

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hemostasis are effected with a low-voltage electrosurgical machine (Bovie). This office procedure with local anesthesia is quick and uncomplicated.

D. Conization of the Cervix

Conization is surgical removal of the entire transformation zone and endocervical canal. It should be reserved for cases of severe dysplasia or cancer in situ (CIN III), particularly those with endocervical extension. The procedure can be performed with the scalpel, the CO2 laser, the needle electrode, or by large-loop excision.

E. Follow-Up

Because recurrence is possible—especially in the first 2 years after treatment—and because the false-negative rate of a single cervical cytologic test is 20%, close follow-up is imperative. Vaginal cytologic examination should be repeated at 3-month intervals for at least 1 year.

Bundrick JB et al: Screening for cervical cancer and initial treatment of patients with abnormal results from Papanicolaou testing. Mayo Clin Proc 2005;80:1063.

Franco EL et al: Vaccination against human Papillomavirus infection: a new paradigm in cervical cancer control. Vaccine 2005;23:2388.

Wright TC Jr et al: 2001 Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120.

Carcinoma of The Cervix

Essentials of Diagnosis

  • Abnormal uterine bleeding and vaginal discharge.

  • Cervical lesion may be visible on inspection as a tumor or ulceration.

  • Vaginal cytology usually positive; must be confirmed by biopsy.

General Considerations

Cancer appears first in the intraepithelial layers (the preinvasive stage, or carcinoma in situ). Preinvasive cancer (CIN III) is a common diagnosis in women 25–40 years of age and is etiologically related to infection with HPV. Two to 10 years are required for carcinoma to penetrate the basement membrane and invade the tissues. After invasion, death usually occurs within 3–5 years in untreated or unresponsive patients.

Clinical Findings

A. Symptoms and Signs

The most common signs are metrorrhagia, postcoital spotting, and cervical ulceration. Bloody or purulent, odorous, nonpruritic discharge may appear after invasion. Bladder and rectal dysfunction or fistulas and pain are late symptoms.

B. Cervical Biopsy and Endocervical Curettage, or Conization

These procedures are necessary steps after a positive Papanicolaou smear to determine the extent and depth of invasion of the cancer. Even if the smear is positive, treatment is never justified until definitive diagnosis has been established through biopsy.

C. “Staging,” or Estimate of Gross Spread of Cancer of the Cervix

The depth of penetration of the malignant cells beyond the basement membrane is a reliable clinical guide to the extent of primary cancer within the cervix and the likelihood of metastases. It is customary to stage cancers of the cervix under anesthesia as shown in Table 17-3. Further assessment may be carried out by abdominal and pelvic CT scanning or MRI.

Complications

Metastases to regional lymph nodes occur with increasing frequency from stage I to stage IV. Paracervical extension occurs in all directions from the cervix. The ureters are often obstructed lateral to the cervix, causing hydroureter and hydronephrosis and consequently impaired kidney function. Almost two-thirds of patients with untreated carcinoma of the cervix die of uremia when ureteral obstruction is bilateral. Pain in the back, in the distribution of the lumbosacral plexus, is often indicative of neurologic involvement. Gross edema of the legs may be indicative of vascular and lymphatic stasis due to tumor.

Vaginal fistulas to the rectum and urinary tract are severe late complications. Hemorrhage is the cause of death in 10–20% of patients with extensive invasive carcinoma.

Prevention

In 2006, the FDA approved a vaccine to prevent cervical cancer caused by HPV types 16, and 18, and to protect against low-grade and precancerous lesions and genital warts caused by HPV types 6, 11, 16, and 18. The vaccine, Gardisil is recommended for all girls and women aged 11 to 26. Girls as young as nine should receive the vaccine if clinically indicated.

Treatment

A. Emergency Measures

Vaginal hemorrhage originates from gross ulceration and cavitation in stage II-IV cervical carcinoma. Ligation and suturing of the cervix are usually not feasible, but ligation of the uterine or hypogastric arteries may be lifesaving when other measures fail. Styptics such as Monsel's solution or acetone are effective, although delayed sloughing may result in further bleeding. Wet vaginal packing is helpful. Emergency irradiation usually controls bleeding.

Table 17-3. FIGO1 staging of cancer of the cervix.

Preinvasive carcinoma
Stage 0 Carcinoma in situ.
Invasive carcinoma
   Stage I Carcinoma strictly confined to the cervix.
      IA Invasive cancer diagnosed only by microscopy.
IA1   Measured invasion of stroma no greater than 3 mm in depth and no wider than 7 mm.
IA2   Measured invasion of stroma greater than 3 mm in depth and no greater than 5 mm in depth and no wider than 7 mm.
      IB Clinical lesions confined to the cervix or preclinical lesions greater than 1A.All gross lesions, even with superficial invasion, are stage IB.
IB1   Clinical lesions no greater than 4 cm.
IB2   Clinical lesions greater than 4 cm.
   Stage II Carcinoma extends beyond the cervix but has not extended to the pelvic wall. The carcinoma involves the vagina but not as far as the lower third.
      IIA No obvious parametrial involvement.
      IIB Obvious parametrial involvement.
   Stage III Carcinoma has extended either to the lowerthird of the vagina or to the pelvic sidewall. All cases of hydronephrosis.
      IIIA Involvement of lower third of vagina. No extension to pelvic sidewall.
      IIIB Extension onto the pelvic wall and/or hydronephrosis or nonfunctioning kidney.
   Stage IV Carcinoma extended beyond the true pelvis or clinically involving the mucosa of the bladder or rectum.
      IVA Spread of growth to adjacent organs.
      IVB Spread of growth to distant organs.
1International Federation of Gynecology and Obstetrics

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B. Specific Measures

1. Carcinoma in situ (stage 0)

In women who have completed childbearing, total hysterectomy is the treatment of choice. In women who wish to retain the uterus, acceptable alternatives include cervical conization or ablation of the lesion with cryotherapy or laser. Close follow-up with Papanicolaou smears every 3 months for 1 year and every 6 months for another year is necessary after cryotherapy or laser.

2. Invasive carcinoma

Microinvasive carcinoma (stage IA) is treated with simple, extrafascial hysterectomy. Stage IB and stage IIA cancers may be treated with either radical hysterectomy or radiation therapy. Stage IIB and stage III and IV cancers are treated with radiation therapy plus concurrent cisplatin-based chemotherapy. Because radical surgery results in fewer long-term complications than irradiation and may allow preservation of ovarian function, it may be the preferred mode of therapy in younger women without contraindications to major surgery.

Prognosis

The overall 5-year relative survival rate for carcinoma of the cervix is 68% in white women and 55% in black women in the United States. Survival rates are inversely proportionate to the stage of cancer: stage 0, 99–100%; stage IA, > 95%; stage IB-IIA, 80–90%; stage IIB, 65%; stage III, 40%; and stage IV, < 20%.

ACOG Practice Bulletin. Diagnosis and treatment of cervical carcinomas, Number 35, May 2002. Obstet Gynecol 2002; 99 (5 Pt 1):855.

Lonky NM: Reducing death from cervical cancer: examining the prevention paradigms. Obstet Gynecol Clin North Am 2002;29:599.

Leiomyoma of the Uterus (Fibroid Tumor)

Essentials of Diagnosis

  • Irregular enlargement of the uterus (may be asymptomatic).

  • Heavy or irregular vaginal bleeding, dysmenorrhea.

  • Acute and recurrent pelvic pain if the tumor becomes twisted on its pedicle or infarcted.

  • Symptoms due to pressure on neighboring organs (large tumors).

General Considerations

Uterine leiomyoma is the most common benign neoplasm of the female genital tract. It is a discrete, round, firm, often multiple uterine tumor composed of smooth muscle and connective tissue. The most convenient classification is by anatomic location: (1) intramural, (2) submucous, (3) subserous, (4) intraligamentous, (5) parasitic (ie, deriving its blood supply from an organ to which it becomes attached), and (6) cervical. A submucous myoma may become pedunculated and descend through the cervix into the vagina.

Clinical Findings

A. Symptoms and Signs

In nonpregnant women, myomas are frequently asymptomatic. However, they can cause urinary frequency, dysmenorrhea, heavy bleeding (often with anemia), or other complications due to the presence of an abdominal mass.

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Occasionally, degeneration occurs, causing intense pain. Infertility may be due to a myoma that significantly distorts the uterine cavity.

B. Laboratory Findings

Hemoglobin levels may be decreased as a result of blood loss, but in rare cases polycythemia is present, presumably as a result of the production of erythropoietin by the myomas.

C. Imaging

Ultrasonography will confirm the presence of uterine myomas and can be used sequentially to monitor growth. When multiple subserous or pedunculated myomas are being followed, ultrasonography is important to exclude ovarian masses. MRI can delineate intramural and submucous myomas accurately. Hysterography or hysteroscopy can also confirm cervical or submucous myomas.

Differential Diagnosis

Irregular myomatous enlargement of the uterus must be differentiated from the similar but symmetric enlargement that may occur with pregnancy or adenomyosis (the presence of endometrial glands and stroma in the myometrium). Subserous myomas must be distinguished from ovarian tumors. Leiomyosarcoma is an unusual tumor occurring in 0.5% of women operated on for symptomatic myoma. It is very rare under the age of 40 and increases in incidence thereafter.

Treatment

A. Emergency Measures

If the patient is markedly anemic as a result of long, heavy menstrual periods, preoperative treatment with depot medroxyprogesterone acetate, 150 mg intramuscularly every 28 days, or danazol, 400–800 mg orally daily, will slow or stop bleeding, and medical treatment of anemia can be given prior to surgery. Emergency surgery is required for acute torsion of a pedunculated myoma. The only emergency indication for myomectomy during pregnancy is torsion; abortion is not an inevitable result.

B. Specific Measures

Women who have small asymptomatic myomas should be examined at 6-month intervals. If necessary, elective myomectomy can be done to preserve the uterus. Myomas do not require surgery on an urgent basis unless they cause significant pressure on the ureters, bladder, or bowel or severe bleeding leading to anemia or unless they are undergoing rapid growth. Cervical myomas larger than 3–4 cm in diameter or pedunculated myomas that protrude through the cervix must be removed. Submucous myomas can be removed using a hysteroscope and laser or resection instruments.

Because the risk of surgical complications increases with the increasing size of the myoma, preoperative reduction of myoma size is desirable. GnRH analogs such as depot leuprolide, 3.75 mg intramuscularly monthly, or nafarelin, 0.2–0.4 mg intranasally twice a day, are used preoperatively for 3- to 4-month periods to induce reversible hypogonadism, which temporarily reduces the size of myomas, suppresses their further growth, and reduces surrounding vascularity.

C. Surgical Measures

Surgical measures available for the treatment of myoma are laparoscopic or abdominal myomectomy and total or subtotal abdominal, vaginal, or laparoscopy-assisted vaginal hysterectomy. Myomectomy is the treatment of choice during the childbearing years. Recent developments include transcatheter bilateral uterine artery embolization, myolysis with MRI-guided high frequency focused ultrasound, or laser cauterization. While these approaches are promising and potentially cost-effective alternatives, randomized clinical trials to compare long-term outcomes of these new methods with conventional therapy are needed.

Prognosis

Surgical therapy is curative. Future pregnancies are not endangered by myomectomy, although cesarean delivery may be necessary after wide dissection with entry into the uterine cavity.

Beinfeld MT et al: Cost-effectiveness of uterine artery embolization and hysterectomy for uterine fibroids. Radiology 2004; 230:207.

Wallach EE et al: Uterine myomas: An overview of development, clinical features, and management. Obstet Gynecol 2004;104: 393.

Carcinoma of the Endometrium

Essentials of Diagnosis

  • Abnormal bleeding is the presenting sign in 80% of cases.

  • Pap smear is frequently negative.

  • After a negative pregnancy test, endometrial tissue is required to confirm the diagnosis.

General Considerations

Adenocarcinoma of the endometrium is the second most common cancer of the female genital tract. It occurs most often in women 50–70 years of age. Some patients will have taken unopposed estrogen in the past; their increased risk appears to persist for 10 or more years after stopping the drug. Obesity, nulliparity, diabetes, and polycystic ovaries with prolonged anovulation and the extended use of tamoxifen for the treatment of breast cancer are also risk factors.

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Abnormal bleeding is the presenting sign in 80% of cases. Endometrial carcinoma may cause obstruction of the cervix with collection of pus (pyometra) or blood (hematometra) causing lower abdominal pain. However, pain generally occurs late in the disease, with metastases or infection.

Papanicolaou smears of the cervix occasionally show atypical endometrial cells but are an insensitive diagnostic tool. Endocervical and endometrial sampling is the only reliable means of diagnosis. Adequate specimens of each can usually be obtained during an office procedure performed following local anesthesia (paracervical block). Simultaneous hysteroscopy can be a valuable addition in order to localize polyps or other lesions within the uterine cavity. Vaginal ultrasonography may be used to determine the thickness of the endometrium as an indication of hypertrophy and possible neoplastic change.

Pathologic assessment is important in differentiating hyperplasias, which often can be treated with cyclic oral progestins.

Prevention

Prompt endometrial sampling for patients who report abnormal menstrual bleeding or postmenopausal uterine bleeding will reveal many incipient as well as clinical cases of endometrial cancer. Younger women with chronic anovulation are at risk for endometrial hyperplasia and subsequent endometrial cancer. They can reduce the risk of hyperplasia almost completely with the use of oral contraceptives or cyclic progestin therapy.

Staging

Examination under anesthesia, endometrial and endocervical sampling, chest radiography, intravenous urography, cystoscopy, sigmoidoscopy, TVS, and MRI will help determine the extent of the disease and its appropriate treatment. The staging is based on the surgical and pathologic evaluation.

Treatment

Treatment consists of total hysterectomy and bilateral salpingo-oophorectomy. Peritoneal material for cytologic examination is routinely taken and lymph node sampling may be done. If invasion deep into the myometrium has occurred or if sampled lymph nodes are positive for tumor, postoperative irradiation is indicated. The role of adjuvant chemotherapy alone or with irradiation is currently under investigation. Palliation of advanced or metastatic endometrial adenocarcinoma may be accomplished with large doses of progestins, eg, medroxyprogesterone, 400 mg intramuscularly weekly, or megestrol acetate, 80–160 mg daily orally.

Prognosis

With early diagnosis and treatment, the overall 5-year survival is 80–85%. With stage I disease, the depth of myometrial invasion is the strongest predictor of survival, with a 98% 5-year survival with less than 66% depth of invasion and 78% survival with 66% or greater invasion.

Amant F et al: Endometrial cancer. Lancet 2005;366:491.

Mariani A et al: Surgical stage I endometrial cancer: predictors of distant failure and death. Gynecol Oncol 2002;87:274.

Carcinoma of the Vulva

Essentials of Diagnosis

  • History of genital warts.

  • History of prolonged vulvar irritation, with pruritus, local discomfort, or slight bloody discharge.

  • Early lesions may suggest or include nonneoplastic epithelial disorders.

  • Late lesions appear as a mass, an exophytic growth, or a firm, ulcerated area in the vulva.

  • Biopsy is necessary to make the diagnosis.

General Considerations

The majority of cancers of the vulva are squamous lesions that classically have occurred in women over 50 years of age. Several subtypes (particularly 16, 18, and 31) of the HPV have been identified in some but not all vulvar cancers. As with squamous cell lesions of the cervix, a grading system of vulvar intraepithelial neoplasia (VIN) from mild dysplasia to carcinoma in situ has been established.

Differential Diagnosis

Biopsy is essential for the diagnosis of VIN and vulvar cancer and should be performed with any localized atypical vulvar lesion, including white patches. Multiple skin-punch specimens can be taken in the office under local anesthesia, with care to include tissue from the edges of each lesion sampled.

Benign vulvar disorders that must be excluded in the diagnosis of carcinoma of the vulva include chronic granulomatous lesions (eg, lymphogranuloma venereum, syphilis), condylomas, hidradenoma, or neurofibroma. Lichen sclerosus and other associated leukoplakic changes in the skin should be biopsied. The likelihood that a superimposed vulvar cancer will develop in a woman with a nonneoplastic epithelial disorder (vulvar dystrophy) ranges from 1% to 5%.

Treatment

A. General Measures

Early diagnosis and treatment of irritative or other predisposing causes, such as lichen sclerosis and VIN,

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should be pursued. A 7:3 combination of betamethasone and crotamiton is particularly effective for itching. After an initial response, fluorinated steroids should be replaced with hydrocortisone because of their skin atrophying effect. For lichen sclerosus, recommended treatment is clobetasol propionate cream 0.05% twice daily for 2–3 weeks, then once daily until symptoms resolve. Application one to three times a week can be used for long-term maintenance therapy.

B. Surgical Measures

High-grade VIN may be treated with a variety of approaches including topical chemotherapy, laser ablation, wide local excision, skinning vulvectomy, and simple vulvectomy. Small, invasive basal cell carcinoma of the vulva should be excised with a wide margin. If the VIN is extensive or multicentric, laser therapy or superficial surgical removal of vulvar skin may be required. In this way, the clitoris and uninvolved portions of the vulva may be spared.

Invasive carcinoma confined to the vulva without evidence of spread to adjacent organs or to the regional lymph nodes is treated with wide local excision and inguinal lymphadenectomy or wide local excision alone if invasion is less than 1 mm. Patients with more advanced disease may receive preoperative radiation, chemotherapy, or both.

Prognosis

Basal cell carcinomas very seldom metastasize, and carcinoma in situ by definition has not metastasized. With adequate excision, the prognosis for both lesions is excellent. Patients with invasive vulvar squamous cell carcinoma 2 cm in diameter or less, without inguinal lymph node metastases, have an 85–90% chance of a 5-year survival. If the lesion is greater than 2 cm and lymph node involvement is present, the likelihood of 5-year survival is approximately 40%.

de Hullu JA et al: Modern management of vulvar cancer. Curr Opin Obstet Gynecol 2004;16:65.

Montana GS: Carcinoma of the vulva: combined modality treatment. Curr Treat Options Oncol 2004;5:85.

Endometriosis

Essentials of Diagnosis

  • Pelvic pain related to menstrual cycle.

  • Dysmenorrhea.

  • Dyspareunia.

  • Increased frequency among infertile women.

General Considerations

Endometriosis is an aberrant growth of endometrium outside the uterus, particularly in the dependent parts of the pelvis and in the ovaries and is the most common cause of secondary dysmenorrhea. While retrograde menstruation is the most widely accepted cause, its pathogenesis and natural course are not fully understood. The overall prevalence in the United States is 6–10% and is fourfold to fivefold greater among infertile women.

Clinical Findings

Women with endometriosis will complain of pelvic pain, which may be associated with infertility, dyspareunia, or rectal pain with bleeding. Initially, pain tends to start 2–7 days before the onset of menses and becomes increasingly severe until flow slackens. With increasing duration of disease, pain may become continuous. Pelvic examination may disclose tender nodules in the cul-de-sac or rectovaginal septum, uterine retroversion with decreased uterine mobility, cervical motion tenderness, or an adnexal mass or tenderness. However, most women with endometriosis have a normal pelvic examination.

Endometriosis must be distinguished from PID, ovarian neoplasms, and uterine myomas. Bowel invasion by endometrial tissue may produce blood in the stool that must be distinguished from bowel neoplasm. Paradoxically, the severity of pain associated with endometriosis may be inversely related to the anatomic extent of the disease.

Imaging is of limited value. Ultrasound examination will often reveal complex fluid-filled masses that cannot be distinguished from neoplasms. MRI is more sensitive and specific than ultrasound, particularly in the diagnosis of adnexal masses. However, the clinical diagnosis of endometriosis is presumptive and usually confirmed by laparoscopy.

Treatment

A. Medical Treatment

Medical treatment, using a variety of hormonal therapies, is effective in the amelioration of pain associated with endometriosis. However, there is no evidence that any of these agents increase the likelihood of pregnancy. Their preoperative use is of questionable value in reducing the difficulty of surgery. Most of these regimens are designed to inhibit ovulation over 4–9 months and lower hormone levels, thus preventing cyclic stimulation of endometriotic implants and decreasing their size. The optimum duration of therapy is not clear, and the relative merits in terms of side effects and long-term risks and benefits show insignificant differences when compared with each other and, in mild cases, with placebo.

  • The GnRH analogs such as nafarelin nasal spray, 0.2–0.4 mg twice daily, or long-acting injectable leuprolide acetate, 3.75 mg intramuscularly monthly, used for 6 months, suppress ovulation. Side effects of vasomotor

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    symptoms and bone demineralization may be relieved by “add-back” therapy with norethindrone, 5–10 mg daily.

  • Danazol is used for 4–6 months in the lowest dose necessary to suppress menstruation, usually 200–400 mg twice daily. Danazol has a high incidence of androgenic side effects, including decreased breast size, weight gain, acne, and hirsutism.

  • Any of the combination oral contraceptives, the contraceptive patch, or vaginal ring may be used continuously for 6–12 months. Breakthrough bleeding can be treated with conjugated estrogens, 1.25 mg daily for 1 week, or estradiol, 2 mg daily for 1 week.

  • Medroxyprogesterone acetate, 100 mg intramuscularly every 2 weeks for four doses and then 100 mg every 4 weeks; add oral estrogen or estradiol valerate, 30 mg intramuscularly, for breakthrough bleeding. Use for 6–9 months.

  • Low-dose oral contraceptives can also be given cyclically; prolonged suppression of ovulation will often inhibit further stimulation of residual endometriosis, especially if taken after one of the therapies mentioned above.

  • Analgesics, with or without codeine, may be needed during menses. NSAIDs may be helpful.

B. Surgical Measures

Surgical treatment of endometriosis—particularly extensive disease—is effective both in reducing pain and in promoting fertility. Laparoscopic ablation of endometrial implants along with uterine nerve ablation significantly reduces pain. Ablation of implants and, if necessary, removal of ovarian endometriomas enhance fertility, although subsequent pregnancy rates are related to the severity of disease. Women with disabling pain who no longer desire childbearing can be treated definitively with total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO).

Prognosis

The prognosis for reproductive function in early or moderately advanced endometriosis is good with conservative therapy. TAH-BSO is curative for patients with severe and extensive endometriosis with pain.

Giudice LC et al: Endometriosis. Lancet 2004;364:1789.

Winkel CA: Evaluation and management of women with endometriosis. Obstet Gynecol 2003;102:397.

Pelvic Organ Prolapse

Cystocele, rectocele, and enterocele are vaginal hernias commonly seen in multiparous women. Cystocele is a hernia of the bladder wall into the vagina, causing a soft anterior fullness. Cystocele may be accompanied by urethrocele, which is not a hernia but a sagging of the urethra following its detachment from the pubic symphysis during childbirth. Rectocele is a herniation of the terminal rectum into the posterior vagina, causing a collapsible pouch-like fullness. Enterocele is a vaginal vault hernia containing small intestine, usually in the posterior vagina and resulting from a deepening of the pouch of Douglas. Two or all three types of hernia may occur in combination. Pelvic organ prolapse is often associated with symptoms of pelvic pressure or a dragging sensation as well as bowel or lower urinary tract dysfunction. Stress urinary incontinence is a frequent symptom.

Supportive measures include a high-fiber diet. Weight reduction in obese patients and limitation of straining and lifting are helpful. Pessaries may reduce cystocele, rectocele, or enterocele temporarily and are helpful in women who do not wish surgery or are chronically ill. The only cure for symptomatic cystocele, rectocele, enterocele, or stress urinary Incontinence is corrective surgery.

Uterine Prolapse

Uterine prolapse most commonly occurs as a delayed result of childbirth injury to the pelvic floor (particularly the transverse cervical and uterosacral ligaments). Unrepaired obstetric lacerations of the levator musculature and perineal body augment the weakness. Attenuation of the pelvic structures with aging and congenital weakness can accelerate the development of prolapse.

In slight prolapse, the uterus descends only part way down the vagina; in moderate prolapse, the corpus descends to the introitus and the cervix protrudes slightly beyond; and in marked prolapse (procidentia), the entire cervix and uterus protrude beyond the introitus and the vagina is inverted. Inability to walk comfortably because of protrusion or discomfort from the presence of a vaginal mass is an indication that surgical treatment should be considered.

Treatment

The type of surgery depends on the extent of prolapse and the patient's age and her desire for menstruation, pregnancy, and coitus. The simplest, most effective procedure is vaginal hysterectomy with appropriate repair of the cystocele and rectocele. If the patient desires pregnancy, a partial resection of the cervix with plication of the cardinal ligaments can be attempted. For elderly women who do not desire coitus, partial obliteration of the vagina is surgically simple and effective. Uterine suspension with sacrospinous cervicocolpopexy may be an effective approach in older women who wish to avoid hysterectomy but preserve coital function. A well-fitted vaginal pessary (eg, inflatable doughnut type, Gellhorn pessary) may give relief if surgery is refused or contraindicated.

Clemons JL et al: Risk factors associated with an unsuccessful pessary fitting trial in women with pelvic organ prolapse. Am J Obstet Gynecol 2004;190:345.

Novara G et al: Surgery for pelvic organ prolapse: current status and future perspectives. Curr Opin Urol 2005;15:256.

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Pelvic Inflammatory Disease (Salpingitis, Endometritis)

Essentials of Diagnosis

  • Uterine, adnexal, or cervical motion tenderness.

  • Absence of a competing diagnosis.

General Considerations

PID is a polymicrobial infection of the upper genital tract associated with the sexually transmitted organisms N gonorrhoeae and Chlamydia trachomatis as well as endogenous organisms, including anaerobes, Haemophilus influenzae, enteric gram-negative rods, and streptococci. It is most common in young, nulliparous, sexually active women with multiple partners. Other risk markers include nonwhite race, douching, and smoking. The use of oral contraceptives or barrier methods of contraception may provide significant protection.

Tuberculous salpingitis is rare in the United States but more common in developing countries; it is characterized by pelvic pain and irregular pelvic masses not responsive to antibiotic therapy. It is not sexually transmitted.

Clinical Findings

A. Symptoms and Signs

Patients with PID may have lower abdominal pain, chills and fever, menstrual disturbances, purulent cervical discharge, and cervical and adnexal tenderness. Right upper quadrant pain (Fitz-Hugh and Curtis syndrome) may indicate an associated perihepatitis. However, diagnosis of PID is complicated by the fact that many women may have subtle or mild symptoms that are not readily recognized as PID.

B. Minimum Diagnostic Criteria

Women with uterine adnexal or cervical motion tenderness should be considered to have PID and be treated with antibiotics unless there is a competing diagnosis such as ectopic pregnancy or appendicitis.

C. Additional Criteria

The following criteria may be used to enhance the specificity of the diagnosis: (1) oral temperature greater than 38.3°C, (2) abnormal cervical or vaginal discharge with white cells on saline microscopy, (3) elevated erythrocyte sedimentation rate, (4) elevated C-reactive protein, and (5) laboratory documentation of cervical infection with N gonorrhoeae or C trachomatis. Endocervical culture should be performed routinely, but treatment should not be delayed while awaiting results.

D. Definitive Criteria

In selected cases where the diagnosis based on clinical or laboratory evidence is uncertain, the following criteria may be used: (1) histopathologic evidence of endometritis on endometrial biopsy, (2) TVS or MRI showing thickened fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex, and (3) laparoscopic abnormalities consistent with PID.

Differential Diagnosis

Appendicitis, ectopic pregnancy, septic abortion, hemorrhagic or ruptured ovarian cysts or tumors, twisted ovarian cyst, degeneration of a myoma, and acute enteritis must be considered. PID is more likely to occur when there is a history of PID, recent sexual contact, recent onset of menses, or an IUD in place or if the partner has a sexually transmitted disease. Acute PID is highly unlikely when recent intercourse has not taken place or an IUD is not being used. A sensitive serum pregnancy test should be obtained to rule out ectopic pregnancy. Culdocentesis will differentiate hemoperitoneum (ruptured ectopic pregnancy or hemorrhagic cyst) from pelvic sepsis (salpingitis, ruptured pelvic abscess, or ruptured appendix). Pelvic and vaginal ultrasonography is helpful in the differential diagnosis of ectopic pregnancy of over 6 weeks. Laparoscopy is often used to diagnose PID, and it is imperative if the diagnosis is not certain or if the patient has not responded to antibiotic therapy after 48 hours. The appendix should be visualized at laparoscopy to rule out appendicitis. Cultures obtained at the time of laparoscopy are often specific and helpful.

Treatment

A. Hospitalization

Patients with acute PID should be admitted for intravenous antibiotic therapy if (1) surgical emergencies such as appendicitis cannot be ruled out, (2) the patient has a tubo-ovarian abscess, (3) the patient is pregnant, (4) the patient is unable to follow or tolerate an outpatient regimen, (5) the patient has not responded clinically to outpatient therapy, or (6) the patient has severe illness, nausea and vomiting, or high fever. In the past, many experts recommended that all patients with PID be hospitalized for bed rest and supervised treatment with parenteral antibiotics. However, a recent large, randomized clinical trial suggests that in women with mild to moderate PID, there is no difference between inpatient and outpatient therapy in short-term clinical outcomes or in long-term reproductive outcomes. Patients with tubo-ovarian abscesses should have direct inpatient observation for at least 24 hours before switching to outpatient parenteral therapy.

B. Antibiotics

Early treatment with appropriate antibiotics effective against N gonorrhoeae, C trachomatis, and the endogenous

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organisms listed above is essential to prevent long-term sequelae. The sexual partner should be examined and treated appropriately.

Two inpatient regimens have been shown to be effective in the treatment of acute PID: (1) Cefoxitin, 2 g intravenously every 6 hours, or cefotetan, 2 g every 12 hours, plus doxycycline, 100 mg intravenously or orally every 12 hours. This regimen is continued for at least 24 hours after the patient shows significant clinical improvement. Doxycycline, 100 mg twice daily, should be continued to complete a total of 14 days therapy. If a tubo-ovarian abscess is present, it is advisable to add oral clindamycin or metronidazole to the doxycycline to provide more effective anaerobic coverage. (2) Clindamycin, 900 mg intravenously every 8 hours, plus gentamicin intravenously in a loading dose of 2 mg/kg followed by 1.5 mg/kg every 8 hours. This regimen is continued for at least 24 hours after the patient shows significant clinical improvement and is followed by either clindamycin, 450 mg four times daily, or doxycycline, 100 mg twice daily, to complete a total of 14 days of therapy.

Limited data exist on other parenteral regimens. Two regimens providing broad-spectrum coverage have been investigated in at least one clinical trial: (1) ofloxacin, 400 mg intravenously every 12 hours, or levofloxacin, 500 mg intravenously once daily, plus metronidazole, 500 mg intravenously every 8 hours; and (2) ampicillin-sulbactam, 3 g intravenously every 6 hours, plus doxycycline, 100 mg intravenously or orally every 12 hours.

Two outpatient regimens are recommended: (1) ofloxacin, 400 mg orally twice daily for 14 days, or levofloxacin, 500 mg orally once daily for 14 days, plus metronidazole, 500 mg orally twice daily, for 14 days; and (2) either a single dose of cefoxitin, 2 g intramuscularly, with probenecid, 1 g orally, or ceftriaxone, 250 mg intramuscularly, plus doxycycline, 100 mg orally twice daily, for 14 days.

C. Surgical Measures

Tubo-ovarian abscesses may require surgical excision or transcutaneous or transvaginal aspiration. Unless rupture is suspected, institute high-dose antibiotic therapy in the hospital, and monitor therapy with ultrasound. In 70% of cases, antibiotics are effective; in 30%, there is inadequate response in 48–72 hours, and intervention is required. Unilateral adnexectomy is acceptable for unilateral abscess. Hysterectomy and bilateral salpingo-oophorectomy may be necessary for overwhelming infection or in cases of chronic disease with intractable pelvic pain.

Prognosis

In spite of treatment, long-term sequelae, including repeated episodes of infection, chronic pelvic pain, dyspareunia, ectopic pregnancy, or infertility, develop in one-fourth of women with acute disease. The risk of infertility increases with repeated episodes of salpingitis: it is estimated at 10% after the first episode, 25% after a second episode, and 50% after a third episode.

Banikarim C et al: Pelvic inflammatory disease in adolescents. Semin Pediatr Infect Dis 2005;16:175.

Sexually transmitted disease treatment guidelines 2006. Centers for Disease Control and Prevention. MMWR Recomm Rep 2006;55(RR11):1.

Ovarian Tumors

Essentials of Diagnosis

  • Vague gastrointestinal discomfort.

  • Pelvic pressure and pain.

  • Many cases of early-stage cancer are asymptomatic.

  • Pelvic examination, CA 125, and ultrasound are mainstays of diagnosis.

General Considerations

Ovarian tumors are common. Most are benign, but malignant ovarian tumors are the leading cause of death from reproductive tract cancer. The wide range of types and patterns of ovarian tumors is due to the complexity of ovarian embryology and differences in tissues of origin (Table 17-4).

In women with no family history of ovarian cancer, the lifetime risk is 1.6%, whereas a woman with one affected first-degree relative has a 5% lifetime risk. With two or more affected first-degree relatives, the risk is 7%. Approximately 3% of women with two or more affected first-degree relatives will have a hereditary ovarian cancer syndrome with a lifetime risk of 40%. Women with a BRCA1 gene mutation have a 45% lifetime risk of ovarian cancer and those with a BRAC2 mutation a 25% risk. These women should be screened annually with TVS and CA 125 testing, and prophylactic oophorectomy is recommended by age 35 or whenever childbearing is completed because of the high risk of disease. The benefits of such screening for women with one or no affected first-degree relatives are unproved, and the risks associated with unnecessary surgical procedures may outweigh the benefits in low-risk women.

Clinical Findings

A. Symptoms and Signs

Unfortunately, most women with both benign and malignant ovarian neoplasms are either asymptomatic or experience only mild nonspecific gastrointestinal symptoms or pelvic pressure. Women with early disease are typically detected on routine pelvic examination. Women with advanced malignant disease may experience abdominal pain and bloating, and a palpable abdominal mass with ascites is often present.

Table 17-4. Ovarian functional and neoplastic tumors.

Tumor Incidence Size Consistency Menstrual Irregularities Endocrine Effects Potential for Malignancy Special Remarks
Follicle cysts Rare in childhood; frequent in menstrual years; never in postmenopausal years. < 6 cm, often bilateral. Moderate Occasional Occasional anovulation with persistently proliferative endometrium None Usually disappear spontaneously within 2-3 months.
Corpus luteum cysts Occasional, in menstrual years. 4-6 cm, unilateral. Moderate Occasional delayed period Prolonged secretory phase None Functional cysts. Intraperitoneal bleeding occasionally.
Theca lutein cysts Occurs with hydatidiform mole, choriocarcinoma; also with gonadotropin or clomiphene therapy. To 4-5 cm, multiple, bilateral. (Ovaries may be ≥ 20 cm in diameter.) Tense Amenorrhea hCG elevated as a result of trophoblastic proliferation None Functional cysts. Hematoperitoneum or torsion of ovary may occur. Surgery is to be avoided.
Inflammatory (tubo-ovarian abscess) Concomitant with acute salpingitis. To 15-20 cm, often bilateral. Variable, painful Menometrorrhagia Anovulation usual None Unilateral removal indicated if possible.
Endometriotic cysts Never in preadolescent or postmenopausal years. Most common in women aged 20-40 years. To 10-12 cm, occasionally bilateral. Moderate to softened Rare None Very rare Associated pelvic endometriosis. Medical treatment or conservative surgery recommended.
Teratoid tumors:
   Benign teratomas (dermoid cysts) Childhood to postmenopause. < 15 cm; 15% are bilateral. Moderate to softened None None Rare Torsion can occur. Partial oophorectomy recommended.
   Malignant teratomas < 1% of ovarian tumors. Usually in infants and young adults. > 20 cm, unilateral. Irregularly firm None Occasionally, hCG elevated All Surgery alone may be curative.
Cystadenoma, cyst-adenocarcinoma Common in reproductive years. Serous: < 25 cm, 33% bilateral; mucinous: up to 1 cm, 10% bilateral. Moderate to softened None None > 50% for serous, about 5% for mucinous Peritoneal implants often occur with serous, rarely with mucinous. If mucinous tumor is ruptured, pseudomyxoma peritonei may occur.
Endometrioid carcinoma 15% of ovarian carcinomas. Moderate, 13% bilateral. Firm None None All Adenocarcinoma of endometrium coexists in 15-30% of cases.
Fibroma < 5% of ovarian tumors. Usually < 15 cm. Very firm None None Rare Ascites in 20% (rarely, pleural fluid).
Arrhenoblastoma Rare. Average age 30 years or more. Often small (< 10 cm), unilateral. Firm to softened Amenorrhea Androgens elevated < 20% Recurrences are moderately sensitive to irradiation.
Theca cell tumor (thecoma) Uncommon. < 10 cm, unilateral. Firm Occasional irregularity Estrogens or androgens elevated < 1%  
Granulosa cell tumor Uncommon. Usually in prepubertal girls or women older than 50 years. May be very small. Firm to softened Menometrorrhagia Estrogens elevated 15-20% Recurrences are moderately sensitive to irradiation.
Dysgerminoma About 1-2% of ovarian tumors. < 30 cm, bilateral in 33%. Moderate to softened None All Very radiosensitive.
Brenner tumor About 1% of ovarian tumors. < 30 cm, unilateral. Firm None Very rare > 50% occur in postmenopausal years.
Secondary ovarian tumors 10% of fatal malignant disease in women. Varies; often bilateral. Firm to softened Occasional Very rare (thyroid, adrenocortical origin) All Bowel or breast metastases to ovary common.

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B. Laboratory Findings

An elevated serum CA 125 (> 35 units) indicates a greater likelihood that an ovarian tumor is malignant. CA 125 is elevated in 80% of women with epithelial ovarian cancer overall but in only 50% of women with early disease. Furthermore, serum CA 125 may be elevated in premenopausal women with benign disease such as endometriosis.

C. Imaging Studies

TVS is useful for screening high-risk women but has inadequate sensitivity for screening low-risk women. Ultrasound is helpful in differentiating ovarian masses that are benign and likely to resolve spontaneously from those with malignant potential. Color Doppler imaging may further enhance the specificity of ultrasound diagnosis.

Differential Diagnosis

Once an ovarian mass has been detected, it must be categorized as functional, benign neoplastic, or potentially malignant. Predictive factors include age, size of the mass, ultrasound configuration, CA 125 levels, the presence of symptoms, and whether the mass is unilateral or bilateral. In a premenopausal woman, an asymptomatic, mobile, unilateral, simple cystic mass less than 7.5 cm may be observed for 4–6 weeks. Most will resolve spontaneously. If the mass is larger or unchanged on repeat pelvic examination and TVS, surgical evaluation is required.

Most ovarian masses in postmenopausal women require surgical evaluation. However, a postmenopausal woman with an asymptomatic unilateral simple cyst less than 5 cm in diameter and a normal CA 125 level may be followed closely with TVS. All others require surgical evaluation.

Laparoscopy may be used when an ovarian mass is small enough to be removed with a laparoscopic approach. If malignancy is suspected, preoperative workup should include chest radiograph, evaluation of liver and kidney function, and hematologic indices.

Treatment

If a malignant ovarian mass is suspected, surgical evaluation should be performed by a gynecologic oncologist. For benign neoplasms, tumor removal or unilateral oophorectomy is usually performed. For ovarian cancer in an early stage, the standard therapy is complete surgical staging followed by abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and selective lymphadenectomy. With more advanced disease, aggressive removal of all visible tumor improves survival. Except for women with low-grade ovarian cancer in an early stage, postoperative chemotherapy is indicated. Several chemotherapy regimens are effective, such as the combination of cisplatin or carboplatin with paclitaxel, with clinical response rates of up to 60–70%.

Prognosis

Unfortunately, approximately 75% of women with ovarian cancer are diagnosed with advanced disease after regional or distant metastases have become established. The overall 5-year survival is approximately 17% with distant metastases, 36% with local spread, and 89% with early disease.

Cannistra SA: Cancer of the ovary. N Engl J Med 2004;351: 2519.

Guppy AE et al: Epithelial ovarian cancer: a review of current management. Clin Oncol 2005;17:399.

Polycystic Ovary Syndrome

Essentials of Diagnosis

  • Clinical or biochemical evidence of hyperandrogenism.

  • Oligoovulation or anovulation.

  • Polycystic ovaries on ultrasonography.

General Considerations

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5–10% of women of reproductive age and is a common source of chronic anovulation. The underlying etiology is unknown, although most of these women have an aberration of gonadotropin stimulation. This is manifested by an increased release of luteinizing hormone (LH) relative to follicle-stimulating hormone (FSH), resulting in an increased production of androstenedione and testosterone by ovarian theca cells. The androstenedione undergoes aromatization to estrone and converted to estradiol in the ovarian granulosa cells. The high estrone levels are believed to cause suppression of pituitary FSH and constant LH stimulation of the ovary results in anovulation, multiple cysts, and theca cell hyperplasia with excess androgen output.

Women with Cushing's syndrome, congenital adrenal hyperplasia, and androgen-secreting adrenal tumors also tend to have high circulating androgen levels and anovulation with polycystic ovaries; these disorders must be ruled out in women with presumed PCOS.

Clinical Findings

PCOS is manifested by hirsutism (50% of cases), obesity (40%), and virilization (20%). Fifty percent of patients have amenorrhea, 30% have abnormal uterine bleeding, and 20% have normal menstruation. In addition, they show insulin resistance and hyperinsulinemia, and these women are at increased risk for early-onset type 2 diabetes. The patients are generally

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infertile, although they may ovulate occasionally. They have an increased long-term risk of cancer of the breast and endometrium because of unopposed estrogen secretion.

Differential Diagnosis

Anovulation in the reproductive years may also be due to (1) premature menopause (high FSH and LH levels); (2) rapid weight loss, extreme physical exertion (normal FSH and LH levels for age), or obesity; (3) discontinuation of hormonal contraceptives (anovulation for 6 months or more occasionally occurs); (4) pituitary adenoma with elevated prolactin (galactorrhea may or may not be present); and (5) hyperthyroidism or hypothyroidism. When amenorrhea has persisted for 6 months or more without a diagnosis, FSH, LH, prolactin, and TSH should be checked. Women with clinical evidence of androgen excess should have total testosterone, DHEA-S, and 17-hydroxyprogesterone measured. A 10-day course of progestin (eg, medroxyprogesterone acetate, 10 mg/d) will cause withdrawal bleeding if estrogen levels are high. This will aid in the diagnosis and prevent endometrial hyperplasia. Because of the high risk of insulin resistance and dyslipidemia, all women with PCOS should have a 2-hour glucose determination after a 75-g glucose load and a lipoprotein profile.

Treatment

In obese patients with PCOS, weight reduction is often effective. If the patient wishes to become pregnant, clomiphene or other drugs can be used for ovulatory stimulation. (See Infertility, this chapter.) The addition of dexamethasone, 0.5 mg at bedtime, to a clomiphene regimen may increase the likelihood of ovulation by suppression of ACTH and any circulating adrenal androgens. For women who are unresponsive to clomiphene, 3- to 6-month courses of the oral hypoglycemic agents metformin, 500 mg three times daily, rosiglitazone 4 mg daily, or pioglitazone 30–45 mg daily may bring resumption of regular cycles and ovulation. These agents reduce the hyperinsulinemia and hyperandrogenemia in PCOS.

If the patient does not desire pregnancy, medroxyprogesterone acetate, 10 mg/d for the first 10 days of each month, should be given. This will ensure regular shedding of the endometrium so that hyperplasia will not occur. If contraception is desired, a low-dose combination oral contraceptive can be used; this is also useful in controlling hirsutism, for which treatment must be continued for 6–12 months before results are seen.

Hirsutism may be managed with epilation and electrolysis. Dexamethasone, 0.5 mg each night, is helpful in women with excess adrenal androgen secretion. If hirsutism is severe, some patients will elect to have a hysterectomy and bilateral oophorectomy followed by estrogen replacement therapy. Spironolactone, an aldosterone antagonist, is also useful for hirsutism in doses of 25 mg three or four times daily. Flutamide, 250 mg daily, and finasteride, 5 mg daily, are also effective for treating hirsutism. Because these three agents are potentially teratogenic, they should be used only in conjunction with secure contraception.

Ehrmann DA: Polycystic ovarian syndrome. N Engl J Med 2005; 352:1223.

Painful Intercourse (Dyspareunia)

Questions related to sexual functioning should be asked as part of the reproductive history. Two helpful questions are, “Are you sexually active?” and “Are you having any sexual difficulties at this time?”

During the pelvic examination, the patient should be placed in a half-sitting position and given a hand-held mirror and then asked to point out the site of pain and describe the type of pain.

Etiology

A. Vulvovaginitis

Vulvovaginitis is inflammation or infection of the vagina. Areas of marked tenderness in the vulvar vestibule without visible inflammation occasionally show lesions resembling small condylomas on colposcopy (see Vaginitis, this chapter).

B. Vaginismus

Vaginismus is voluntary or involuntary contraction of muscles around the introitus. It results from fear, pain, sexual trauma, or having learned negative attitudes toward sex during childhood.

C. Remnants of the Hymen

The hymen is usually adequately stretched during initial intercourse, so that pain does not occur subsequently. In some women, the pain of initial intercourse may produce vaginismus. In others, a thin or thickened rim or partial rim of hymen remains after several episodes of intercourse, causing pain.

D. Insufficient Lubrication of the Vagina

See vaginal atrophy in the section on Menopausal Syndrome, this chapter.

E. Infection, Endometriosis, Tumors, or Other Pathologic Conditions

Pain occurring with deep thrusting during coitus is usually due to acute or chronic infection of the cervix, uterus, or adnexa; endometriosis; adnexal tumors; or adhesions resulting from prior pelvic disease or operation. Careful history taking and a pelvic examination will generally help in the differential diagnosis.

F. Vulvodynia

This is the most frequent cause of dyspareunia in premenopausal women. It is characterized by a sensation of

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burning along with other symptoms including pain, itching, stinging, irritation, and rawness. The discomfort may be constant or intermittent, focal or diffuse, and experienced as either deep or superficial. There are generally no physical findings except minimal erythema that may be associated with a subset of vulvodynia, vulvar vestibulitis. Vulvar vestibulitis is normally asymptomatic, but the pain is associated with touching or pressure on the vestibule such as with vaginal entry or insertion of a tampon.

Treatment

A. Vulvovaginitis

Lesions resembling warts on colposcopy or biopsy should be treated in the appropriate way (see Vaginitis). Irritation from spermicides may be a factor. The couple may be helped by a discussion of noncoital techniques to achieve orgasm until the infection subsides.

B. Vaginismus

Sexual counseling and education on anatomy and sexual functioning may be appropriate. The patient can be instructed in self-dilation, using a lubricated finger or test tubes of graduated sizes. Before coitus (with adequate lubrication) is attempted, the patient—and then her partner—should be able to easily and painlessly introduce two fingers into the vagina. Penetration should never be forced, and the woman should always be the one to control the depth of insertion during dilation or intercourse. Injection of botulinum toxin has been used successfully in refractory cases.

C. Remnants of the Hymen

In rare situations, manual dilation of a remaining hymen under general anesthesia is necessary. Surgery should be avoided.

D. Insufficient Lubrication of the Vagina

If inadequate sexual arousal is the cause, sexual counseling is helpful. Lubricants may be used during sexual foreplay. For women with low plasma estrogen levels, use of a lubricant during coitus is sometimes sufficient. If not, estrogen vaginal cream or an estradiol vaginal ring may be used. The ring may be worn continuously and replaced every 3 months. Concomitant progestin therapy is not needed with the ring.

E. Infection, Endometriosis, Tumors, or Other Pathologic Conditions

Medical treatment of acute cervicitis, endometritis, or salpingitis and temporary abstention from coitus usually relieve pain. Hormonal or surgical treatment of endometriosis may be helpful. Dyspareunia resulting from chronic PID or any condition causing extensive adhesions or fixation of pelvic organs is difficult to treat without extirpative surgery. Couples can be advised to try coital positions that limit deep thrusting and to use manual and oral sexual techniques.

F. Vulvodynia

Since the cause of vulvodynia is unknown, management is difficult. Few treatment approaches have been subjected to methodologically rigorous trials. A variety of topical agents have been tried, although only topical anesthetics (eg, estrogen cream and a compounded mixture of topical amitriptyline 2% and baclofen 2% in a water washable base) have been useful in relieving vulvodynia. Useful oral medications include tricyclic antidepressants, such as amitriptyline in gradually increasing doses from 10 mg/d to 75–100 mg/d; various selective serotonin reuptake inhibitors; and anticonvulsants, such as gabapentin starting with 300 mg three times a day and increasing to 1200 mg three times a day. Biofeedback and physical therapy, with a physical therapist experienced with the treatment of vulvar pain, have been shown to be helpful. Surgery—usually consisting of vestibulectomy—has been useful for women with introital dyspareunia.

Haefner HK et al: The vulvodynia guideline. J Low Genit Tract Dis 2005;9:40.

Infertility

A couple is said to be infertile if pregnancy does not result after 1 year of normal sexual activity without contraceptives. About 25% of couples experience infertility at some point in their reproductive lives; the incidence of infertility increases with age. The male partner contributes to about 40% of cases of infertility, and a combination of factors is common.

Diagnostic Survey

During the initial interview, the clinician can present an overview of infertility and discuss a plan of study. Separate private consultations are then conducted, allowing appraisal of psychosexual adjustment without embarrassment or criticism. Pertinent details (eg, sexually transmitted disease or prior pregnancies) must be obtained. The ill effects of cigarettes, alcohol, and other recreational drugs on male fertility should be discussed. Prescription drugs that impair male potency should be discussed as well. The gynecologic history should include queries regarding the menstrual pattern. The present history includes use and types of contraceptives, douches, libido, sex techniques, frequency and success of coitus, and correlation of intercourse with time of ovulation. Family history includes repeated abortions and maternal DES use.

General physical and genital examinations are performed on both partners. Basic laboratory studies include complete blood count, urinalysis, cervical culture for Chlamydia, serologic test for syphilis, rubella antibody determination, and thyroid function tests. Tay-Sachs screening should be offered if both parents are Ashkenazi Jews as well as couples of French-Canadian or Cajun ancestry; sickle cell screening should be offered if both parents are black.

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The patient is instructed to chart her basal body temperature orally daily on arising and to record on a graph episodes of coitus and days of menstruation. Self-performed urine tests for the midcycle LH surge enhance temperature observations relating to ovulation. Couples should be advised that coitus resulting in conception occurs during the 6-day period ending with the day of ovulation.

The male partner is instructed to bring a complete ejaculate for analysis. Men must abstain from sexual activity for at least 3 days before the semen is obtained. A clean, dry, wide-mouthed bottle for collection is preferred. Condoms should not be used, as the protective powder or lubricant may be spermicidal. Semen should be examined within 1–2 hours after collection. Semen is considered normal with the following minimum values: volume, 1.5–5 mL; concentration, 20 million sperm per milliliter; motility, 60%; and normal forms, 35%. If the sperm count is abnormal, further evaluation includes a search for exposure to environmental and workplace toxins, alcohol or drug abuse, and hypogonadism.

A. First Testing Cycle

While the contribution of cervical factors to infertility is controversial, most gynecologists include a postcoital test in their workup. The test is scheduled for just before ovulation (eg, day 12 or 13 in an expected 28-day cycle). Preovulation timing can be enhanced by serial urinary LH tests. The patient is examined within 6 hours after coitus. The cervical mucus should be clear, elastic, and copious owing to the influence of the preovular estrogen surge. (The mucus is scantier and more viscid before and after ovulation.) A good spinnbarkeit (stretching to a fine thread 4 cm or more in length) is desirable. A small drop of cervical mucus should be obtained from within the cervical os and examined under the microscope. The presence of five or more active sperm per high-power field constitutes a satisfactory postcoital test. If no spermatozoa are found, the test should be repeated (assuming that active spermatozoa were present in the semen analysis). Sperm agglutination and sperm immobilization tests should be considered if the sperm are immotile or show ineffective tail motility.

The presence of more than three white blood cells per high-power field in the postcoital test suggests cervicitis in the woman or prostatitis in the man. When estrogen levels are normal, the cervical mucus dried on the slide will form a fern-like pattern when viewed with a low-power microscope. This type of mucus is necessary for normal sperm transport.

The serum progesterone level should be measured at the midpoint of the secretory phase (21st day); a level of > 3 ng/mL confirms ovulation.

B. Second Testing Cycle

Hysterosalpingography using an oil dye is performed within 3 days following the menstrual period. This x-ray study will demonstrate uterine abnormalities (septa, polyps, submucous myomas) and tubal obstruction. A repeat x-ray film 24 hours later will confirm tubal patency if there is wide pelvic dispersion of the dye. This test has been associated with an increased pregnancy rate by some observers. If the woman has had prior pelvic inflammation, one should give doxycycline, 100 mg twice daily, beginning immediately before and for 7 days after the x-ray study.

C. Further Testing

  • Gross deficiencies of sperm (number, motility, or appearance) require repeat analysis. Zona-free hamster egg penetration tests are available to evaluate the ability of human sperm to fertilize an egg.

  • Obvious obstruction of the uterine tubes requires assessment for microsurgery or in vitro fertilization.

  • Absent or infrequent ovulation requires additional laboratory evaluation. Elevated FSH and LH levels indicate ovarian failure causing premature menopause. Elevated LH levels in the presence of normal FSH levels confirm the presence of polycystic ovaries. Elevation of blood prolactin (PRL) levels suggests pituitary microadenoma.

  • Ultrasound monitoring of folliculogenesis may reveal the occurrence of unruptured luteinized follicles.

  • Endometrial biopsy in the luteal phase associated with simultaneous serum progesterone levels will rule out luteal phase deficiency.

D. Laparoscopy

Approximately 25% of women whose basic evaluation is normal will have findings on laparoscopy explaining their infertility (eg, peritubal adhesions, endometriotic implants).

Treatment

A. Medical Measures

Fertility may be restored by appropriate treatment in many patients with endocrine imbalance, particularly those with hypothyroidism or hyperthyroidism. Antibiotic treatment of cervicitis is of value. In women with abnormal postcoital tests and demonstrated antisperm antibodies causing sperm agglutination or immobilization, condom use for up to 6 months may result in lower antibody levels and improved pregnancy rates.

Women who engage in vigorous athletic training often have low sex hormone levels; fertility improves with reduced exercise and some weight gain.

B. Surgical Measures

Excision of ovarian tumors or ovarian foci of endometriosis can improve fertility. Microsurgical relief of tubal obstruction due to salpingitis or tubal ligation will reestablish fertility in a significant number of cases. In special instances of cornual or fimbrial block, the prognosis with newer surgical techniques has become much better. Peritubal adhesions or endometriotic implants often can be treated via laparoscopy or

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via laparotomy immediately following laparoscopic examination if prior consent has been obtained.

With varicocele in the male, sperm characteristics are often improved following surgical treatment.

C. Induction of Ovulation

1. Clomiphene citrate

Clomiphene citrate stimulates gonadotropin release, especially LH. Consequently, plasma estrone (E1) and estradiol (E2) also rise, reflecting ovarian follicle maturation. If E2 rises sufficiently, an LH surge occurs to trigger ovulation.

After a normal menstrual period or induction of withdrawal bleeding with progestin, one should give 50 mg of clomiphene orally daily for 5 days. If ovulation does not occur, the dosage is increased to 100 mg orally daily for 5 days. If ovulation still does not occur, the course is repeated with 150 mg daily and then 200 mg daily for 5 days, with the addition of chorionic gonadotropin, 10,000 units intramuscularly, 7 days after clomiphene.

The rate of ovulation following this treatment is 90% in the absence of other infertility factors. The pregnancy rate is high. Twinning occurs in 5% of these patients, and three or more fetuses are found in rare instances (< 0.5% of cases). An increased incidence of congenital anomalies has not been reported. Painful ovarian cyst formation occurs in 8% of patients and may warrant discontinuation of therapy. Several studies have suggested a twofold to threefold increased risk of ovarian cancer with the use of clomiphene for more than 1 year.

In the presence of increased androgen production (DHEA-S > 200 mcg/dL), the addition of dexamethasone, 0.5 mg, or prednisone, 5 mg, at bedtime, improves the response to clomiphene. Dexamethasone should be discontinued after pregnancy is confirmed.

2. Bromocriptine

Bromocriptine is used only if PRL levels are elevated and there is no withdrawal bleeding following progesterone administration (otherwise, clomiphene is used). To minimize side effects (nausea, diarrhea, dizziness, headache, fatigue), bromocriptine should be taken with meals. The initial dosage is 2.5 mg once daily, increased to two or three times daily in increments of 1.25 mg. The drug is discontinued once pregnancy has occurred.

3. Human menopausal gonadotropins (hMG)

hMG or recombinant FSH is indicated in cases of hypogonadotropism and most other types of anovulation (exclusive of ovarian failure). Because of the complexities, laboratory tests, and expense associated with this treatment, these patients should be referred to a specialist.

4. Gonadotropin-releasing hormone (GnRH)

Hypothalamic amenorrhea unresponsive to clomiphene will be reliably and successfully treated with subcutaneous pulsatile GnRH. Use of this substance will avoid the dangerous ovarian complications and the 25% incidence of multiple pregnancy associated with hMG, although the overall rate of ovulation and pregnancy is lower than when hMG is used.

D. Treatment of Endometriosis

See above.

E. Treatment of Inadequate Transport of Sperm

Intrauterine insemination of concentrated washed sperm has been used to bypass a poor cervical environment associated with scant or hostile cervical mucus. The sperm must be handled by sterile methods, washed in sterile saline or tissue culture solutions, and centrifuged. A small amount of fluid (0.5 mL) containing the sperm is then instilled into the uterus.

F. Artificial Insemination in Azoospermia

If azoospermia is present, artificial insemination by a donor usually results in pregnancy, assuming female function is normal. The use of frozen sperm is currently preferable to fresh sperm because the frozen specimen can be held pending cultures and blood test results for sexually transmitted diseases, including HIV infection.

G. Assisted Reproductive Technologies (ART)

Couples who have not responded to traditional infertility treatments, including those with tubal disease, severe endometriosis, oligospermia, and immunologic or unexplained infertility, may benefit from in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT), and zygote intrafallopian transfer (ZIFT). These techniques are complex and require a highly organized team of specialists. All of the procedures involve ovarian stimulation to produce multiple oocytes, oocyte retrieval by TVS-guided needle aspiration, and handling of the oocytes outside the body. With IVF, the eggs are fertilized in vitro and the embryos transferred to the uterine fundus. Intracytoplasmic sperm injection (ICSI) allows fertilization with a single sperm. It was originally intended for couples with male factor infertility, but it is now used in approximately half of all IVF procedures in the United States.

GIFT involves the placement of sperm and eggs in the uterine tube by laparoscopy or minilaparotomy. With ZIFT, fertilization occurs in vitro, and the early development of the embryo occurs in the uterine tube after transfer by laparoscopy or minilaparotomy. The later two procedures are used infrequently. In ART cycles using fresh, nondonor eggs, the overall rate of live births per cycle for the 399 programs reporting results in the United States in 2003 was 28.3%. Age is an important determinant of success—for couples under the age of 35, the average rate of live birth was 43% per cycle, while the rate for women over 42 was 5.9%. In 2003, 34.2% of pregnancies were multiple.

Prognosis

The prognosis for conception and normal pregnancy is good if minor (even multiple) disorders can be identified and treated; it is poor if the causes of infertility are severe, untreatable, or of prolonged duration (over 3 years).

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It is important to remember that in the absence of identifiable causes of infertility, 60% of couples will achieve a pregnancy within 3 years. Couples with unexplained infertility who do not achieve pregnancy within 3 years should be offered ovulation induction or assisted reproductive technology. Also, offering appropriately timed information about adoption is considered part of a complete infertility regimen.

Centers for Disease Control and Prevention, American Society for Reproductive Medicine: 2003 Assisted Reproductive Technology Success Rates. 2005, Atlanta, GA. http://www.cdc.gov/ART/ART2003/index.htm

Frey KA et al: Initial evaluation and management of infertility by the primary care physician. Mayo Clin Proc 2004;79:1439.

Contraception

Voluntary control of childbearing benefits women, men, and their children. Contraception should be available to all women and men of reproductive ages. Education about contraception and access to contraceptive pills or devices are especially important for sexually active teenagers and for women following childbirth or abortion.

1. Oral Contraceptives

Combined Oral Contraceptives

A. Efficacy and Methods of Use

Oral contraceptives have a perfect use failure rate of 0.3% and a typical use failure rate of 8%. Their primary mode of action is suppression of ovulation. The pills can be initially started on the first day of the menstrual cycle, the first Sunday after the onset of the cycle or on any day of the cycle. If started on any day other than the first day of the cycle, a backup method should be used. There are also pills packaged to be taken continuously for 84 days, followed by 7 days of placebos. If an active pill is missed at any time, and no intercourse occurred in the past 5 days, two pills should be taken immediately and a backup method should be used for 7 days. If intercourse occurred in the previous 5 days, emergency contraception should be used immediately, and the pills restarted the following day. A backup method should be used for 5 days.

B. Benefits of Oral Contraceptives

Noncontraceptive benefits of oral contraceptives include lighter menses, reducing the likelihood of anemia. Dysmenorrhea is relieved for most women. Functional ovarian cysts are less likely with oral contraceptive use. The risk of ovarian and endometrial cancer is decreased. The risks of salpingitis and ectopic pregnancy may be diminished. Acne is usually improved. The frequency of developing myomas is lower in long-term users (> 4 years). There is a beneficial effect on bone mass.

C. Selection of an Oral Contraceptive

Any of the combination oral contraceptives containing 35 mcg or less of estrogen are suitable for most women. There is some variation in potency of the various progestins in the pills, but there are essentially no clinically significant differences for most women among the progestins in the low-dose pills. Women who have acne or hirsutism may benefit from use of one of the pills containing the third-generation progestins, desogestrel, drospirenone, or norgestimate, as they are the least androgenic. A combination regimen with 84 active and 7 inert pills that results in only four menses per year is available. The low-dose oral contraceptives commonly used in the United States are listed in Table 17-5.

Table 17-5. Commonly used low-dose oral contraceptives.

Name Progestin Estrogen (Ethinyl Estradiol) Cost per Month1
COMBINATION
Alesse 0.1 mg levonorgestrel 20 mcg $35.32
Loestrin 1/20
Microgestin 1/20
1 mg norethindrone acetate 20 mcg $50.33
$28.66
Mircette 0.15 mg desogestrel 20 mcg $41.30
Loestrin 1.5/30
Microgestin 1.5/30
1.5 mg norethindrone acetate 30 mcg $50.33
$28.94
Lo-Ovral
Low-ogestrel
0.3 mg norgestrel 30 mcg $37.54
$30.52
Nordette
Levlen
Levora
0.15 mg levonorgestrel 30 mcg $50.33
$36.50
$30.93
Ortho-Cept
Desogen
0.15 mg desogestrel 30 mcg $48.33
$34.02
Yasmin 3 mg drospirenone 30 mcg $43.94
Brevicon
Modicon
Necon 0.5/35
0.5 mg norethindrone 35 mcg $45.83
$52.71
$32.14
Demulen 1/35
Zovia 1/35E
1 mg ethynodiol diacetate 35 mcg $37.07
$29.88
Norinyl 1/35
Ortho-Novum 1/35
Necon 1/35
1 mg norethindrone 35 mcg $46.19
$48.33
$29.47
Ortho-Cyclen 0.25 mg norgestimate 35 mcg $46.13
Ovcon 35 0.4 mg norethindrone 35 mcg $42.92
COMBINATION: OTHER
Seasonale 0.15 mg levonorgestrel 30 mcg $51.13
TRIPHASIC
Estrostep 1.0 mg norethindrone acetate (days 1-5)
1.0 mg norethindrone acetate (days 6-12)
1.0 mg norethindrone acetate (days 13-21)
20 mcg
30 mcg
35 mcg
$42.92
Cyclessa 0.1 mg desogestrel (days 1-7)
0.125 mg desogestrel (days 8-14)
0.15 mg desogestrel (days 15-21)
25 mcg $39.52
Ortho-Tri-Cyclen Lo 0.18 norgestimate (days 1-7)
0.21 norgestimate (days 8-14)
0.25 norgestimate (days 15-21)
25 mcg $44.07
Triphasil
Trivora
Tri-Levlen
0.05 mg levonorgestrel (days 1-6)
0.075 mg levonorgestrel (days 7-11)
0.125 mg levonorgestrel (days 12-21)
30 mcg
40 mcg
30 mcg
$31.90
$27.49
$34.88
Ortho-Novum 7/7/7 0.5 mg norethindrone (days 1-7)
0.75 mg norethindrone (days 8-14)
1 mg norethindrone (days 15-21)
35 mcg $46.13
Ortho-Tri-Cyclen 0.15 mg norgestimate (days 1-7)
0.215 mg norgestimate (days 8-14)
0.25 mg norgestimate (days 15-21)
35 mcg $41.99
Tri-Norinyl 0.5 mg norethindrone (days 1-7)
1 mg norethindrone (days 8-16)
0.5 mg norethindrone (days 17-21)
35 mcg $44.08
PROGESTIN-ONLY MINIPILL
Ortho Micronor
Nor-QD
0.35 mg norethindrone to be taken continuously (None) $56.13
$48.80
Ovrette 0.075 mg norgestrel to be taken continuously (None) $35.34
1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25, No. 1, January 2006. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

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D. Drug Interactions

Several drugs interact with oral contraceptives to decrease their efficacy by causing induction of microsomal enzymes in the liver, by increasing sex hormone-binding globulin, and by other mechanisms. Some commonly prescribed drugs in this category are phenytoin, phenobarbital (and other barbiturates), primidone, carbamazepine, and rifampin. Women taking these drugs should use another means of contraception for maximum safety.

E. Contraindications and Adverse Effects

Oral contraceptives have been associated with many adverse effects; they are contraindicated in some situations and should be used with caution in others (Table 17-6).

1. Myocardial infarction

The risk of heart attack is higher with use of oral contraceptives, particularly with pills containing 50 mcg of estrogen or more. Cigarette smoking, obesity, hypertension, diabetes, or hypercholesterolemia increases the risk. Young nonsmoking women have minimal increased risk. Smokers over age 35 and women with other cardiovascular risk factors should use other methods of birth control.

2. Thromboembolic disease

An increased rate of venous thromboembolism is found in oral contraceptive users, especially if the dose of estrogen is 50 mcg or more. While the overall risk is very low (15 per 100,000 woman-years), several studies have reported a twofold increased risk in women using oral contraceptives containing the progestins gestodene (not available in the United States) or desogestrel compared with women using oral contraceptives with levonorgestrel and norethindrone. Women in whom thrombophlebitis develops should stop using this method, as should those at risk for thrombophlebitis because of surgery, fracture, serious injury, or immobilization. Women with a known thrombophilia should not use oral contraceptives.

Table 17-6. Contraindications to use of oral contraceptives.

Absolute contraindications
   Pregnancy
   Thrombophlebitis or thromboembolic disorders (past or present)
   Stroke or coronary artery disease (past or present)
   Cancer of the breast (known or suspected)
   Undiagnosed abnormal vaginal bleeding
   Estrogen-dependent cancer (known or suspected)
   Benign or malignant tumor of the liver (past or present)
   Uncontrolled hypertension
   Diabetes with vascular disease
   Age over 35 and smoking > 15 cigarettes daily
   Known thrombophilia
   Migraine with aura
   Active hepatitis
   Surgery or orthopedic injury requiring prolonged immobilization
Relative contraindications
   Migraine without aura
   Hypertension
   Cardiac or renal disease
   Diabetes
   Gallbladder disease
   Cholestasis during pregnancy
   Sickle cell disease (S/S or S/C type)
   Lactation

3. Cerebrovascular disease

Overall, a small increased risk of hemorrhagic stroke and subarachnoid hemorrhage and a somewhat greater increased risk of thrombotic stroke has been found; smoking, hypertension, and age over 35 years are associated with increased risk. Women should stop using contraceptives if such warning symptoms as severe headache, blurred or lost vision, or other transient neurologic disorders develop.

4. Carcinoma

A relationship between long-term (3–4 years) oral contraceptive use and occurrence of cervical dysplasia and cancer has been found in various studies. A 2002 study showed that there is no increased risk of breast cancer in women aged 35–64 who are current or former users of oral contraceptives. Women with a family history of breast cancer or women who started oral contraceptive use at a young age are not at increased risk. Combination oral contraceptives reduce the risk of endometrial carcinoma by 40% after 2 years of use and 60% after 4 or more years of use. The risk of ovarian cancer is reduced by 30% with pill use for less than 4 years, by 60% with use for 5–11 years, and by 80% after 12 or more years. Rarely, oral contraceptives have been associated with the development of benign or malignant hepatic tumors; this may lead to rupture of the liver, hemorrhage, and death. The risk increases with higher dosage, longer duration of use, and older age.

5. Hypertension

Oral contraceptives may cause hypertension in some women; the risk is increased with longer duration of use and older age. Women in whom hypertension develops while using oral contraceptives should use other contraceptive methods. However, with regular blood pressure monitoring, nonsmoking women under the age of 40 with well-controlled mild hypertension may use oral contraceptives.

6. Headache

Migraine or other vascular headaches may occur or worsen with pill use. If severe or frequent headaches develop while using this method, it should be discontinued. Women with migraine headaches with an aura should not use oral contraceptives.

7. Lactation

Combined oral contraceptives can impair the quantity and quality of breast milk. While it is preferable to avoid the use of combination oral contraceptives during lactation, the effects on milk quality are small and are not associated with developmental abnormalities in infants. Combination oral contraceptives

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should be started no earlier than 6 weeks postpartum to allow for establishment of lactation. Progestin-only pills, levonorgestrel implants, and depot medroxyprogesterone acetate are alternatives with no adverse effects on milk quality.

8. Other disorders

Depression may occur or be worsened with oral contraceptive use. Fluid retention may occur. Patients who had cholestatic jaundice during pregnancy may develop it while taking birth control pills.

F. Minor Side Effects

Nausea and dizziness may occur in the first few months of pill use. A weight gain of 2–5 lb commonly occurs. Spotting or breakthrough bleeding between menstrual periods may occur, especially if a pill is skipped or taken late; this may be helped by switching to a pill of slightly greater potency (see section C, above). Missed menstrual periods may occur, especially with low-dose pills. A pregnancy test should be performed if pills have been skipped or if two or more menstrual periods are missed. Depression, fatigue, and decreased libido can occur. Chloasma may occur, as in pregnancy, and is increased by exposure to sunlight.

Progestin Minipill

A. Efficacy and Methods of Use

Formulations containing 0.35 mg of norethindrone or 0.075 mg of norgestrel are available in the United States. Their efficacy is similar to that of combined oral contraceptives. The minipill is believed to prevent conception by causing thickening of the cervical mucus to make it hostile to sperm, alteration of ovum transport (which may account for the higher rate of ectopic pregnancy with these pills), and inhibition of implantation. Ovulation is inhibited inconsistently with this method. The minipill is begun on the first day of a menstrual cycle and then taken continuously for as long as contraception is desired.

B. Advantages

The low dose and absence of estrogen make the minipill safe during lactation; it may increase the flow of milk. It is often tried by women who want minimal doses of hormones and by patients who are over age 35. They lack the cardiovascular side effects of combination pills. The minipill can be safely used by women with sickle cell disease (S/S or S/C).

C. Complications and Contraindications

Minipill users often have bleeding irregularities (eg, prolonged flow, spotting, or amenorrhea); such patients may need regular pregnancy tests. Ectopic pregnancies are more frequent, and complaints of abdominal pain should be investigated with this in mind. The absolute contraindications and many of the relative contraindications listed in Table 17-6 apply to the minipill. Minor side effects of combination oral contraceptives such as weight gain and mild headache may also occur with the minipill.

Hatcher RA et al: Contraceptive Technology 18th edition 2004. Ardent Media, New York.

Reproductive Health and Research; World Health Organization: Medical Eligibilty Criteria for Contraceptive Use. WHO/RHR 2004, Geneva. http://www.who.int/reproductive-health/publications/mec/index.htm

Reproductive Health and Research; World Health Organization: Selected Practice Recommendations for Contraceptive Use. WHO/RHR 2004, Geneva. http://www.who.int/reproductive-health/publications/spr/index.htm

Seibert C et al: Prescribing oral contraceptives for women older than 35 years of age. Ann Intern Med 2003;138:54.

2. Contraceptive Injections & Implants (Long-Acting Progestins)

The injectable progestin medroxyprogesterone acetate (DMPA) is approved for contraceptive use in the United States. There is extensive worldwide experience with this method over the past 3 decades. The medication is given as a deep intramuscular injection of 150 mg every 3 months and has a contraceptive efficacy of 99.7%. A subcutaneous preparation, containing 104 mg of DMPA is available in the United States. Common side effects include irregular bleeding, amenorrhea, weight gain, and headache. It is associated with bone mineral loss that is usually reversible after discontinuation of the method. Users commonly have irregular bleeding initially and subsequently develop amenorrhea. Ovulation may be delayed after the last injection. Contraindications are similar to those for the minipill.

A monthly injectable containing both depot medroxyprogesterone acetate and an estrogen, estradiol cypionate (Lunelle), has been available in the United States, although it is not being marketed currently. It is highly effective, with a first-year pregnancy rate of 0.2% and a side effect profile similar to that of oral contraceptives.

The other long-acting progestin contraceptive is the Norplant system, a contraceptive implant containing levonorgestrel that is no longer available in the United States. The system consists of six small Silastic capsules that are inserted subcutaneously in the inner aspect of the upper arm. They release daily and provide highly effective contraception for 5 years. In the first year of use, Norplant is 99.8% effective. Contraceptive effectiveness drops slightly in succeeding years, but even in the fifth year it is more effective than the combination pill. The most common side effects include irregular bleeding and spotting, amenorrhea, headache, acne, and weight gain. Irregular bleeding is the most common reason for discontinuation. Hormone levels drop rapidly after removal of the implants, and there is no delay in the return of fertility. Contraindications are similar to those for the minipill. Insertion of the implants requires a minor surgical procedure under local anesthesia. Removal is also

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done under local anesthesia and may be more difficult than insertion. Removal may be facilitated by the “U” technique, involving use of a modified vasectomy clamp through a 4-mm incision parallel to the implants between implants three and four.

Berenson AB et al: Effects of hormonal contraception on bone mineral density after 24 months of use. Obstet Gynecol 2004; 103:899.

Kaunitz AM: Beyond the pill: new data and options in hormonal and intrauterine contraception. Am J Obstet Gynecol 2005; 192:998.

World Health Organization: WHO Statement on Hormonal Contraception and Bone Health 2005 http://www.who.nt/reproductive-health/family_planning/docs/hormonal_contraception_ bone_health.pdf

3. Other Hormonal Methods

A transdermal contraceptive patch containing 150 mcg norelgestromin and 20 mcg ethinyl estradiol and measuring 20 cm2 is available. The patch is applied to the lower abdomen, upper torso, or buttock once a week for 3 consecutive weeks, followed by 1 week without the patch. It appears that the average steady-state concentration of ethinyl estradiol with the patch is approximately 60% higher than with a 35 mcg pill. However, there is currently no evidence for an increased incidence of estrogen-related side effects. The mechanism of action, side effects, and efficacy are similar to those associated with oral contraceptives, although compliance may be better.

A contraceptive vaginal ring that measures 54 mm in diameter and releases 120 mcg of etonogestrel and 15 mcg of ethinyl estradiol daily is available. The ring is soft and flexible and is placed in the upper vagina for 3 weeks, removed, and replaced 1 week later. The efficacy, mechanism of action, and systemic side effects are similar to those associated with oral contraceptives. In addition, users may experience an increased incidence of vaginal discharge.

Veres S et al: A comparison between the vaginal ring and oral contraceptives. Obstet Gynecol 2004;104:555.

4. Intrauterine Devices

IUDs available in the United States include the Mirena (which releases levonorgestrel) and the copper-bearing TCu380A. The mechanism of action of IUDs is thought to involve either spermicidal or inhibitory effects on sperm capacitation and transport. IUDs are not abortifacients.

The Mirena is effective for 5 years, and the TCu380A for 10 years. The hormone-containing IUDs have the advantage of reducing cramping and menstrual flow.

The IUD is an excellent contraceptive method for most women. The devices are highly effective, with failure rates similar to those achieved with surgical sterilization. Nulliparity is not a contraindication to IUD use. Women who are not in mutually monogamous relationships should use condoms for protection from sexually transmitted diseases. The Mirena may have a protective effect against upper tract infection similar to that of the oral contraceptives.

Insertion

Insertion can be performed during or after the menses, at midcycle to prevent implantation, or later in the cycle if the patient has not become pregnant. Most clinicians wait for 6–8 weeks postpartum before inserting an IUD. When insertion is performed during lactation, there is greater risk of uterine perforation or embedding of the IUD. Insertion immediately following abortion is acceptable if there is no sepsis and if follow-up insertion a month later will not be possible; otherwise, it is wise to wait until 4 weeks postabortion.

Contraindications & Complications

Contraindications to use of IUDs are outlined in Table 17-7.

A. Pregnancy

A copper-containing IUD can be inserted within 5 days following a single episode of unprotected mid-cycle coitus as a postcoital contraceptive. An IUD should not be inserted into a pregnant uterus. If pregnancy occurs as an IUD failure, there is a greater chance of spontaneous abortion if the IUD is left in situ (50%) than if it is removed (25%). Spontaneous abortion with an IUD in place is associated with a high risk of severe sepsis, and death can occur rapidly. Women using an IUD who become pregnant should have the IUD removed if the string is visible. It can be removed at the time of abortion if this is desired. If the string is not visible and the patient wants to continue the pregnancy, she should be informed of the serious risk of sepsis and, occasionally, death with such pregnancies. She should be informed that any flu-like

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symptoms such as fever, myalgia, headache, or nausea warrant immediate medical attention for possible septic abortion.

Table 17-7. Contraindications to IUD use.

Absolute contraindications
   Pregnancy
   Acute or subacute pelvic inflammatory disease or purulent cervicitis
   Significant anatomic abnormality of uterus
   Unexplained uterine bleeding
   Active liver disease (Mirena only)
Relative contraindications
   History of pelvic inflammatory disease since the last pregnancy
   Lack of available follow-up care
   Menorrhagia or severe dysmenorrhea (copper IUD)
   Cervical or uterine neoplasia
IUD = intrauterine device.

Since the ratio of ectopic to intrauterine pregnancies is increased among IUD wearers, clinicians should search for adnexal masses in early pregnancy and should always check the products of conception for placental tissue following abortion.

B. Pelvic Infection

There is an increased risk of pelvic infection during the first month following insertion. The subsequent risk of pelvic infection appears to be primarily related to the risk of acquiring sexually transmitted infections. Infertility rates do not appear to be increased among women who have previously used the currently available IUDs. At the time of insertion, women with an increased risk of sexually transmitted diseases should be screened for gonorrhea and Chlamydia. Women with a history of recent or recurrent pelvic infection are not good candidates for IUD use.

C. Menorrhagia or Severe Dysmenorrhea

The copper IUD can cause heavier menstrual periods, bleeding between periods, and more cramping, so it is generally not suitable for women who already suffer from these problems. However, hormone-releasing IUDs can be tried in these cases, as they often cause decreased bleeding and cramping with menses. NSAIDs are also helpful in decreasing bleeding and pain in IUD users.

D. Complete or Partial Expulsion

Spontaneous expulsion of the IUD occurs in 10–20% of cases during the first year of use. Any IUD should be removed if the body of the device can be seen or felt in the cervical os.

E. Missing IUD Strings

If the transcervical tail cannot be seen, this may signify unnoticed expulsion, perforation of the uterus with abdominal migration of the IUD, or simply retraction of the string into the cervical canal or uterus owing to movement of the IUD or uterine growth with pregnancy. Once pregnancy is ruled out, one should probe for the IUD with a sterile sound or forceps designed for IUD removal, after administering a paracervical block. If the IUD cannot be detected, pelvic ultrasound will demonstrate the IUD if it is in the uterus. Alternatively, obtain anteroposterior and lateral x-rays of the pelvis with another IUD or a sound in the uterus as a marker, to confirm an extrauterine IUD. If the IUD is in the abdominal cavity, it should generally be removed by laparoscopy or laparotomy. Open-looped all-plastic IUDs such as the Lippes Loop can be left in the pelvis without danger, but ring-shaped IUDs may strangulate a loop of bowel and copper-bearing IUDs may cause tissue reaction and adhesions.

Perforations of the uterus are less likely if insertion is performed slowly, with meticulous care taken to follow directions applicable to each type of IUD.

ACOG Committee on Practice Bulletins-Gynecology: ACOG practice bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 59, January 2005. Intrauterine device. Obstet Gynecol 2005;105:223.

5. Diaphragm & Cervical Cap

The diaphragm (with contraceptive jelly) is a safe and effective contraceptive method with features that make it acceptable to some women and not others. Failure rates range from 6% to 16%, depending on the motivation of the woman and the care with which the diaphragm is used. The advantages of this method are that it has no systemic side effects and gives significant protection against pelvic infection and cervical dysplasia as well as pregnancy. The disadvantages are that it must be inserted near the time of coitus and that pressure from the rim predisposes some women to cystitis after intercourse.

The cervical cap (with contraceptive jelly) is similar to the diaphragm but fits snugly over the cervix only (the diaphragm stretches from behind the cervix to behind the pubic symphysis). The cervical cap is more difficult to insert and remove than the diaphragm. The main advantages are that it can be used by women who cannot be fitted for a diaphragm because of a relaxed anterior vaginal wall or by women who have discomfort or develop repeated bladder infections with the diaphragm. However, failure rates are 16% (typical use) and 9% (perfect use) in nulliparous women and 32% (typical use) and 26% (perfect use) in parous women.

Because of the small risk of toxic shock syndrome, a cervical cap or diaphragm should not be left in the vagina for over 12–18 hours, nor should these devices be used during the menstrual period.

6. Contraceptive Foam, Cream, Film, Sponge, Jelly, & Suppository

These products are available without prescription, are easy to use, and are fairly effective, with typical failure rates of 10–22%. All contain the spermicide nonoxynol-9, which also has some virucidal and bactericidal activity. Nonoxynol-9 does not appear to adversely affect the vaginal colonization of hydrogen peroxide-producing lactobacilli. A 2002 study suggests that nonoxynol-9 is not protective against HIV infection, particularly in women who have frequent intercourse.

Raymond EG et al: Contraceptive effectiveness and safety of five nonoxynol-9 spermicides: a randomized trial. Obstet Gynecol 2004;103;430.

Van Damme L et al: Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 2002;360:971.

7. Condom

The male condom of latex or animal membrane affords good protection against pregnancy—equivalent to that of

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a diaphragm and spermicidal jelly; latex (but not animal membrane) condoms also offer protection against many sexually transmitted diseases, including HIV. When a spermicide, such as vaginal foam, is used with the condom, the failure rate approaches that of oral contraceptives. The disadvantages of condoms are dulling of sensation and spillage of semen due to tearing, slipping, or leakage with detumescence of the penis.

A female condom made of polyurethane is available in the United States. The reported failure rates range from 5% to 21%; the efficacy is comparable to that of the diaphragm. This is the only female-controlled method that offers significant protection from both pregnancy and sexually transmitted diseases.

Holmes KK et al: Effectiveness of condoms in preventing sexually transmitted infections. Bull World Health Organ 2004;82: 454.

8. Contraception Based on Awareness of Fertile Periods

These methods are most effective when the couple restricts intercourse to the postovular phase of the cycle or uses a barrier method at other times. Well-instructed, motivated couples may be able to achieve low pregnancy rates with fertility awareness methods. However, properly done randomized clinical trials comparing the efficacy of most of these methods with other contraceptive methods do not exist.

Grimes DA et al: Fertility awareness-based methods for contraception: systematic review of randomized controlled trials. Contraception 2005;72:85.

“Symptothermal” Natural Family Planning

The basis for this approach is patient-observed increase in clear elastic cervical mucus, brief abdominal midcycle discomfort (“mittelschmerz”), and a sustained rise of the basal body temperature about 2 weeks after onset of menstruation. Unprotected intercourse is avoided from shortly after the menstrual period, when fertile mucus is first identified, until 48 hours after ovulation, as identified by a sustained rise in temperature and the disappearance of clear elastic mucus.

Calendar Method

After the length of the menstrual cycle has been observed for at least 8 months, the following calculations are made: (1) The first fertile day is determined by subtracting 18 days from the shortest cycle, and (2) the last fertile day is determined by subtracting 11 days from the longest cycle. For example, if the observed cycles run from 24 to 28 days, the fertile period would extend from the sixth day of the cycle (24 minus 18) through the 17th day (28 minus 11). Day 1 of the cycle is the first day of menses.

Basal Body Temperature Method

This method indicates the safe time for intercourse after ovulation has passed. The temperature must be taken immediately upon awakening, before any activity. A slight drop in temperature often occurs 12–24 hours before ovulation, and a rise of about 0.4°C occurs 1–2 days after ovulation. The elevated temperature continues throughout the remainder of the cycle. Data suggest that the risk of pregnancy increases starting 5 days prior to the day of ovulation, peaks on the day of ovulation, and then rapidly decreases to zero by the day after ovulation.

Standard Days Method

This fertility awareness method requires the use of a set of beads that reminds the couple to avoid intercourse (or use a barrier method of contraception) during days 8 through 19 of the menstrual cycle. The beads are in a circle and color-coded to show the days when a woman is likely to become pregnant and the days that are “safe” during the cycle. A movable ring is repositioned to a new bead each day starting on the first day of menses. In a small multicenter trial, the perfect use failure rate was 5% and the typical use failure rate was 12%. The method is applicable to women with a history of menstrual cycles between 29 and 32 days.

Arevalo M et al: Efficacy of a new method of family planning: the Standard Days Method. Contraception 2002;65:333.

TwoDay Method

The TwoDay method requires that women be able to identify cervical secretions by observation or touching them in underwear or toilet paper, by touching the genitals, or by the sensation of wetness in the genital area or on underwear. The woman then uses a two-question algorithm to determine whether she is fertile. She asks herself: 1) Did I note secretions today? and 2) Did I note secretions yesterday? If the answer to either of these questions is “yes,” she should consider herself fertile. In a multicenter study of 450 women, effectiveness with perfect use was 96.5% and with typical use 76.3%.

Arevelo M et al: Efficacy of the new TwoDay Method of family planning. Fertil Steril 2004;82:885.

9. Emergency Contraception

If unprotected intercourse occurs in midcycle and the woman is certain she has not inadvertently become pregnant earlier in the cycle, the following regimens are effective in preventing implantation. These methods should be started as soon as possible and within 120 hours after unprotected coitus. (1) Levonorgestrel, 0.75 mg given in two doses 12 hours apart (available in the United States prepackaged as Plan B),

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has a 1% failure rate, when taken within 72 hours, and is associated with less nausea and vomiting than the following combination regimen. A recent study has demonstrated that levonorgestrel, 1.5 mg as a single dose, given within 72 hours after intercourse, is slightly more effective than the two-dose regimen. It remains efficacious up to 120 hours after intercourse, though less so compared with earlier use. (2) Ethinyl estradiol, 50 mcg, with 0.5 mg norgestrel (available in the United States prepackaged as Preven), given in a regimen of two tablets initially followed by two tablets 12 hours later. A comparable regimen includes four pills 12 hours apart of Lo/Ovral, Nordette, or Levlen, or the same regimen with the yellow pills of Triphasil or Tri-Levlen. The failure rate is approximately 3%, and antinausea medication should be provided. Mifepristone, 10 mg as a single dose, has been shown to have the same failure rate as the levonorgestrel regimen. It is not currently available at this dose in the United States.

IUD insertion within 5 days after one episode of unprotected midcycle coitus will also prevent pregnancy; copper-bearing IUDs have been tested for this purpose. Information on clinics or individual clinicians providing emergency contraception in the United States may be obtained by calling 1–888-668–2528.

American College of Obstetricians and Gynecologists: ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists, Number 69, December 2005. Emergency contraception. Obstet Gynecol 2005;106:1443.

von Hertzen H et al: Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomized trial. Lancet 2002;360:1803.

10. Abortion

Since the legalization of abortion in the United States in 1973, the related maternal mortality rate has fallen markedly, because illegal and self-induced abortions have been replaced by safer medical procedures. Abortions in the first trimester of pregnancy are performed by vacuum aspiration under local anesthesia or with medical regimens. Dilation and evacuation, a variation of vacuum aspiration is generally used in the second trimester. Techniques utilizing intra-amniotic instillation of hypertonic saline solution or various prostaglandins regimens, along with medical or osmotic dilators are occasionally used after 18 weeks. Overall, legal abortion in the United States has a mortality rate of less than 1:100,000. Rates of morbidity and mortality rise with length of gestation. Currently in the United States, 87% of abortions are performed before 13 weeks' gestation and only 1.4% are performed after 20 weeks. If abortion is chosen, every effort should be made to encourage the patient to seek an early procedure. While numerous state laws limiting access to abortion and a federal law banning a rarely-used variation of dilation and evacuation have been enacted, abortion remains legal and available until fetal viability under Roe v. Wade.

Complications resulting from abortion include retained products of conception (often associated with infection and heavy bleeding) and unrecognized ectopic pregnancy. Immediate analysis of the removed tissue for placenta can exclude or corroborate the diagnosis of ectopic pregnancy. Women who have fever, bleeding, or abdominal pain after abortion should be examined; use of broad-spectrum antibiotics and reaspiration of the uterus are frequently necessary. Hospitalization is advisable if acute salpingitis requires intravenous administration of antibiotics. Complications following illegal abortion often need emergency care for hemorrhage, septic shock, or uterine perforation.

Rh immune globulin should be given to all Rh-negative women following abortion. Contraception should be thoroughly discussed and contraceptive supplies or pills provided at the time of abortion. Prophylactic antibiotics are indicated; for example a one-dose regimen of doxycycline, 200 mg orally 1 hour before the procedure. Many clinics prescribe tetracycline, 500 mg four times daily for 5 days after the procedure, as presumptive treatment for Chlamydia.

Long-term sequelae of repeated induced abortions have been studied, but as yet there is no consensus on whether there are increased rates of fetal loss or premature labor. It is felt that such adverse sequelae can be minimized by performing early abortion with minimal cervical dilation or by the use of osmotic dilators to induce gradual cervical dilation. A population-based study showed no evidence of an increased risk of breast cancer in women who had undergone an induced abortion.

Mifepristone (RU 486) is approved by the FDA as an oral abortifacient; the dose is 600 mg orally on day 1. It is followed by 400 mcg orally of misoprostol (a prostaglandin) on day 3. This combination is 95% successful in terminating pregnancies of up to 9 weeks' duration with minimum complications. Although not approved by the FDA for this indication, a combination of intramuscular methotrexate, 50 mg/m2 of body surface area, followed 7 days later by vaginal misoprostol, 800 mcg, was 98% successful in terminating pregnancy at 8 weeks or less. Minor side effects, such as nausea, vomiting, and diarrhea, are common with these regimens. There is a 5–10% incidence of hemorrhage or incomplete abortion requiring curettage. There is a recent report of four deaths occurring within 1 week of medical abortion, associated with endometritis and toxic shock caused by Clostridium sordellii. To improve diagnosis and treatment of this entity, clinicians should be aware of the constellation of presenting symptoms of tachycardia, hypotension, edema, hemoconcentration, profound leukocytosis, and absence of fever.

ACOG: ACOG practice bulletin: Clinical management guidelines of Obstetrician-Gynecologists. Number 67, October 2005. Medical management of abortion. Obstet Gynecol 2005;106:871.

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Fischer M et al: Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 2005;353:2352.

Grimes DA et al: Induced abortion: an overview for internists. Ann Intern Med 2004;140:620.

11. Sterilization

In the United States, sterilization is the most popular method of birth control for couples who want no more children. Although sterilization is reversible in some instances, reversal surgery in both men and women is costly, complicated, and not always successful. Therefore, patients should be counseled carefully before sterilization and should view the procedure as final.

Vasectomy is a safe, simple procedure in which the vas deferens is severed and sealed through a scrotal incision under local anesthesia. Long-term follow-up studies on vasectomized men show no excess risk of cardiovascular disease. Several studies have shown a possible association with prostate cancer, but the evidence is weak and inconsistent.

Female sterilization procedures include laparoscopic bipolar electrocoagulation, or plastic ring application on the uterine tubes, or minilaparotomy with Pomeroy tubal resection. The advantages of laparoscopy are minimal postoperative pain, small incisions, and rapid recovery. The advantages of minilaparotomy are that it can be performed with standard surgical instruments under local or general anesthesia. However, there is more postoperative pain and a longer recovery period. The cumulative 10-year failure rate for all methods combined is 1.85%, varying from 0.75% for postpartum partial salpingectomy and laparoscopic unipolar coagulation to 3.65% for spring clips; this fact should be discussed with women preoperatively. Some studies have found an increased risk of menstrual irregularities as a long-term complication of tubal ligation, but findings in different studies have been inconsistent. A new method of transcervical sterilization, Essure, is approved by the FDA. The method involves the placement of an expanding microcoil of titanium into the proximal uterine tube under hysteroscopic guidance. The efficacy rate at 1 year is 99.8%.

Magos A et al: Hysteroscopic tubal sterilization. Obstet Gynecol Clin North Am 2004;31:705.

Pollack A et al: ACOG practice bulletin. Benefits and risks of sterilization. Obstet Gynecol 2003;102:647.

Rape

Essentials of Diagnosis

  • Women neither secretly want to be raped nor do they expect, encourage, or enjoy rape.

  • Rape is always a terrifying experience in which most victims fear for their lives.

  • The rapist is usually a hostile man who uses sexual intercourse to terrorize and humiliate a woman.

General Considerations

Rape, or sexual assault, is legally defined in different ways in various jurisdictions. Clinicians and emergency department personnel who deal with rape victims should be familiar with the laws pertaining to sexual assault in their own state. From a medical and psychological viewpoint, it is essential that persons treating rape victims recognize the nonconsensual and violent nature of the crime. About 95% of reported rape victims are women. Penetration may be vaginal, anal, or oral and may be by the penis, hand, or a foreign object. The absence of genital injury does not imply consent by the victim. The assailant may be unknown to the victim or, more frequently, may be an acquaintance or even the spouse.

“Unlawful sexual intercourse,” or statutory rape, is intercourse with a female before the age of majority even with her consent.

Rape represents an expression of anger, power, and sexuality on the part of the rapist. The rapist is usually a hostile man who uses sexual intercourse to terrorize and humiliate a woman. Women neither secretly want to be raped nor do they expect, encourage, or enjoy rape.

Rape involves severe physical injury in 5–10% of cases and is always a terrifying experience in which most victims fear for their lives. Consequently, all victims suffer some psychological aftermath. Moreover, some rape victims may acquire sexually transmissible disease or become pregnant.

Because rape is a personal crisis, each patient will react differently. The rape trauma syndrome comprises two principal phases. (1) Immediate or acute: Shaking, sobbing, and restless activity may last from a few days to a few weeks. The patient may experience anger, guilt, or shame or may repress these emotions. Reactions vary depending on the victim's personality and the circumstances of the attack. (2) Late or chronic: Problems related to the attack may develop weeks or months later. The lifestyle and work patterns of the individual may change. Sleep disorders or phobias often develop. Loss of self-esteem can rarely lead to suicide.

Clinicians and emergency department personnel who deal with rape victims should work with community rape crisis centers whenever possible to provide ongoing support and counseling.

General Office Procedures

The clinician who first sees the alleged rape victim should be empathetic. Begin with a statement such as, “This is a terrible thing that has happened to you. I want to help.”

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  • Secure written consent from the patient, guardian, or next of kin for gynecologic examination and for photographs if they are likely to be useful as evidence. If police are to be notified, do so, and obtain advice on the preservation and transfer of evidence.

  • Obtain and record the history in the patient's own words. The sequence of events, ie, the time, place, and circumstances, must be included. Note the date of the LMP, whether or not the woman is pregnant, and the time of the most recent coitus prior to the sexual assault. Note the details of the assault such as body cavities penetrated, use of foreign objects, and number of assailants. Note whether the victim is calm, agitated, or confused (drugs or alcohol may be involved). Record whether the patient came directly to the hospital or whether she bathed or changed her clothing. Record findings but do not issue even a tentative diagnosis lest it be erroneous or incomplete.

  • Have the patient disrobe while standing on a white sheet. Hair, dirt, and leaves, underclothing, and any torn or stained clothing should be kept as evidence. Scrape material from beneath fingernails and comb pubic hair for evidence. Place all evidence in separate clean paper bags or envelopes and label carefully.

  • Examine the patient, noting any traumatized areas that should be photographed. Examine the body and genitals with a Wood light to identify semen, which fluoresces; positive areas should be swabbed with a premoistened swab and air-dried in order to identify acid phosphatase. Colposcopy can be used to identify small areas of trauma from forced entry especially at the posterior fourchette.

  • Perform a pelvic examination, explaining all procedures and obtaining the patient's consent before proceeding gently with the examination. Use a narrow speculum lubricated with water only. Collect material with sterile cotton swabs from the vaginal walls and cervix and make two air-dried smears on clean glass slides. Wet and dry swabs of vaginal secretions should be collected and refrigerated for subsequent acid phosphatase and DNA evaluation. Swab the mouth (around molars and cheeks) and anus in the same way, if appropriate. Label all slides carefully. Collect secretions from the vagina, anus, or mouth with a premoistened cotton swab, place at once on a slide with a drop of saline, and cover with a coverslip. Look for motile or nonmotile sperm under high, dry magnification, and record the percentage of motile forms.

  • Perform appropriate laboratory tests as follows. Culture the vagina, anus, or mouth (as appropriate) for N gonorrhoeae and Chlamydia. Perform a Papanicolaou smear of the cervix, a wet mount for Trichomonas vaginalis, a baseline pregnancy test, and VDRL test. A confidential test for HIV antibody can be obtained if desired by the patient and repeated in 2–4 months if initially negative. Repeat the pregnancy test if the next menses is missed, and repeat the VDRL test in 6 weeks. Obtain blood (10 mL without anticoagulant) and urine (100 mL) specimens if there is a history of forced ingestion or injection of drugs or alcohol.

  • Transfer clearly labeled evidence, eg, laboratory specimens, directly to the clinical pathologist in charge or to the responsible laboratory technician, in the presence of witnesses (never via messenger), so that the rules of evidence will not be breached.

Treatment

Give analgesics or sedatives if indicated. Administer tetanus toxoid if deep lacerations contain soil or dirt particles.

Give ceftriaxone, 125 mg intramuscularly, to prevent gonorrhea. In addition, give metronidazole, 2 g as a single dose, and azithromycin 1 g orally or doxycycline, 100 mg twice daily for 7 days to treat chlamydial infection. Incubating syphilis will probably be prevented by these medications, but the VDRL test should be repeated 6 weeks after the assault.

Prevent pregnancy by using one of the methods discussed under Emergency Contraception, if necessary (this chapter).

Vaccinate against hepatitis B. Consider HIV prophylaxis (see Chapter 31).

Make sure the patient and her family and friends have a source of ongoing psychological support.

Cantu M et al: Evaluation and management of the sexually assaulted woman. Emerg Med Clin North Am 2003;21:737.

Menopausal Syndrome

Essentials of Diagnosis

  • Cessation of menses due to aging or to bilateral oophorectomy.

  • Elevation of FSH and LH levels.

  • Hot flushes and night sweats (in 80% of women).

  • Decreased vaginal lubrication; thinned vaginal mucosa with or without dyspareunia.

General Considerations

The term “menopause” denotes the final cessation of menstruation, either as a normal part of aging or as the result of surgical removal of both ovaries. In a broader sense, as the term is commonly used, it denotes a 1- to 3-year period during which a woman adjusts to a diminishing and then absent menstrual flow and the physiologic changes that may be associated—hot flushes, night sweats, and vaginal dryness.

The average age at menopause in Western societies today is 51 years. Premature menopause is defined as ovarian failure and menstrual cessation before age 40;

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this often has a genetic or autoimmune basis. Surgical menopause due to bilateral oophorectomy is common and can cause more severe symptoms owing to the sudden rapid drop in sex hormone levels.

There is no objective evidence that cessation of ovarian function is associated with severe emotional disturbance or personality changes. However, mood changes toward depression and anxiety can occur at this time. Furthermore, the time of menopause often coincides with other major life changes, such as departure of children from the home, a midlife identity crisis, or divorce. These events, coupled with a sense of the loss of youth, may exacerbate the symptoms of menopause and cause psychological distress.

Clinical Findings

A. Symptoms and Signs

1. Cessation of menstruation

Menstrual cycles generally become irregular as menopause approaches. Anovular cycles occur more often, with irregular cycle length and occasional menorrhagia. Menstrual flow usually diminishes in amount owing to decreased estrogen secretion, resulting in less abundant endometrial growth. Finally, cycles become longer, with missed periods or episodes of spotting only. When no bleeding has occurred for 1 year, the menopausal transition can be said to have occurred. Any bleeding after this time warrants investigation by endometrial curettage or aspiration to rule out endometrial cancer.

2. Hot flushes

Hot flushes (feelings of intense heat over the trunk and face, with flushing of the skin and sweating) occur in 80% of women as a result of the decrease in ovarian hormones. Hot flushes can begin before the cessation of menses. An increase in pulsatile release of GnRH from the hypothalamus is believed to trigger the hot flushes by affecting the adjacent temperature-regulating area of the brain. Hot flushes are more severe in women who undergo surgical menopause. Flushing is more pronounced late in the day, during hot weather, after ingestion of hot foods or drinks, or during periods of tension. Occurring at night, they often cause sweating and insomnia and result in fatigue on the following day.

3. Vaginal atrophy

With decreased estrogen secretion, thinning of the vaginal mucosa and decreased vaginal lubrication occur and may lead to dyspareunia. The introitus decreases in diameter. Pelvic examination reveals pale, smooth vaginal mucosa and a small cervix and uterus. The ovaries are not normally palpable after the menopause. Continued sexual activity will help prevent tissue shrinkage.

4. Osteoporosis

Osteoporosis may occur as a late sequela of menopause.

B. Laboratory Findings

Serum FSH and LH levels are elevated. Vaginal cytologic examination will show a low estrogen effect with predominantly parabasal cells, indicating lack of epithelial maturation due to hypoestrinism.

Treatment

A. Natural Menopause

Education and support from health providers, midlife discussion groups, and reading material will help most women having difficulty adjusting to the menopause. Physiologic symptoms can be treated as follows.

1. Vasomotor symptoms

Oral conjugated estrogens, 0.3 mg or 0.625 mg, estradiol, 0.5 or 1 mg, or estrone sulfate, 0.625 mg; or estradiol can be given transdermally as skin patches that are changed once or twice weekly and secrete 0.05–0.1 mg of hormone daily. When either form of estrogen is used, add a progestin (medroxyprogesterone acetate) to prevent endometrial hyperplasia or cancer. The hormones can be given in several differing regimens. Give estrogen on days 1–25 of each calendar month, with 5–10 mg of medroxyprogesterone acetate added on days 14–25. Withhold hormones from day 26 until the end of the month, when the endometrium will be shed, producing a light, generally painless monthly period. Alternatively, give the estrogen along with 2.5 mg of medroxyprogesterone acetate daily, without stopping. This regimen causes some initial bleeding or spotting, but within a few months it produces an atrophic endometrium that will not bleed. If the patient has had a hysterectomy, a progestin need not be used.

Data from the Women's Health Initiative (WHI) study suggest that women should not use combination progestin-estrogen therapy for more than 3 or 4 years. In this study, the increased risk of cardiovascular disease, cerebrovascular disease, and breast cancer with this regimen outweighed the benefits. Women who cannot find relief with alternative approaches may wish to consider continuing use of combination therapy after a thorough discussion of the risks and benefits. Alternatives to hormone therapy for vasomotor symptoms include selective serotonin reuptake inhibitors such as paroxetine 12.5 mg or 25 mg/d, venlafaxine 75 mg/d. Gabapentin, an antiseizure medication, is also effective at 900 mg/d. Clonidine given orally or transdermally, 100–150 mcg daily, may also reduce the frequency of hot flushes, but its use is limited by side effects, including dry mouth, drowsiness, and hypotension.

2. Vaginal atrophy

An estradiol vaginal ring that can be left in place for 3 months and is suitable for long-term use provides effective relief of vaginal atrophy. There is minimal systemic absorption of estradiol with the ring, and progestin therapy to protect the endometrium is unnecessary. Short-term use of estrogen vaginal cream will relieve symptoms of atrophy, but because of variable absorption, therapy with either the vaginal ring or systemic hormone replacement is preferable. Testosterone propionate 1–2%, 0.5–1 g, in a vanishing cream base used in the same manner is also

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effective if estrogen is contraindicated. A bland lubricant such as unscented cold cream or water-soluble gel can be helpful at the time of coitus.

3. Osteoporosis

(See also discussion in Chapter 26.) Women should ingest at least 800 mg of calcium daily throughout life. Nonfat or low-fat milk products, calcium-fortified orange juice, green leafy vegetables, corn tortillas, and canned sardines or salmon consumed with the bones are good dietary sources. In addition, 1 g of elemental calcium should be taken as a daily supplement at the time of the menopause and thereafter; calcium supplements should be taken with meals to increase their absorption. Vitamin D, 400 units/d from food, sunlight, or supplements, is necessary to enhance calcium absorption. A daily program of energetic walking and exercise to strengthen the arms and upper body helps maintain bone mass.

Women most at risk for osteoporotic fractures should consider bisphosphonates, raloxifene, or hormone replacement therapy. This includes white and Asian women, especially if they have a family history of osteoporosis; are thin, short, cigarette smokers, and physically inactive; or have had a low calcium intake in adult life.

B. Risks of Hormone Therapy

Double-blinded randomized, controlled trials have shown no overall cardiovascular benefit with estrogen-progestin replacement therapy in a group of postmenopausal women with or without established coronary disease. Both in the WHI trial and the Heart and Estrogen/Progestin Replacement Study (HERS), the overall health risks (increased risk of coronary heart events, strokes, thromboembolic disease, breast cancers, gallstones) exceeded the benefits from the use of combination estrogen and progesterone. Progestins counteract some but not all favorable effects of estrogen. Women who have been receiving long-term estrogen-progestin hormone replacement therapy (HRT), even in the absence of complications should be encouraged to stop, especially if they do not have menopausal symptoms. An ancillary study of the WHI study showed that not only did estrogen-progestin HRT not benefit cognitive function but there was a small increased risk of cognitive decline in that group compared with women in the placebo group. The unopposed estrogen arm of the WHI trial demonstrated a decrease in the risk of hip fracture, a small but nonsignificant decrease in breast cancer, but an increased risk of stroke and no evidence of protection from coronary heart disease. The study also showed a small increase in the combined risk of mild cognitive impairment and dementia with estrogen use compared with placebo, similar to the estrogen-progestin arm. (See also discussions of estrogen and progestin replacement therapy in Chapter 26.)

C. Surgical Menopause

The abrupt hormonal decrease resulting from oophorectomy generally results in severe vasomotor symptoms and rapid onset of dyspareunia and osteoporosis unless treated. Estrogen replacement is generally started immediately after surgery. Conjugated estrogens 1.25 mg, estrone sulfate 1.25 mg, or estradiol 2 mg is given for 25 days of each month. After age 45–50 years, this dose can be tapered to 0.625 mg of conjugated estrogens or equivalent.

Anderson GL: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701.

National Institutes of Health: National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann Intern Med 2005;142:1003.

Rapp SR et al: Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2663.

Rossouw JE et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321.

Shumaker SA et al: Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004;291:2947.