Algunas Cuestiones sobre el Estudio de las Actitudes

B. Diagnosis is by determination of bone mineral density (BMD). The four most widely used methods for assessing bone density are single-photon

absorptiometry, dual-photon absorptiometry, dual-energy x-ray absorptiometry, and quantitative CT. BMD should be measured in any postmenopausal patient who presents with a fracture. Other candidates for BMD determination are all women older than 65 years, postmenopausal women under age 65 with one or more risk factors, and women in whom decreased BMD would influence the decision to initiate HRT. BMD is best measured at the hip and is

predictive of hip fracture and fracture at other sites. T-values are assigned and are scored as standard deviations above or below the mean BMD of a young woman of approximately 25 years. Normal bone T-scores are above –1.0; osteopenia T-scores are between –1.0 and –2.5; osteoporosis T-scores are at or below –2.5. For each reduction in bone mass of one standard deviation, the risk of fracture doubles.

A prospective study found that patients on HRT had increased spine and hip BMD, whereas women receiving placebo had a decrease in BMD. Although retrospective studies reveal decreased incidence of spine and hip fractures in patients on HRT, no large prospective study has demonstrated that estrogen prevents fractures. However, a 12-month study of 75 women with osteoporosis who used transdermal estrogen found that HRT patients had fewer vertebral fractures than did patients in the placebo group.

V. Alternative therapies may be advised for a patient with contraindications to estrogen use.

A. Alendronate sodium is a bisphosphonate approved for prevention and treatment of osteoporosis. Bisphosphonates are a class of drugs analogous to the physiologically occurring inorganic pyrophosphates and are inhibitors of bone resorption. The U.S. Food and Drug Administration (FDA) has approved alendronate 5 mg daily for prevention of osteoporosis and 10 mg daily for treatment. A formulation with a once-weekly dose of 70 mg has been released.

Treatment with oral alendronate not only prevents bone loss but progressively increases the bone mass of the spine, hip, and total body. It also reduces the risk of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.

B. Risedronate sodium, also an oral bisphosphonate, has been recently approved by the FDA for the same indications as alendronate. Recommended dosing is 5 mg daily for prevention and treatment of osteoporosis. A 2-year prospective study of postmenopausal women with normal lumbar spine BMD values found that patients receiving 5 mg daily had an increase in spine and femoral trochanter BMD, whereas patients in the placebo group experienced decreases in BMD at both sites. The benefits of treatment are sustained: 1 year after cessation of therapy, lumbar spine BMD was 2.3% lower than baseline in patients given risedronate but 5.6% lower in patients receiving placebo.

C. Side effects of alendronate and risedronate include heartburn, esophageal irritation, esophagitis, abdominal pain, and diarrhea. Oral calcium

supplementation may interfere with the absorption of bisphosphonates. The patient should take each dose after an overnight fast while sitting in the upright position and should follow by drinking a glass of water. The patient must remain upright and not eat for 30 minutes after administration. Long-term side effects are unknown.

D. Raloxifene hydrochloride is a selective estrogen receptor modulator. It has estrogen-like effects on bone and the cardiovascular system, but antiestrogen effects on the breast and uterus. Raloxifene has received FDA approval for the prevention and treatment of osteoporosis. A daily dose of 60 mg is

recommended. A study involving postmenopausal women both with and without osteoporosis found that patients treated with raloxifene daily for 2 years had statistically significant increases in lumbar spine and hip BMD compared to patients receiving placebo, who had decreased BMD. Side effects include hot flashes and leg cramps. There is an increased risk of thromboembolic events with raloxifene use. However, a trial involving postmenopausal women with osteoporosis found a decreased risk of breast cancer in these patients.

E. Calcitonin, a peptide hormone, inhibits bone resorption by decreasing osteoclast activity. It may also have an analgesic effect. Because calcitonin is

degraded when taken orally, parenteral administration is required. A nasal form of salmon calcitonin, Miacalcin 200 IU daily, has been used effectively in the treatment of postmenopausal osteoporosis. It can also be administered in a 100-IU dose subcutaneously or intramuscularly every other day. Calcitonin, in both injectable and nasal spray preparations, is also effective in preventing early postmenopausal bone loss. Side effects of calcitonin therapy include nausea and flushing. Rhinitis and epistaxis may occur with intranasal dosing. There are no long-term adverse effects.

VI. Heart disease. Firm recommendations regarding HRT and primary prevention of heart disease require the results of ongoing clinical trials. One in two women will die from cardiovascular disease (CVD) or stroke. In contrast, one in nine women develop breast cancer. Epidemiologic studies have demonstrated that women using HRT have a 40–50% lower risk of death from CVD than those not on HRT.

Clinical research to date. One study demonstrated that long-term use of estrogen in a postmenopausal woman was associated with reduced overall mortality risk. This risk reduction occurred primarily through a reduction in cardiovascular-related deaths. In one report, the use of estrogen was associated with a

decrease in serum levels of low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol. These effects occur with both oral and vaginal administration of ethinyl estradiol, and with oral, but not vaginal, use of conjugated estrogens. The transdermal patch has not been shown to have the same beneficial effect on lipid levels as other routes of delivery.

The Heart and Estrogen/Progestin Replacement Study (HERS) studied the effect of estrogen on prevention of recurrent CVD events. Postmenopausal

women with CVD and an intact uterus received 0.625 mg conjugated equine estrogen along with 2.5 mg medroxyprogesterone acetate or placebo. There was no significant difference between the HRT group and the placebo group in CVD events after 4 years of follow-up. However, the HRT group had a higher risk of a second CVD event during the first year of therapy than did the placebo group. The relative risk showed a trend downward with each successive year. During the first year of treatment, HRT patients had a 14% decrease in low-density lipoprotein cholesterol and an 8% increase in high-density lipoprotein cholesterol, but a 10% increase in triglycerides. Progesterone was found to attenuate the estrogen effect on lipid profile. HRT patients had an increased incidence of

thromboembolic events and pulmonary emboli. The American Heart Association recently concluded that there are insufficient data to support initiation of HRT for the sole purpose of primary prevention of CVD. Furthermore, initiation and continuation should be predicated on established noncoronary benefits and risks, possible coronary benefits and risks, and patient preference. The American Heart Association also recommends that HRT not be initiated for the secondary prevention of CVD.

VII. Other benefits of HRT. The vagina, urethra, and bladder trigone have high estrogen receptor concentrations. The loss of estrogen that accompanies

menopause thus leads to urogenital atrophy. The atrophic vulva loses most of its collagen, adipose tissue, and water-retaining ability, and becomes flattened and thin. Sebaceous glands remain intact, but secretions decrease. Vaginal shortening and narrowing occur, and the vaginal walls become thin, lose elasticity,

and become pale in color. The atrophic vagina secretes less, which causes vaginal dryness. Dyspareunia is the most common complaint related to vaginal atrophy. The treatment of urogenital atrophy is an indication for HRT, and the mainstay of therapy is systemic or local estrogen.

The effect of estrogen deficiency on the urethra and bladder is associated with urethral syndrome, which is characterized by recurrent episodes of urinary frequency and urgency with dysuria. Estrogen therapy relieves urgency, urge incontinence, and dysuria, and may protect against recurrent lower urinary tract infections. Estrogen therapy does not, however, improve stress incontinence.

VIII. Side effects and contraindications of HRT include pregnancy, estrogen-dependent neoplasms, distant or recent history of breast cancer, undiagnosed vaginal bleeding, acute vascular thrombosis or emboli, and severe liver disease. Side effects include breast tenderness, uterine bleeding, and bloating. Many women suffer the effects of estrogen deficiency after treatment for endometrial cancer. Women traditionally have not been offered HRT after being diagnosed and treated for endometrial cancer, because of the theoretical risk that dormant cancer cells may be activated by HRT. Many experts believe that, for women with a history of endometrial cancer, the proven risks of long-term estrogen deficiency far outweigh the presumed risk of cancer recurrence, and reports suggest that HRT can be prescribed safely after appropriate treatment for endometrial cancer.

Long-term risks of HRT are especially a concern of patients. The most controversial issue is the association between breast cancer and HRT. Some studies have demonstrated an increased risk of breast cancer in women taking HRT, but others have not. The reanalysis of 51 studies by the Collaborative Group on Hormonal Factors in Breast Cancer demonstrated an increased risk of 6 cases per 1000 with 10 years of continuous HRT. The effect was reduced with discontinuation of therapy, and almost disappeared 5 years after discontinuation. Data from the Iowa Women's Health Study, however, revealed that HRT exposure was associated with a higher risk of developing invasive breast cancer with a favorable prognosis than with developing ductal carcinoma in situ or invasive ductal or lobular carcinoma. Another study examined the risk of breast cancer in women with a previous histologic diagnosis of benign breast disease and found that estrogen replacement therapy does not significantly increase the risk of invasive breast disease. This study concludes that estrogen replacement therapy is not contraindicated in these patients. Recently published results from the Breast Cancer Detection Project indicate a small but statistically significant increased risk of breast cancer in estrogen-progestin users compared to users of estrogen alone.

The increased risk of endometrial cancer in women with an intact uterus taking unopposed estrogen is well established. The two- to threefold greater risk of developing endometrial cancer is eliminated by the addition of at least 12 days of progestin therapy each month.

There are other demonstrated risks of HRT. Oral HRT raises serum triglyceride levels. The Nurses Health Study found a relative risk ratio of 1.5–2.0 for

development of gallbladder disease in HRT users. During the initial year of HRT, there is a slightly increased risk of excess cases of deep venous thrombosis of approximately 1:5000, as demonstrated in two studies. Another study found 1:20,000 excess cases of pulmonary embolism.

IX. Management of perimenopause. Because of the changing hormonal milieu, complaints of irregular bleeding are very common during the climacteric. If

episodes of bleeding occur more often than every 21 days, last longer than 8 days, are very heavy, or occur after a 6-month interval of amenorrhea, particularly if such bleeding occurs in an irregular pattern, an evaluation must be undertaken to rule out neoplasm.

Oral contraceptive pills (OCPs) are recommended for estrogen supplementation in the perimenopausal woman. Benefits of this therapy, in addition to relief of vasomotor symptoms, are contraception, decreased risk of endometrial and ovarian cancers, establishment of regular menses, and increased bone density. An OCP with 20 µg of ethinyl estradiol and 150 µg of desogestrel has the same efficacy and side effects as OCPs with 30 or 35 µg of estrogen, yet carry virtually no increased risk of coagulation pathology. The transition from OCPs to HRT is recommended when the FSH level is higher than 20 IU/mL on day 6 or 7 of the pill-free week. A blood sample can be obtained annually starting at age 50 years to determine the serum FSH level; however, because of variability in FSH levels in perimenopausal women, the measurement is not always accurate. An alternative is to allow the patient to continue to take low-dose OCPs into her midfifties and to change to HRT empirically. As with a menopausal woman, the perimenopausal patient should receive calcium and vitamin D supplementation, maintain a healthy diet, engage in regular exercise, and avoid smoking.

40. BENIGN VULVAR LESIONS

The Johns Hopkins Manual of Gynecology and Obstetrics

40. BENIGN VULVAR LESIONS

Carolyn J. Alexander, Cornelia Liu Trimble and Edward Trimble

Infections

I. Infections. Many benign lesions of the vulva are infectious. A number of these infections can involve squamous epithelium elsewhere. The vulva and perineum have estrogen and progesterone receptors and thus are subject to stronger hormonal influences than skin elsewhere. Furthermore, as the vulva and perineum are often sequestered by clothing, they are prone to chronic dampness from perspiration.

A. Bacterial infections. Common bacterial infections include those that cause folliculitis ( Staphylococcus), furuncles (Staphylococcus), and Bartholin's gland abscesses (polymicrobial). Treatment strategies should focus on hygiene measures, with sitz baths and antibiotic treatment if necessary.

B. Sexually transmitted diseases (STDs). When an STD is suspected, assessment for other STDs should be considered and a Pap smear should be taken.

1. Syphilis

a. The primary lesion is a painless, indurated papule that can be 2 cm in diameter. This lesion progresses to a shallow ulcer with raised edges, which resolves in 2–8 weeks. Inguinal lymph nodes may be shotty. The chancres may be multiple and, on the vulva, may be superinfected. The diagnosis can be made by dark-field microscopic examination.

b. Vulvar manifestations of secondary syphilis include soft, nontender papules that may be larger than the primary lesions.

c. The pathognomonic lesions of tertiary syphilis are condylomata lata, which are large, raised gray-white lesions with a moist appearance.

d. For treatment, see Chap. 24, Infections of the Genital Tract.

2. Chancroid may present as a tender, nonindurated vulvar ulcer with a friable purulent erythematous base. The incubation period ranges from 3 to 10 days. These lesions typically are quite painful. Bilateral inguinal adenopathy is common. Because the causative organism, Haemophilus ducreyi, is difficult to culture, biopsy and Gram staining are often necessary for diagnosis. For treatment options, refer to Chap.24, Infections of the Genital Tract.

3. Granuloma inguinale is a contagious, chronic STD caused by Calymmatobacterium granulomatis. The lesions are painless papules or ulcers with rolled borders and a friable base that are granulomatous and locally destructive. Histologic or cytologic demonstration of the Donovan body, which is highlighted with Wright or Giemsa staining, is diagnostic. Although the acute lesion responds to tetracycline, surgery may be indicated in later, chronic stages to remove areas of chronic infection and distortion.

4. Lymphogranuloma venereum is a chronic STD more frequently seen in men than in women that is caused by three serotypes of Chlamydia trachomatis, L1, L2, and L3. Phase one is erosion of the skin, forming a primary lesion that may present as a papule, a shallow ulcer, or a small, herpetiform lesion.

This arises after an incubation period of 3–12 days. Phase two involves inguinal lymphadenopathy; a bubo is an enlarged inguinal lymph node. This generally occurs 10–30 days after initial infection but may occur 4–6 months later. Phase three involves fibrosis and destruction. Chronic, untreated infection can lead to proctocolitis and bowel strictures, progressive vulvar induration and fibrosis, and, in some cases, stenosis of the urethra and vagina.

The diagnosis is based on positive serologic test results, isolation of the organism, or histologic identification of the bacterium. Effective antibiotics include tetracycline, sulfadiazine, chloramphenicol, erythromycin, and rifampin. If surgery is indicated for repair of strictures or fistulas, patients should receive antibiotics for several months before the operation. For treatment options, refer to Chap. 24, Infections of the Genital Tract.

5. Gonorrhea often presents as an acute inflammatory reaction in the region of the urethra, or at Bartholin's or Skene's glands. Diagnosis is made by culture.

C. Viral infections

1. Herpes simplex virus (HSV) infection is the most common cause of vulvar ulcers.

HSV type 1 is typically associated with oral infections, although it can produce genital lesions. HSV type 2 is more often the cause of lesions of the lower genital tract. The infection is highly contagious. It may be preceded by malaise, fever, or a prodromal tingling sensation at the site of the eventual lesion.

Recurrent ulcers are often in the same location. They are frequently painful. Of note, viral shedding may persist for several weeks after the ulcers have resolved, although this is much more likely with a primary infection. Recurrences are usually milder than primary lesions. Treatment for both the initial lesions and recurrences consists of acyclovir, 200 mg, five times a day for 10 days.

According to the American College of Obstetricians and Gynecologists, women with primary HSV infection at any time during pregnancy should be treated with antiviral therapy. Cesarean delivery should be performed on women with first-episode HSV infection who have active genital lesions at delivery and on pregnant women with prodromal symptoms at delivery. Expectant management of patients with preterm labor or preterm premature rupture of membranes and active HSV infection may be warranted.

2. Condyloma acuminatum, or venereal warts, are caused by the human papillomavirus (HPV) infection. HPV types 6 and 11 are the most common types producing exophytic lesions on the lower genital tract. These lesions are frequently multifocal, papillary, verrucous, or papular. Malignant transformation is uncommon. The exophytic lesions may be pruritic and may become superinfected. Although they may regress spontaneously during pregnancy or other immunocompromised states, they may instead flourish.

a. Approximately 1% of all sexually active adults (aged 15–49) either have or have had genital warts. The highest rates occur in sexually active women younger than 25 years.

b. Treatment consists of the following (please refer to Chap. 24, Infections of the Genital Tract, for dosing details):

1. Trichloroacetic acid 80–90%, or 2. Imiquimod (Aldara) 5% cream, or 3. Podophyllin 0.5% solution or gel, or 4. Cryotherapy, or

5. Systemic and intralesional interferon

c. A Pap smear of the cervix should be obtained. Only a very small percentage of those infected with HPV actually develop genital warts. Infection with HPV (types 16, 18, 31, 33) typically does not manifest as exophytic lesions but rather as vulvar intraepithelial neoplasia and is covered in more detail in the section on squamous carcinomas.

3. Molluscum contagiosum virus is a poxvirus that is spread by close contact. The lesions are multiple, small, umbilicated papules filled with white, waxy material. Most patients are entirely asymptomatic. Although the diagnosis is most often made clinically, histologic demonstration of intracytoplasmic molluscum bodies is pathognomonic. Therapy consists of curettage and excision of the lesions under local anesthesia.

II. Inflammatory lesions

A. In Crohn's disease, cutaneous ulcerations occur in areas where there is close apposition of skin, such as the vulva and submammary areas. Vulvar ulcers may precede GI symptoms by months or even years. Crohn's disease ulcers are typically multiple, linear, and deep and can cause a granulation tissue response. They may become secondarily infected or result in draining fistulas, or both. Lymphadenopathy is rare.

B. Behçet's syndrome is a triad of relapsing oral ulcers, genital ulcers, and ocular inflammation. Other findings include acne, cutaneous nodules,

thrombophlebitis, and colitis. Uveitis is less frequent than genital ulcerations, which are small and deep and may result in fenestration of the labia. They tend to resolve spontaneously, but systemic corticosteroids are the most widely used and effective treatment. Sitz baths and careful hygiene of the area is

thrombophlebitis, and colitis. Uveitis is less frequent than genital ulcerations, which are small and deep and may result in fenestration of the labia. They tend to resolve spontaneously, but systemic corticosteroids are the most widely used and effective treatment. Sitz baths and careful hygiene of the area is