Update in Women's Health

Issues Affecting Women of Reproductive Age

Important articles of significance for women of reproductive age included an examination of the significance of asymptomatic bacteriuria in young sexually active women, an analysis of factors involved in delayed access to HIV care, and an assessment of the association between oral contraceptive use and breast cancer risk in patients with a family history of breast cancer.

More Than 90% of Cases of Asymptomatic Bacteriuria Resolve without Developing into an Infection

Although asymptomatic bacteriuria is common in young women, little is known about its pathogenesis, natural history, risk factors, and temporal association with symptomatic urinary tract infections (UTIs). To evaluate these factors, Hooton and colleagues conducted a prospective cohort study of nonpregnant women 18 to 40 years of age. The 796 participants were patients at a university student health center or a health maintenance organization (HMO) in Seattle, Washington, from 1989 to 1994 and were about to start or had just started a new method of contraception.

Baseline evaluation included a standardized interview, testing of a midstream urine specimen to evaluate pyuria and bacteriuria, and testing of blood and saliva samples to determine ABO-blood group secretor status. Women kept diaries to record the days on which the following occurred: sexual intercourse, use and type of contraception, vaginal and urinary symptoms, and antibiotic use. They also provided urine samples monthly for 6 months.

Asymptomatic bacteriuria was defined as the presence of at least 10⁵ colony-forming units [CFUs] of a urinary pathogen per mL in a culture obtained from an asymptomatic woman. A symptomatic UTI was defined as 1) the presence of dysuria, urinary frequency, or urgency and 2) at least 10²CFUs of a urinary pathogen per mL, a health care provider diagnosis of UTI, or antibiotic treatment for urinary symptoms.

The prevalence of asymptomatic bacteriuria was 5% (95% CI, 4% to 6%) in the university group and 6% (CI, 5% to 8%) in the HMO group; 22% of patients had at least one episode of asymptomatic bacteriuria. Episodes of asymptomatic bacteriuria lasting longer than 2 months were rare, occurring in only 3 participants (0.8%) in the university group and 1 participant (0.2%) in the HMO group.

For both groups combined, 8% of the 295 cultures with 10⁵ or more CFUs of urinary pathogens per mL were followed by a symptomatic UTI within 1 week, compared with 1% of cultures with fewer than 10⁵ CFUs/mL (P < 0.001). Of the 34 cultures with bacteriuria and pyuria, a symptomatic UTI occurred in 15% within 1 week. In multivariate analyses, recent use of a diaphragm plus spermicide and recent sexual intercourse were strongly associated with asymptomatic bacteriuria in both groups. The Escherichia coli strains that caused asymptomatic bacteriuria did not differ from those that caused symptomatic UTIs.

The researchers concluded that asymptomatic bacteriuria is common in young sexually active women but that it rarely persists. More than 90% of cases resolved without developing into an infection. For the internist, the important message is that asymptomatic bacteriuria in young sexually active women is common and usually transient and thus does not have to be treated. Given the small percentage of cases of bacteriuria that develop into symptomatic UTIs, routine screening urinalyses are not warranted in healthy sexually active women. The reason that symptomatic UTIs occur in only a small proportion of women with bacteriuria is not clear. The development of a UTI may reflect additional virulence factors not measured in this study, or may result from a complex interplay between expression of virulence factors and variation in the host environment.

Women Are More Likely Than Men To Delay HIV Care

To assess the characteristics of HIV-positive persons who delay seeking medical care, Stein and colleagues studied 2864 patients, 18 years of age or older, who had sought non–emergency department HIV care between 1996 and 1997. Study participants, recruited from 196 providers in 79 metropolitan and rural areas, completed a one-time computer-assisted cross-sectional interview. Direct questions concerned age, race, education, insurance status, intravenous drug use, household composition, and other HIV-infected household members. The following question assessed delay in medical care due to caregiving responsibilities: “In the last 6 months, have you ever put off going to the doctor for HIV care because taking care of someone else was more important to you?” The investigators performed bivariate analyses and multiple logistic regression modeling to determine whether demographic, clinical, and household composition variables were associated with delay in seeking care.

Twenty-three percent of the 2864 participants were women. Women were more likely than men to be living with children younger than 17 years of age (45% vs. 6%; P < 0.01) and were more likely to report delay in HIV care as a result of caregiving in the previous 6 months (14% vs. 8%; P < 0.001). The first logistic regression model did not include CD4 cell count or report of the presence of a child in the household. This model found that being a woman (odds ratio, 1.7 [CI, 1.2 to 2.4]), having no medical insurance (odds ratio, 2.2 [CI, 1.3 to 3.5]), and having public insurance (odds ratio, 2.2 [CI, 1.3 to 3.7]) were associated with delay in seeking HIV care. Race, education, and intravenous drug use were not associated with delay in care. In the model that included CD4 cell count greater than 0.500 × 10⁹cells/L and the presence of a child in the household, being a woman was no longer significant (odds ratio, 1.3 [CI, 0.8 to 1.8]), but having a child in the household was associated with delay in seeking care (odds ratio, 1.8 [CI, 1.2 to 2.6]). A CD4 cell count greater than 0.500 × 10⁹cells/L was also associated with delay in care (odds ratio, 1.9 [CI, 1.3 to 2.8]).

The researchers concluded that delay in seeking care was associated with having public insurance or no insurance and with a CD4 cell count greater than 0.500 × 10⁹cells/L and that women were more likely to delay care than men. Most of the difference in delay in care between women and men was attributable to the presence of children in the household and women delaying care for themselves because of caregiving responsibilities. Lack of insurance or reliance on public insurance, a marker for low-income status, was also associated with delay in seeking care. Women with HIV infection, especially those with public or no health insurance, need supportive services to seek health care for themselves. Health care providers should recognize the caregiving responsibilities of their patients, especially low-income women, and work to alleviate the effect of these responsibilities in their own care. When on-site child care is not available, telephone contact, extended hours, and home services may provide some avenues to ensure that a woman's health needs are not delayed.

Women Who Have Used High-Dose Contraceptives and Have a First-Degree Relative with Breast Cancer May Be at Higher Risk for the Disease

In a retrospective follow-up of family members of a historical cohort study, Grabrick and colleagues examined whether family history influences breast cancer risk in women who use oral contraceptives. The original study looked at a population-based cohort with 504 incident cases of breast cancer between 1944 and 1952. The follow-up, conducted from 1991 to 1996, studied all first-degree (sisters and daughters) and second-degree (granddaughters and nieces) relatives and persons related by marriage (for example, a woman married to the son or brother of woman with breast cancer). Living participants able to respond self-reported their history of breast cancer and information on oral contraceptive use over the telephone.

The response rate for 92% of the families was 93%. The investigators used Cox proportional-hazards regression to analyze the data. Analyses controlled for year of birth, known breast cancer risk factors, duration of oral contraceptive use, and mammography use. The authors stratified the analysis by contraceptive use before and after 1975 because formulations used before 1975 more commonly contained high-dose estrogen (≥ 50 µg of ethinyl estradiol) whereas those used thereafter more often contained low-dose estrogen (≤ 35 µg of ethinyl estradiol). The authors also stratified analyses by number of family members with breast cancer; they defined high-risk families as those in which three or more family members had breast or ovarian cancer.

The authors found 239 cases of breast cancer. The overall association of breast cancer and ever use of oral contraceptives in the entire cohort was weak (relative risk, 1.4 [CI, 1.0 to 2.0]). First-degree relatives who had used oral contraceptives had a significantly increased risk for breast cancer than nonusers (relative risk, 3.3 [CI, 1.6 to 6.7]). No association between oral contraceptive use and breast cancer was seen in second-degree relatives (relative risk, 1.2 [CI, 0.8 to 2.0]) or persons related by marriage (relative risk, 1.2 [CI, 0.8 to 1.9]).

None of the following potential confounders changed the association: parity, age at birth of first child, education, body mass index, alcohol intake, smoking, age at menarche or menopause, oophorectomy, or number of mammograms. The risk for breast cancer from oral contraceptive use was 4.6 (CI, 2.0 to 10.7) in first-degree relatives who had at least three blood relatives with breast or ovarian cancer and 11.4 (CI, 2.3 to 56.4) in first-degree relatives who had at least five blood relatives with breast or ovarian cancer. The study had insufficient power to analyze risk based on estrogen dose in the oral contraceptive.

In summary, oral contraceptive use by women who have first-degree relatives with breast cancer was associated with a more than threefold risk for breast cancer. Women who had second-degree relatives with breast cancer did not have an increased risk. The findings were even more pronounced in families at high risk for ovarian and breast cancer.

The study's strengths are the use of a population-based breast cancer cohort, a high participation rate, validation of self-reports, and control for potential confounders. First-degree relatives, however, had taken oral contraceptives when the dose of ethinyl estradiol was higher (50 to 100 µg) than in today's preparations (<35 µg); therefore, findings in this group preclude a statement about the risk from current low-dose oral contraceptives. Clinicians should consider this association, however, when counseling women who have first-degree relatives with breast cancer about contraception options. For women from high-risk families, the potential increased risk for breast cancer associated with oral contraceptives must be balanced against the beneficial effect of oral contraceptives in decreasing the risk for ovarian cancer.

Breast Cancer Treatment

Women with Metastatic Breast Cancer Who Receive High-Dose Chemotherapy plus Stem-Cell Transplants Do Not Survive Longer Than Those Receiving Conventional Chemotherapy

Stadtmauer and colleagues' randomized trial evaluated the benefit of high-dose chemotherapy plus autologous bone marrow transplantation compared with conventional chemotherapy in women with metastatic breast cancer who had already achieved an induction response. The study sample consisted of women, 18 to 60 years of age, with non–central nervous system metastatic breast cancer who had not previously received chemotherapy for metastatic disease.

Participants who achieved an induction response were randomly assigned to the experimental group (high-dose chemotherapy with cyclophosphamide, carboplatin, and thiotepa, followed by autologous stem-cell transplantation) or the control group (conventional-dose therapy with cyclophosphamide, methotrexate, and fluorouracil) for up to 2 years.

The primary end point was survival. Secondary end points included time to progression and moderate to severe adverse side effects. The study had 85% power to detect doubling of median survival.

Of the 553 women initially enrolled for induction chemotherapy, 268 (48%) were ineligible for randomization, 208 did not achieve partial or complete remission, 57 did not meet other eligibility criteria, and 3 died. Of 285 patients with partial or complete responses, only 199 (70%) were randomly assigned; 48 withdrew consent, and 38 withdrew from the study for unknown reasons.

The overall 3-year survival rate was 32% in the chemotherapy plus transplant group compared with 38% in the conventional chemotherapy group; median time to progression was 9.6 months and 9.0 months, respectively (P > 0.2). The rate of moderate to severe adverse reactions, including leukopenia, thrombocytopenia, anemia, and infection, was higher in the chemotherapy plus transplant group.

The authors concluded that, contrary to the initial promise of uncontrolled trials (1-3) and one randomized trial later discredited for falsified data (4), bone marrow transplantation offers no benefit over conventional therapy for metastatic breast cancer. This study illustrates that (despite the desperation of critically ill patients), women are not well served when we bypass clinical trials and offer experimental therapy off-trial. Moreover, it confirms the wisdom of performing controlled clinical trials early in the lifetime of new treatments.

Hormone Replacement Therapy

Estrogen–Progestin Use May Be Associated with an Increased Risk for Breast Cancer Compared with Estrogen Use Alone

The preponderance of epidemiologic data suggests that women who use hormone replacement therapy have an increased risk for breast cancer (5, 6). Whether the combination of estrogen plus progestin confers a greater risk than does estrogen alone is unknown. Schairer and colleagues conducted a cohort study using follow-up data (1980 to 1995) from the Breast Cancer Detection Demonstration Project, in which 46 355 postmenopausal women participated.

The authors considered the following confounders in the analysis: race, period of follow-up, age at first live birth, age at menopause, family history of breast cancer, history of benign breast disease, clinical breast examinations, mammographies, education, and body mass index. Outcomes were cases of breast cancer.

Compared with no use, ever use of estrogen and estrogen–progestin were both associated with slightly increased relative risk for breast cancer (relative risk, 1.1 [CI, 1.0 to 1.3] and 1.3 [CI, 1.0 to 1.6], respectively). Compared with nonusers, the relative risk for breast cancer increased by 0.01 (CI, 0.002 to 0.03) per year of use of estrogen alone and 0.08 (CI, 0.02 to 0.16) per year of use of estrogen–progestin.

Schairer and colleagues categorized women by body mass index: 24.4 kg/m²or less and greater than 24.4 kg/m². Associations with duration of estrogen or estrogen–progestin use were seen only in women with a lower body mass index.

The authors conclude that estrogen–progestin use may be associated with an increase in breast cancer risk beyond the risk associated with estrogen alone. The increased risk for breast cancer associated with estrogen use only and estrogen–progestin use may be most significant in lean women.

Although the study results suggest an increased risk of estrogen–progestin compared with estrogen alone, the overlapping confidence intervals indicate that the results are also compatible with no difference in risk. In support of the authors' conclusions, however, Ross and colleagues' recent case–control study (including 1897 case-patients and 1637 neighborhood controls) showed similar results (6). In that study, the odds ratio was 1.24 (CI, 1.07 to 1.45) per 5 years of use of combined estrogen–progestin and 1.06 (CI, 0.97 to 1.15) for estrogen use only. Risk estimates were higher for women who took sequential estrogen–progestin therapy than for those who took continuous combined estrogen–progestin therapy, but the differences were not statistically significant (6).

Clinicians should consider the increased risk for breast cancer when talking with patients about risks and benefits of hormone replacement therapy. Given the extensive data on the risk for endometrial cancer with unopposed estrogen, clinicians should not advise women to discontinue progestin therapy and continue taking unopposed estrogen solely to avoid breast cancer. No conclusive evidence favors one progestin regimen over another.

Functional or Cognitive Outcomes Did Not Improve after Estrogen Treatment in Women with Established Alzheimer Disease

To determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate Alzheimer disease, Mulnard and colleagues conducted a randomized clinical trial at 32 U.S. sites.

The participants were 120 women older than 60 years of age with mild to moderate Alzheimer disease and a Mini-Mental State Examination (MMSE) score of 12 to 28. All participants had had a hysterectomy. The investigators randomly assigned women to receive 0.625 mg of estrogen, 1.25 mg of estrogen, or placebo. The main outcome was change in the Alzheimer Disease Cooperative Study's version of the Clinical Global Impression of Change 7-point scale; other outcomes included MMSE score, Clinical Dementia Rating Scale, mood measure, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living. Throughout the trial, a caregiver administered the investigational agent.

Because findings in the two estrogen groups did not significantly differ, the investigators combined them into one group. The study had 81% power to detect a 29% difference in the proportion of patients whose cognitive function worsened in the two groups; the authors chose a large effect size to ensure clinical significance.

A total of 97 women completed the study. Twenty-five women withdrew: 7 in the placebo group (2 because of adverse events), 7 in the 0.625-mg estrogen group (7 because of adverse events), and 9 in the 1.25-mg estrogen group (4 because of adverse events). At 12-month follow-up, 74% of patients receiving placebo had worse scores on the Alzheimer Disease Cooperative Study's version of the Clinical Global Impression of Change compared with 80% of those in the combined estrogen group; this difference was not significant. The difference in the clinical dementia rating score significantly favored the placebo group (mean change, 0.5 for the combined estrogen group vs. 0.2 for placebo; P < 0.01). Most secondary cognitive outcome variables did not significantly differ between groups. Four cases of deep venous thrombosis and four episodes of vaginal bleeding developed in the estrogen group.

The results suggest that estrogen does not improve functional or cognitive outcomes in women with established Alzheimer disease. On the basis of these results, estrogen has no role in treating established Alzheimer disease. This study, however, provides no information on whether estrogen may be useful in the primary prevention of the disease. The role of estrogen for primary prevention is being assessed in the Women's Health Initiative and the Preventing Postmenopausal Memory Loss in Alzheimer's with Replacement Estrogens Study.

Osteoporosis

Osteoporosis remains an important topic in women's health. Previous Updates in Women's Health reviewed new pharmacologic therapies for postmenopausal women with osteoporosis. As the number of new therapies grows, questions on how to monitor the ongoing effectiveness of these therapies emerge. We review a study that provides important information on monitoring therapy by using bone mineral density. We also report on a new potential risk factor for falls and fractures in elderly women.

Treatment for Osteoporosis Should Continue for Patients Who Lose Bone Mineral Density during the First Year of Osteoporosis Therapy

There has been debate about how often to repeat bone densitometry after initial screening and how the results should affect therapeutic decisions. Cummings and colleagues analyzed two randomized, placebo-controlled trials (the Fracture Intervention Trial [FIT] and the Multiple Outcomes of Raloxifene Evaluation [MORE] trial) to assess whether women who lose bone mineral density (BMD) during the first year of osteoporosis treatment continue to lose BMD if treatment continues for more than 1 year. The FIT participants—postmenopausal women with a femoral neck BMD of 0.68 g/cm² or less—were randomly assigned to receive 5 mg of alendronate per day or placebo for 2 years. Women in the MORE study were postmenopausal and 80 years of age or younger; their BMD of the femoral neck or lumbar spine was at least 2.5 SDs below the mean for normal young adult women, or they had one moderate or two mild vertebral fractures. They were randomly assigned to receive 60 or 120 mg of raloxifene per day or placebo for 3 years. In both studies, BMD was measured at baseline, 12 months, and 24 months.

In FIT, women receiving alendronate gained an average of 2.2% in total hip BMD and 4.5% in spine BMD. Most women in this group (82%) gained BMD in the first year, but in 1.4% of the participants total hip BMD decreased by more than 4%. In both the alendronate and placebo groups, those who lost the most BMD during the first year of alendronate treatment were most likely to gain BMD during the second year. Changes in spinal BMD did not predict changes in hip BMD. Results were similar for women who received raloxifene: Those who lost BMD in the first year were most likely to gain BMD in the second year, and those who gained the most BMD in the first year were most likely to lose BMD in the second year.

Thus, the few patients who lose BMD during the first year of alendronate or raloxifene treatment are likely to gain BMD with continued treatment. This phenomenon shows the principle of regression to the mean: Individuals with measurements that differ from the mean for a population tend to have repeated measurements that are closer to the mean, and this tendency is greatest for those whose initial measurements are farthest from the mean. The same phenomenon is true for women receiving placebo.

The results of this study have several practical implications. First, the findings suggest that treatment should be continued in patients who initially lose BMD, because most patients gain BMD with continued treatment. Loss of BMD, however, should still prompt questions about adherence to therapy and about whether patients are taking the medication correctly. Second, unusually large gains in BMD after the first year of treatment and loss of BMD the second year probably reflect the random-error measurement of BMD rather than resistance to the medication. Third, change in measurement at a second skeletal site does not appear to predict change in hip BMD during the second year of treatment. Fourth, in women who are not receiving therapy, unexpected losses or unusually large changes in BMD are also probably due to random measurement error. Clinicians should consider confirming large changes in BMD with repeated testing before changing management. Finally, this study calls into question the value of monitoring osteoporosis treatment with yearly measurement of BMD. As with any diagnostic test, if the results do not change management, it may be best not to order the test. Although measurement of BMD may be valuable in prompting questions about adherence and proper use of medication among patients with BMD loss, physicians can incorporate these questions into routine follow-up examinations.

Urge Incontinence Is a Major Risk Factor for Falls and Consequent Fractures

Falls are associated with substantial morbidity and mortality in elderly persons; approximately 10% to 15% of falls cause fracture. Identifying elderly persons at risk for falling and intervening to reduce modifiable risks are likely to improve clinical outcomes. Brown and colleagues studied whether urinary incontinence is associated with falls and fractures in older women. Participants in the Study of Osteoporotic Fractures were community-dwelling white women, 65 years of age and older, recruited from 1986 through 1988 from four geographic areas of the United States.

A self-administered questionnaire given in 1994–1996 asked about type and frequency of incontinence in the preceding 12 months. Urge incontinence was defined by the following statement: “When I have the urge to urinate and can't get to the toilet fast enough.” Stress incontinence was defined as “Leakage of urine when I cough, sneeze, laugh, lift, stand up or exercise.”

The investigators mailed women postcards every 4 months and asked them to contact the study staff if any falls or fractures occurred. Telephone interviews assessed the circumstances of the fall or fracture. The authors confirmed all fractures by reviewing radiographs.

The authors created multivariate models using repeated-measures methods to predict falls and nonspine fractures as outcomes. Models were adjusted for age; frailty; living situation; medical history; medication use; falls in the previous year; alcohol and caffeine use; and regular walking exercise and functional assessments of balance, strength, and speed.

During follow-up, 25% of women reported weekly urge incontinence, 19% reported weekly stress incontinence, and 12% reported both types of incontinence. Fifty-five percent reported at least one fall, and 8.5% had at least one fracture. The annual fracture rate was 3%.

In the multivariate models, urge incontinence was associated with falls (odds ratio, 1.26 [CI, 1.14 to 1.40]) and fractures (odds ratio, 1.34 [CI, 1.06 to 1.69]), but stress incontinence was not. There was a dose–response effect: The risk for falls and fractures was greater with more frequent urge incontinence.

In conclusion, in this community-based group of women, urge incontinence, but not stress incontinence, was associated with increased risk for both falls and fractures. A dose response was seen—higher risks for falls and fractures were associated with more frequent urge incontinence. On the basis of a fall rate of 25%, the attributable risk for fractures due to urge incontinence was 0.9%; the attributable risk percentage was 30%. Because incontinence appears to be a major risk for falls—and therefore fractures—in community-dwelling elderly women, physicians should consider asking patients about symptoms of urge incontinence and initiating therapy not only to relieve symptoms but to possibly prevent fractures.

Cancer Screening

Cytologic Test Results in Previously Screened Postmenopausal Women Are More Likely To Be False Positive Than True Positive

Because the incidence of cervical dysplasia declines with age, the screening of postmenopausal women with previously normal Papanicolaou (Pap) smears is controversial. In addition, data on whether hormone replacement therapy affects cervical cytologic findings are conflicting. Sawaya and colleagues sought to determine the predictive value of an abnormal cervical smear in postmenopausal women with recent normal Pap smears and to determine the independent effect of oral estrogen plus progestin on the development of cytologic abnormalities.

Cervical smears were collected prospectively during the Heart and Estrogen/progestin Replacement Study (HERS), a randomized, double-blind trial of 2763 postmenopausal women younger than 80 years of age with coronary artery disease and an intact uterus. Women received estrogen plus progestin or placebo. Cervical smears were obtained during annual visits. Abnormal smears were defined as those showing atypical squamous cells of unknown significance (ASCUS), atypical glandular cells of undetermined significance (AGCUS), low-grade squamous intraepithelial lesion (LGSIL), or high-grade squamous intraepithelial lesion (HGSIL). The investigators obtained information on the 2-year follow-up of abnormal Pap smears by using a questionnaire sent to clinical personnel at each study site and data collected as part of the study protocol. Copies of diagnostic test results and pathology reports were also obtained.

The final histologic status for each woman was classified as normal (a nondysplastic process, such as atrophy, cervicitis, inflammation), low-grade histologic condition (human papillomavirus or grade I cervical intraepithelial neoplasia [CIN I]), high-grade histologic condition (CIN II to III or vaginal intraepithelial neoplasia grades II to III), and unknown (results could not be located or did not meet criteria for normal).

Of the 2561 women with normal baseline smears (mean age, 66.7 years), 89% were white and 60% had 12 or fewer years of education. Seventy-eight women (3%) had an abnormal smear 1 year after the baseline smear, and 32 (1.4%) had an abnormal smear 2 years after the baseline smear.

Most new cytologic abnormalities were ASCUS (67.3%) and AGCUS (21.0%). A total of 231 interventions were done, including 112 cervical smears, 33 colposcopies, and 21 cervical biopsies. Ninety-four (85.5%) of the final histologic abnormalities were normal; 6 were a low-grade histologic condition, 2 were high-grade histologic conditions (CIN I or II and grade III vaginal intraepithelial neoplasia), 1 was endometrial hyperplasia without atypia, and 7 were unknown. No women had CIN II or III or invasive cancer.

The positive predictive value of any smear abnormality (ASCUS, AGCUS, LGSIL, HGSIL) predicting a final high-grade cervical histologic abnormality was 0.0% (CI, 0% to 5%) within the first year of a normal Pap smear and 0.9% (CI, 0.0% to 3.0%) (1 of 110 women) within 2 years of the normal Pap smear. In hormone-treated women, the incidence of new cytologic abnormalities was nonsignificantly higher (relative hazard, 1.36 [CI, 0.93 to 1.99]), largely because of a nonsignificant increased incidence of ASCUS (relative hazard, 1.58 [CI, 0.99 to 2.52]).

These results suggest that cervical abnormalities are rare in postmenopausal women with previously normal Pap smears. Furthermore, the cytologic abnormalities are much more likely to be false positive than true positive, and the positive predictive value is low. The study focused on high-grade abnormalities as an end point because of the clinical importance of high-grade lesions compared with low-grade lesions. Because many low-grade cervical abnormalities will regress spontaneously, the utility of early aggressive treatment of these lesions is unclear. Treatment with oral estrogen plus progestin did not significantly affect the incidence of cytologic abnormalities.

The women in this study were at low risk for cervical cancer and had normal baseline Pap smears. These results are not generalizable to women at high risk for cervical cancer, those with a history of abnormal Pap smears, or those who have never had a Pap smear. These results support the practice of not performing cervical smears in postmenopausal women who have had a normal smear in the past 2 years. Women who choose to be screened should be informed of the likelihood of false-positive results. Although this study does not specifically address the issue of when to discontinue cervical cancer screening in postmenopausal women, these results indirectly support the U.S. Preventive Services Task Force recommendation to discontinue screening at 65 years of age in women with a history of normal cervical smears.

Sexual Dysfunction

Compared with Placebo, Transdermal Testosterone Treatment Marginally Improves Sexual Function and Psychological Well-Being in Women Who Have Had Oophorectomy

Testosterone use in women with sexual dysfunction has received considerable media attention. However, few controlled studies have addressed its efficacy for this indication, and those that have done so used doses high enough to cause virilizing effects. The use of testosterone in women who have undergone surgical menopause is particularly compelling because testosterone levels in these women sharply decline after oophorectomy; in contrast, ovarian production of testosterone in women with natural menopause declines by only about 50%. In this manufacturer-sponsored study, Shifren and colleagues evaluated the effects of physiologic doses of transdermal testosterone in 75 healthy women who reported decreased sexual function after undergoing hysterectomy and bilateral salpingo-oophorectomy before natural menopause.

Study participants ranged in age from 31 to 56 years, were in stable monogamous relationships, had low serum total or free testosterone levels, and had lower than average scores on the Brief Index of Sexual Functioning for Women. They also reported impaired sexual function since the surgery. The investigators excluded women who were using serotonin reuptake inhibitors, had psychiatric illness, or had dyspareunia.

After a 4-week baseline period, women began three consecutive 12-week treatment periods during which they received, in random order, two placebo patches, one placebo and one active patch (150 µg/d), and two active patches (300 µg/d). All women also received a concomitant daily dose of 0.625 mg of oral conjugated equine estrogen. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual function diary completed daily via telephone the last 28 days of each treatment period.

Serum free testosterone level remained normal during the placebo period and increased to mid-normal and high-normal range during treatment with 150 and 300 µg of testosterone per day, respectively. The mean serum levels of total testosterone and dihydrotestosterone also increased and exceeded the respective normal ranges during treatment with 300 µg of testosterone per day.

The mean composite score on the Brief Index of Sexual Functioning for Women, expressed as a percentage of the mean value for normal women, increased from a mean (± SD) of 52% ± 27% at baseline to 72% ± 38% during the placebo period, 74% ± 37% during treatment with 150 µg of testosterone per day, and 81% ± 37% during treatment with 300 µg of testosterone per day (P = 0.05 for comparison with placebo).

Testosterone at 300 µg per day resulted in increased scores for frequency of sexual activity and orgasm in the Brief Index of Sexual Functioning for Women (P = 0.03 for both comparisons with placebo) but did not significantly affect scores on relationship satisfaction, thoughts–desire, arousal, receptivity–initiation, or problems affecting sexual function. Descriptive analyses of the frequency of sexual activity dimension of the Brief Index of Sexual Functioning showed that at the 300-µg/d dosage, the percentage of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from baseline. The positive well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose (P = 0.04, P = 0.03, and P = 0.04, respectively, compared with placebo), but the scores on the telephone-based diary did not increase significantly.

The investigators performed a post hoc analysis of the Brief Index of Sexual Functioning composite score, stratified by age, by comparing subgroups of women younger than the median age of 48 years with patients 48 years of age and older. During the placebo period, the score increased from a baseline of 50% ± 28% in the younger women to 80% ± 42%; scores did not increase further during testosterone treatment. In contrast, in the older women, the composite score increased from 53% ± 27% at baseline to 63% ± 36% during the placebo period, to 77% ± 37% with 150 µg of testosterone per day (P = 0.03), and to 81% ± 38% with 300 µg of testosterone per day (P = 0.003).

Hirsutism and acne scores, frequency of hot flashes, serum lipid levels, fasting glucose or insulin levels, and liver function test results were not significantly associated with testosterone treatment. One serious adverse event, an episode of depression, may have been related to treatment.

The researchers concluded that, in women who have undergone hysterectomy and oophorectomy and have impaired sexual function, 300 µg of transdermal testosterone per day plus oral estrogens was associated with mild improvement in sexual function (as measured by the Brief Index of Sexual Functioning for Women) and with improvements in depressed mood and positive well-being. The 150-µg/d dosage showed no benefit over placebo.

For reasons that are not clear, the benefits of transdermal testosterone were restricted to women 48 years of age and older. The study was done in a very selected population. Results are not generalizable to women who undergo natural menopause or who have coexisting conditions, such as depression or dyspareunia, that would have excluded them from this study.

The patients tolerated the treatment well in the short term. However, because the 300-µg testosterone patch resulted in a mean serum total testosterone level greater than the upper limit of normal, longer-term studies are needed to assess whether long-term daily use of the 300-µg patch is associated with clinically important androgenic effects, such as hirsutism, acne, and lipid abnormalities.

If long-term safety is established, transdermal testosterone may be appropriate treatment for selected women when it becomes commercially available. To our knowledge, no controlled trials have examined the efficacy and tolerability of the testosterone preparations currently available in the United States for this indication. The strong placebo effect found in Shifren and colleagues' study suggests that enhanced attention to impaired sexual functioning, perhaps by improving communication among couples, can alone substantially improve sexual functioning. Clinicians should be reminded to carefully assess both physical and psychosocial factors affecting sexual functioning before attempting pharmacologic interventions.