Susan R. Johnson

The Effects of Tibolone in Older Postmenopausal Women

BACKGROUND Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. METHODS In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. RESULTS During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. CONCLUSIONS Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)

Symptom Relief and Side Effects of Postmenopausal Hormones: Results From the Postmenopausal Estrogen/Progestin Interventions Trial

Objective To assess pair-wise differences between placebo, estrogen, and each of three estrogen-progestin regimens on selected symptoms. Methods This was a 3-year, multicenter, double-blind, placebo-controlled trial in 875 postmenopausal women aged 45–64 years at baseline. Participants were assigned randomly to one of five groups: 1) placebo, 2) daily conjugated equine estrogens, 3) conjugated equine estrogens plus cyclical medroxyprogesterone acetate, 4) conjugated equine estrogens plus daily medroxyprogesterone acetate, and 5) conjugated equine estrogens plus cyclical micronized progesterone. Symptoms were self-reported using a checklist at 1 and 3 years. Factor analysis reduced 52 symptoms to a set of six symptom groups. Results In intention-to-treat analyses at 1 year, each active treatment demonstrated a marked, statistically significant, protective effect against vasomotor symptoms compared with placebo (odds ratios [ORs] 0.17–0.28); there was no additional benefit of estrogen-progestin over estrogen alone. Only progestin-containing regimens were significantly associated with higher levels of breast discomfort (OR 1.92–2.27). Compared with placebo, women randomized to conjugated equine estrogens reported no increase in perceived weight. Those randomized to medroxyprogesterone acetate reported less perceived weight gain (OR 0.61–0.69) than placebo. Anxiety, cognitive, and affective symptoms did not differ by treatment assignment. Analyses restricted to adherent women were not materially different than those using intention-to-treat, except that women adherent to medroxyprogesterone acetate and micronized progesterone regimens reported fewer musculoskeletal symptoms (OR 0.62–0.68). Conclusion These results confirm the usefulness of postmenopausal hormone therapy for hot flashes, show convincingly that estrogen plus progestin causes breast discomfort, and demonstrate little influence of postmenopausal hormones on anxiety, cognition, or affect.

TRANSVAGINAL ULTRASONOGRAPHY COMPARED WITH ENDOMETRIAL BIOPSY FOR THE DETECTION OF ENDOMETRIAL DISEASE

BACKGROUND Transvaginal ultrasonography is a noninvasive procedure that may be used to detect endometrial disease. However, its usefulness in screening for asymptomatic disease in postmenopausal women before or during treatment with estrogen or estrogen-progesterone replacement is not known. METHODS We compared the sensitivity and specificity of transvaginal ultrasonography and endometrial biopsy for the detection of endometrial disease in 448 postmenopausal women who received estrogen alone, cyclic or continuous estrogen-progesterone, or placebo for three years. RESULTS Concurrent ultrasonographic and biopsy results were available for 577 examinations in the 448 women, 99 percent of whom were undergoing routine annual follow-up. Endometrial thickness was less than 5 mm in 45 percent of the examinations, 5 to 10 mm in 41 percent, more than 10 mm in 12 percent, and not measured in 2 percent, and it was higher in the women receiving estrogen alone than in the other groups. Biopsy detected 11 cases of serious disease: 1 case of adenocarcinoma, 2 cases of atypical simple hyperplasia, and 8 cases of complex hyperplasia. Biopsy also detected simple hyperplasia in 20 cases. At a threshold value of 5 mm for endometrial thickness, transvaginal ultrasonography had a positive predictive value of 9 percent for detecting any abnormality, with 90 percent sensitivity, 48 percent specificity, and a negative predictive value of 99 percent. With this threshold, a biopsy would be indicated in more than half the women, only 4 percent of whom had serious disease. CONCLUSIONS Transvaginal ultrasonography has a poor positive predictive value but a high negative predictive value for detecting serious endometrial disease in asymptomatic postmenopausal women.

Menopausal symptoms and treatment-related effects of estrogen and progestin in the women's health initiative

OBJECTIVE: To estimate the effects of estrogen plus progestin (E+P) therapy on menopausal symptoms, vaginal bleeding, gynecologic surgery rates, and treatment-related adverse effects in postmenopausal women. METHODS: Randomized, double-blind, placebo-controlled trial of 16,608 postmenopausal women, ages 50–79 (mean ± standard deviation 63.3 ± 7.1) years, with intact uterus, randomized to one tablet per day containing 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or placebo (n = 8,102), and followed for a mean of 5.6 years. Change in symptoms and treatment-related effects were analyzed at year 1 in all participants. Bleeding and gynecologic surgery rates were analyzed through study close-out. RESULTS: Baseline symptoms did not differ between the treatment groups. More women assigned to E+P than placebo reported relief of hot flushes (85.7% versus 57.7%, respectively; odds ratio 4.40; 95% confidence interval 3.40–5.71), night sweats (77.6% versus 57.4%; 2.58; 2.04–3.26), vaginal or genital dryness (74.1% versus 54.6%; 2.40; 1.90–3.02), joint pain or stiffness (47.1% versus 38.4%; 1.43; 1.24–1.64), and general aches or pains (49.3% versus 43.7%; 1.25; 1.08–1.44). Women asymptomatic at baseline who were assigned to E+P more often developed breast tenderness (9.3% versus 2.4%, respectively; 4.26; 3.59–5.04), vaginal or genital discharge (4.1% versus 1.0%; 4.47; 3.44–5.81), vaginal or genital irritation (4.2% versus 2.8%; 1.52; 1.27–1.81), and headaches (5.8% versus 4.7%; 1.26; 1.08–1.46) than women on placebo. Estrogen plus progestin treatment prevented the onset of new musculoskeletal symptoms. Vaginal bleeding was reported by 51% of women on E+P and 5% of women on placebo at 6 months; most bleeding was reported as spotting. Gynecologic surgeries (hysterectomy and dilation and curettage) were performed more frequently in women assigned to E+P (3.1% versus 2.5% for hysterectomy, hazard ratio = 1.23, P = .026; 5.4% versus 2.4% for dilation and curettage, hazard ratio = 2.23, P < .001). CONCLUSION: Estrogen plus progestin relieved some menopausal symptoms, such as vasomotor symptoms and vaginal or genital dryness, but contributed to treatment-related effects, such as bleeding, breast tenderness, and an increased likelihood of gynecologic surgery. LEVEL OF EVIDENCE: I

The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants.

The postmenopausal hormone therapy (PHT) component of the Women’s Health Initiative (WHI) is composed of two randomized, placebo-controlled, double-blind trials in postmenopausal women aged 50 to 79 years at initial screening, testing the effects of estrogen alone (E-alone) and estrogen plus progestin (E P) on coronary heart disease (CHD) as the primary outcome, hip and other fractures and colorectal cancer as secondary outcomes, and pulmonary embolism, breast and endometrial cancers as potential risks. The design and rationale of the PHT trials, including general eligibility and exclusion criteria and considerations regarding sample size and statistical power, have been described previously (1). Postmenopausal hormones have been initiated in menopausal women for the treatment of vasomotor symptoms, mood disturbances, vaginal dryness, and prevention of rapid bone loss for several decades. Despite a paucity of data on effects of initiating hormone use in older women, postmenopausal hormones have also been promoted for the prevention of CHD, osteoporotic fractures, and other diseases that occur years after menopause (2). It is generally recommended (2) that women with a uterus be prescribed a combination of estrogen and progestin to prevent endometrial

The postmenopausal estrogen/progestin interventions study: primary outcomes in adherent women

OBJECTIVE To assess the efficacy of unopposed estrogen, and three estrogen/progestin regimens on selected heart disease risk factors among adherent women and to contrast those results with efficacy among all women in the PEPI study. DESIGN A 3-year, multicenter, randomized, double-blinded, placebo-controlled clinical trial. PARTICIPANTS A total of 847 healthy postmenopausal women aged 45 to 64 years of age with no known contraindication to hormone therapy, who attended their 36 month clinical visit. INTERVENTION Participants were randomized in equal numbers to one of the following treatments: (1) placebo; (2) conjugated equine estrogen (CEE) 0.625 mg daily; (3) CEE 0.625 daily plus medroxyprogesterone acetate (MPA) 10 mg, days 1-12; (4) CEE 0.625 daily plus MPA 2.5 mg daily; or (5) CEE 0.625 daily plus micronized progesterone (MP) 200 mg, days 1-12. ANALYSIS Analyses are based on adherent women, where adherence is defined as taking at least 80% of pills at each 6-month visit. RESULTS Adherence rates were high in all groups except women with a uterus assigned to unopposed CEE. The difference in HDL-C levels resulting from the CEE vs. CEE+MP was approximately three times larger than in the intent-to-treat analyses, reaching statistical significance (P < 0.05). In each active treatment, LDL-C decreased 10-15%. Triglycerides increased 15-20% in each opposed CEE arm and over 25% in the CEE only arm; this difference was not statistically significant. Fibrinogen increased by 7% among placebo adherers, but decreased or remained fairly stable among the active arm adherers. Systolic blood pressure increased 3-5% in all treatment arms. Women adherent to the CEE+MPA arms had twice the increase of 2 h glucose levels as women adherent to CEE only, or CEE+MP (8-9% vs. 3-4%). Two-hour insulin levels decreased 3-12% for all arms. The patterns of change for fibrinogen, SBP, 2 h glucose and insulin were similar to those from the intent-to-treat analyses. CONCLUSIONS In analyses limited to adherent women, all active treatments, compared to placebo, continued to have similar and favorable effects on LDL-cholesterol and fibrinogen and no significant effects on blood pressure or insulin levels. Given the overall high adherence rates in PEPI, the results are similar to the intent-to-treat analyses, as expected. Only the trend of HDL-C to have a larger increase in the CEE only arm (in the intent-to-treat analyses) gained statistical significance in analyses restricted to adherers.

Menopause and hormone replacement therapy

Menopause is a normal part of life of most women and can be made easier with appropriate information about the events that occur. For those women who desire help for bothersome menopausal symptoms, effective therapy can be offered. The use of HRT for prevention is more complex. Several large randomized clinical trials, including the Womens Health Initiative (WHI) and the Heart and Estrogen Replacement Therapy Study (HERS) in the United States, are currently underway. These trials, which have as end points clinical events such as myocardial infarction, sudden death, fractures, and cancer, will provide answers to many of the questions raised in this discussion. Until the results of these trials are available, clinicians must be prudent in their recommendations and should keep their patients apprised of the relevant uncertainties of preventive HRT.

The natural history of primary dysmenorrhoea: a longitudinal study

Objective  To describe the prevalence, severity, course and predictive factors of primary dysmenorrhoea in women of all reproductive ages.

Perinatal Vertical Transmission of Human Papillomavirus and Subsequent Development of Respiratory Tract Papillomatosis

This study prospectively examined the potential for human papillomavirus (HPV) to be transmitted vertically to newborns during delivery. Exfoliated cervical cells were extracted from 72 pregnant women during the third trimester and again during labor prior to delivery, and tested for the presence of HPV DNA. These results were compared with HPV DNA specimens from their newborns, who were sampled by exfoliated cells from the oral-pharyngeal cavity and vulva or tissue from the foreskin 24 to 72 hours after delivery. Among the mothers, 18.1% (13 of 72) typed HPV-positive by the ViraPap/ViraType DNA hybridization technique. Two neonates (2.8% or 2 of 72) tested positive from oral-pharyngeal specimens. This finding supports the hypothesis that respiratory tract papillomatosis may develop as a result of perinatal vertical transmission of HPV. Furthermore, this study suggests that neither cesarean section nor prepartum treatment of HPV lesions will always protect against neonatal acquisition of HPV.

Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol.

OBJECTIVE: To investigate uterine effects of unopposed ultralow-dose transdermal estradiol administered to postmenopausal women for 2 years. METHODS: Postmenopausal women (n = 417), aged 60–80 years, with a uterus and with bone mineral density that was normal for age (z score ≥–2.0) were randomly assigned to receive unopposed transdermal estradiol (14 μg per day) or identical placebo patch. We evaluated effects on endometrial histology, vaginal bleeding, and vaginal epithelial cell maturation. RESULTS: At baseline, estradiol and placebo groups were similar in age (67 ± 5 years) and in median baseline serum estradiol level (4.8 pg/mL, interquartile range 2.7, 8.0 pg/mL). In the estradiol group, median estradiol level increased to 8.6 pg/mL, (interquartile range 4.4, 13.9 pg/mL, P < .001). In the estradiol group, focal atypical endometrial hyperplasia developed in 1 woman, and adenosarcoma of the uterus developed in 1 woman. The placebo group had no endometrial hyperplasia. Endometrial proliferation occurred in 8.5% of the estradiol group and in 1.1% of the placebo group (P = .06). Incidence of vaginal bleeding was 12.4% in the estradiol group and 8.6% in the placebo group (P = .3). Vaginal epithelial cells showed greater maturation in the estradiol group than in the placebo group (P < .001) but less than typically observed with standard doses of estrogen. CONCLUSION: During 2 years of treatment with ultralow-dose unopposed estradiol, treatment and placebo groups had similar rates of endometrial hyperplasia, endometrial proliferation, and vaginal bleeding. This therapy apparently causes little or no endometrial stimulation. LEVEL OF EVIDENCE: I