Transdermal hormone therapy and the risk of stroke and venous thrombosis.

Recent case-control and cohort studies have indicated that the transdermal administration of postmenopausal estrogen therapy is not associated with an increased risk of cardiovascular complications, specifically stroke and venous thrombosis. These studies have prompted the clinical promotion of transdermal treatment as 'safer'. There are reasons, however, to be cautious regarding postmenopausal transdermal hormone therapy, especially in regard to stroke. Previous reports linking postmenopausal estrogen therapy and the risk of stroke have not yielded consistent results, finding it difficult to adjust for all confounding factors, including compliance with treatment. Age of the population studies may be a critical issue. Notably, the risk of stroke with oral estrogen was not increased in the Women's Health Initiative when women with prior cardiovascular disease or those older than 60 years were excluded. There does appear to be a dose-response relationship with stroke, similar to that observed with estrogen-progestin contraceptives, and this may be a problem when studying standard doses of transdermal treatment, in that many women receiving transdermal estrogen display lower estrogen blood levels when compared with oral treatment. Clinicians should administer low doses of estrogen to women with risk factors for stroke, and the transdermal route of administration is indicated for women at high risk for venous thrombosis and for older postmenopausal women, especially for women with stroke risk factors. In a recent study, Renoux and colleagues from McGill University in Montreal performed a nested case-control study deriving the data from a cohort of women in the UK General Practice Research Database (GPRD). Current use of oral and transdermal hormone therapy, based on recorded prescriptions, was compared to no use in 15 710 cases and 59 958 controls. The adjusted rate ratio (RR) for stroke for current use of transdermal estrogens, with or without a progestin, was not increased (RR 0.95; 95% confidence interval (CI) 0.75-1.20) compared with a significant increase associated with oral estrogen, with or without a progestin (RR 1.28; 95% CI 1.15-1.42). This would amount to an attributal risk of 0.8 additional strokes per 1000 women per year. There was an indication of a dose-response relationship; a significant increase in risk was observed with transdermal estrogen doses greater than 50 microg. The case-control study by Renoux and colleagues is the first major analysis to compare transdermal and oral hormone therapy and conclude that, compared with an increased risk of stroke with oral therapy, there was no increased risk with transdermal treatment at a dose of 50 microg or less. This report is about as strong an observational study as can be achieved. Large numbers of cases (15 710) and controls (59 958) were available for analysis using the well-known UK GPRD. The use of this computerized database precludes selection bias by the investigators and recall bias by the women in the study. The results support the growing conventional wisdom that transdermal therapy at standard doses is free of the cardiovascular risks associated with oral therapy.

Low-dose hormone therapy in postmenopausal women in China.

OBJECTIVE: To review the experience of menopausal symptoms and low-dose hormone therapy (HT) in postmenopausal women in China. DESIGN: Literature review and critical summaries of available prospective, clinical trials (randomized, controlled trials, RCTs). RESULTS: Chinese women experience menopausal symptoms less frequently compared with women in developed countries, and the prevalence of menopausal symptoms is less in women of southern China than in women of northern China. The majority of postmenopausal Chinese women lack knowledge about HT, and the usage rate of HT is low in these women compared to that in women of developed countries. Some RCTs investigated the efficacy and safety of low- or ultra-low-dose HT, including conjugated equine estrogen, estradiol valerate, transdermal estradiol, nylestriol alone or in combination with progesterone, and tibolone in postmenopausal Chinese women. These RCTs reported that low- or ultra-low-dose HT relieved menopausal symptoms and prevented bone loss as well as standard-dose HT and was less likely to induce side-effects, including irregular vaginal bleeding and breast tenderness; there may be dose-dependent effects of HT. No study evaluated the effects of low-dose HT on cardiovascular events or breast mammographic density/risk of breast cancer. CONCLUSIONS: More RCTs are required to confirm efficacy and to assess the safety of low- or ultra-low-dose HT for a long-term period in a large group of postmenopausal women.

Practical guidelines for postmenopausal hormone therapy.

The fourth Amsterdam Menopause Symposium (2-4 October 2004) was dedicated to practical recommendations to guide clinicians after the confusion, concerns, and controversies generated by study results over the previous several years. Those recommendations are summarized in this deliberately concise and user-friendly document, always recognizing that each clinician must help women with their decision-making according to individual needs, desires, and understanding of benefits and risks.

Tibolone: clinical recommendations and practical guidelines. A report of the International Tibolone Consensus Group.

An international multidisciplinary panel of experts in the management of the menopause met at the 4th Amsterdam Menopause Symposium in October 2004 to determine the specific place of tibolone, a synthetic steroid with a unique clinical profile, within the wide range of currently available postmenopausal therapy options. The consensus was that tibolone is a valuable treatment option for women with climacteric complaints. As well as relieving vasomotor symptoms, tibolone has positive effects on sexual well-being and mood, and improves vaginal atrophy and urogenital symptoms. Prevention of bone loss with tibolone is comparable to that seen with estrogen therapy (ET) and estrogen/progestogen therapy (EPT). As tibolone rarely causes endometrial proliferation, no additional progestogen is required. It also has good tolerability, being associated with a low incidence of vaginal bleeding and of breast pain. Tibolone does not increase mammographic density. Absolute numbers of women at increased risk for breast cancer are estimated to be low or absent with both tibolone and ET, and the risk with tibolone should be significantly lower than that with EPT. Tibolone might therefore be preferable to EPT in certain women who have not been hysterectomised. Based on the evidence available, the panel proposed a number of subgroups of postmenopausal women with vasomotor symptoms in whom tibolone might have added value; these included women with sexual dysfunction, mood disorders, fibroids and urogenital complaints, as well as those with breast tenderness or high mammographic breast density with EPT use.

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To determine the endometrial safety of lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). DESIGN: Randomized, double-blind, placebo-controlled study (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Healthy, postmenopausal women (n = 2,673) with an intact uterus. INTERVENTION(S): Patients received CEE 0.625 mg/day, CEE 0.625/MPA 2.5 mg/day, CEE 0.45 mg/day, CEE 0.45/MPA 2.5 mg/day, CEE 0.45/MPA 1.5 mg/day, CEE 0.3 mg/day, CEE 0.3/MPA 1.5 mg/day, or placebo for 1 year. Endometrial biopsies were evaluated at baseline, cycle 6, and year 1 using a centralized protocol. MAIN OUTCOME MEASURE(S): Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed CEE. RESULT(S): Endometrial hyperplasia rates ranged from 0 to 0.37% for all CEE/MPA doses. Twenty-nine of the 32 cases of endometrial hyperplasia developed in women who were administered CEE 0.625 mg or CEE 0.45 mg. The incidence of endometrial hyperplasia increased with age for patients administered CEE alone. As expected, there were some inconsistencies among pathologists' ratings in the numbers of hyperplasias and incidence rates for the CEE-alone regimens. There were too few cases of hyperplasia in the combination groups to evaluate consistency among pathologists. CONCLUSION(S): One year of treatment with lower doses of CEE/MPA provides endometrial protection comparable to commonly prescribed doses. These regimens may be used by clinicians to individualize hormone replacement therapy in postmenopausal women.

The effect of varying low-dose combinations of norethindrone acetate and ethinyl estradiol (femhrt) on the frequency and intensity of vasomotor symptoms.

OBJECTIVE: To determine whether there is a significant reduction in frequency and severity of hot flashes in symptomatic postmenopausal women who are administered continuously different dose combinations of norethindrone acetate and ethinyl estradiol. DESIGN: Two randomized clinical trials (Study 1 and Study 2) were conducted in which study participants recorded in daily diaries the frequency of their hot flashes. Study 2 participants also recorded the number of mild, moderate, or severe hot flashes they experienced. In Study 1, a total of 219 postmenopausal women reporting vasomotor symptoms were placed randomly into groups to receive either a placebo or 1 of 4 treatments (0.2 mg/1 microg; 0.5 mg/2.5 microg; 1 mg/5 microg; or 1 mg/10 microg norethindrone acetate/ethinyl estradiol). In Study 2, a total of 266 highly symptomatic postmenopausal women were placed randomly to receive either a placebo or 1 of 3 treatment groups [0.5 mg/2.5 microg; 1 mg/5 microg; or 1 mg/10 microg norethindrone acetate (NA)/ethinyl estradiol (EE)]. Total duration of treatment was 16 weeks in Study 1 and 12 weeks in Study 2. Study 1 subjects had to have at least 10 hot flashes during the week before randomization. Study 2 subjects had to have at least 56 moderate to severe hot flashes during the week before randomization. RESULTS: In both studies, there was a dose-related decrease in hot flash frequency with the highest dose (1 mg NA/10 microg EE) group that had the greatest response. Significant differences from placebo (p < 0.05, Dunnett's test) occurred within 4 weeks in Study 1 for hot flash frequency with a percent reduction in frequency ranging from 33% for placebo to 84% for both the 1 mg NA/10 microg EE and 1 mg NA/5 microg EE dose groups. Likewise, Study 2 significant reductions in hot flash frequency occurred by Week 2 for 1 mg NA/10 microg EE, Week 3 for 1 mg NA/5 microg EE, and Week 5 for 0.5 mg NA/2.5 microg EE (p < 0.05, Dunnett's test). This dose effect was also apparent with regard to severity. In addition, more subjects had clinically meaningful reductions in hot flash frequency or elimination as the dose combinations increased. CONCLUSION: There were significant reductions in hot flash frequency and severity with continuous treatment with norethindrone acetate and ethinyl estradiol combinations. The time at which significant reductions were observed, as well as the magnitude of the response, were dose dependent. The opportunity for lower-dose options of a new continuous-combined hormone replacement therapy provides therapeutic flexibility for women who are recently menopausal.

Health benefits of oral contraceptives.

A sizeable literature corroborates the multiple health benefits of oral contraceptive use. The first estrogen/progestin combination pills were marketed to treat a variety of menstrual disorders. Although currently used oral contraceptives no longer carry FDA-approved labeling for these indications, they remain important therapeutic options for a variety of gynecologic conditions. Well-established gynecologic benefits include a reduction in dysmenorrhea and menorrhagia, iron-deficiency anemia, ectopic pregnancy, and PID. Although older, higher-dose pills reduced the incidence of ovarian cysts, low-dose pills suppress follicular activity less consistently. Nevertheless, cycle-related symptoms, including functional cysts, dysmenorrhea, chronic pelvic pain, and ovulation pain (mittelschmerz), generally improve. Women with polycystic ovary syndrome note improvement in bleeding patterns and a reduction in acne and hirsutism. Symptoms from endometriosis also improve with oral contraceptive therapy. Current data suggest that oral contraceptive therapy increases bone density and that past use decreases fracture risk. Oral contraceptives also improve acne, a major health concern of young women. Oral contraceptives provide lasting reduction in the risk of two serious gynecologic malignancies--ovarian and endometrial cancer. The data with respect to ovarian cancer are compelling enough to recommend the use of oral contraceptives to women at high risk by virtue of family history, positive carrier status of the BRCA mutations, or nulliparity, even if contraception is not required. Health care providers must counsel women regarding these benefits to counteract deeply held public attitudes and misconceptions regarding oral contraceptive use. Messages should focus on topics of interest to particular groups of women. The fact that oral contraceptives increase bone mineral density and reduce ovarian cancer is of great interest to women in their forties and helps influence use and compliance in this group. In contrast, the beneficial effects of oral contraceptives on acne resonates with younger women. Getting the good news out about the benefits of oral contraceptives will enable more women to take advantage of their positive health effects.

Vaginal bleeding in postmenopausal women taking low-dose norethindrone acetate and ethinyl estradiol combinations. The FemHRT Study Investigators.

OBJECTIVE: To determine the effect of continuous combined treatment with norethindrone acetate and ethinyl estradiol (E2) on vaginal bleeding, spotting, or bleeding and/or spotting in postmenopausal women. METHODS: Two randomized clinical trials were conducted in which participants recorded information on the daily occurrence of vaginal bleeding or spotting. In study 1, 219 postmenopausal women reporting at least ten hot flushes per week were randomized to placebo or one of four treatment groups (0.2 mg norethindrone acetate/1 microg ethinyl E2, 0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). In study 2, 266 postmenopausal women reporting at least 56 moderate to severe hot flushes were randomized to placebo or one of three treatment groups (0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). The total duration of treatment was 16 weeks in study 1 and 12 weeks in study 2. In both studies, subjects reported in daily diaries whether they had either bleeding or spotting. RESULTS: In study 1, there was a significantly greater relative risk (RR) for bleeding in the group receiving 1 mg norethindrone acetate/10 microg ethinyl E2 at study weeks 4 and 8 (RR = 1.36 and 95% confidence interval [CI] 1.01, 1.83; RR = 1.37 and 95% CI 1.1, 1.72; respectively) compared with placebo, but not at study weeks 12 or 16. The group receiving 1 mg norethindrone acetate/5 microg ethinyl E2 also had a significantly greater risk at weeks 4 and 8 (RR = 1.5 and 95% CI 1.15, 1.96; RR = 1.33 and 95% CI 1.00, 1.77; respectively), whereas the other dose combinations did not differ from placebo. Results from study 2 were similar to those of study 1. CONCLUSION: Although there was a greater risk for bleeding and/or spotting at the higher doses of norethindrone acetate and ethinyl E2, this risk declined over time. If compliance with hormone replacement therapy regimens is influenced at least in part by vaginal bleeding, the combined norethindrone acetate/ethinyl E2 regimen investigated in these studies may provide a treatment option.

Therapeutic controversy: The safety of third-generation oral contraceptives.

PIP: This paper presents the contributions of Drs. Barbieri, Speroff, Walker, and McPherson to the debate on the safety of third-generation oral contraceptives (OCs). In the overview by Barbieri, the issues of how to assess the quality of the evidence and developing a meaningful framework for integrating an analysis of the benefits and risks of a contraceptive hormone are discussed. He also reflects on the leadership role the endocrinologist must assume in better defining the pharmaco-endocrinology of gestodene and desogestrel. Speroff concludes that modern low-dose OCs are very safe. It was noted that the use of OCs yields an overall improvement in individual health, and from a public health point of view the collection of effects associated with OCs leads to a decrease in the cost of health care. In contrast, Walker argues that low-estrogen OCs containing desogestrel and gestodene carry a modestly elevated risk of venous thromboembolism in comparison to other low-estrogen OCs in widespread use. This statement is supported by McPherson, who emphasizes that the risk associated with OCs is real and should be avoided.^ieng

Role of progesterone in normal breast physiology.

The extant literature indicates that progesterone significantly influences normal mammary growth and differentiation. However, most breast tissue research is conducted using malignant cells, in which the progesterone activity differs greatly from that in normal cells. Although progesterone has been demonstrated to support cyclic proliferation in the breast during the menstrual cycle and pregnancy, in vitro studies have been inconsistent in their assessments of progesterone's role in proliferation. Similarly, mitotic activity in the breast reaches its peak during the progesterone-dominant luteal phase of the menstrual cycle, and therefore some researchers claim that progesterone plays a major role in breast cancer; however, several clinical observations have found evidence dismissing progesterone as a key factor. Thus, researchers seek to expand our current understanding of the role of progesterone in breast physiology.