Progestogens and venous thromboembolism among postmenopausal women using hormone therapy

Hormone therapy (HT) is the most effective treatment for correcting menopausal symptoms after menopause. HT initially consisted of estrogens alone and progestogens were secondly added to estrogens for preventing the risk of endometrial cancer associated to estrogens use. Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is a major harmful effect of HT. It is now well known that oral and transdermal estrogens are differentially associated with VTE risk but progestogens may be another important determinant of the thrombotic risk among HT users. Both randomized controlled trials and meta-analysis of observational studies suggested that the VTE risk was higher among users of estrogens plus progestogens than among users of estrogens alone. With respect to the different pharmacological classes of progestogens, there is evidence for a deleterious effect of medroxyprogesterone acetate on VTE risk. In addition, observational studies showed that norpregnane derivatives were significantly associated with an increased VTE risk whereas micronized progesterone could be safe with respect to thrombotic risk. The effect of tibolone on VTE risk remains uncertain. In conclusion, progestogens may have differential effects on VTE risk according to the molecules and therefore represent an important potential determinant of the thrombotic risk among postmenopausal women using estrogens.     

New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits

Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.     

Changing use of hormone therapy among minority women since the Women's Health Initiative

OBJECTIVE: There has been a significant shift in the use of hormone therapy (HT) among nonminority women since the publication of results of the Women's Health Initiative (WHI). Little is known about how the WHI results affected minority populations. This survey measured patterns of HT use among inner city women after publication of the WHI results, identified factors involved in the decision to continue or discontinue HT, and characterized the symptom burden and the experience of women who attempted to discontinue HT. DESIGN: We conducted a cross-sectional survey of 101 English- and Spanish-speaking women in an inner city general internal medicine clinic from August 2003 to April 2004. All women had been taking HT at the time of the publication of the WHI results. The survey included questions on patient-reported experience with HT, symptoms of menopause, and use of alternative treatments. RESULTS: Overall, 101 of 142 (71%) eligible women agreed to participate. The mean age of participants was 60 years; 43% were African American and 46% were Hispanic. The mean duration of HT use was 9.6 years. Three quarters (74%) had heard about the WHI findings, and 87% had attempted to stop taking HT after their publication. The most common reason for attempting to stop HT was concern about an increased risk of cancer or a general increase in risk to health. Of those who stopped HT, the vast majority (85%) reported vasomotor symptoms, and 26% restarted HT, mostly to treat those symptoms. CONCLUSIONS: Nearly all minority women in this small sample attempted to stop HT use after the results of the WHI were published. Restarting HT for treatment of symptoms was common.     

The woman patient after WHI

An epidemic of fear and distrust has infected women (and physicians) after publication of the Women's Health Initiative (WHI). The overinflated negative data emerging from the oestroprogestinic arm of WHI have frightened women and gave rise to the most difficult emotions to cope with. Keywords such as cancer, death and hormones combined together, have potentiated an avoidant attitude towards hormonal therapy (HT) driven more emotionally than rationally. This negative aura has not been dissipated by the positive data from the oestrogen-only arm of WHI. This paper will discuss: women's different emotional reactions to and coping strategies for HT-related fear after WHI; the communication skills physicians should use in focusing on positive messages emerging from WHI; predictors of current HT use; the meaning of the higher use of HT in postmenopausal highly-educated women and women gynaecologists; the importance of increasing healthy life-styles as a taking of responsibility towards aging by every woman; shifting from passivity to active sharing of the decision making process with the caring physician; and the use of an individually tailored HT, when appropriate, as part of an active strategy in the pursuit of a longer health expectancy.     

Women's views of the climacteric at the time of low menopausal hormone use, Estonia 1998

OBJECTIVES: This study examined women's opinions about the climacteric and hormone therapy (HT) after menopause and compared women's and physicians' opinions in a country of low-HT use. METHODS: In 1998, a postal questionnaire was sent to a random sample of 2000 Estonian 45-64-year-old women; 69% (n=1312) responded. In 1999, a postal questionnaire was sent to a random sample of 500 Estonian gynaecologists and general practitioners; 68% (n=342) responded. RESULTS: Mean age at menopause was 49.8 years (S.D. 4.0), and there was no difference by socioeconomic classes or by age in self-rated health. Ten percent of women reported having used HT, with 3% currently using it. Most women reported some symptoms, with vasomotor symptoms more frequently reported by 50-54 years old; women most often reported tiredness (48%). Half of the women but under a fifth of physicians considered the climacteric a normal phase of life. Women's awareness about HT was low and about half had no opinion on its health effects. Half of the women had visited a gynaecologist, older women less so. Women with contacts with health care were more aware of HT. CONCLUSIONS: Women reported symptoms by age-group as similarly found in high-HT use countries and it verifies that many symptoms experienced were not due to menopause. As in other low-HT use countries, women were unfamiliar with HT and their attitudes were traditional, although physicians' attitudes were more positive. Estonian women seemed to have escaped the period of the preventive use of HT.     

Different effects of oral conjugated equine estrogens and transdermal estrogen on undercarboxylated osteocalcin concentration in postmenopausal women

OBJECTIVE: Undercarboxylated osteocalcin (ucOC) is a sensitive marker of vitamin K status, and triglyceride (TG) has been shown to be the main transporter of vitamin K. In the present study, we examined the difference between ucOC concentrations in postmenopausal women receiving hormone therapy (HT) with oral conjugated equine estrogens (CEE) and transdermal estradiol (TE2). We also examined the associations of ucOC concentration with estradiol concentration and TG. DESIGN: Ninety-two postmenopausal women were recruited for this study. Serum concentrations of ucOC, intact osteocalcin, estradiol, and TG were measured before and after 12 months of HT. Forty-six women received oral administration of 0.625 mg of CEE and 2.5 mg of medroxyprogesterone acetate daily, and 46 women received transdermal administration of 50 mug of 17beta-estradiol twice weekly and 2.5 mg of medroxyprogesterone acetate daily. RESULTS: The ucOC concentration in women during HT with oral CEE was significantly (P < 0.01) lower than that in women during HT with TE2. Serum estradiol concentrations during HT with CEE showed a significant inverse correlation with ucOC concentrations and the ratio of ucOC/OC during HT (P < 0.05 and P < 0.01, respectively). In addition, the serum ucOC concentration in women with an increased percentage of change in TG was significantly (P < 0.01) lower than that in women with a decreased percentage of change in TG during HT with oral CEE. CONCLUSION: The effect of HT with TE2 on ucOC concentration in women is weaker than the effect of HT with oral CEE. Suppression of ucOC concentration in postmenopausal women during HT with oral CEE might be associated with the effect of vitamin K through increased TG induced by oral CEE.     

Effects of two continuous hormone therapy regimens on C-reactive protein and homocysteine

OBJECTIVE: To compare the effects of two continuous hormone therapy (HT) regimens on the cardiovascular risk markers, C-reactive protein (CRP) and homocysteine. DESIGN: A prospective study in which 43 postmenopausal women were randomly assigned to either tibolone 2.5 mg/day (n = 20) or 0.625 mg/day conjugated equine estrogens (CEE) plus continuous medroxyprogesterone acetate (MPA) 5 mg/day (n = 23). Serum levels of CRP, homocysteine, vitamin B12, and folate were determined before and during 12 weeks of therapy. RESULTS: C-reactive protein levels were increased by tibolone (76%; P < 0.001) and CEE+MPA (81%; P < 0.001). Neither tibolone nor CEE+MPA had any significant effect on homocysteine levels, but there was a significant difference between the effects of treatment over time (P = 0.046). Both tibolone and CEE+MPA reduced vitamin B12 levels (11%; P < 0.001, and 8%; P < 0.01, respectively), but had no statistically significant effect on folate levels. Individual changes in homocysteine levels were negatively associated with changes in vitamin B12 levels (r = -0.68; P < 0.01) after tibolone therapy. CONCLUSION: Both tibolone and CEE plus MPA increased CRP levels and reduced levels of vitamin B12. Neither therapy had any significant effect on homocysteine levels. Further long-term studies into the effect of HRT on these markers, and the relationship to cardiovascular disease risk, are required.     

Nitric oxide in postmenopausal women taking three different HRT regimens

OBJECTIVE: To search and compare the effects of three different HRT regimens on nitric oxide levels of postmenopausal women. METHODS: Four groups of postmenopausal women were included in this prospective, randomised, placebo controlled study. 34 women used 0.625 mg conjugated estrogen continuously combined with 5 mg medroxyprogesterone acetate, 32 women used 2.5 mg tibolone, 26 women used 50 mcg transdermal estrogen alone continuously and 32 women used placebo for 12 months. Before the treatment and after 1 year, serum NO (nitrate/nitrite) and some other biochemical parameters were evaluated. RESULTS: All HRT using groups had increased serum nitric oxide levels significantly compared to placebo group and also there was not any difference among three HRT using groups concerning to increases in nitric oxide levels. CONCLUSION: Both conjugated estrogen combined with continuous progestin and transdermal estrogen alone and also tibolone increases serum nitric oxide levels of postmenopausal women equally for 12-months of treatment.     

Comparison of transdermal estradiol and tibolone for the treatment of oophorectomized women with deep residual endometriosis

Study objective: To compare the effect of HRT with transdermal estradiol and that of treatment with tibolone in post-menopausal women with residual endometriosis. Materials and Methods: 21 women with residual pelvic endometriosis after bilateral oophorectomy with or without hysterectomy were enrolled in the study and were randomized to HRT with transdermal estradiol 50 mg twice weekly (n=10) associated with cyclic medroxyprogesterone acetate 10 mg daily in women who preserved uterus, and to treatment with tibolone 2.5 mg administered orally once a day (n=11). The duration of both treatments was scheduled to last at least 12 months. Residual endometriosis was located in the bowel wall in four patients, in the rectovaginal septum in six and deeply in the retroperitoneal pelvic space in six. All women were symptomatic before oophorectomy. Results: All the women were followed for 12 months. No patient suspended therapy because of side effects. Four patients of the estradiol group experienced moderate pelvic pain during treatment compared with only one patient in the tibolone group. One patient in the estradiol group reported severe dyspareunia. Conclusion: Although our series is very small, it seems that tibolone may be a safe hormonal treatment for post-menopausal women with residual endometriosis.     

Effects of tibolone on bone quality in ovariectomized monkeys

OBJECTIVE: The purpose of this report is to examine the effects of two doses of tibolone on bone quality (bone biomarkers, bone density, and bone strength) in ovariectomized cynomolgus monkeys fed high-fat diets. DESIGN: Ovariectomized cynomolgus monkeys were randomized into one of five treatment groups: placebo-treated control, tibolone (0.2 mg/kg/day), tibolone (0.05 mg/kg/day), conjugated equine estrogens (Premarin, 0.042 mg/kg/day), and conjugated equine estrogens plus medroxyprogesterone acetate (0.042 and 0.167 mg/kg/day, respectively). Bone quality was assessed by determining bone strength and density in vertebrae and femora collected after 24 months of treatment. RESULTS: Monkeys treated for 24 months with tibolone had increased bone mineral density in the distal femur and improved biomechanical properties in the midshaft femur compared with placebo-treated ovariectomized monkeys, as did monkeys treated with conjugated equine estrogens with or without medroxyprogesterone acetate. No treatment effects were seen in lumbar vertebra bone density or strength. There was no significant difference between tibolone and estrogen on biomechanical properties of the femur. CONCLUSION: These data show that tibolone is comparable to conjugated equine estrogens with or without medroxyprogesterone acetate in decreasing bone turnover and increasing bone strength in ovariectomized monkeys.     

Tibolone, oral or transdermal hormone replacement and colour Doppler analysis: a prospective, randomised pilot study

Objective: To compare the plasma thromboxane, the plasma viscosity and the Doppler flow modifications induced by tibolone and by oral or transdermal continuous combined hormone replacement therapy. Methods: Forty-two post-menopausal patients underwent either on: oral daily treatment with tibolone (2.5 mg) (Group I; n=14); or continuous oral administration of 0.625 mg conjugated equine estrogens + medroxyprogesterone 5 mg per day (Group II; n=14); or continuous estradiol transdermal supplementation, at a dose of 50 μg per day, + medroxyprogesterone 5 mg per day (Group III; n=14). The duration of the study was 6 months and the patients were submitted to transvaginal ultrasonographic evaluation of pelvic organs; Doppler analysis of the uterine, internal carotid and ophthalmic arteries; thromboxane and plasma viscosity assays in basal condition, and at 1, 3 and 6 months from the beginning of the study. Results: Although the endometrial thickness increased significantly, there were no cases in which it exceeded the normal range (≤5 mm). In all the three groups, the pulsatility index of the uterine, internal carotid and ophthalmic arteries significantly decreased during the therapy showing a reduced impedance since the first month of treatment. Similar variations were observed for the peak systolic blood flow velocity of the internal carotid and ophthalmic arteries. Hormone replacement therapy and tibolone induced a deep, significant and rapid decrease in plasma thromboxane and plasma viscosity levels. Conclusions: Hormone replacement therapy and tibolone seem to have beneficial effects on vascular and hemorrheological parameters.     

Recent reversal of trends in hormone therapy use in a European population

OBJECTIVE: The impact of the Women's Health Initiative (WHI) randomized trial results published in July 2002 indicating that hormone therapy (HT) is potentially harmful for the heart and the mammary gland of naturally postmenopausal women was assessed for the first time in a European population. DESIGN: This study continuously monitored HT use from 1994 through 2003 in a population-based random sample of 5,758 women aged 35 to 74 years residing in Geneva (city and canton), Switzerland, yielding 1,938 naturally postmenopausal women with an intact uterus and 206 artificially postmenopausal women. Women in the former subgroup weighed substantially less than their WHI trial counterparts but were not otherwise at lower risk for cardiovascular disease. RESULTS: Among the naturally postmenopausal women with an intact uterus, current HT use increased from 29% to 46% (P < 0.0001) through July 2002 and then decreased abruptly to 31% in 2003. Current HT use remained stable (range, 38%-46%; trend P = 0.92) among the artificially postmenopausal women. CONCLUSIONS: Successive annual increases from 1994 through 2001 in the prevalence of current HT use by postmenopausal women living in Geneva were dramatically reversed to the level in 1994 just after the results of the WHI trial were published, but only for naturally postmenopausal women with an intact uterus. Approximately one in three of the latter women who stopped using HT may also have lost its beneficial effects on bone health.