M.J. van der Mooren

Postmenopausal hormone replacement, risk estimators for coronary artery disease and cardiovascular protection

Menopause, regardless of age at onset, is associated with a marked increase in coronary artery disease (CAD) risk. A large body of observational clinical studies repeatedly demonstrated favorable associations between postmenopausal hormone replacement therapy (HRT) and cardiovascular morbidity, mortality, and risk factors. Estrogens may act in a gender-specific way on vascular endothelial cells and other components of the vessel wall, enhancing the synthesis and release of nitric oxide (NO) and other vasodilators, and by inhibiting the synthesis and release of vasoconstricting agents, thus favoring vasodilation. Menopause-related changes in metabolic cardiovascular risk factors are identifiable, as are HRT-related changes in these factors. The metabolic effects include changes in lipoprotein (a), coagulation and fibrinolysis as well as homocysteine metabolism. The various actions of estrogen alone and combined with progestogen on the vascular system are reviewed. Furthermore, the outcome of the recently published Heart and estrogen/progestin replacement study (HERS) data are put in perspective. In addition, we outline the present data on the effects of raloxifene, a new second generation selective estrogen receptor modulator (SERM), which has been shown to favorably alter several markers of cardiovascular risk in postmenopausal women.

Effects of hormone replacement therapy on blood platelets.

Background Hormone replacement therapy (HRT) increases the risk of cardiovascular morbidity in postmenopausal women under certain circumstances. Part of this effect may be the result of the influence of HRT on blood platelets. We studied the effect of short‐term oral hormone replacement therapy (unopposed oestradiol or sequentially combined oestradiol and trimegestone or dydrogesterone) on platelet activation parameters in healthy postmenopausal women.

Oral, more than transdermal, oestrogen therapy lowers asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo‐controlled study

Objective.  To compare the effects of oral and transdermal hormone therapy (HT) on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in postmenopausal women.

Effects of transdermal and oral postmenopausal hormone therapy on vascular function a randomized placebo-controlled study in healthy postmenopausal women

Objective: To compare the effect of transdermal and oral estrogen therapy, the latter with or without the addition of gestodene, on plasma concentrations of markers of endothelial function and on ultrasonographic parameters of vascular function in healthy postmenopausal women. Design: In a 15-month, randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily doses of placebo (n = 49), 50 μg of transdermal 17ß-estradiol (tE2, n = 33), 1 mg of oral E2 (oE2, n = 37), or 1 mg of oral estradiol combined with 25 μg of gestodene (oE2+ G, n = 33) for 13 cycles of 28 days, followed by four washout cycles with placebo in each group. At baseline and in cycles 4, 13, and 17, we measured plasma levels of endothelial markers and ultrasonographic markers of vascular function (pulsatility index [PI] and, at baseline and cycle 13, arterial stiffness). Results: Compared with placebo, we found reductions in soluble vascular cell adhesion molecule (oE2, P < 0.01; oE2+ G, P < 0.001), sE-selectin (oE2 + G, P < 0.05), von Willebrand factor (tE2, P < 0.05), and divergent effects in PI and stiffness parameters in the carotid artery. We found no effect on PI in the retinal and femoral arteries, or on stiffness parameters in the femoral and brachial artery. Conclusions: Oral hormone therapy reduced plasma levels of adhesion molecules, whereas transdermal estrogen therapy reduced von Willebrand factor. Effects on ultrasonographic parameters of vascular function in the carotid artery were inconclusive.

Changes in the withdrawal bleeding pattern and endometrial histology during 17β-estradiol : dydrogesterone therapy in postmenopausal women : a 2 year prospective study

OBJECTIVE To describe changes in the withdrawal bleeding pattern and endometrial histology during a sequential 17 beta-estradiol-dydrogesterone regimen in postmenopausal women. DESIGN Open-label, non-comparative, prospective study. SETTING Gynecological outpatient department of a university hospital. PATIENTS Twenty-seven healthy non-hysterectomized postmenopausal women. INTERVENTIONS Continuous micronized 17 beta-estradiol supplementation, 2 mg daily, and cyclic administration of dydrogesterone, 10 mg daily for the first half of each 28 day treatment cycle. MAIN OUTCOME MEASURES Changes in the characteristics of the withdrawal bleeding pattern and the endometrial biopsy histology during 2 years of treatment. RESULTS The initial withdrawal bleeding was comparable to normal menstruation with respect to amount and duration. During the 2 years of treatment the bleeding showed a significant tendency to become shorter with less blood loss. This was mainly the result of the decrease (P < 0.001) in the number of days per cycle with bleeding grade II (normal menstruation). None of the women developed endometrial hyperplasia, and in almost all women the given hormone replacement therapy regimen induced secretory or atrophic changes of the endometrium. CONCLUSIONS This sequential 17 beta-estradiol-dydrogesterone regimen can be regarded as safe with respect to the prevention of endometrial disease and appeared to foster patient compliance.

Acceptability and patterns of endometrial bleeding in estradiol-based HRT regimens: a comparative study of cyclical sequential combinations of trimegestone or norethisterone acetate.

Objective This randomized, double-blind, multicenter study was planned to compare the efficacy and tolerance of a novel oral regimen containing estradiol (2.0 mg) sequentially combined with trimegestone, at a daily dose of either 0.25 mg or 0.5 mg, with a standard hormone replacement therapy containing estradiol and norethisterone acetate (E2 + NETA) in the treatment of climacteric symptoms. Methods The study was conducted over 13 cycles, each of 28 days, and involved 487 subjects, of whom 349 completed the study. Results All three treatments were equally effective in alleviating hot flushes and showed a progressive and significant reduction in the value of the Kupperman index. The treatments diminished equally effectively urogenital signs and symptoms. All treatments were well tolerated and the incidences of adverse events associated with each treatment were similar across the treatment groups. The duration of expected withdrawal bleeding was shorter in the estradiol + trimegestone 0.5 mg group than in the estradiol + trimegestone 0.25 mg or E2 + NETA group. Conclusion All treatments were effective and well tolerated, providing significant relief from climacteric symptoms. Treatment with estradiol + trimegestone 0.5 mg provided the most favorable bleeding pattern.

Bleeding patterns and endometrial histology during administration of low-dose estradiol sequentially combined with dydrogesterone

OBJECTIVE To determine bleeding patterns and endometrial response in postmenopausal women taking low-dose (1 mg) estradiol in a sequential combined formulation with 5 or 10 mg dydrogesterone. METHODS A total of 151 postmenopausal women were allocated randomly to 5 or 10 mg dydrogesterone during cycle days 15-28 in a sequential oral formulation with 1 mg estradiol continuously during 13 cycles of 28 days. Occurrence of vaginal bleeding was recorded daily and analyzed in accordance with World Health Organization (WHO) standards. Endometrial biopsies, obtained at baseline and cycle days 25-27 of the final treatment cycle, were interpreted independently by two pathologists. RESULTS The study was completed by 131 women (87%). The percentage of women with bleeding (mean +/- SD) was 57.2 +/- 3.6% in the 1/5-mg group and 65.8 +/- 4.2% in the 1/10-mg group (p < 0.001); cross-sectional analysis showed that, in every cycle, there were more women with bleeding in the 1/10-than in the 1/5-mg group (p < 0.001). With regard to the day of onset of bleeding, the mean difference between groups was 1.4 +/- 1.1 days (p < 0.001). There was no difference in duration of bleed (5 days), or intensity or incidence of intermittent bleeding (3-14% per cycle). Both regimens resulted in high rates of amenorrhea in each cycle (26-49%), but only 14/151 (9%) women were amenorrheic throughout. Three patients (2%) discontinued owing to bleeding problems. Endometrial protection was adequate in 98.3% (1/5-mg group) and 98.5% (1/10-mg group) with only one case of proliferation (1/10-mg group) and one of simple hyperplasia (1/5-mg group). CONCLUSIONS The bleeding pattern associated with low-dose (1 mg) estradiol sequentially combined with 5 or 10 mg dydrogesterone shows a high rate of amenorrhea in each cycle; there is a dydrogesterone dose effect on the occurrence and day of onset of bleeding. Bleeding episodes that occur show a regular pattern and are of slight intensity. The endometrial safety of both regimens is high.

Cardiovascular protection by postmenopausal hormone replacement therapy — the point of lower oestrogen dosages

The recent paper from the Nurses’ Health Study (NHS) by Grodstein et al. [1] is a strong argument for renewed confidence in the future of hormone replacement therapy (HRT) as a tool for primary prevention of coronary artery disease (CAD) in postmenopausal women. In their observational cohort study including 70 533 postmenopausal women, in whom 1258 major coronary events and 767 strokes were identified between 1976 and 1996, the authors compared data of women treated with 0.3 mg conjugated oestrogens (CE) with those treated with higher dosages (0.625 mg and 1.25 mg CE). Lowering the oestrogen dosage did not attenuate the CAD risk reduction observed with conventional dosages (0.625 mg: RR 0.54 [95% CI, 0.44–0.67]), and still resulted in a relative risk of 0.58 (95% CI, 0.37–0.92). Data on stroke also indicated a reduced risk by lower oestrogen dosage. Regrettably, the study design did not allow estimating risks within the 1st year of use. Despite the observational design of the study, the authors provide us with plausible arguments that we can rely on their results. The suggested superiority of the randomised controlled design, as used in the Heart and Estrogen/Progestin Replacement Study (HERS) [2], the Estrogen Replacement and Atherosclerosis (ERA) [3] trial, and the Women’s Health Initiative (WHI), appears not entirely valid. The NHS was also capable of detecting a short-term increase in coronary events in women with established CAD [4]. Furthermore, in the NHS no substantial differences in lifestyle factors were detected between users and non-users, and confounding variables were carefully adjusted for in their statistical analyses, implicating that their results can not solely be explained by a healthy user effect. So, why exclusively trust on data provided by randomised controlled trials, which are so hard to get, if there is such a well designed and reliable cohort study as the NHS? The HERS data may be true, but reality may also have been slightly exaggerated, since ERA did not come up with the same risk increase in the 1st year. Most likely, HRT given in conventional dosages as used in the HERS and ERA trial are of no cardiovascular benefit for women with established CAD, at least not within 3–4 years of treatment. What limits the value of these studies is * Tel.: +31-244-43244; fax: +31-244-44422. E-mail address: mj.vandermooren@azvu.nl (M.J. van der Mooren).

Less mammographic density after nasal versus oral administration of postmenopausal hormone therapy

ABSTRACT Objective Nasal administration gives a more acute but shorter rise in serum hormone levels than oral administration and may therefore have less effect on the fibroglandular tissue in the breasts. We studied the change in mammographic breast density after nasal vs. oral administration of postmenopausal hormone therapy (PHT). Methods We studied participants in a randomized, controlled trial on the impact of nasal vs. oral administration of PHT (combined 17β-estradiol plus norethisterone) for 1 year. Two radiologists classified mammographic density at baseline and after 1 year into four categories. Also, the percentage density was calculated by a computer-based method. The main outcome measure was the difference in the proportion of women with an increase in mammographic density category after 1 year between the nasal and oral groups. Also, the change in the percentage density was calculated. Results The study group comprised 112 healthy postmenopausal women (mean age 56 years), of whom 53 received oral and 59 intranasal PHT. An increase in mammographic density category after 1 year was seen in 20% of the women in the nasal group and in 34% of the oral group. This resulted in a non-significant difference in the proportion of women in whom mammographic breast density had increased by 214% (95% confidence interval (CI) 230% to 2.7%). The mean change in percentage density was 21.2% in the nasal group and + 1.2% in the oral group, yielding a 22.4% differential effect (95% CI 27.3% to 2.5%). Conclusions One year of nasal PHT gave a smaller, although not statistically significant, increase in mammographic density than oral PHT. Remaining issues are the relation between the route of administration of PHT and breast complaints and breast cancer risk.

WS17: Newcomers WS17‐01Hormone replacement therapy reduces impedance to flow in different vascular beds

An HRT‐associated reduction of the pulsatility index (PI) has been reported in the literature, although cross‐sectional studies have shown conflicting data. In a prospective, controlled study we randomized 30 healthy postmenopausal women (mean age 52 ± 3 years) into two groups. Women in the HRT group (N = 15) received 1 mg micronized 17β‐estradiol daily (E2) sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28‐day cycle during 12 months, and, thereafter, 2 mg E2 combined with 10 mg dydrogesterone for a period of 3 months. The control group (N = 15) received no treatment. Color Doppler ultrasound was used to measure the impedance to flow (pulsatility index [PI]) within the uterine, central retinal and ophthalmic arteries in the E2‐phase at baseline and after 3, 12 and 15 months. Compared to controls, 12 months of HRT was associated with a significant decrease in the mean PI of the uterine artery of −39% (HRT −25%, controls +14%) and in that of the central retinal artery of −29% (HRT −9%, controls +20%). After 3 months this effect was already evident. During HRT, the reductions in mean PI of the uterine and central retinal arteries vs. baseline were larger (both P = 0.002) in the women with high pretreatment PI values when compared to those with low pretreatment values. The baseline PI of the uterine artery correlated positively with age and with duration of amenorrhoea (r = 0.42, P = 0.01 and r = 0.48, P = 0.008, respectively). Our 12‐month study expanded on earlier reports of a reduced PI of the uterine artery. We used a combined regimen containing a low‐dose of oestrogens. These results are important because the recent trend is to recommend combined HRT that contain lower dosages of oestrogens than before. Furthermore, a 29% reduction of the PI of the central retinal artery was observed, which suggests that HRT has a positive influence on the impedance of the cerebral circulation. From the point of view of atherothrombotic risk these observations are beneficial and possibly helpful in understanding the decreased risk of cardiovascular disease, and of the impairment of cognitive functions associated with oestrogens in epidemiological data.