Tomi S. Mikkola

Estrogen and postmenopausal estrogen/progestin therapy: effect on endothelium-dependent prostacyclin, nitric oxide and endothelin-1 production

It is well documented that postmenopausal estrogen/progestin therapy (HRT) protects women against cardiovascular disorders. However, the mechanism(s) by which this protection is mediated remains largely unresolved, because beneficial effects of estrogen on the blood lipid profile account for only 20-30% of the overall protection. Growing evidence suggests that estrogen has direct effects on the blood vessel wall indicating that vascular endothelium may play a key role in mediating these effects by producing vasoactive factors, such as prostacyclin (PGI2), nitric oxide (NO) and endothelin-1 (ET-1). In vitro estrogen stimulates endothelial PGI2 and NO production, whereas ET-1 production is not affected. Moreover, in vivo studies indicate that estrogen and HRT increase PGI2 and NO production, whereas ET-1 production decreases. These effects are evidently mediated through estrogen receptors in endothelial cells. Thus, estrogen and HRT lead to the dominance of vasodilatory and antiaggregatory agents released by the endothelial cells. This may be an important new mechanism in the cardiovascular protection mediated by estrogen and HRT.

Evidence for a role of hot flushes in vascular function in recently postmenopausal women.

OBJECTIVE: Observational studies indicate that postmenopausal hormone therapy (HT) prevents cardiovascular disease, but randomized clinical trials have not confirmed this effect. Hot flushes were more likely to be present in women starting HT in observational studies, whereas these symptoms were mild or absent among women attending randomized clinical trials. We hypothesized that vascular function may differ in women with and without vasomotor hot flushes. METHODS: One hundred forty-three recently postmenopausal women showing a broad range of variation in hot flushes were studied with radial artery tonometry. Pulse wave analyses were assessed at baseline and after nitroglycerin and salbutamol challenges. Wilcoxon signed rank test was used for paired comparisons after challenges with nitroglycerin and salbutamol. RESULTS: Neither baseline arterial stiffness nor endothelial function differed between women without or with mild, moderate, or severe hot flushes. However, after nitroglycerin challenge, the time to the onset of the reflected wave (dependent on pulse wave velocity) was 9.5% longer (P=.014), and the time to the first systolic peak (dependent on the rapid phase of ventricular ejection) was 13.9% longer (P=.025) in women with severe hot flushes as compared with asymptomatic women. CONCLUSION: Women with severe vasomotor hot flushes show greater vascular responsiveness to nitroglycerin than women without hot flushes. This may partially explain the conflicting data between observational and randomized HT studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www. clinicaltrials.gov, NCT00668603 LEVEL OF EVIDENCE: II

Management of cardiovascular risk in the perimenopausal women: a consensus statement of European cardiologists and gynecologists

Cardiovascular risk is poorly managed in women, especially during the menopausal transition when susceptibility to cardiovascular events increases. Clear gender differences exist in the epidemiology, symptoms, diagnosis, progression, prognosis and management of cardiovascular risk. Key risk factors that need to be controlled in the perimenopausal woman are hypertension, dyslipidemia, obesity and other components of the metabolic syndrome, with the avoidance and careful control of diabetes. Hypertension is a particularly powerful risk factor and lowering of blood pressure is pivotal. Hormone replacement therapy is acknowledged as the gold standard for the alleviation of the distressing vasomotor symptoms of the menopause, but the findings of the Womens Health Initiative (WHI) study generated concern for the detrimental effect on cardiovascular events. Thus, hormone replacement therapy cannot be recommended for the prevention of cardiovascular disease. Whether the findings of WHI in older postmenopausal women can be applied to younger perimenopausal women is unknown. It is increasingly recognized that hormone therapy is inappropriate for older postmenopausal women no longer displaying menopausal symptoms. Both gynecologists and cardiovascular physicians have an important role to play in identifying perimenopausal women at risk of cardiovascular morbidity and mortality, and should work as a team to identify and manage risk factors, such as hypertension.

Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality.

Objective:Data on the health benefits and risks of postmenopausal hormone therapy (HT) are derived mainly from the use of conjugated equine estrogens. Estradiol-based regimens may have a different risk-benefit profile. We evaluated the risk of death caused by coronary heart disease (CHD), stroke, or any disease among users of estradiol-based HT regimens in a nationwide study in Finland. Methods:A total of 489,105 women who used HT from 1994 to 2009 (3.3 million HT exposure years), as indicated in the nationwide reimbursement register and the national Cause of Death Register, were followed. A total of 28,734 HT users died during follow-up; among the deaths, 3,843 were caused by CHD and 2,464 were caused by stroke. Mortality risk in HT users with varying duration of exposure (⩽1 y, >1 to 3 y, >3 to 5 y, >5 to 10 y, or >10 y) was compared with that in an age-matched background population. Results:Risk of CHD death was significantly reduced by 18% to 54% in HT users and was positively related to HT exposure time. Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time. Risk of all-cause mortality was reduced in HT users by 12% to 38%, almost in linear relationship with duration of exposure. All these risk reductions were comparable in women initiating HT before age 60 years and women initiating HT at age 60 years or older. Conclusions:In absolute terms, the risk reductions mean 19 fewer CHD deaths and 7 fewer stroke deaths per 1,000 women using any HT for at least 10 years.

Effect of aerobic training on hot flushes and quality of life--a randomized controlled trial.

Abstract Background and objective. To estimate whether aerobic training has an effect on frequency of hot flushes or quality of life. Design. A randomized controlled trial. Participants and setting. Symptomatic, sedentary women (n = 176), 43–63 years, no current use of hormone therapy. Intervention. Unsupervised aerobic training for 50 minutes four times per week during 6 months. Outcomes. Hot flushes as measured with Womens Health Questionnaire (WHQ) and Health-Related Quality of Life (HRQoL, SF-36), daily reported hot flushes on phone-based diary, cardiorespiratory fitness (CRF), and body composition. Results. Intervention group had larger decrease in the frequency of night-time hot flushes based on phone diary (P for month × group = 0.012), but not on WHQ scale. Intervention group had less depressed mood (P = 0.01) than control women according to change in WHQ score. Changes in WHQ score in depressed mood (P = 0.03) and menstrual symptoms (P = 0.01) in the intervention group were significantly dependent on frequency of training sessions. HRQoL was improved among the intervention group women in physical functioning (P = 0.049) and physical role limitation (P = 0.017). CRF improved (P = 0.008), and lean muscle mass increased (P = 0.046) significantly in the intervention group as compared to controls. Conclusions. Aerobic training may decrease the frequency of hot flushes and improve quality of life among slightly overweight women.

Postmenopausal hormone therapy before and after the women's health initiative study: what consequences?

This review focuses on the question of whether the Womens Health Initiative (WHI) was a test of primary versus secondary cardiovascular benefits of postmenopausal hormone therapy. Evidence is presented to support the conclusion that the WHI was a secondary intervention trial and that primary cardiovascular benefits of hormone therapy are rational, likely, but not yet proven. The review makes clear that hormone therapy is not a ‘cardiovascular drug’ for the treatment of coronary heart disease; but rather that the public health debate is whether hormone therapy, used for the treatment of menopausal symptoms, provides any cardiovascular benefits that might offset its risk.

Increased Cardiovascular Mortality Risk in Women Discontinuing Postmenopausal Hormone Therapy

CONTEXT Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk. OBJECTIVE We evaluated the risk of cardiac or stroke death after the discontinuation of HT. Design, Patients, Interventions, and Main Outcome Measures: Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n = 3177) or stroke (n = 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users. RESULTS Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16-1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72-0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47-1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85-0.94). The cardiac (2.30; 2.12-2.50) and stroke (2.52; 2.28-2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51-2.48). CONCLUSIONS Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT.

Sex differences in age-related cardiovascular mortality.

Introduction Sex-related physiological differences result in different expressions of diseases for men and women. Data are contradicting regarding the increase in the female risk for cardiovascular disease (CVD) at mid-life. Thus, we studied possible sex differences in age-adjusted mortality for CVD and non-vascular diseases stratifying our findings by specific age groups. Methods Over one million deaths (1 080 910) reported to the Finnish nationwide Causes of Death Register in 1986–2009 were analyzed. A total of 247 942 male deaths and 278 752 female deaths were of CVD origin, the remaining deaths were non-vascular. The annual mortality rates were calculated per 100 000 mid-year population, separately for men and women in 5-year age categories. Results The age-standardized risk of death from CVD was 80% higher for men (442/100 000) than for women (246/100 000). After age 45–54 the male CVD mortality rate elevated parallel to the non-vascular mortality, whereas in women the CVD mortality elevated considerably more rapidly than the non-vascular mortality from age 60 years onwards. Conclusions Heart disease mortality in men accelerates at a relatively young age, but in women the risk shows a steep increase at approximately 60 years of age. These data emphasize the need to identify and prevent risk factors for CVD, especially in women in their mid-life years.

Is the pregnancy hormone relaxin an important player in human heart failure

The pregnancy hormone relaxin has been raised as a new compensatory mediator of cardiac origin in heart failure (HF). We set out to assess the role of relaxin in pressure overload‐induced human HF.

Postmenopausal Hormone Therapy Increases Retinal Blood Flow and Protects the Retinal Nerve Fiber Layer

PURPOSE To investigate whether postmenopausal hormone therapy (HT) increases retinal and ONH blood flow (BF) and protects ONH topography and the function of retinal ganglion cells in postmenopausal women (PMW). The effect of estradiol (E(2)) treatment on retinal tissue perfusion was also investigated in ovariectomized rats, an animal model for menopause. METHODS Sixty-four healthy PMW were recruited, 29 of whom never used HT ( HT) and 35 of whom had used HT (+HT) continuously since the onset of menopause. Blood flow of the inferotemporal retinal artery (ITRA), peripapillary retina, and ONH rim were measured in one eye. The ONH stereometric parameters and the pattern electroretinogram (PERG) were also measured. In ovariectomized rats, the retinal tissue perfusion was assessed using the BF tracer N-isopropyl-p-[(14)C]-iodoamphetamine ([(14)C]-IMP) in rats treated with either E(2) (n = 7) or placebo (n = 5). RESULTS Compared with the HT group, the +HT group presented significantly greater BF of the ITRA (P = 0.006), greater rim volume for the entire ONH region (P = 0.032), and greater rim volume (P = 0.042), height variation contour (P = 0.011), mean thickness (P = 0.033), and cross-sectional area (P = 0.020) of the retinal nerve fiber layer for the inferotemporal region of the ONH when adjusted for age, ocular perfusion pressure, and age at menarche. In ovariectomized rats, E(2) treatment significantly increased retinal perfusion in a range of 22% to 45%. CONCLUSIONS These findings indicate that estrogens and HT increase retinal blood flow and protect the retinal nerve fiber layer.