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Background: The association between use of menopausal hormone therapy and risk of cutaneous melanoma is highly debated. We investigated the issue in a Finnish nationwide cohort of women ages 50 years or older., Methods: All women who had purchased hormone therapy between 1994 and 2007 were identified from the national Medical Reimbursement Registry and linked to the Finnish Cancer Registry. We calculated standardized incidence ratios (SIR) to compare incidence of cutaneous melanoma among hormone therapy users with that of the general population., Results: During a mean follow-up of 15.6 years, 1,695 incident cutaneous melanoma cases were identified among 293,570 women who had used hormone therapy for at least 6 months. The SIRs for women who used unopposed estrogen therapy and combined estrogen-progestin therapy (EPT) for 6 to 59 months were 1.20 [95% confidence interval (CI), 1.06-1.35] and 1.00 (95% CI, 0.87-1.14; P heterogeneity = 0.04). The SIRs for women who used estrogen therapy and EPT for at least 60 months were 1.37 (95% CI, 1.22-1.52) and 1.23 (95% CI, 1.13-1.34; P heterogeneity = 0.15). We did not find significant differences between oral and transdermal administrations, nor between doses of estrogens., Conclusions: Use of hormone therapy, especially estrogen therapy, was associated with an increased risk of cutaneous melanoma. EPT use of less than 5 years was not associated with an increased risk of cutaneous melanoma., Impact: Our results add to the growing body of epidemiologic evidence that the use of unopposed estrogens in menopause increases the risk of cutaneous melanoma, while the addition of progestins might counteract the detrimental effect., (©2019 American Association for Cancer Research.)

Objective: Recent data have indicated that menopausal hot flashes may be a determinant for cardiovascular health. Therefore, we studied the impact of hot flashes on insulin resistance, one of the most powerful markers of cardiovascular health, in recently postmenopausal women., Methods: We studied 143 recently postmenopausal (amenorrhea 6-36 mo) healthy and normal-weight women without previous hormone therapy use. The women prospectively recorded the number and severity of hot flashes for 2 weeks, and a validated total symptom score, the hot flash weekly weighted score, was calculated for each woman. Insulin resistance was assessed from fasting blood levels of glucose and insulin with the homeostasis model assessment., Results: In 12 women, the assessment of insulin (n = 11) or glucose (n = 1) failed, and they were excluded from further analysis. Thus, hot flashes were absent in 19, mild in 32, moderate in 27, and severe in 53 women. The levels of glucose or insulin, or HOMA showed no differences between these groups, nor was insulin resistance related to the number or severity of hot flashes or to the levels of C-reactive protein or sex hormone-binding globulin. Overall, insulin resistance showed a positive association with body mass index (mean difference, 0.058; 95% CI, 0.015-0.102; P = 0.009) and a negative association with level of estradiol (mean difference, -0.002; 95% CI, -0.003 to -0.001; P = 0.009)., Conclusions: Insulin resistance may not be involved in hot flash-related changes in cardiovascular health. However, because of the small sample size, these findings need to be interpreted with caution.

Hot flushes are complained of by approximately 75% of all postmenopausal women, and hormone therapy (HT) is the most effective way to alleviate them. Hot flushes are characterized by altered vascular function and sympathetic nervous system activity. Hot flushes occurred more often in women attending large, non-randomized observational studies (e.g. Nurses' Health Study), where HT use protected against cardiovascular disease (CVD). However, they were absent (or mild) in randomized HT trials where HT use was accompanied with an elevated risk for CVD. Hot flushes, if a factor for cardiovascular health, could partly explain the conflict between observational and randomized trials. Several cross-sectional studies imply that hot flushes are detrimental to the cardiovascular system. However, the data are not uniform, and hot flushes were recalled retrospectively or during HT use. In our prospective study hot flushes were accompanied with a vasodilatory effect during endothelial testing, and this was related to the severity of hot flushes. Night-time hot flushes were followed with transient rises in ambulatory blood pressure (BP). However, no effect of hot flushes on diurnal BP was detected. The use of estradiol showed no harmful effects on endothelial function in women with hot flushes, but in non-flushing women oral, but not transdermal, estradiol led to vasoconstrictive changes. Estradiol complemented with medroxyprogesterone acetate eliminated the vasoconstrictive effect of sole oral estradiol. Thus, both oral and transdermal estradiol are applicable in flushing women, whereas a transdermal route should be favored in non-flushing women if used e.g. for bone protection.

Objective To study the possible association between menopausal hot flushes and bone mineral density. Design Observational study. Setting University clinic. Population Healthy women ( n = 143) with or without hot flushes, 6-36 months postmenopausal after participating in a 6-month hormone therapy trial. Methods The women prospectively recorded the number and severity of hot flushes for 2 weeks. Bone mineral density in lumbar and hip bones was measured with dual-energy X-ray absorptiometry at recruitment and reassessed in 114 women approximately 6.2 years later. Main outcome measures Hot flushes and bone mineral density. Results At recruitment, hot flushes were absent in 22 women, mild in 32, moderate in 28, and severe in 61. Lumbar bone mineral densities in non-flushing women (1.130 ± 0.022 g/cm2; mean ± SEM), and in those with mild (1.088 ± 0.024 g/cm2), moderate (1.082 ± 0.030 g/cm2) or severe (1.102 ± 0.019 g/cm2) hot flushes did not differ, nor were there differences in hip bone mineral densities between the four study groups. During the follow-up, lumbar bone mineral density decreased by a mean of 0.4 ± 0.1% a year in women not using hormone therapy, and increased by 0.1 ± 0.2% a year in hormone therapy users ( p = 0.019). The respective non-significant changes in left and right total hip bone mineral densities were - −0.6 ± 0.01 and −1.0 ± 0.1 for the non-users, and −0.4 ± 0.1 and −0.6 ± 0.2 for hormone therapy users. These changes in bone mineral density bore no relation to the hot flush status at baseline. Conclusion In recently menopausal women, hot flushes do not appear to determine bone mass density. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. Blood pressure (BP) is one of the most powerful determinants of cardiovascular risk in women. This risk may differ between post-menopausal women with and without vasomotor hot flushes, possibly indicating different vascular responses to hormone therapy (HT). Thus, we compared in a clinical trial the effect of HT on ambulatory BP in normotensive, recently post-menopausal women with or without severe hot flushes. Methods. A total of 147 women recorded prospectively their hot flushes for 2 weeks; 70 women were symptomatic (≥7 moderate/severe hot flush episodes/day), whereas 77 women were defined as asymptomatic (≤3 mild hot flush episodes/day). Women were treated for 6 months with either transdermal estradiol, oral estradiol with or without medroxyprogesterone acetate, or placebo. Results. In symptomatic women decreases in BPs were seen during estradiol use. In contrast, in asymptomatic women receiving oral but not transdermal estradiol, increases in 24-h and day-time systolic and diastolic BPs were encountered. Conclusion. Hot flushes modify the HT-mediated responses in ambulatory BP. In asymptomatic women oral but not transdermal estradiol show potentially harmful cardiovascular effect by increasing BP. Our results give additional justification to prescribing HT primarily for the treatment of troublesome hot flushes and avoiding HT in women without vasomotor symptoms. [ABSTRACT FROM AUTHOR]

Background. Menopausal hot flushes may be a marker for a difference in vascular function. We studied the associations between hot flushes of varying severity and ambulatory blood pressure (BP) and heart rate (HR). Methods. A total of 147 women with onset of menopause within the preceding 6–36 months reported no hot flushes ( n = 23) or mild ( n = 33), moderate ( n = 30), or severe ( n = 61). Ambulatory BP and HR were registered for 24 hours. The variables, analyzed separately for day-time and night-time, were compared among the four study groups. Results. Hot flushes failed to show any relationship to mean day- or night-time BP, nocturnal dipping of BP, or HR. However, severe night-time hot flushes were accompanied by elevations in systolic BP (4.1 ± 10.5 mmHg, P = 0.061), diastolic BP (3.1 ± 6.8 mmHg, P = 0.032), and heart rate (3.0 ± 7.2 beats/minute, P = 0.043). Conclusion. Hot flushes are not associated with ambulatory BP or heart rate in normotensive, recently post-menopausal women, although severe night-time hot flush episodes are followed by significant elevations in BP and heart rate. The latter may be of clinical significance. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Current recommendations for hormone therapy (HT) are mainly based on findings from studies using standard dose regimens in older women who had a different health profile from those who start HT soon after the onset of menopause. Methods: We, therefore, reviewed controlled trials assessing the efficacy, safety and tolerability of low-dose oral continuous combined HT (cc-HT) started for treatment of climacteric symptoms. This review is limited to oral cc-HT regimens over sequential regimens as most postmenopausal women prefer not to have a return of uterine bleeding, and to studies of at least 2 years in duration. Results: Low-dose cc-HT is effective in alleviating climacteric symptoms and in maintaining bone density over prolonged periods, although no data were available regarding fracture risk. No increased risk of coronary heart disease, venous thrombo-embolism or stroke during the use of low-dose cc-HT was reported in the long-term studies and no definitive evidence for an increased risk of breast cancer was found. Breakthrough bleeding during the first months of use is less common than with standard dose HT and amenorrhoea is achieved in most women over time. These regimens are safe for the endometrium and are well tolerated, with a low incidence of adverse events compared with standard doses. Conclusions: Current evidence from controlled trials indicates that low-dose oral cc-HT appears effective and safe. This makes it a good choice for the alleviation of climacteric symptoms, and for this purpose long-term administration of low-dose cc-HT does not seem to impose serious health risks. However, more long-term study data and direct head-to-head comparisons between various low-dose preparations are needed to support or rectify the safety aspects. [Copyright &y& Elsevier]

Objective The Women's Health Initiative (WHI) study clarified the indications and contraindications for postmenopausal hormone therapy (HT). We studied the impact of the WHI results on the risk of fatal stroke in HT users in Finland. Study design Retrospective analysis setting : Nationwide registers on postmenopausal HT use and causes of death between 1995 and 2009. Population Women ≥40 years ( n = 290,272) using systemic estradiol-based postmenopausal HT. Methods Follow-up started from the first HT purchase during the pre-WHI era (1995–2001) and post-WHI era (2002–2009). Main outcome measures Stroke deaths in HT users were compared with that in the age-matched background population and expressed as standardized mortality ratio (SMR) with 95% confidence intervals. Results Overall, 311 HT users died due to stroke. The exposure to HT ≤1 year was associated with a similarly reduced 22% (0.67–0.91) risk of stroke death in the pre-WHI era and in the post-WHI era 27% (0.55–0.94). The risk reductions for HT exposure of 1–8 years in the pre-WHI era (47%, 0.42–0.65) did not differ from that in the post-WHI era (32%, 0.48–0.94). The discontinuation of HT was accompanied by a significant 33% (1.02–1.72) increase in stroke death risk in the pre-WHI era and a non-significant 32% (0.84–1.99) increase in the post-WHI era within the first post-treatment year, but no longer after 1–8 years. Conclusions The change in prescribing policy after the WHI study did not affect the risk of fatal stroke in Finnish HT users. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To compare the responses of heart rate and blood pressure to various autonomic tests in women with and without pre-treatment hot flushes during estradiol and estradiol+medroxyprogesterone acetate (MPA) use. Study design and main outcome measures: Hundred and fifty recently postmenopausal women (72 with and 78 without hot flushes) were randomized to receive transdermal estradiol (1mg/day), oral estradiol (2mg/day) alone or in combination with MPA (5mg/day), or placebo for six months. Cardiovascular responsiveness was comprehensively assessed with controlled and deep breathing, active orthostatic test, Valsalva maneuver and handgrip test. Results: Hot flushes were accompanied with a significant reduction (−2.2±0.7 vs. 1.3±1.1beats/min, p =0.03) in resting heart rate during estradiol-only treatment; the route of estradiol administration was no factor in this regard. This effect was attenuated by the addition of MPA to oral estradiol. Hot flushes were also associated with reduced maximal heart rate in response to handgrip during the use of estradiol-only therapy (−2.2±1.3 vs. 2.8±1.5beats/min, p =0.038); again, the MPA addition eliminated this effect. Hot flushes were accompanied with lowered resting but augmented blood pressure responses to handgrip test during all hormone regimens, whereas in women without hot flushes estradiol-only regimen tended to elevate diastolic resting blood pressure. Conclusions: Hot flushes appear as determinants for cardiovascular responses to hormone therapy. Estradiol-only therapy causes beneficial changes in cardiovascular regulation in flushing women, and these are blunted, in part, by the addition of MPA. [Copyright &y& Elsevier]

Abstract: Objectives: During menopausal transition autonomic balance is known to shift towards sympathetic dominance, but the role of vasomotor hot flushes in this phenomenon is not understood. We compared cardiovascular autonomic responsiveness between women with and without hot flushes. Study design and main outcome measures: One hundred fifty recently postmenopausal healthy women with varying degree of hot flushes (none, mild, moderate, severe) underwent comprehensive cardiovascular autonomic nervous testing (controlled and deep breathing, active orthostatic test, Valsalva manoeuvre and handgrip test) assessing both sympathetic and parasympathetic activity. The responses of heart rate, heart rate variability and blood pressure in these tests were evaluated. Results: Responses in heart rate showed differences between the study groups only in the Valsalva manoeuvre where the tachycardia ratio in all symptomatic women was lower (p =0.041) than in women without hot flushes. Neither change in the heart rate variability analyses nor the blood pressure responses were affected by hot flush status. However, there was a non-significantly higher maximum systolic (140 (112–182)mmHg vs. 135 (102–208)mmHg) and diastolic blood pressure (94 (72–112)mmHg vs. 90 (66–122)mmHg) following the handgrip test in women without hot flushes vs. all the symptomatic women. Conclusions: Menopausal hot flushes seem to be associated with a possibly increased sympathetic preponderance without an effect on parasympathetic activity in cardiovascular autonomic responses. This may imply a potentially negative impact on cardiovascular health in women experiencing hot flushes. [Copyright &y& Elsevier]

Abstract: Objectives: To determine whether co-administration of soy during tibolone treatment would prevent tibolone-induced dyslipoproteinemia in postmenopausal monkeys and women. Methods: Surgically postmenopausal cynomolgus monkeys (n =18) were assigned randomly to one of four dietary regimens in a Latin Square crossover design, such that all animals received all diets for 14 weeks with a 4-week washout period: (1) casein/lactalbumin (CL); (2) tibolone (Tib, 1.25mg/day women''s equivalent); (3) soy (138mg isoflavones/day women''s equivalent); (4) Soy+Tib. Postmenopausal women on tibolone treatment were randomized to receive soy powder (52g of soy protein containing 112mg isoflavones) or placebo (containing 52g of milk protein) daily in a crossover trial for 8 weeks with a 4-week washout period. Results: Monkeys given Tib alone had ∼14% increase in plasma LDL+VLDL-C; whereas those given soy combined with tibolone had significant (∼22%) reductions. Tib treated monkeys had reductions in plasma HDL-C of about 48% vs. no reductions in Soy+Tib. In postmenopausal women using tibolone, soy reduced plasma LDL-C concentrations by ∼10% from baseline without a change in HDL-C. Conclusions: Co-administration of soy during tibolone treatment improved the lipoprotein profile in both monkeys and women; however, the effects were more robust in monkeys. [Copyright &y& Elsevier]

Objective: To determine the effects of soy-derived isoflavones on vaginal epithelium and the endometrium. Design: Double-blind, randomized, placebo-controlled crossover trial. Setting: Outpatient clinic of a university hospital. Patient(s): Sixty-four postmenopausal women with a history of breast cancer. Intervention(s): The women took (in a randomized order) 114 mg of isolated isoflavonoids or placebo in tablets daily for 3 months; the treatment regimens were crossed over after a 2-month washout period. The subjects were studied before and on the last day of each treatment period. Main outcome measure(s): Vaginal dryness, maturation index (MI) of vaginal epithelium, endometrial thickness, histology, and expression of estrogen (E) and progesterone (P) receptors and the proliferation marker Ki-67 in the endometrium. Result(s): Isolated isoflavones did not relieve vaginal dryness. Maturation index values remained unchanged during the isoflavone regimen, but decreased during the placebo regimen. No changes were found in any of the variables measured in the endometrium. Conclusion(s): Daily administration of 114 mg of isolated isoflavones for 3 months had no effect on the subjective perception of vaginal dryness or on objective findings in the vagina or endometrium. This implies safety with regard to the endometrium. [Copyright &y& Elsevier]