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Objective: Receptors for estrogen and progesterone are present in the pelvic floor, and therefore, postmenopausal hormone therapy may affect its function. We compared the former use of estradiol-progestogen postmenopausal hormone therapy in nonhysterectomized women with a uterine prolapse surgery (N = 12,072) and control women (N = 33,704)., Methods: The women with a history of uterine prolapse operation were identified from the Finnish National Hospital Discharge Register, and the control women from the Finnish Central Population Register. The use of hormone therapy was traced from the national drug reimbursement register, and the odd ratios with 95% CIs for prolapse were calculated by using the conditional logistic regression analysis., Results: The women with uterine prolapse had used hormone therapy more often than control women (N = 4,127; 34.2% vs N = 9,189; 27.3%; P < 0.005). The use of hormone therapy was accompanied by significant (23%-53%) elevations in the risk for prolapse, being higher with longer exposure. The risk elevations (33%-23%) were comparable between sole norethisteroneacetate-estradiol and sole medroxyprogesteroneacetate-estradiol therapy. The use of estradiol in combination with a levonorgestrel releasing intrauterine device was accompanied by a 52% elevation., Conclusions: The postmenopausal use of estradiol in combination with various progestogen regimens may weaken the pelvic floor, resulting in uterine prolapse. This data should be incorporated into the information given to the users of estradiol-progestogen hormone therapy.

Objective: The aim of the study was to evaluate the risk of cardiac and stroke deaths in women who discontinue postmenopausal hormone therapy (HT)., Methods: We analyzed the risk of death due to cardiac (n = 5,204) and cerebrovascular (n = 3,434) causes in Finnish women who discontinued systemic HT during 1994 to 2013 (n = 432,775). The risks were compared with those in the age-matched female background population and with those in age-matched HT users. Women diagnosed with cardiac or cerebrovascular events within 1 year before discontinuation of HT were excluded (n = 8,711)., Results: Women younger than 60 years at discontinuation of HT showed a significantly increased risk of cardiac death (after ≤5 y of HT exposure, standardized mortality ratio [SMR] 1.52, 95% CI 1.13-2.00; after >5 y of exposure, SMR 2.08, 95% CI 1.44-2.90) and stroke death (after ≤5 y of exposure, SMR 2.62, 95% CI 2.07-3.28; after >5 y of exposure, SMR 3.22, 95% CI 2.29-4.40) during the first year after treatment as compared with age-matched female background population. When compared with HT users, elevations in risks of cardiac and stroke deaths were even higher. Increased mortality risks were limited to the first post-HT year because increases in risks vanished or markedly decreased when the follow-up time was extended over more than 1 year., Conclusions: Discontinuation of postmenopausal HT may be associated with increased risk of cardiac and stroke death in the first posttreatment year. Further investigation is required to evaluate causality of the observed associations.

Context: In postmenopausal women, adipose tissue (AT) levels of estrogens exceed circulating concentrations. Although increased visceral AT after menopause is related to metabolic diseases, little is known about differences in estrogen metabolism between different AT depots., Objective: We compared concentrations of and metabolic pathways producing estrone and estradiol in abdominal subcutaneous and visceral AT in postmenopausal women., Design, Setting, Patients, and Interventions: AT and serum samples were obtained from 37 postmenopausal women undergoing surgery for nonmalignant gynecological reasons. Serum and AT estrone, estradiol, and serum estrone sulfate (E1S) concentrations were quantitated using liquid chromatography-tandem mass spectrometry. Activity of steroid sulfatase and reductive 17β-hydroxysteroid dehydrogenase enzymes was measured using radiolabeled precursors. Messenger RNA (mRNA) expression of estrogen-converting enzymes was analyzed by real-time reverse transcription quantitative polymerase chain reaction., Results: Estrone concentration was higher in visceral than subcutaneous AT (median, 928 vs 706 pmol/kg; P = 0.002) and correlated positively with body mass index (r = 0.46; P = 0.011). Both AT depots hydrolyzed E1S to estrone, and visceral AT estrone and estradiol concentrations correlated positively with serum E1S. Compared with visceral AT, subcutaneous AT produced more estradiol from estrone (median rate of estradiol production, 1.02 vs 0.57 nmol/kg AT/h; P = 0.004). In visceral AT, the conversion of estrone to estradiol increased with waist circumference (r = 0.65; P = 0.022), and estradiol concentration correlated positively with mRNA expression of HSD17B7 (r = 0.76; P = 0.005)., Conclusions: Both estrone and estradiol production in visceral AT increased with adiposity, but estradiol was produced more effectively in subcutaneous fat. Both AT depots produced estrone from E1S. Increasing visceral adiposity could increase overall estrogen exposure in postmenopausal women., (Copyright © 2017 Endocrine Society)

Objective: The aim of the study was to compare the effects of different hormone therapies on cardiac repolarization in recently postmenopausal women with and without hot flashes., Methods: We recruited 150 healthy women: 72 with and 78 without hot flashes. They were randomized and treated for 6 months with transdermal estradiol (1 mg/day), oral estradiol (OE) alone (2 mg/day) or combined with medroxyprogesterone acetate (MPA; 5 mg/day), or placebo. Cardiac repolarization was assessed by measuring QT intervals, rate-dependence of QT-end interval, and T waves from 24-hour electrocardiographic recording before and during hormone therapy, comprising a total of over 20 million QT-interval measurements., Results: Hot flashes were accompanied with shortened median T-peak - T-end interval (at RR interval of 700, 800, and 900 ms; P = 0.040, 0.020, and 0.032; η = 0.35, 0.39, and 0.37; respectively) during the use of OE but not transdermal estradiol. In contrast, the addition of MPA to OE lengthened the maximal QT-end (at RR interval of 500 ms, P = 0.016, η = 0.27) and the maximal T-peak - T-end interval (at RR interval of 500 and 600 ms; P = 0.016 and 0.032; η = 0.25 and 0.22, respectively). These effects were not seen in women without hot flashes., Conclusions: Hot flashes predict beneficial shortening in cardiac repolarization during OE, but not if MPA is combined with OE. These data may provide one explanation for MPA-related cardiac hazards in epidemiological studies.

Objective: Data are controversial on the impact of postmenopausal hormone therapy (HT) on breast cancer mortality. We analyzed nationwide Finnish data on breast cancer mortality risk in women using HT consisting of estradiol-only therapy (ET) or estrogen-progestogen therapy (EPT)., Methods: In total, 489,105 women using HT in 1994 to 2009, traced from the nationwide reimbursement register, were followed from the HT initiation (3.3 million cumulative exposure years) to breast cancer death (n = 1,578 women). The observed deaths were compared with those in the age-standardized background population., Results: The breast cancer mortality risk was reduced in all HT users with exposure for at most 5 years (standardized mortality ratio 0.56; CI 0.52-0.60), more than 5 to 10 years (0.46; 0.41-0.51), or more than 10 years (0.62; 0.56-0.68). A significantly larger risk reduction was detected in the 50 to 59 years age group (0.33; 0.29-0.37) compared with 60 to 69 (0.64; 0.59-0.70) or 70 to 79 (0.78; 0.69-0.87) years age groups. The death risk reductions in ET users tended to be larger in all age groups compared with EPT users, with a significant difference only in the 70 to 79 years age group (0.66; 0.57-0.76 vs 0.88; 0.77-1.00). The age at HT initiation, regardless whether ET or EPT, showed no association with breast cancer mortality., Conclusions: In the Finnish unselected population, breast cancer is fatal in 1 of 10 patients. Our data imply that this risk is prevalent in 1 of 20 patients with history of HT use. This is an important message for women considering or already using HT.

Objective: Menopausal hot flushes are associated with elevated activity of the sympathetic nervous system and may be related to increased risk for cardiovascular events. Sympathetic activation may trigger severe arrhythmias by modulating cardiac repolarization. The aim of this study was to evaluate the impact of hot flushes on cardiac repolarization in postmenopausal women with and without hot flushes., Methods: We assessed 150 recently postmenopausal healthy women-72 with hot flushes and 78 without hot flushes. They underwent 24-hour electrocardiographic recording, comprising a total of over 10,000,000 QT-interval measurements. The cardiac repolarization was assessed by measuring QT-intervals, heat rate dependence of QT-end intervals, and T-waves., Results: The maximal QT-end interval was shorter in women with hot flushes compared with those without hot flushes (481 ± 64 ms vs 493 ± 50 ms; P = 0.046). There were no differences between the rate dependence of QT-end intervals and T-wave measures between the groups. During the night-time hot flush period, we detected a steeper rate-dependence of QT-end intervals and a longer maximal T-peak-T-end interval (117 ± 54 ms vs 111 ± 56 ms; P < 0.001) compared with the control period., Conclusions: Women with hot flushes did not have clinically significant differences in ambulatory cardiac repolarization measurements compared with asymptomatic women. However, a sudden sympathetic surge occurring during the night-time hot flush may have direct effects on cardiac repolarization.

Study Question: Does the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke., Summary Answer: The use of VE reduces the risk for cardiovascular mortality., What Is Known Already: A growing number of women use VE for post-menopausal genitourinary symptoms. Although this therapy is intended to have only local effects, estrogen is absorbed into the blood circulation and thus VE use may also have systemic effects., Study Design, Size, Duration: We studied a nationwide cohort in Finland 1994-2009 during which post-menopausal women (n = 195 756) initiated the use of VE (age [mean ± SD] 65.7 ± 10.9 years). Follow-up data gathered 1.4 million women-years and we assessed the mortality risk due to CHD (n= 9656) or stroke (n = 4294)., Participants/materials, Setting, Methods: The mortality risk in VE users was compared with that in the age-matched background population (standardized mortality ratio; [SMR]; 95% confidence interval) and related to various durations of exposure to VE (1 to ≤3, >3 to ≤5, >5 to ≤10 and >10 years)., Main Results and the Role of Chance: The use of VE was accompanied by decreases in the risk for CHD and stroke death. The risk reduction for CHD death was highest for >3 to ≤5 years exposure (SMR 0.64; 0.57-0.70) and for stroke for >5 to ≤10 years exposure (SMR 0.64; 0.57-0.72). The risk reductions for both CHD and stroke mortality were detected in all age groups with the highest risk reduction being in women aged 50-59 years (SMR 0.43; 0.19-0.88 and SMR 0.21; 0.06-0.58, respectively)., Limitations, Reasons for Caution: Our series lack a placebo arm and thus, may harbor a healthy woman bias. Moreover, data on clinical variables such as weight, smoking, blood pressure and family background were unobtainable for this study. Women using both VE and systemic hormone therapy (HT) were included in the comparator background population. This should not cause any significant error because the proportion of women using VE or other HT was modest (<10% in age-matched population) and because the use of systemic HT also reduces death risks in the same population. Our data cannot be directly applied for local regimens containing conjugated equine estrogens, because they are absorbed differently and may show effects that differ from those of estradiol., Wider Implications of the Findings: In 1000 women using VE for up to 10 years, a maximum of 24 fewer CHD deaths and 18 fewer stroke deaths is likely to occur., Study Funding/competing Interests: This work was supported by unrestricted grants from the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Läkaresällskapet, the Orion Farmos Research Foundation, the Paavo Nurmi Foundation and a special governmental grant for health sciences research. The funding sources had no role in the study design, data handling or manuscript preparation. EPID Research is a company that performs financially supported studies for several pharmaceutical companies. Dr Korhonen, Dr Hoti and MSc Vattulainen, employed by Epid Research, report financial activities from several other pharmaceutical companies outside the submitted work. Dr Mikkola has been a speaker and/or received consulting fees from Mylan and Novo Nordisk. Dr Tuomikoski has been a speaker and/or received consulting fees from Orion and Mylan. The remaining authors report no conflict of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Adipose tissue is an important extragonadal site for steroid hormone biosynthesis. After menopause, estrogens are synthesized exclusively in peripheral tissues from circulating steroid precursors, of which the most abundant is dehydroepiandrosterone sulfate (DHEAS). Our aim was to study activity of steroid sulfatase, an enzyme hydrolyzing DHEAS, and expression of steroid-converting enzyme genes in subcutaneous and visceral adipose tissue derived from pre- and postmenopausal women., Design: Serum and paired abdominal subcutaneous and visceral adipose tissue samples were obtained from 18 premenopausal and seven postmenopausal women undergoing elective surgery for non-malignant reasons in Helsinki University Central Hospital., Methods: To assess steroid sulfatase activity, radiolabeled DHEAS was incubated in the presence of adipose tissue homogenate and the liberated dehydroepiandrosterone (DHEA) was measured. Gene mRNA expressions were analyzed by quantitative RT-PCR. Serum DHEAS, DHEA, and estrogen concentrations were determined by liquid chromatography-tandem mass spectrometry., Results: Steroid sulfatase activity was higher in postmenopausal compared to premenopausal women in subcutaneous (median 379 vs 257 pmol/kg tissue per hour; P=0.006) and visceral (545 vs 360 pmol/kg per hour; P=0.004) adipose tissue. Visceral fat showed higher sulfatase activity than subcutaneous fat in premenopausal (P=0.035) and all (P=0.010) women. The mRNA expression levels of two estradiol-producing enzymes, aromatase and 17β-hydroxysteroid dehydrogenase type 12, were higher in postmenopausal than in premenopausal subcutaneous adipose tissue., Conclusions: Steroid sulfatase activity in adipose tissue was higher in postmenopausal than in premenopausal women suggesting that DHEAS, derived from the circulation, could be more efficiently utilized in postmenopausal adipose tissue for the formation of biologically active sex hormones., (© 2016 European Society of Endocrinology.)

Estrone is the most abundant estrogen after the menopause. We developed a liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for determination of estrone in adipose tissue. Subcutaneous adipose tissue from the breast was collected during elective surgery in postmenopausal women undergoing mastectomy for treatment of breast cancer (n=13) or reduction mammoplasty (controls, n=11). Homogenized adipose tissue was extracted with organic solvents and the estrone fraction was purified by LH-20 column chromatography from the excess of lipids. The concentration of estrone was analyzed by LC-MS/MS. The method was accurate with an intra-assay variation of 8% and an interassay variation of 10%. The median concentration of estrone in subcutaneous adipose tissue from the breast did not differ between breast cancer and control women, 920 pmol/kg and 890 pmol/kg, respectively. In breast cancer patients but not in the controls, breast adipose tissue estrone levels correlated positively with the serum estrone concentration. In conclusion, the new method provides a reliable means to measure estrone concentrations in adipose tissue in postmenopausal women., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Context: It has been shown that breast tumor actively produces and metabolizes steroid hormones. However, little is known about the possible mechanisms through which the nonmalignant adipose tissue contributes to steroid hormone metabolism., Objective: We compared the metabolic pathways producing active estradiol in breast sc adipose tissue of postmenopausal women with or without breast cancer., Design and Setting: Serum and adipose tissue samples were obtained during elective surgery., Patients: We studied postmenopausal women undergoing mastectomy due to an estrogen receptor-positive breast tumor (n = 14) and women undergoing breast reduction mammoplasty (n = 14)., Interventions: Estrone, estradiol, and estradiol fatty acyl ester concentrations were determined by liquid chromatography-tandem mass spectrometry. mRNA expression levels of estrogen-converting enzymes were analyzed by quantitative RT-PCR., Results: Estradiol concentration in breast sc adipose tissue was lower in women with cancer than in controls (median 33 vs 62 pmol/kg; P = .002), whereas the serum concentrations did not differ. Also, the mRNA expression for 17β-hydroxysteroid dehydrogenase type 12 was lower in the adipose tissue of women with cancer compared with controls (0.19 ± 0.10 vs 0.37 ± 0.21, P = .018)., Conclusions: Estrogen metabolism is differentially regulated in the adipose tissue of women with or without cancer. In the sc adipose tissue proximal to breast tumor 17β-hydroxysteroid dehydrogenase type 12 expression is lower than in controls, which could indicate that the conversion of estrone to estradiol is decreased. Further studies are needed to establish the clinical significance of our findings in the development and growth of breast cancer in postmenopausal women.

Objective: Because premenstrual symptoms in fertile age resemble menopausal symptoms, many women with premenstrual symptoms fear that they have an increased risk for developing vasomotor symptoms in menopause. We investigated the impact of premenstrual symptoms on the occurrence and severity of menopausal vasomotor symptoms and quality of life., Methods: One hundred fifty recently postmenopausal healthy women recorded hot flashes prospectively (23, none; 34, mild; 30, moderate; 63, severe), and their quality of life was assessed using the Women's Health Questionnaire. We measured the occurrence of premenstrual symptoms in fertile age using the Premenstrual Symptoms Screening Tool and calculated a premenstrual score reflecting symptom severity., Results: One hundred seven women (89.2%) reported premenstrual symptoms (median score, 7.0; range, 0-38), which had impaired work efficiency or social relations in 64 women (53.3%). The occurrence of premenstrual symptoms was similar in women with and without hot flashes of different magnitudes, as the mean (SEM) premenstrual score was 7.8 (1.4) for no hot flashes, 5.0 (1.0) for mild hot flashes, 7.7 (1.3) for moderate hot flashes, and 9.4 (1.2) for severe hot flashes (P = 0.10). The severity of premenstrual symptoms failed to correlate with the severity of postmenopausal hot flashes (r = 0.087, P = 0.346). A history of premenstrual symptoms was associated with impaired memory and concentration capacity (r = -0.448, P < 0.001), depressive mood (r = -0.263, P = 0.02), sleep problems (r = -0.282, P = 0.01), and feeling less attractive (r = -0.260, P = 0.02) during the first menopausal years., Conclusions: The occurrence of premenstrual symptoms in fertile age is associated with impaired quality of life, but not hot flashes, in recently postmenopausal women.

In women, cardiovascular disease (CVD) accounts for about half of all deaths in Western countries. It is generally accepted that endogenous estrogen protects premenopausal women from CVD. However, whether postmenopausal hormone therapy (HT) confers cardiovascular benefit or harm remains controversial. One of the most pronounced factors modifying the cardiovascular effects of HT is age or time since menopause at the initiation of HT. Recently also the impact of hot flushes on CVD risk and the outcomes of HT has gained attention. This review summarizes the newest data regarding HT and CVD in recently postmenopausal women aged 50-59 years in light of the results from older HT trials. The aim is to help clinicians counsel their patients regarding the individual risks and benefits associated with HT use in this age group, where HT use is most prevalent.

Objective: To compare in controlled cardiovascular autonomic function tests the effects of hormone therapy (HT) on heart rate variability (HRV) responses in postmenopausal women with and without pretreatment hot flushes., Design: A randomized placebo-controlled trial., Setting: Finland, Helsinki University Central Hospital., Population: A total of 150 recently postmenopausal and healthy women with prospectively evaluated hot flushes., Methods: Women (72 with and 78 without hot flushes) were randomized to receive estradiol alone or in combination with medroxyprogesterone acetate or placebo for 6 months. Time and frequency domain measures of HRV were assessed at baseline and after HT with short-term recordings during paced quiet and deep breathing and with active orthostatic tests, both under carefully controlled laboratory conditions to avoid confounding factors present in long-term ambulatory HRV measurements., Main Outcome Measures: Responses of time and frequency domain measures of HRV to HT., Results: At baseline HRV was similar in women with and without hot flushes. Pretreatment hot flushes did not associate with changes in time domain parameters of HRV during controlled quiet or deep breathing or active orthostatic tests after different types of HT. However, HT reduced HRV in very low frequency power in women with pretreatment hot flushes (from 371 ± 40 to 258 ± 28 ms(2) , p = 0.018). HT did not have an effect on other frequency domain measures during quiet breathing or active orthostatic tests., Conclusions: Hormone therapy did not significantly modify the HRV responses in women with or without hot flushes under controlled short-term measurements of the cardiovascular autonomic nervous system., (© 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: The aim of the study was to compare the responses of heart rate variability (HRV) with hormone therapy in recently postmenopausal women with and without vasomotor hot flashes., Methods: Seventy-two women with and 78 women without hot flashes were randomized to receive transdermal estradiol gel (1 g/day), oral estradiol alone (2 mg/day), oral estradiol combined with medroxyprogesterone acetate (MPA; 5 mg/day), or placebo for 6 months. Time- and frequency-domain measures of HRV were assessed using 24-hour electrocardiographic recordings at baseline and after hormone therapy., Results: At baseline, the cardiac variables were similar in women with and without hot flashes. In women with hot flashes, the mean 24-hour heart rate and nighttime heart rate showed a tendency toward reduction in estradiol-only users compared with those taking placebo and those taking estradiol combined with MPA. In women with hot flashes, oral estradiol versus transdermal estradiol reduced nighttime HRV in the time domain (triangular index, -27 ± 36 vs +8 ± 36, P = 0.042). In women without hot flashes, the use of oral estradiol with MPA reduced time-domain HRV (SD of all normal-to-normal intervals; -11 ± 13 ms, P = 0.048, and square root of the mean of the sum of the squares of differences between adjacent normal-to-normal intervals; -6 ± 8 ms, P = 0.036). The women with hot flashes had more supraventricular ectopic beats when using oral estradiol with MPA than when using oral estradiol only (71 ± 128 vs 12 ± 11, P = 0.018)., Conclusions: Oral estrogen, especially when combined with MPA, may have adverse effects on HRV in women with and without hot flashes, whereas transdermal estradiol showed no such effects. Furthermore, women with hot flashes receiving oral estrogen combined with MPA are possibly more prone to cardiac arrhythmias than are women using estrogen only.

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 © 2011 Elsevier Ireland Ltd. All rights reserved.)

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 (>or=7 moderate/severe hot flush episodes/day), whereas 77 women were defined as asymptomatic (

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.

Objective: The aim of this study was to investigate whether cardiovascular autonomic reactivity and risk profile are associated with the frequency and severity of hot flashes in recently postmenopausal women., Methods: A total of 150 postmenopausal women with varying degrees of severity of hot flashes (none, mild, moderate, or severe) underwent 24-hour electrocardiographic recording. The function of the autonomic nervous system was assessed via heart rate variability in time and frequency domains. The effects of hot flashes on cardiac autonomic function were studied by assessing heart rate variability in the presence and absence of symptoms., Results: There were no differences in mean heart rate, heart rate extremes, or total number of ectopic beats between women without and women with mild, moderate, or severe hot flashes. However, most women (14/17, 82%) with frequent ventricular ectopic beats and all women with ventricular runs belonged to the symptomatic groups. Although there were no differences in 24-hour or nighttime heart rate variability between the study groups, the very-low-frequency spectral component of heart rate variability increased by 72% (P < 0.001) during the hot flash period compared with the control period and was accompanied by an increase in heart rate (3%; P < 0.001)., Conclusions: Cardiovascular risk markers based on heart rate variability failed to show an association with the frequency and severity of hot flashes in recently postmenopausal women. However, during a hot flash episode, there were signs of altered autonomic control of heart rate, which may be involved in the regulatory mechanisms of hot flashes.

Objective: Menopausal hot flashes may affect vascular function and perhaps explain conflicting data on cardiovascular disease (CVD) between observational and randomized hormone therapy (HT) studies. We prospectively assessed hot flash status in recently postmenopausal women and related it to a number of biochemical vascular surrogate markers for CVD., Methods: Healthy, nonsmoking women (n = 150) exhibiting a broad range (no, mild, moderate, severe) of hot flashes and an onset of menopause within the previous 0.5 to 3 years were studied with laboratory tests for lipids, lipoproteins, apolipoproteins, high-sensitivity C-reactive protein, and sex hormone-binding globulin., Results: Apart from marked differences in hot flashes, the groups showed comparable levels of estrone, estradiol, or free estradiol index. The levels of total cholesterol (3.7-9.1 mmol/L) were similar between the groups (P = 0.744), and hypercholesterolemia (>6.5 mmol/L) was encountered equally often (P = 0.699). No difference was seen in high-, low-, or very low-density lipoproteins, triglycerides, apolipoprotein A-1, apolipoprotein B (or their ratio), or lipoprotein(a) between the groups. The levels of sex hormone-binding globulin and high-sensitivity C-reactive protein correlated negatively with each other (r = -0.204; P = 0.013) but showed no dependence on hot flashes (P = 0.531 and P = 0.215, respectively)., Conclusions: No baseline difference in lipid or nonlipid CVD risk factors was observed between women with hot flashes (potential HT users) and women with no or mild hot flashes (potential HT nonusers). This may imply that hot flash status per se cannot explain the difference between observational and randomized trials.

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.

Context: The 17beta-estradiol fatty acid esters are hormone derivatives with long-lasting estrogenic effect. They are transported in serum lipoproteins and thought to be sequestered in adipose tissue., Objective: Our objective was to determine the 17beta-estradiol fatty acid ester concentrations in serum and adipose tissue in women of various hormonal states., Design: After several chromatographic steps separating esterified from free estradiol, time-resolved fluoroimmunoassay was used as a quantifying tool., Participants: Samples were obtained from pregnant women undergoing cesarean section (n = 13), or premenopausal (n = 8) and postmenopausal women (n = 6) during gynecological surgery., Main Outcome Measures: 17beta-Estradiol and 17beta-estradiol fatty acid ester concentrations in serum, and visceral and sc adipose tissue were examined., Results: The ratio of esterified to free estradiol in plasma increased with decreasing estradiol level from 0.5% in pregnant, to 15% in premenopausal and 110% in postmenopausal women. Estradiol esters constituted about 10% of the free estradiol present in adipose tissue in pregnancy. In nonpregnant women, most of the adipose tissue estradiol was in esterified form, the median ester to free ratio being elevated to 150-490%. After menopause, the overwhelming majority of estradiol in both free and esterified form was present in adipose tissue., Conclusions: The overall higher ester to free estradiol ratio in adipose tissue than in serum indicates active esterification capacity in adipose tissue. The predominance of esterified and free estradiol in postmenopausal adipose tissue compared with serum suggests in situ production and storage. Whether the estradiol esters have an independent physiological role in adipose tissue remains to be clarified.

Objective: Based on the low cardiovascular risk in Asian populations, phytoestrogens are believed to provide vascular benefits. To elucidate the mechanisms behind the possible cardiovascular effects of phytoestrogens, we evaluated reverse cholesterol transport by assessing the capacity of serum to promote cholesterol efflux in postmenopausal women treated with isolated isoflavones., Design: Thirty postmenopausal women were treated in a randomized, placebo-controlled, crossover trial with isoflavones or placebo for 3 months interrupted by a 2-month washout period. Serum samples were collected before and after each treatment period, and the cholesterol efflux potential was investigated by using H-cholesterol--labeled Fu5AH cells in culture., Results: Serum promoted 20.2% +/- 3.0% and 19.9% +/- 3.4% (mean +/- SD) cholesterol efflux after isoflavonoid treatment and after placebo treatment, respectively. Thus, the isoflavone treatment did not affect serum cholesterol efflux. We also studied separately women who produced high concentrations of the isoflavone metabolite equol into serum because some studies suggest that equol could exert favorable vascular effects. However, there was no difference in serum cholesterol efflux capacity between the equol producers (n = 15) and non-equol producers (n = 15)., Conclusions: In conclusion, isoflavone treatment did not affect serum cholesterol efflux potential in postmenopausal women. Based on our findings, isolated isoflavones do not provide vascular benefits by improving cholesterol efflux.

This review focuses on the question of whether the Women's 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.

Background and Purpose: Tibolone is a tissue-specific compound that has favorable effects on bone and menopausal symptoms without stimulating endometrium or breast, but lowers concentrations of plasma high-density lipoprotein (HDL) cholesterol (HDLC). This study was designed to determine whether the HDL lowering with tibolone exacerbated common or internal carotid artery atherosclerosis and to evaluate tibolone treatment relative to conjugated equine estrogens (CEE) alone or in combination with medroxyprogesterone acetate (MPA)., Methods: Carotid artery atherosclerosis was compared in groups of surgically postmenopausal cynomolgus monkeys treated with CEE, CEE+MPA, or either of 2 doses of tibolone versus untreated monkeys., Results: Despite a 30% to 52% lowering of HDLC with tibolone, there was no significant effect on carotid artery atherosclerosis. CEE and CEE+MPA, however, inhibited carotid artery atherosclerosis by approximately 60%., Conclusions: In surgically postmenopausal cynomolgus monkeys, CEE and CEE+MPA inhibited common and internal carotid artery atherosclerosis. Despite the potentially adverse effects of tibolone on HDLC, tibolone did not exacerbate atherosclerosis.

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]

Objectives: The role of postmenopausal hormone therapy (HT) in the incidence of acute coronary syndrome (ACS) has been studied extensively, but less is known of the impact of HT on the mortality risk due to an ACS.Study Design and Main Outcome Measures: We extracted from a population-based ACS register, FINAMI, 7258 postmenopausal women with the first ACS. These data were combined with HT use data from the National Drug Reimbursement Register; 625 patients (9%) had used various HT regimens. The death risks due to ACS before admission to hospital, 2-28, or 29-365days after the incident ACS were compared between HT users and non-users with logistic regression analyses.Results: In all follow-up time points, the ACS death risks in HT ever-users were smaller compared to non-users. Of women with HT ever use, 42% died within one year as compared with 52% of non-users (OR 0.62, p<0.001). Most deaths (84%) occurred within 28days after the ACS, and in this group 36% of women with ever use of HT (OR 0.73, p=0.002) and 30% of women with ≥5year HT use (OR 0.54, p<0.001) died as compared to 43% of the non-users. Age ≤60 or >60 years at the HT initiation was accompanied with similar reductions in ACS mortality risk.Conclusions: Postmenopausal HT use is accompanied with reduced mortality risk after primary ACS. [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]