Pregnancy-associated risk factors for future cardiovascular disease - early prevention strategies warranted.

We summarize convincing evidence that future cardiovascular disease (CVD) risk increases one-fold to four-fold for women with a history of pregnancy complicated by hypertensive disorders, gestational diabetes, fetal growth restriction, placental abruption and preterm birth. A concomitant occurrence of two or more complications in the same pregnancy further potentiates the risk. These women should be informed of their future CVD risks during the postpartum check-up taking place after delivery, and also, if needed, treated, for example, for persisting high blood pressure. In these women with high blood pressure, check-up should take place within 7-10 days, and if severe hypertension, within 72 h. Women without diagnostic signs and symptoms should be examined for the first time 1-2 years postpartum and then at intervals of 2-3 years for a complete CVD risk profile including clinical and laboratory assessments. Women should be informed for future CVD risks and their effective prevention with healthy lifestyle factors. Combined oral contraceptives should be avoided or used with caution. If laboratory or other clinical findings indicate, then vigorous treatments consisting of non-medical and medical (antihypertensives, statins, antidiabetic and anti-obesity therapies) interventions should be initiated early with liberal indications and with ambitious therapeutic goals. Low-dose aspirin and menopausal hormone therapy should be used in selected cases. Active control and treatment policies of these women with pregnancy-related risks will likely result in decreases of CVD occurrence in later life.

Postmenopausal hormone therapy in prior pre-eclamptic women: a nationwide cohort study in Finland.

OBJECTIVE: We compared the trends of hormone therapy (HT) use among women with and without a history of pre-eclampsia. METHODS: This national cohort study consisted of women with a pre-eclamptic pregnancy (n = 31,688) or a normotensive pregnancy (n = 91,726) (controls) during 1969-1993. The data on their use of HT during 1994-2019 were traced from the National Medicine Reimbursement Register. RESULTS: Both women with a history of pre-eclampsia and controls initiated HT at a mean age of 49.9 years. Cumulative HT™ use during the total follow-up did not differ between the groups (31.1% vs. 30.6%, p = 0.066). However, HT use in previously pre-eclamptic women was less common in 1994-2006 (20.2% vs. 22.4%, p < 0.001) and more common in 2007-2019 (22.1% vs. 21.1%, p < 0.001) than in controls. This trend was also seen in the annual changes of HT starters. Women with a history of pre-eclampsia used HT for a shorter time (6.3 vs. 7.1 years, p < 0.001). CONCLUSIONS: In contrast to controls, HT use in previously pre-eclamptic women increased during the last half of the follow-up. This may reflect the changes in the international recommendations, the increased awareness of pre-eclampsia-related cardiovascular risk later in life and the aim to diminish this risk with HT.

Current treatments for female primary stress urinary incontinence.

Stress urinary incontinence (SUI) affects millions of women worldwide. Pelvic floor muscle training is the first-line treatment for SUI, and if this fails, midurethral sling surgery has become the gold-standard treatment. More recently, complications from midurethral mesh slings, particularly chronic pain and dyspareunia, have become a major concern. Although traditional SUI treatments, such as colposuspension and fascia slings, are used, the future of SUI treatment likely will rely on less invasive alternatives. Modern bulking agents could have the potential to become a first-line treatment for SUI, but further long-term studies are needed. Patients should be involved in decision-making prior to any surgery to ensure that they are aware of the risks and also any reasonable treatment alternatives. Furthermore, the effectiveness of a procedure should be balanced with its invasiveness and possible risks to provide women individually with the best possible treatment option.

Childhood growth predicts higher bone mass and greater bone area in early old age: findings among a subgroup of women from the Helsinki Birth Cohort Study.

We examined the associations between childhood growth and bone properties among women at early old age. Early growth in height predicted greater bone area and higher bone mineral mass. However, information on growth did not improve prediction of bone properties beyond that predicted by body size at early old age. INTRODUCTION: We examined the associations between body size at birth and childhood growth with bone area, bone mineral content (BMC), and areal bone mineral density (aBMD) in early old age. METHODS: A subgroup of women (n = 178, mean 60.4 years) from the Helsinki Birth Cohort Study, born 1934-1944, participated in dual-energy X-ray absorptiometry (DXA) measurements of the lumbar spine and hip. Height and weight at 0, 2, 7, and 11 years, obtained from health care records, were reconstructed into conditional variables representing growth velocity independent of earlier growth. Weight was adjusted for corresponding height. Linear regression models were adjusted for multiple confounders. RESULTS: Birth length and growth in height before 7 years of age were positively associated with femoral neck area (p < 0.05) and growth in height at all age periods studied with spine bone area (p < 0.01). Growth in height before the age of 7 years was associated with BMC in the femoral neck (p < 0.01) and birth length and growth in height before the age of 7 years were associated with BMC in the spine (p < 0.05). After entering adult height into the models, nearly all associations disappeared. Weight gain during childhood was not associated with bone area or BMC, and aBMD was not associated with early growth. CONCLUSIONS: Optimal growth in height in girls is important for obtaining larger skeleton and consequently higher bone mass. However, when predicting bone mineral mass among elderly women, information on early growth does not improve prediction beyond that predicted by current height and weight.

New evidence for cardiac benefit of postmenopausal hormone therapy.

Coronary artery disease (CAD) is still the most common killer of western women. Coronary arteries, expressing estrogen receptors, are a target for estrogen action. Prior to the Women's Health Initiative (WHI) study, postmenopausal hormone therapy (HT) was widely advocated for primary prevention of CAD, but such use was criticized after the WHI publication. However, new data accumulated in the USA and in Europe indicate that the use of estradiol-based HT regimens does not endanger the heart, but rather, it significantly reduces the incidence of CAD events and mortality. This effect may be related to the presence of hot flushes before HT initiation, because they may indicate a greater responsiveness of the cardiovascular system to HT. To get maximal cardioprotective efficacy of HT, a woman should initiate HT as soon as symptoms occur, and preferably within the first 10 postmenopausal years. Recent guidelines for optimal use of HT recommend pauses of HT at 1-2-year intervals to see whether hot flushes and other symptoms still persist. However, new data question the safety of this policy, because acute withdrawals of estradiol from the circulation may predispose to potentially fatal CAD events. All these data support modernized guidelines for optimal HT use.

Lactation is associated with greater maternal bone size and bone strength later in life.

SUMMARY: The association between lactation and bone size and strength was studied in 145 women 16 to 20 years after their last parturition. Longer cumulative duration of lactation was associated with larger bone size and strength later in life. INTRODUCTION: Pregnancy and lactation have no permanent negative effect on maternal bone mineral density but may positively affect bone structure in the long term. We hypothesized that long lactation promotes periosteal bone apposition and hence increasing maternal bone strength. METHODS: Body composition, bone area, bone mineral content, and areal bone mineral density of whole body and left proximal femur were assessed using DXA, and cross-sectional area and volumetric bone mineral density of the left tibia shaft were measured by pQCT in 145 women (mean age 48 years, range 36-60 years) 16 to 20 years after their last parturition. Hip (HSI) and tibia strength indexes (TBSI) were calculated. Medical history and lifestyle factors including breastfeeding patterns and durations were collected via a self-administered questionnaire. Weight change during each pregnancy was collected from personal maternity tracking records. RESULTS: Sixteen to 20 years after the last parturition, women who had breastfed in total more than 33 months in their life, regardless of the number of children, had greater bone strength estimates of the hip (HSI = 1.92 vs. 1.61) and the tibia (TBSI = 5,507 vs. 4,705) owing to their greater bone size than mothers who had breastfed less than 12 months (p < 0.05 for all). The differences in bone strength estimates were independent of body height and weight, menopause status, use of hormone replacement therapy, and present leisure time physical activity level. CONCLUSION: Breastfeeding is beneficial to maternal bone strength in the long run.

Plasma nitrite/nitrate levels in women with postmenopausal hot flushes.

AIM: To study a possible association between the potent vasodilatory nitric oxide and postmenopausal hot flushes. METHODS: We compared the release of nitric oxide in 150 recently menopausal women reporting no (n = 23), mild (n = 34), moderate (n = 30), or severe (n = 63) hot flushes. Plasma samples, collected after a 48-h arginine-poor diet, were assessed for the metabolites of nitric oxide (NOx), using the Griess reaction. RESULTS: Levels of NOx showed no association with the severity of hot flushes. Furthermore, no relationships with individual hot flushes and serum levels of estradiol or high-sensitivity C-reactive protein were detected. CONCLUSIONS: These preliminary data indicate that nitric oxide appears not to be a factor in hot flushes and might not be related to their etiology. Since a fasting plasma NOx measurement may not reflect what happens at the time of the hot flush episode, in future studies there should be an attempt to assess nitric oxide release during a concomitant hot flush.

Hot flushes and biochemical markers for cardiovascular disease: a randomized trial on hormone therapy.

INTRODUCTION: Menopausal hot flushes may affect the responses of various vascular risk factors to hormone therapy (HT). We compared the responses of biochemical markers for cardiovascular diseases to HT in recently postmenopausal women with tolerable or intolerable hot flushes. METHODS: Healthy, non-smoking freshly postmenopausal women (n = 150) with no previous HT use were studied. Seventy-two women reported intolerable hot flushes (> or =7 moderate/severe episodes/day) and 78 women tolerable hot flushes (< or =3 mild episodes/day). The participants were treated in randomized order with either transdermal estradiol gel (1 mg), oral estradiol valerate (2 mg) with or without medroxyprogesterone acetate (5 mg), or placebo for 6 months. Treatment-induced changes in lipids, lipoproteins, apolipoproteins, sex hormone binding globulin (SHBG) and high-sensitivity C-reactive protein were compared. The trial is registered in the US National Institutes of Health Clinical Research Registry (no. NCT00668603). RESULTS: Pretreatment hot flush status was not related to the responses of these markers to different forms of HT. However, when all active regimens were evaluated together as a post-hoc analysis, 7/10 markers showed a tendency toward greater beneficial changes in women with intolerable hot flushes. Furthermore, in women with intolerable hot flushes and with HT use, the increases in SHBG (Spearman's rho = - 0.570, p < 0.001) were related to the reductions in hot flushes during the use of HT. CONCLUSIONS: Hot flushes appear to be no significant determinant for the responses of vascular markers to HT use.

Cardiovascular risk assessment in postmenopausal women: the role of the gynecologist.

The gynecologist is often the only physician a woman consults on a regular basis and therefore gynecologists play a crucial role in the primary prevention of cardiovascular disease. Cardiovascular risk factors in women entering the menopausal transition are poorly managed, partly due to the fact that primary-care physicians, gynecologists and cardiovascular physicians often fail to identify cardiovascular risk factors and also undertreat women at increased cardiovascular risk. Furthermore, most women are not well informed about their cardiovascular risk profile. Gynecologists and cardiologists should work together as a team in identifying and managing cardiovascular risk factors. European cardiologists and gynecologists have written a Consensus statement and a short guide to help menopause physicians to assess and manage the cardiovascular risk in women.

Impact of soy supplementation on sex steroids and vascular inflammation markers in postmenopausal women using tibolone: role of equol production capability.

OBJECTIVES: Tibolone is often taken concurrently with soy. Tibolone, soy and equol-producing capacity each affect vascular health, whereas their concomitant effects are unknown. We studied the effects of soy on sex steroids and vascular inflammation markers in long-term tibolone users. METHODS: Postmenopausal women (n = 110) on tibolone were screened with a soy challenge to find 20 equol producers and 20 non-producers. All women were treated for 8 weeks in a cross-over trial with soy (52 g of soy protein containing 112 mg of isoflavones) or placebo. Serum estrone, 17beta-estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet-selectin (P-selectin) were assessed. RESULTS: Soy decreased (7.1%) the estrone level, significantly (12.5%) only in equol producers (from 80.2 +/- 10.8 to 70.3 +/- 7.0 pmol/l; p = 0.04). Testosterone was reduced (15.5%; from 586 +/- 62.6 to 495 +/- 50.1 pmol/l, p = 0.02) during soy treatment, and more markedly in equol producers than non-producers (22.1% vs. 10.0%). No changes appeared in SHBG, CRP or ICAM-1, but VCAM-1 increased (9.2%) and P-selectin decreased (10.3%) during soy treatment. CONCLUSIONS: Soy modified the concentrations of estrone, testosterone and some endothelial markers. Equol production enforced these effects. Soy supplementation may be clinically significant in tibolone users.

Individual differences in equol production capability modulate blood pressure in tibolone-treated postmenopausal women: lack of effect of soy supplementation.

OBJECTIVES: Equol, a gut bacterial metabolite of the isoflavone daidzein, has been associated with beneficial health effects. Recent studies indicate that women with intestinal capacity to convert daidzein to equol also have the capacity to alter steroid metabolism and bioavailability of estrogens. METHODS: We evaluated whether individual equol production capability, while not consuming soy supplement, was associated with lower blood pressure in postmenopausal women using tibolone. In addition, in a randomized, placebo-controlled, cross-over trial we assessed the effect of soy supplementation on blood pressure in both equol-producing (n = 20) and non-equol-producing (n = 20) women using tibolone. Blood pressure was recorded with a validated oscillometric technique. RESULTS: The circulating equol levels rose 20-fold in the equol producers and 1.9-fold in the non-equol producers. At baseline, systolic blood pressure (129.9 +/- 2.6 vs. 138.5 +/- 3.1 mmHg, p = 0.02), diastolic blood pressure (72.2 +/- 1.5 vs. 76.6 +/- 1.3 mmHg, p = 0.01) and mean arterial blood pressure (93.5 +/- 1.7 vs. 99.9 +/- 1.8 mmHg, p = 0.007) were lower in equol producers compared to non-equol producers. Soy supplementation had no effect on blood pressure in either group, whereas the baseline differences persisted. CONCLUSIONS: Postmenopausal women using tibolone characterized as equol producers had lower blood pressure compared to non-equol producers. Soy supplementation for 2 months had no blood pressure-lowering effect.

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 Women's 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.

Impaired geometric properties of tibia in older women with hip fracture history.

UNLABELLED: This study evaluated side-to-side differences in tibial mineral mass and geometry in women with previous hip fracture sustained on average 3.5 years earlier. Both tibial mineral mass and geometry were found to be reduced in the fractured leg. INTRODUCTION: The purpose of this study was to evaluate side-to-side differences in tibial mineral mass and geometry after hip fracture and to assess the determinants of such differences. METHODS: Thirty-eight 60- to 85-year-old women with a previous hip fracture and 22 same-aged control women without fractures participated in the study. Bone characteristics of the distal tibia and tibial shaft of both legs were assessed using pQCT in order to compare the side-to-side differences of tibias between the two groups. RESULTS: The subjects with fracture history had significantly (p < OR = 0.05, analysis of covariance) larger side-to-side differences than the controls in tibial shaft BMC (-4.9% vs. -0.5%), cortical area (-5.2% vs. 0.1%) and polar moment of inertia (I(polar)) (-5.6% vs. -0.8%) and in distal tibia BMC (-5.1% vs. -1.4%) and I(polar) (-7.5% vs. -2.4%). In the fracture patients, the side-to-side differences in muscle characteristics explained 23 to 44% of the variances in the side-to-side differences in bone mass and geometry. CONCLUSIONS: Hip fracture results in reduced bone mass and impaired bone geometry in the tibia of the affected limb in older women. Muscle-induced loading may have a considerable role in the recovery of bone mineral mass and geometry after hip fracture.

Hormone therapy and cardiovascular disease--still much to be learnt.

Results from the recent randomized clinical trials indicating that hormone therapy (HT) does not provide cardiovascular protection, but potential harm, are in profound disagreement with the sound evidence from numerous observational and experimental studies. While the observational studies have mainly assessed symptomatic recently menopausal women, the randomized trials have studied symptomless elderly postmenopausal women with established coronary heart disease or various risk factors for cardiovascular disease. Thus, the recent trials have revealed only that HT does not provide secondary cardiovascular benefits. Since primary cardiovascular benefits of HT are rational but not yet proven in clinical trials, new studies are in demand. Until more data from recently menopausal symptomatic women are available, we need to base our decisions on existing evidence and good clinical practice. Although the potential of HT to provide cardiovascular benefits is decreased by advancing age and time since menopause, this should not preclude the use of individualized HT in younger postmenopausal women.

Cardiovascular consequences of hormone therapy in postmenopausal women: Messages to clinicians.

Results from the recent randomized clinical trials indicating that hormone therapy (HT) does not provide cardiovascular protection, but potentially harm are in profound disagreement with the sound evidence from numerous observational and experimental studies. While the observational studies have mainly assessed symptomatic recently menopausal women, the randomized trials have studied symptomless elderly postmenopausal women with established coronary heart disease or various risk factors for cardiovascular disease. Therefore, the recent trials have only revealed that HT does not provide secondary cardiovascular benefits. Since primary cardiovascular benefits of HT are rational but not yet proven in clinical trials, new studies are in demand. Until more data from recently menopausal symptomatic women are available, we need to base our decisions on existing evidence and good clinical practice. Although the potential of HT to provide cardiovascular benefits is decreased by advancing age and time since menopause, this should not preclude the use of individualized HT in younger postmenopausal women. (Reprod Med Biol 2005; 4: 1- 6).

Administration of transdermal estrogen without progestin increases the capacity of plasma and serum to stimulate prostacyclin production in human vascular endothelial cells.

OBJECTIVE: To determine whether transdermal hormone replacement therapy modifies the ability of plasma or serum to regulate the synthesis of prostacyclin and that of endothelin-1 by cultured human umbilical vein endothelial cells. DESIGN: Prospective, randomized study. SETTING: Department of Obstetrics and Gynecology, Helsinki University Central Hospital. PATIENT(S): Thirteen postmenopausal women with climacteric symptoms. INTERVENTIONS: Transdermal 17beta-E2 (50 microg/d) continuously combined with norethisterone acetate, (250 microg/d) on days 15-28 of the treatment cycles for 6 months. MAIN OUTCOME MEASURE(S): Levels of prostacyclin's metabolite 6-keto-prostaglandin F1alpha and of endothelin-1 released by cultured human umbilical vein endothelial cells. RESULT(S): Plasma and serum during the E2-only phase of hormone replacement therapy enhanced prostacyclin production by 20% +/- 8% (mean +/- SEM) and 23% +/- 11%, respectively. Plasma or serum taken during the E2 + norethisterone acetate phase failed to affect prostacyclin production. Hormone replacement therapy induced no change in the capacity of plasma or serum to release endothelin-1. CONCLUSION(S): Transdermal hormone replacement therapy during the E2-only phase increased the capacity of plasma and serum to enhance production of vasoprotective prostacyclin in human vascular endothelial cells, without affecting production of endothelin-1. Addition of norethisterone acetate prevented this stimulation.

Task effects on fatigue symptoms in overnight driving.

This study examined the effects of task and time-on-task on fatigue symptoms in overnight driving. Four participants drove an instrumented car 1200 km overnight and completed the same trip as passengers on another night. Subjective ratings of drowsiness, eye blink frequency and duration, microsleeps, and steering-wheel inputs were analysed as a function of time-on-task, and for separate samples when meeting oncoming heavy vehicles. Four video cameras were used to monitor the road view and the face of both the driver and passenger. In terms of eye closure duration, the reported microsleeps were shorter while driving (mean = 0.7 s, SD = 0.2 s) than as a passenger (mean = 2.6 s, SD = 2.0 s). Blink frequency increased with time-on-task as expected, indicating tiredness, and decreased when approaching an oncoming heavy vehicle, indicating attentive response to a potential critical situation. No consistent effect of time-on-task on high-frequency steering-wheel inputs when meeting oncoming heavy vehicles was found. The results raise the important question of what makes a driver wake from a microsleep earlier than a passenger and, given proper monitoring of long eyelid closures, what the proper intervention should be.

Reduced viability of human vascular endothelial cells cultured on Matrigel.

Optimal vascular homeostasis requires efficient control of both proliferation and elimination of vascular endothelial cells. Programmed cell death, or apoptosis, is the main mechanism controlling cell elimination, and it is an essential component of vascular formation. Human vascular endothelial cells die in vitro, if prevented from obligatory survival factors like growth factors or attachment and cell spreading, but very little is known about the mechanisms controlling endothelial cell elimination. Signaling from the extracellular matrix affects the behavior and functions of human umbilical vein endothelial cells (HUVECs), and we have recently demonstrated the beneficial effects of plating on the reconstituted extracellular matrix Matrigel, on the inducible nitric oxide production of freshly isolated HUVECs. In this work we observed that cultured HUVECs formed typical capillary-like structures on Matrigel, but unexpectedly, after 24-48 hours their viability was gradually lost. Viability was measured with an assay based on mitochondrial reduction of reagent XTT. No decrease in viability was seen in freshly isolated HUVECs or in cultured fibroblasts during this time. It is known that cells often turn into apoptosis if they receive conflicting information from their surroundings, and apparently signaling from Matrigel to HUVECs, while at their in vitro proliferating phenotype, resulted in launching of the apoptotic machinery. Thus, proliferating and differentiated phenotypes of endothelial cells seemed to have different sensitivity to signals that induce apoptosis.

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.