CVD (cardiovascular disease) is the leading cause of death for women. Considerable progress has been made in both our understanding of the complexities governing menopausal hormone therapy and our understanding of the cellular and molecular mechanisms underlying hormone and hormone receptor function. Understanding the interplay of atherosclerosis and sex steroid hormones and their cognate receptors at the level of the vessel wall has important ramifications for clinical practice. In the present review, we discuss the epidemiology of CVD in men and women, the clinical impact of sex hormones on CVD, and summarize our current understanding of the pathogenesis of atherosclerosis with a focus on gender differences in CVD, its clinical presentation and course, and pathobiology. The critical animal and human data that pertain to the role of oestrogens, androgens and progestins on the vessel wall is also reviewed, with particular attention to the actions of sex hormones on each of the three key cell types involved in atherogenesis: the endothelium, smooth muscle cells and macrophages. Where relevant, the systemic (metabolic) effects of sex hormones that influence atherogenesis, such as those involving vascular reactivity, inflammation and lipoprotein metabolism, are discussed. In addition, four key current concepts in the field are explored: (i) total hormone exposure time and coronary heart disease risk; (ii) the importance of tissue specificity of sex steroid hormones, critical timing and the stage of atherosclerosis in hormone action; (iii) biomarkers for atherosclerosis with regard to hormone therapy; and (iv) the complex role of sex steroids in inflammation. Future studies in this field will contribute to guiding clinical treatment recommendations for women and help define research priorities.

The mechanisms that mediate the cardioprotective action of steroid hormones in postmenopausal women are poorly understood. To study the inter-relationship between female steroid hormones and cardiac natriuretic peptides, plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured in postmenopausal women, both before and after oestrogen replacement therapy. A total of 22 healthy postmenopausal women (mean age 51.9±4.6 years) were enrolled in the study; all had been postmenopausal for at least 1 year and all reported climacteric symptoms accompanied by increased levels of follicle-stimulating hormone (>30m-i.u./ml) and luteinizing hormone (>20m-i.u./ml), and a reduction in oestradiol (<25pg/ml). All women were given hormone replacement therapy with transdermal oestradiol, either patch (50 μ g/24 h) or gel (1mg/day), cyclically combined with oral dihydrogesterone (10mg/day for 12 days/month, on days 19-30 of the month). ANP and BNP were measured directly in plasma samples with specific and sensitive immunoradiometric assays before and after hormone replacement therapy (transdermal oestradiol combined with oral dihydrogesterone). Body weight, arterial blood pressure and echocardiographic examination values did not change after hormone replacement therapy. As expected, serum oestradiol increased significantly and gonadotropins decreased as an effect of the hormone replacement therapy. On average, both ANP and BNP had increased significantly after 3 months of hormone replacement therapy [ANP: before treatment, 17.6±9.6pg/ml; after, 23.6±5.6pg/ml ( P = 0.0173); BNP: before treatment, 12.6±10.2pg/ml; after, 19.8±14.0pg/ml ( P <0.0001)]. Our study indicates that hormone replacement therapy for a period of 3 months induces a rise in the circulating levels of cardiac natriuretic hormones in postmenopausal women. Our data also suggest the working hypothesis that cardiac natriuretic peptides may play an important role in mediating the cardioprotective effects of female steroid sex hormones in women throughout life.

The effects of combined oestrogen/progestin hormone replacement therapy (HRT) on platelet aggregation were studied using women on HRT or placebo. The study involved 32 postmenopausal women (aged 50–75 years) who were enrolled in a double-blind randomized controlled trial, and who received either oral continuous combined HRT (Kliogest ® ; 2 mg of oestradiol+1 mg of norethisterone) or placebo for a minimum of 6 months. Platelet aggregation was measured by whole-blood impedance aggregometry in response to the agonists collagen, arachidonic acid and ADP. To determine whether the effects of oestrogen on platelets were influenced by platelet-derived nitric oxide, exposure to collagen was repeated in the presence of the nitric oxide synthase inhibitor N G -monomethyl- L -arginine ( L -NMMA). Mean platelet volume was similar in the two groups. Compared with the placebo group, the women on HRT had similar rates and maximum values of platelet aggregation in response to collagen, arachidonic acid and ADP. Addition of L -NMMA did not alter the aggregation response to collagen in either the HRT or the placebo group. In conclusion, postmenopausal women on oral combined continuous HRT comprising oestradiol and norethisterone had similar whole-blood platelet aggregation rates and maximum platelet aggregation responses to higher doses of platelet agonists when compared with those on placebo. The endogenous platelet nitric oxide system did not appear to affect aggregation in either group.

The effects of hormone deficiency at the menopause on muscle strength was examined in 10 healthy middle-aged women (1-3 years post-menopause) in a longitudinal trial over 39 weeks. Performance was compared with that of age-matched females ( n = 11) taking a course of hormone replacement therapy (HRT). Muscle strength of the quadriceps was measured isometrically at 90° of knee flexion and at angular velocities of 1.05, 2.09 and 3.13 rad/s using an isokinetic dynamometer. Hand grip strength was assessed by means of a portable dynamometer. Measurements were taken every 13 weeks for 39 weeks. Significant decreases in isometric strength (-10%) and dynamic leg strength at 1.05 rad/s (-9%) were found in the post-menopausal women over 39 weeks. There was no change in strength in the HRT group. There were also no changes in leg strength at higher angular velocities or in grip strength for either the post-menopausal group or those taking HRT. While HRT preserved muscle strength, there was no evidence of a strengthening effect on skeletal muscle within this short period of treatment. A rapid loss of leg strength occurs post-menopausally in hormone-depleted women. HRT may offer protection against muscle weakness, although the hormone responsible for regulating strength is not evident using this model.

1. The objectives of the study were: (i) to investigate the serum concentrations of vascular endothelial growth factor (VEGF) in pregnant and non-pregnant women; and (ii) to study the relationship between the levels of maternal serum VEGF and the serum concentrations of human chorionic gonadotrophin (hCG) and progesterone during the first trimester. 2. Total immunoreactive VEGF was measured by competitive RIA using recombinant human VEGF 165 and a polyclonal antiserum. Serum VEGF was measured in 60 non-pregnant women of child-bearing age. These data were compared with serum VEGF measured in 363 women between 41 and 91 days of gestation. 3. The median serum VEGF concentration was 1.10 μg/l (interquartile range 0.91–1.30) in the nonpregnant women and 2.13 μg/l (interquartile range 1.62–2.77) in the pregnant women. Serum levels of VEGF were significantly higher among the pregnant cohort ( P < 0.0001). Serum VEGF concentration was positively correlated with gestational age, increasing until ten completed weeks of pregnancy. Serum VEGF was negatively correlated with maternal height and weight, and positively correlated with serum hCG and serum progesterone ( P ≤ 0.0001 in all cases). Serum VEGF was lower in the pregnant women who smoked ( P = 0.06). 4. Our data show a positive and highly significant correlation between maternal serum levels of VEGF and hormones reflecting placental function (hCG, progesterone). We speculate that VEGF production is increased by progesterone and hCG, and that VEGF has a positive influence on trophoblast development. VEGF may also be involved in the initiation of the maternal cardiovascular adaptation to pregnancy.

1. Changes in blood pressure during the normal menstrual cycle are not well documented, and previous studies have given conflicting results. 2. Thirty normotensive women and ten mildly hypertensive women measured their blood pressure at home each morning for 6 weeks, under standardized conditions, using a UA-751 semi-automatic sphygmomanometer. All had normal menstrual cycles and subjects entered the study at difference phases of the cycle. 3. Blood pressure was higher at the onset of menstruation than at most other phases of the cycle (systolic blood pressure, P < 0.05; diastolic blood pressure, P < 0.001). Adjusted diastolic blood pressure was higher in the follicular than in the luteal phase (mean difference 1.23 mmHg, P < 0.001). Similarly, blood pressure was lower during days 17–26 than during the remainder of the cycle (adjusted mean difference in systolic blood pressure −0.65 mmHg, P = 0.07; adjusted mean difference in diastolic blood pressure − 1.19 mmHg, P < 0.001). 4. Similar patterns were seen in normotensive and hypertensive subjects, and changes in plasma 17β-oestradiol and progesterone concentrations were also similar in the two groups.

1. Raynaud's phenomenon is a condition which primarily affects women and it must be assumed that hormonal influences are responsible. 2. To further investigate this assumption the effect of cyclic sex hormone fluctuations on the digital vascular reactivity of ten normal young women was studied by the diagnostic techniques of thermal entrainment of finger blood flow and Doppler ultrasound mapping of the digital arteries. 3. In the immediate pre-ovulatory period the results obtained were comparable with those found in patients with established Raynaud's phenomenon, suggesting that oestrogen has an important modulating effect in vivo on reflex peripheral vasomotor responses to thermal stimuli. 4. ‘Primary’ Raynaud's phenomenon may represent an exaggerated response to oestrogen.

1. The effect of progesterone on renal haemodynamics and intrarenal sodium handling was evaluated in thirteen normal men on a constant diet. Clearances were measured during maximal water diuresis and again 4–7 days later, this time 3 h after progesterone was given intramuscularly. Seven additional studies were performed 3 days after progesterone administration. Another four tests were performed on volunteers who had manifested renal ‘escape’ from the sodium-retaining effect of deoxycorticosterone acetate. 2. In acute progesterone studies glomerular filtration rate was unchanged, whereas effective renal plasma flow increased, so that filtration fraction decreased significantly. A similar increase in urinary sodium occurred whether subjects received a low or high sodium diet. Indices which related to the distal delivery of filtrate (fractional urine flow and the sum of fractional free water and sodium clearances) increased significantly in both groups. The progesterone-induced increase in sodium excretion was not related to changes in plasma renin activity, renin substrate or urinary aldosterone. After 3 days of progesterone, the increase of sodium excretion was less than in the acute studies and urinary aldosterone increased two- to four-fold. Progesterone failed to produce an acute increase in urinary sodium in subjects hyperexpanded by administration of exogenous mineralocorticoids. 3. Results suggest that the acute natriuretic action of progesterone is in part independent of aldosterone inhibition and that progesterone may inhibit sodium reabsorption at proximal as well as distal sites in the nephron.