Svetlana Vujovic1 , Miomira Ivovic1, Milina Tančić-Gajić1, Ljiljana V. Marina1, Zorana Arizanovic1, Srdjan Popovic1, Aleksandar Djogo1, Marija Barac1, Branko Barac1, Milena Brkic1 and Dragan Micić1
(1)
Faculty of Medicine, Clinic of Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia
Svetlana Vujovic
Email: prof.svetlana.vujovic@gmail.com
It is well known that hypertension can be primary or secondary. However, among secondary causes of hypertension, gender-specific hypertension is one lately recognized.
There is a special group of women reaching climacterium and the menopause with previously low normal blood pressure. In that vulnerable period of their lives, blood pressure becomes unstable with the variations reaching high normal values, or mild hypertension, decreasing their quality of life. In such situations, women visit cardiologists, who suggest to them to take antihypertensive drugs. Unfortunately, such a therapy has no success because it decreases blood pressure too much. Estradiol fluctuations influence blood pressure, and therapy has to be completely different.
Decreasing testosterone levels in males induces hypertension with changes in glucose metabolism, insulin sensitivity, sympathetic activity, etc.
Obviously, gender-dependent etiology of hypertension exists. Sex hormones control blood pressure. There is insufficient knowledge about the effects of estradiol, testosterone, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) on blood pressure control [1].
Hypoestrogenia increases blood pressure independently of age [2]. In Turner syndrome, blood pressure is detected even without the presence of coarctation of aorta, renal abnormalities, and infections. Comparing blood pressure in women with premature ovarian insufficiency (POI), women with Turner syndrome have higher blood pressure [3]. Such a finding helps us to conclude that the loss of second X chromosome has a negative impact on blood pressure. Men with Klinefelter syndrome (XXY), having one X or more, have no hypertension. Ely [4] found that the presence of SRY increases sympathetic activity in men.
23.1 Gender-Specific Hypertension in Women in the Menopause
On the onset of the climacterium, estradiol levels are normal and progesterone decreases, inducing cycle irregularities and mild blood pressure instability. One year after the last menstruation, menopause begins with characteristically low estradiol levels. In that specific part of women’s life, increase of blood pressure is observed. Cardiovascular diseases, as a consequence, are the main causes of women's deaths. Decreasing the estradiol level in the biology of women triggers many diseases. Nine times more women die from cardiovascular diseases than from breast carcinomas.
The role of physicians is to correct hormonal status on time, in climacterium, individually, preventing diseases and improving quality of life.
Hyperlipidemia, hypertension, and atherosclerosis during menopause induce cardiovascular diseases by many mechanisms (Table 23.1).
Table 23.1
Hypoestrogenia and cardiovascular risks
|
Glucose increase |
|
Insulin resistance |
|
Increase in diastolic blood pressure |
|
Hyperlipidemia |
|
Vasoconstriction |
|
Changes in smooth muscle cells of blood vessels |
|
Changes in collagen content |
Atrial cardiomyocytes have phenotype partly that of endocrine cells [5]. Polypeptide hormones acting in paracrine/autocrine fashion are C-type natriuretic peptide, adrenomedullin, proadrenomedullin, N terminal peptide, and endothelin 1.
Direct correlation exists between estrogen and lipid levels. Estradiol therapy has favorable effects on lipid levels (Table 23.2).
Table 23.2
Estradiol effects on lipids
|
Increases hepatic excretion of apolipoproteins |
|
Decreases transcription of lipoprotein lipase |
|
Regulates PPARalfa expression |
|
Decreases adipocyte proliferation |
|
Decreases PAI, IL-6, CRP, apolipoproteins A, B, D, E, lipoprotein a |
Estradiol therapy can have acute and chronic effects on blood vessels. It acts as calcium antagonist and antioxidant. By decreasing angiotensin II and angioconverting enzyme, estrogen therapy dilatates blood vessels by decreasing vasoconstriction induced by acetilholin. Positive effects of estrogens on cardiovascular system are shown in Table 23.3.
Table 23.3
Positive effects of estrogen therapy
|
Interaction with renin-angiotensin-aldosterone system |
|
Interaction with autonomous nervous system |
|
Anti-inflammatory effects |
|
Vasodilatation |
|
Decrease of vascular and myocardial hypertrophy |
|
Decrease of endothelin 1 |
Hypertension is the cause of deaths in 62 % subjects with cardiovascular insults and 49 % with ischemic heart disease. The main cause of plaque instability is the rupture of fissure. Hypertension directly induces cerebral hemorrhage and leads to renal disease.
Kannel [6] found that 27 % of women and 37 % of men have hypertension. Highly normal blood pressure (130–139/85–89 mmHg) induces twice higher risk for cardiovascular disease. Of all women with hypertension, 37.8 % develop it in menopause. Only 10 mmHg decrease of blood pressure decreases insult 30 % and myocardial infarction 23 % [7]. In a sample of 56 million subjects, the World Health Organization found in 1999 that hypertension causes 38 % of all deaths.
Factors increasing blood pressure in the menopause are increased sympathetic activity, oxidative stress, abdominal obesity, hyperinsulinism, and reduced arterial elasticity. Lack of estradiol diminishes the elasticity of arteries during 5–20 years [8].
Hypoestrogenia increases inflammatory cytokines, prostaglandins, plasminogen activator inhibitor (PAI) inducing necrosis, inflamed cell infiltrate, fibrosis, pathological tissue remodeling, and organ dysfunction.
The increase of blood pressure is mainly due to a shift of the autonomic control of the autonomous nervous system towards a prevalence of sympathetic tone together with a greater activity of renin-angiotensin-aldosterone system. Deleterious effects of hyperaldosteronism are shown in Table 23.4. In such a situation, hypertension develops with the following consequences: heart remodeling, left ventricle fibrosis, kidney nephrosclerosis, and arteriole remodeling.
Table 23.4
Deleterious effects of hyperaldosteronism
|
Prothrombotic activity |
|
Hypertension |
|
Endothelial dysfunction |
|
Autonomous nervous system dysfunction |
|
Potassium loss |
|
Natrium retention |
|
Ventricular arrhythmias |
|
Myocardial fibrosis and necrosis |
Hypoestrogenia induces insulin resistance, hyperinsulinemia, natrium retention, and hypertension [9]. Estrogen therapy increases natrium excretion and prevents edema (Table 23.5).
Table 23.5
Effects of estrogen induced natrium excretion
|
Better baroreceptor function |
|
Vascular fibrosis prevention |
|
Better diastolic function |
|
Decreasing hypertension |
|
Decreasing ectopic activity from ventricles |
|
Decreasing PAI |
|
Decreasing mortality rate from cardiac insufficiency |
According to all previously mentioned, estroprogestagen therapy during climacterium is necessary in order to prevent cardiovascular diseases, achieving longer life expectancy and better quality of life.
23.2 Gender-Specific Hypertension in Men with Involutive Hypoandrogenism
Involutive hypoandrogenism is defined by the presence of typical symptoms in aging male and testosterone levels below 11 nM/L (Endocrine Society Consensus). From the age of 40 years, testosterone levels decline about 1 % per year leading to decreased vitality, lower energy, erectile dysfunction, lower muscle mass strength, decreased bone density, depression, irritability, increased abdominal adipose tissue, insomnia, loss of concentration, etc.
Testosterone receptors are widespread on blood vessels. Blood vessels represent two-thirds of brain weight. The weight of endothelium, as the biggest endocrine gland, is 3 kg. The greatest density of testosterone receptors is on the coronary blood vessels. So, decreasing testosterone levels during aging represents proinflammatory status inducing hyperinsulinism, hyperlipidemia, hypertension, cardiovascular diseases, and shorter life expectancy. Testosterone therapy has cardioprotective effects (Table 23.6).
Table 23.6
Effects of testosterone therapy
|
Decrease |
Increase |
|
Interleukin 1 beta |
Anti-inflammatory cytokines |
|
Tumor necrosis factor alpha |
|
|
PAI-I |
|
|
Low-density lipoprotein-c |
|
|
Cholesterol |
|
|
Adhesive molecules |
Testosterone induces changes in apolipoprotein levels. Apolipoprotein B (ApoB) is an atherogenic particle, while ApoA is antiatherogenic. Increased ratio of ApoB/ApoA is typical for men with low testosterone levels. Many studies [10, 11] found that testosterone therapy increases apo A1 and decreases Apo B preventing cardiovascular diseases.
Lipoprotein a (Lpa) is an important factor for lipid metabolism. It is a predictor of cardiovascular diseases. Lipoprotein a has the role in fibrin synthesis and fibrinolysis. It interacts with macrophages, forms foam cells, and deposes cholesterol into the plaque.
Studies performed in diabetic men showed that testosterone therapy with 100 mg weekly decreases adipose tissue by 14 % and increases muscle mass by 7 %. As well, testosterone increases expression of genes for glucose transport and has a role of PPAR gamma.
During the first 6 h of myocardial infarction, testosterone levels are very low and estradiol is high in men. Testosterone therapy dilatates blood vessels. Traish [12] found that testosterone improves myocardial perfusion. Webb [13] demonstrated that testosterone infusion prolongs period of 30 min from myocardial ischemia during physical activity.
A negative correlation was found between testosterone and blood pressure independently of other factors [14, 15].
Hughes [16] found that men with hypertension have lower testosterone and androstenedion levels compared to controls.
In men over 70 years of age, testosterone levels decrease about 50 % in majority of men, compared to maximal levels [17]. Postorchidectomy, due to carcinoma, blood pressure increases. Testostosterone therapy normalizes blood pressure [18].
23.3 Conclusion
Understanding the role of gonadal steroids on the etiology of secondary hypertension appropriate therapy can be given instead of standard antihypertensive drugs. The main principle in the endocrinology is to reach the optimal level of all hormones. With carefully titrating doses of estradiol or testosterone, cardiovascular diseases will be prevented, life expectancy will be prolonged, and better quality of life will be achieved.
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