Bruno Imthurn

Sex hormones and hypertension

Gender has an important influence on blood pressure, with premenopausal women having a lower arterial blood pressure than age-matched men. Compared with premenopausal women, postmenopausal women have higher blood pressures, suggesting that ovarian hormones may modulate blood pressure. However, whether sex hormones are responsible for the observed gender-associated differences in arterial blood pressure and whether ovarian hormones account for differences in blood pressure in premenopausal versus postmenopausal women remains unclear. In this review, we provide a discussion of the potential blood pressure regulating effects of female and male sex hormones, as well as the cellular, biochemical and molecular mechanisms by which sex hormones may modify the effects of hypertension on the cardiovascular system.

Circulating Nitric Oxide (Nitrite/Nitrate) Levels in Postmenopausal Women Substituted With 17β-Estradiol and Norethisterone Acetate A Two-Year Follow-up Study

Postmenopausal women (PMW) have an increased risk of cardiovascular disease that is attenuated by hormone replacement therapy (HRT). Inasmuch as hypertension and atherosclerosis are associated with diminished endothelium-derived nitric oxide (NO), we investigated whether HRT augments NO release in PMW. We determined serum levels of nitrite/nitrate (NO2 + NO3) at baseline and during the 6th, 12th, and 24th months of the study in two groups of PMW. One group (HRT-PMW, n = 13) received continuous transdermal administration of 17 beta-estradiol (Estraderm-TTS-50) supplemented with oral norethisterone acetate (NETA) on days 1 through 12 of each month, and the other group (control PMW, n = 13) did not receive HRT. Blood samples in the HRT-PMW group were collected without regard to whether subjects were taking NETA at the time of blood sampling. Serum NO2 + NO3 levels increased in HRT-PMW for the duration of the study, whereas serum NO2 + NO3 levels remained unchanged in control PMW. When all samples regardless of timing of collection with respect to NETA treatment were included in the statistical analysis, the change in NO2 + NO3 levels in HRT-PMW was significantly greater compared with the change in control PMW (P = .037). Likewise, when only those samples collected when estradiol-treated subjects were not taking oral NETA were included in the statistical analysis, the change in NO2 + NO3 levels in the HRT-PMW group remained significant (P = .047) compared with control PMW.(ABSTRACT TRUNCATED AT 250 WORDS)

Phytoestrogens Inhibit Growth and MAP Kinase Activity in Human Aortic Smooth Muscle Cells

-Estrogens are known to induce cardioprotective effects by inhibiting smooth muscle cell (SMC) growth and neointima formation. However, the use of estrogens as cardioprotective agents is limited by carcinogenic effects in women and feminizing effects in men. If noncarcinogenic and nonfeminizing estrogenlike compounds, such as natural phytoestrogens, afford cardioprotection, this would provide a safe method for prevention of cardiovascular disease in both men and women. Therefore, we evaluated and compared in human aortic SMCs the effects of phytoestrogens (formononetin, genistein, biochanin A, daidzein, and equol) on 2.5% fetal calf serum-induced proliferation (3H-thymidine incorporation and cell number), collagen synthesis (3H-proline incorporation), and total protein synthesis (3H-leucine incorporation) and on PDGF-BB (25 ng/mL)-induced migration (modified Boydens chambers). Moreover, the effects of phytoestrogens on PDGF-BB (25 ng/mL)-induced mitogen-activated protein kinase (MAP kinase) activity in SMCs was also studied. Phytoestrogens inhibited proliferation, collagen and total protein synthesis, migration, and MAP kinase activity in a concentration-dependent manner and in the following order of potency: biochanin A>genistein>equol>daidzein>formononetin. In conclusion, our studies provide the first evidence that in human aortic SMCs phytoestrogens inhibit mitogen-induced proliferation, migration and extracellular matrix synthesis and inhibit/downregulate MAP kinase activity. Thus, phytoestrogens may confer protective effects on the cardiovascular system by inhibiting vascular remodeling and neointima formation and may be clinically useful as a safer substitute for feminizing estrogens in preventing cardiovascular disease in both women and men.

Clinically Used Estrogens Differentially Inhibit Human Aortic Smooth Muscle Cell Growth and Mitogen-Activated Protein Kinase Activity

Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology; however, whether such effects are mediated in part by estrogen receptors is unknown. The purpose of this study was to evaluate whether the actions of clinically used estrogens on human aortic SMC biology are mediated by estrogen receptors. We examined the effects of various clinically used estrogens in the presence and absence of ICI 182,780, an estrogen receptor antagonist, on cultured human aortic SMC DNA synthesis ([(3)H]thymidine incorporation), cellular proliferation (cell counting), cell migration (modified Boyden chamber), collagen synthesis ([(3)H]proline incorporation), and mitogen-activated protein kinase activity. FCS-induced DNA synthesis, cell proliferation, collagen synthesis, platelet-derived growth factor-induced SMC migration, and mitogen-activated protein kinase activity were significantly inhibited by physiological (10(-9) mol/L) concentrations of 17beta-estradiol and low concentrations (10(-8) to 10(-7) mol/L) of 17beta-estradiol, estradiol valerate, estradiol cypionate, and estradiol benzoate but not by estrone, estriol, 17alpha-estradiol, or estrone sulfate. The inhibitory effects of 17beta-estradiol and other inhibitory estrogens were completely reversed by 100 micromol/L ICI 182,780, and the rank-order potency of various estrogens to inhibit SMC biology matched their rank-order affinity for estrogen receptors. The inhibitory effects of estrogens on SMC biology are in part receptor-mediated. Because the cardioprotective effects of hormone replacement therapy are most likely mediated by modification of SMC biology, whether hormone replacement therapy protects a given postmenopausal woman against cardiovascular disease will depend partially on the affinity of the estrogen for estrogen receptors in vascular SMCs.

Hormone Replacement Therapy and Cardiovascular Disease: What Went Wrong and Where Do We Go From Here?

Observational studies in humans and experimental studies in animals and isolated cells supported the widely held belief that hormone replacement therapy protects the cardiovascular system from disease. To nearly everyone’s astonishment, the Women’s Health Initiative Study and the Heart and Estrogen/Progestin Replacement Study overturned the conclusion that hormone replacement therapy protects the cardiovascular system and, in fact, supported the opposite view that such therapy may actually increase the risk of cardiovascular disease. This review addresses 2 questions: what went wrong and where do we go from here?

CYP450- and COMT-Derived Estradiol Metabolites Inhibit Activity of Human Coronary Artery SMCs

Abstract—The purpose of this study is to test the hypothesis that the inhibitory effects of estradiol in human coronary vascular smooth muscle cells are mediated via local conversion to methoxyestradiols via specific cytochrome P450s (CYP450s) and catechol-O-methyltransferase (COMT). The inhibitory effects of estradiol on serum-induced cell activity (DNA synthesis, cell number, collagen synthesis, and cell migration) were enhanced by 3-methylcholantherene, phenobarbital (broad-spectrum CYP450 inducers), and &bgr;-naphthoflavone (CYP1A1/1A2 inducer) and were blocked by 1-aminobenzotriazole (broad-spectrum CYP450 inhibitor). Ellipticine, &agr;-naphthoflavone (selective CYP1A1 inhibitors), and pyrene (selective CYP1B1 inhibitor), but not ketoconazole (selective CYP3A4 inhibitor) or furafylline (selective CYP1A2 inhibitor), abrogated the inhibitor effects of estradiol on cell activity, a profile consistent with a CYP1A1/CYP1B1-mediated mechanism. The inhibitory effects of estradiol were blocked by the COMT inhibitors OR486 and quercetin. The estrogen receptor antagonist ICI 182,780 blocked the inhibitory effects of estradiol, but only at concentrations that also blocked the metabolism of estradiol to hydroxyestradiols (precursors of methoxyestradiols). Western blot analysis revealed that coronary smooth muscle cells expressed CYP1A1 and CYP1B1. Moreover, these cells metabolized estradiol to hydroxyestradiols and methoxyestradiols, and the conversion of 2-hydroxyestradiol to 2-methoxyestradiol was blocked by OR486 and quercetin. These findings provide evidence that the inhibitory effects of estradiol on coronary smooth muscle cells are largely mediated via CYP1A1- and CYP1B1-derived hydroxyestradiols that are converted to methoxyestradiols by COMT.

BMI : new aspects of a classical risk factor for hypertensive disorders in pregnancy

HDP (hypertensive diseases in pregnancy) are one of the leading causes of maternal and fetal mortality and morbidity. BMI (body mass index) is an established risk factor for pre-eclampsia, but its role in HELLP syndrome is unknown. We therefore investigated BMI as a risk factor in the development of HELLP syndrome. At the beginning of pregnancy, BMI was measured in 1067 women with a history of HDP and 1063 controls. Diagnoses of HDP were classified according to ISSHP (International Society for the Study of Hypertension in Pregnancy) and BMI according to WHO (World Health Organization) criteria. After verification of exclusion criteria and matching for confounders, 687 women with hypertensive diseases in pregnancy and 601 controls remained for statistical evaluation by chi(2) test and multiple logistic regressions. As a continuous variable, the increase in BMI was associated with an increase in the development of gestational hypertension {OR (odds ratio), 1.1 [95% CI (confidence interval) 1.062-1.197]} and pre-eclampsia [OR, 1.1 (95% CI, 1.055-1.144)]}, but not for HELLP syndrome. According to WHO definitions, overweight women (BMI > or =25 and <30 kg/m(2)) had a 2-fold (95% CI, 1.365-2.983) risk and obese women (BMI > or =30 kg/m(2)) had a 3.2-fold (95% CI, 1.7-5.909) risk of developing pre-eclampsia when compared with women of normal weight (BMI > or =15.5 and <25 kg/m(2)). Being overweight or having obesity had no effect on the risk of HELLP syndrome. As an increased BMI is correlated with the risk of developing pre-eclampsia but not HELLP syndrome, both diseases have a different risk profile. This finding supports that underlying physiological mechanisms in pre-eclampsia vary from those in HELLP syndrome.

Effects of the progestagen‐only contraceptive implant Implanon® on cardiovascular risk factors

Objective  Epidemiological studies on the cardiovascular risk of progestagen‐only contraceptives are rare. With the present study we aimed to investigate the effect of the low‐dose etonogestrel‐releasing contraceptive implant Implanon® on cardiovascular risk factors, including markers of inflammation.

Headache frequency and intensity in female migraineurs using desogestrel-only contraception: a retrospective pilot diary study.

Background Migraine seems to be substantially related to hormonal changes. However, migraine, but also the use of combined oral contraceptives (COC), is associated with an increased risk for vascular events. Therefore progestagen-only contraception is an important alternative to combined preparations. Clinical observations and one pilot study demonstrate that the use of desogestrel 75 µg may have a positive impact on migraine. Aim The aim of this retrospective analysis of prospectively collected headache diaries was to study the effect of desogestrel 75 µg on headache frequency, intensity and use of acute medication in premenopausal women with migraine in a clinical setting. Methods Patients’ charts were included from women who wanted to use desogestrel 75 µg as a contraceptive and had kept headache diaries over six months (three months pretreatment and three months during treatment). Out of 58 women, 38 women had completed headache diaries for this period. Incomplete diaries (n = 12), side effects (n = 5) and loss to follow-up (n = 3) were the reasons for the exclusion of 20 women. The three months (total of 90 days) before and after initiation of the progestin were compared. Results Days with migraine (5.2 vs. 3.7), days with all kind of headache (8.3 vs. 6.5) and days with use of any headache medication (5.7 vs. 3.5) were significantly reduced at follow-up after three months. In addition there was a reduction in headache intensity (p < 0.0001). The reduction in number of days with use of triptans was not significant (p < 0.14). Conclusion In the 38/58 migraineurs with complete diaries there was a statistically significant decrease in migraine days, headache intensity and medication use. Tension-type headache days decreased but were not significant. Our preliminary data are promising, but should be interpreted cautiously because they were obtained in a small population of women visiting a specialty hormone and migraine clinic. Randomised controlled trials need to be conducted to substantiate our results.

Oviduct cells express the cyclic AMP-adenosine pathway.

Abstract The extracellular cAMP-adenosine pathway refers to the local production of adenosine mediated by cAMP egress into the extracellular space, conversion of cAMP to AMP by ectophosphodiesterase (PDE), and the metabolism of AMP to adenosine by ecto-5′-nucleotidase. The goal of this study was to assess whether the cAMP-adenosine pathway is expressed in oviduct cells. Studies were conducted in cultured bovine oviduct cells (mixed cultures of fibroblasts and epithelial cells, 1:1 ratio). Confluent monolayers of oviduct cells were exposed to cAMP (0.01–100 μmol/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol/L, an inhibitor of both extracellular and intracellular PDE activity), 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX, 100 μmol/L, a xanthine that can inhibit extracellular or ecto-PDE activity at high concentrations), or α,β-methylene-adenosine-5′-diphosphate (AMPCP, 100 μmol/L, an ecto-5′-nucleotidase inhibitor) for 0–60 min. The medium was then sampled and assayed for AMP, adenosine, and inosine. Addition of exogenous cAMP to oviduct cells increased extracellular levels of AMP, adenosine, and inosine in a concentration- and time-dependent manner. This effect was attenuated by blockade of total (extracellular and intracellular) PDE activity (IBMX), ecto-PDE activity (DPSPX), or ecto-5′-nucleotidase (AMPCP). The functional relevance of the cAMP-adenosine pathway is supported by the findings that treatment with adenylyl cyclase stimulants (forskolin plus isoproterenol) resulted in the egress of cAMP (97% extracellular) into the extracellular space and its conversion into adenosine. The extracellular cAMP-adenosine pathway exists in oviduct cells and may play an important role in regulating the biology and physiology of the oviduct. This pathway also may play a critical role in regulating sperm function, fertilization, and early embryo development.