10/27/2011

Menopausal Symptoms And Cardiovascular Health

by Etsuko Ueda, October 2011

Effects of Menopause on Cardiovascular Health
Epidemiological data indicate that the incidence of cardiovascular disease is greater in men aged 30~50 yr old compared with women of similar age. Among women, the incidence of cardiovascular disease is greater in postmenopausal compared with premenopausal women, and the advantage women had over men before menopause largely diminishes in postmenopause years.
Menopause and risk of cardiovascular disease: the Framingham study.  W B Kannel, M C Hjortland, P M McNamara, T Gordon 1976
Age at menopause as a risk factor for cardiovascular mortality. Y T van der Schouw, Y van der Graaf, E W Steyerberg, J C Eijkemans, J D Banga 1996
Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis: The Tromso Study. O Joakimsen, K H Bonaa, E Stensland-Bugge, B K Jacobsen 2000
Sex differences and the effects of sex hormones on hemostasis and vascular reactivity.  D W Schwertz, S Penckofer 2001

The unavoidable implication is that the ovarian hormones (estradiol and progesterone) somehow protect women against cardiovascular diseases. Many experiments have been conducted on women and men as well as animals, and there is no doubt that the ovarian hormones exert profound effects on cardiovascular functions.
The ovarian hormones affect blood supply through blood vessel dilation, contraction, and permeability by directly acting upon the layers of the blood vessel walls as well as through autonomic nerve system (for a review of underlying mechanism, see Gender, sex hormones, and vascular tone., Julia M. Orshal and Raouf A. Khalil, 2004).
Amongst, the most studied seems what is known as endothelium dependent flow-mediated dilation, a mechanism of the inside vessel walls to sense the blood flow increase and adjust the vessel size accordingly. Nitric oxide is considered to be the main mediator of blood vessel dilation (to relax vascular smooth muscles), and ovarian hormones can facilitate the endothelium's production of Nitric Oxide (For a review, see Hormonal modulation of endothelial NO production.  Sue P Duckles, Virginia M Miller, 2010).
The amount of blood supplied to a certain part of body is constantly changing reflecting the changes in conditions and needs. When there is a heat build-up in the body, surface blood flow increases to radiate the heat. When eating, blood supply to the digestive system increases to activate digestive function. When engaging in mental activity, blood flow to the brain is increased. When a certain group of muscles are used, blood flow to those muscles increases, and so forth.
Part of it is controlled by the autonomic nerve system neurotransmitter acetylcholine and co-transmitters such as calcitonin gene-related peptide (CGRP), part of it is controlled by flow-mediated dilation, and both of which are dependent on the endothelium's ability to produce NO and other blood vessel dilating substances as opposed to the contracting substances such as endothelin.
If the vascular smooth muscles do not relax and expand when there is more blood flow to the area, the blood flow speed, resistance, and pressure increase, which causes more ware and tare to the heart and the vessels, meanwhile the blood supply itself is reduced, depriving the cells of necessary oxygen and nutrients. In other words, endothelium dependent dilation is an important indicator of blood supply and cardiovascular health and risk in general. (for an overview, see Endothelial Dysfunction and Coronary Artery Disease, Paulo R. A. Caramori, Alcides J. Zago 1997).
The endothelium dependent flow-mediated dilation is not a measure of stiffness, although stiffness can reduce endothelium dependent flow-mediated dilation (Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium., Xinqi Peng, Saptarsi Haldar, Shailesh Deshpande, Kaikobad Irani, David A Kass, 2003). In general, the strength of endothelium dependent dilation is evaluated relative to endothelium independent dilation, which can be induced by administering NO producing substances such as nitroglycerin, glyceryl trinitrate or sodium nitroprusside, and is thought to be equally affected by stiffness as endothelium dependent dilation.
The endothelium dependent flow-mediated dilation is a reflection of how much endothelium is stimulated by the shear stress generated by the blood flow increase (Wall Shear Stress - an Important Determinant of Endothelial Cell Function and Structure - in the Arterial System in vivo. Discrepancies with Theory., Robert S Reneman, Theo Arts, Arnold P G Hoeks, 2006). In other words, the ability to expand the blood vessel diameter is a reflection of the endothelium's ability to sense and react to the shear stress with NO production, which in turn relaxes the vascular smooth muscle.
The endothelium dependent flow-mediated dilation is a well established phenomena that can be used in clinical evaluation as a sign of "the fundamental and very early step in the development of atherosclerosis" ([Regulation and dysfunction of endothelium-dependent vasomotricity. What can be applied to clinical practice?], J M Halimi, Y Lebranchu 2003). 
It is also well established that low estrogen + progesterone state (post menopause or early follicular phase in normal menstrual cycle) reduces endothelium dependent flow-mediated dilation, and a higher estrogen + progesterone state (supplementation or late follicular to mid luteal phase) increases endothelium dependent dilation.
Young reproductive age women show an overwhelming pattern of increased systemic vascular reactivity (measured by flow-mediated dilation) and reduced blood pressure during the late follicular phase right before ovulation, corresponding to the estradiol and NO levels. It is reflected on both central (aortic) and peripheral blood pressures, which were lowest during late follicular phase (Central, peripheral and resistance arterial reactivity: fluctuates during the phases of the menstrual cycle. Eric J Adkisson, et. al. 2010).
In addition to the expansion of blood vessel diameter, the effects can be shown at its underlying bio-chemical levels, as amount of NO production, number of estrogen receptors, and amount of the proteins involved in the NO production (Vascular Endothelial Estrogen Receptor {alpha} is Modulated by Estrogen Status and Related to Endothelial Function and eNOS in Healthy Women.  Kathleen M Gavin, Douglas R Seals, Annemarie E Silver, Kerrie L Moreau 2009). During a normal menstrual cycle, they observed that the estradiol level changed more than 2 time and progesterone level more than 5 times from the early follicular low hormone phase (2-6 d after onset of menses) to early luteal high hormone phase (24-48h after positive ovulation test). Corresponding to this change, the number of estrogen receptors in endothelium were 30% less in low hormone phase compared to high hormone phase.


Endothelium dependent dilation and menopause
Since menopause is a result of ovarian hormone decline, there is little surprise that compared to young reproductive age women, postmenopausal women show reduced endothelial dependent dilation (Comparison of forearm endothelial function between premenopausal and postmenopausal women with or without hypercholesterolemia. Mitsuhiro Sanada,et. al. 2003). During the early postmenopause years (48 to 63 yrs olds were tested) estradiol level is comparable to low estradiol phase of normal menstrual cycle and so is the number of estrogen receptors. The progesterone level is much lower than that of early follicular, and the flow-mediated dilation can be even lower (by about 30%) than the early to mid follicular phase (2-8 d after onset of menses) (Vascular Endothelial Estrogen Receptor {alpha} is Modulated by Estrogen Status and Related to Endothelial Function and eNOS in Healthy Women.  Kathleen M Gavin, Douglas R Seals, Annemarie E Silver, Kerrie L Moreau 2009).
We sought to determine whether menopausal status or postmenopausal hypercholesterolemia affects forearm resistance artery endothelial function. We studied the forearm resistance artery endothelial function in 75 Japanese women: 25 premenopausal volunteers, 25 postmenopausal women with normal serum low-density lipoprotein (LDL) cholesterol concentrations, and 25 hypercholesterolemic postmenopausal women. Excluded from the study were patients with hypertriglyceridemia, hypertension, or diabetes, cigarette smokers. The forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin (NTG) administration was measured by strain-gauge plethysmography. The serum concentrations of lipoprotein (a)[Lp(a)] were significantly higher in the hypercholesterolemic postmenopausal group than in the other two groups (P<0.01). These lipid parameters were similar between the premenopausal and postmenopausal women with normal cholesterol. The FBF responses to reactive hyperemia were significantly lower in the postmenopausal hypercholesterolemic women than in the other two groups (P<0.01). The reactive hyperemia also was impaired in the postmenopausal group with normal cholesterol as compared with the premenopausal group (P<0.01). Increases in FBF after NTG were similar between the three groups. By stepwise multivariate analysis, menopausal status and serum LDL cholesterol was the significant predictor of forearm endothelial function. These findings suggest that reactive hyperemia is impaired in forearm resistance arteries after menopause, especially in postmenopausal women with hypercholesterolemia.
Compared to young reproductive age women, men of similar age show lower endothelium dependent flow-mediated dilation comparable to that of low estrogen + progesterone phase of women (Modulation of Endothelium-Dependent Flow-Mediated Dilatation of the Brachial Artery by Sex and Menstrual Cycle, Masayoshi Hashimoto, et. al. 1995). Postmenopausal women without hormone therapy show endothelium dependent flow-mediated dilation as low as that of age matched men. (Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels., K K Koh, J W Son, J Y Ahn, S K Lee, H Y Hwang, D S Kim, D K Jin, T H Ahn, E K Shin 2001). These observations correspond well to the epidemiological findings that the cardiovascular health advantage the reproductive age women have over men largely diminishes with menopause.
Another key factor that is under hormonal influence and has impact on cardiovascular health is the sympathetic nerve activity. There too women have advantage over men, and the advantage does not seem to completely disappear after menopause even in women with hypertension, although menopausal symptoms are associated to hyperactive sympathetic nerve activity and underactive para sympathetic nerve activity.
The effect of gender on the sympathetic nerve hyperactivity of essential hypertension. A J Hogarth, A F Mackintosh, D A S G Mary 2006
Sympathetic nerve hyperactivity of essential hypertension is lower in postmenopausal women than men. A J Hogarth, J Burns, A F Mackintosh, D A S G Mary, 2008
Caffeine and Blood Pressure Response: Sex, Age, and Hormonal Status.  Noha H Farag, et. Al. 2010

After surgical menopause, endothelial function rapidly declines: 1 week after ovariectomy, significant decreases of flow-mediated dilatation were observed (Rapid changes of flow-mediated dilatation after surgical menopause. Masahide Ohmichi, et. al. 2003). 
The deterioration reaches maximum in 12 weeks in rats (measured by dilation response to ACh) (Long-term effects of ovariectomy and estrogen replacement treatment on endothelial function in mature rats., Farzad Moien-Afshari, Emma Kenyon, Jonathan C Choy, Bruno Battistini, Bruce M McManus, Ismail Laher, 2003). 12 weeks sounds consistent with my personal experience. I started to notice the unmistakable signs of menopausal symptoms in full swing about 3 months after stopping estrogen.
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall,Vancouver, BC, Canada V6T 1Z3.
OBJECTIVES: Estrogen replacement therapy (ERT) improves blood flow through various mechanisms including an augmented release of nitric oxide (NO). We report on the long-term effects of estrogen loss on vascular function and endothelial regulation. METHODS: Male, female, ovariectomized and ovariectomized+ERT treated rats were used. Female rats were ovariectomized at 12 weeks of age and received ERT via subcutaneously implanted 90-day release pellets. Vasodilation to acetylcholine (ACh) was studied in tail artery segments; arterial blood was collected for measurements of 17-beta-estradiol and stable metabolites of NO (nitrate/nitrite). Some arterial segments were harvested for TUNEL staining to determine endothelial apoptosis. RESULTS: Ovariectomy caused a rapid loss of estradiol that was negated by ERT. Likewise, there was also a loss in plasma NO. Loss of ACh-mediated dilations were age-dependent and were significant in males and untreated ovariectomized rats, with the change being maximal after 12 weeks of ovariectomy. After 12 weeks post-ovariectomy, there were no time dependent changes in ACh sensitivity in either group. Dilations to ACh were maintained in females and age-matched ERT ovariectomized rats over time. TUNEL staining of the endothelium (at 6 months of age) revealed apoptotic changes with the rank order male>ovariectomized>female, or ERT treated ovariectomized female rats. CONCLUSIONS: In a rat model of surgical menopause, loss of endothelial function is maximal 12 weeks after ovariectomy. Apoptosis of endothelial cells is greatest in arteries from male rats. Our data suggests that early ERT treatment may be an important consideration for reducing endothelium-dependent vascular dysfunction.
Note: Hormonal status is by no means the only thing that affect endothelial function. The release of NO by the endothelial cell can be up-regulated by estrogens, exercise, dietary factors, etc., and down-regulated by oxidative stress, smoking, oxidized low-density lipoproteins, etc (for a review, see Endothelial Dysfunction and Vascular Disease., Paul M Vanhoutte, Hiroaki Shimokawa H, Eva H C Tang, Michel Feletou, 2009).
Since the menopausal symptoms such as hot flashes are also related to the drop in ovarian hormones, you would expect a substantial correlation between menopausal symptoms and cardiovascular health.
As expected, the severity of hot flash is associated with a reduced endothelium dependent flow-mediated dilation early in menopause. However, its expected consequence such as atherosclerosis (measured as carotid intima-media thickness), does not seem to develop until later in menopause (Endothelial Function, But Not Carotid Intima-Media Thickness, Is Affected Early in Menopause and Is Associated with Severity of Hot Flushes., Aris Bechlioulis, et. al. 2010).
Results: FMD was significantly lower in early menopausal women compared with controls (5.43 +/- 2.53 vs. 8.74 +/- 3.17%, P < 0.001), whereas IMT did not differ between groups (P > 0.8). Severity of hot flushes was the most important independent predictor for FMD (P < 0.001) in menopausal women. Women with moderate/severe/very severe hot flushes had impaired FMD in contrast to women with no/mild hot flushes or controls. Women with no/mild hot flushes did not differ compared with controls. Age and systolic blood pressure were the main determinants of IMT (both P = 0.004). ER polymorphisms were not associated with vascular parameters. Conclusions: Impairment of endothelial function is present in the early menopausal years, whereas carotid IMT is not affected.
Interestingly, the menopausal symptoms seem to be the one affected by the factors influencing the cardiovascular health. Not the other way round. In other words, the severity of menopausal symptoms seems to be another manifestation of cardiovascular health. A significant correlation between the severity of menopausal symptoms and factors known to increase cardiovascular disease risk such as stress, smoking, and less physically active was observed in a large multi-racial/ethnic sample of 16,065 women aged 40-55 years in the U.S. (Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age., E B Gold, B Sternfeld, J L Kelsey, C Brown, C Mouton, N Reame, L Salamone, R Stellato 2000).
Department of Epidemiology and Preventive Medicine, University of California, Davis 95616, USA. ebgold@ucdavis.edu
A community-based survey was conducted during 1995-1997 of factors related to menopausal and other symptoms in a multi-racial/ethnic sample of 16,065 women aged 40-55 years. Each of seven sites comprising the Study of Women's Health across the Nation (SWAN) surveyed one of four minority populations and a Caucasian population. The largest adjusted prevalence odds ratios for all symptoms, particularly hot flashes or night sweats (odds ratios = 2.06-4.32), were for women who were peri- or postmenopausal. Most symptoms were reported least frequently by Japanese and Chinese (odds ratios = 0.47-0.67 compared with Caucasian) women. African-American women reported vasomotor symptoms and vaginal dryness more (odds ratios = 1.17-1.63) but urine leakage and difficulty sleeping less (odds ratios = 0.64-0.72) than Caucasians. Hispanic women reported urine leakage, vaginal dryness, heart pounding, and forgetfulness more (odds ratios = 1.22-1.85). Hot flashes or night sweats, urine leakage, and stiffness or soreness were associated with a high body mass index (odds ratios = 1.15-2.18 for women with a body mass index > or =27 vs. 19-26.9 kg/m2). Most symptoms were reported most frequently among women who had difficulty paying for basics (odds ratios = 1.15-2.05), who smoked (odds ratios = 1.21-1.78), and who rated themselves less physically active than other women their age (odds ratios = 1.24-2.33). These results suggest that lifestyle, menstrual status, race/ethnicity, and socioeconomic status affect symptoms in this age group.
In Sweden, a large population-based sample of 5523 women, aged 46 to 57 years was studied. Hot flash and night sweats were analyzed against common cardiovascular health indicators such as cholesterol, BMI, and blood pressures. A small but significant correlation emerged (Menopausal Complaints Are Associated With Cardiovascular Risk Factors., Gerrie-Cor M Gast., et. al. 2008).
Taken together, these observations suggest that the severity of menopausal symptoms such as hot flashes reflect much more than the hormonal decline.
According to a review by Gambacciani and Pepe, 2009 (Vasomotor symptoms and cardiovascular risk. ) Menopausal hot flushes correlate with lower level of plasma antioxidant activity, an increased cardiovascular reactivity to stressful situations, elevated cholesterol, higher sympathetic nerve activity, impaired flow-mediated dilation, hypertension and a higher risk of aortic calcification. All the available findings indicate that hot flushes can be seen as a marker for underlying vascular changes among mid-life, otherwise healthy, menopausal women.
When you examine the people who have succumbed to cardiovascular illnesses, impairment of endothelium dependent dilation seems always present. Impaired endothelium-dependent dilation was observed both at the coronary and peripheral circulation in post-menopausal women with angina and normal coronary angiograms (Acute and mid-term combined hormone replacement therapy improves endothelial function in post-menopausal women with angina and angiographically normal coronary arteries. M Sitges, et al. 2001). Elderly ischemic stroke patients (58.3% male, median age 73 years) show impaired endothelial dependent dilation corresponding with the severity and poor outcome (Brachial arterial flow mediated dilation in acute ischemic stroke., D Santos-Garcia, M Blanco, J Serena, S Arias, M Millan, M Rodriguez-Yanez, R Leira, A Davalos, J Castillo, 2009). Menopausal women with hypertension show reduced endothelium dependent flow-mediated dilation (Effect of estrogen replacement therapy on endothelial function in peripheral resistance arteries in normotensive and hypertensive postmenopausal women. Y Higashi, et.al. 2001). Conversely, people with reduced endothelium dependent flow-mediated dilation are likely to progress to the next stage of the disease process such as hypertension (Flow-mediated vasodilation and the risk of developing hypertension in healthy postmenopausal women.  Rosario Rossi, 2004).

Effects of hormone therapy
It is well established that menopausal hormone therapy improves endothelial dependent dilation.
Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. E H Lieberman, et. at.,1994, (oral estradiol at a dose of 1 mg/d or 2 mg/d)
Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women.  J A McCrohon, et. al. 1996. (premenopause, postmenopause 2+yrs users of standard ET or HRT, postmenopause never users : 9.6, 6.2, 4.4%)
Effects of transdermal and oral estrogen supplementation on endothelial function, inflammation and cellular redox state. H Kawano, et al. 2003 (The flow-mediated endothelium-dependent dilation of the brachial artery increased for both. However, serum levels of thioredoxin (a marker of the cytoprotective antioxidant system) decreased for both, and high-sensitivity C-reactive protein (hs-CRP) incresed for oral Premarin. 12 weeks, No progesterone.)
Hormone replacement effects on endothelial function measured in the forearm resistance artery in normocholesterolemic and hypercholesterolemic postmenopausal women. Mitsuhiro Sanada, et. al. 2002, (conjugated equine estrogen (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) daily for 6 months)
Blood pressure control and hormone replacement therapy in postmenopausal women at risk for coronary heart disease.  James A McCubbin, Suzanne G Helfer, Fred S Switzer 3rd, Thomas M Price 2002
BACKGROUND: Coronary heart disease (CHD) in women is strongly associated with estrogen deprivation. For example, risk for CHD increases dramatically after menopause. However, the role of hormone replacement therapy (HRT) in CHD prevention currently is unresolved. To better understand CHD in women, the precise mechanisms by which estrogen affects circulatory function require clarification. Evidence suggests that exogenous estrogen may affect blood pressure (BP) control, but its interaction with other CHD risk factors has not been systematically characterized. The present study examines the role of mildly elevated resting BP, family history of CHD, and HRT on BP responses to stress in postmenopausal women. METHODS: Postmenopausal women on long-term HRT were recruited along with a control group of postmenopausal women not on HRT. These women were divided into higher versus lower risk for CHD on the basis of resting BP and family history of CHD. BP control mechanisms were assessed before, during, and after a computer-controlled laboratory stressor. RESULTS: Results indicate that women with elevated resting BP and positive family history of CHD have exaggerated BP reactivity to stress and that HRT inhibits this effect. CONCLUSIONS: This study suggests that unmedicated postmenopausal women with mildly elevated resting BP and positive family history of CHD have altered BP control as indicated by exaggerated BP responses to stress. HRT eliminates the cumulative effect of resting BP and family history on BP reactivity, suggesting that the circulatory effects of estrogen replacement may operate, at least in part, through normalization of BP reactivity in higher-risk postmenopausal women.
Hormone therapy's relation to atherosclerosis has been observed as expected. As you get older, the effects of no hormone therapy become more pronounced.
Arterial intima-media thickness: site-specific associations with HRT and habitual exercise., Kerrie L Moreau, Anthony J Donato, Douglas R Seals, Frank A Dinenno, Sharon D Blackett, Greta L Hoetzer, Christopher A Desouza, Hirofumi Tanaka 2002
Department of Kinesiology and Applied Physiology University of Colorado at Boulder, Colorado 80309, USA. moreauk@colorado.edu
We determined the site-specific relations of hormone replacement therapy (HRT) and habitual exercise status with intima-media thickness (IMT) in both elastic (carotid) and muscular (femoral) arteries in 77 healthy postmenopausal women: 43 women were sedentary (20 no-HRT and 23 HRT users) and 34 women were endurance trained (14 no-HRT and 20 HRT users). Femoral IMT was not different among the sedentary HRT and endurance-trained no-HRT and HRT groups, but was lower (P < 0.005) in these three groups than in the sedentary no-HRT women. There were no significant group differences in carotid IMT. However, in older women (> or =65 yrs) carotid IMT was smaller (P < 0.05) in HRT compared with no-HRT women. We conclude that both endurance training and HRT status are independently associated with a smaller IMT and these effects are evident primarily in muscular arteries. These results suggest that HRT and habitual exercise may protect postmenopausal women against cardiovascular disease through influences on IMT. The site-specific relations may be due to a greater number of smooth muscle cells and plasticity of muscular arteries compared with elastic arteries and/or differences in heterogeneous influences such as metabolic requirements and hydrostatic pressures.
The effect of hormone therapy is almost immediate (within 24 hours, if not instant).
Acute and mid-term combined hormone replacement therapy improves endothelial function in post-menopausal women with angina and angiographically normal coronary arteries. M Sitges, et al. 2001 (Impaired endothelium-dependent vasodilation exists both at the coronary and peripheral circulation in post-menopausal women with angina and normal coronary angiograms. Flow-mediated dilation improves in these women after short (24 h) and mid-term (6 weeks) therapy with 50microg transdermal oestradiol irrespective of concomitant medroxyprogesterone use. An abnormal coronary artery response to acetylcholine was observed in all women as well as impaired brachial flow-mediated dilation. Brachial flow-mediated dilation significantly increased after 24 h of 100 microg/day oestradiol treatment, clear trend for blood clot in 6 weeks)
Menopausal hormone therapy can restore the endothelium dependent flow-mediated dilation and cardiovascular health advantage. It has been confirmed by many researchers with various types of estrogen, progesterone, or the combination of the two. However, it is very important to note that all studies that used anything other than transdermal estradiol + natural progesterone (=bioidentical to human's) and bothered to look at various cardiovascular health indicators, observed diminished endothelium dependent dilation effects or unwanted side effects such as higher blood coagulation and inflammation factors, and blood clot risk (for a review, see Safe Use of Hormones: the Hard Evidence). Amongst, the Women's Health Initiative (WHI) clinical trial results may be still fresh in many people's mind (for a review of WHI studies, see Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Jacques E. Rossouw, et. al. 2009).
According to Sitruk-Ware's review, progesterone substitute drugs, such as medroxyprogesterone acetate (Provera, Amen, Cycrin), and norethindrone acetate (Aygestin, Norlutate), exert a partial detrimental effect on the beneficial actions of estrogens with regard to lipid changes, atheroma development, or vasomotion. (Progestins and cardiovascular risk markers., R Sitruk-Ware, 2000, Different cardiovascular effects of progestins according to structure and activity., A Nath, R Sitruk-Ware, 2008, )
When patients who suffered ischemic colitis were examined, none were using natural progesterone. They were using conjugated estrogens (Premarine), conjugated estrogens plus medroxyprogesterone acetate, 17beta-estradiol plus norethisterone, or estradiol valerate plus norgestrel, all of which turned out to be the cause of the rare ischemic colitis (Ischemic colitis in postmenopausal women taking hormone replacement therapy., S Zervoudis, T Grammatopoulos, G Iatrakis, G Katsoras, C Tsionis, I Diakakis, C Calpaktsoglou, S Zafiriou 2008).
Department of Gynaecology,'Lito' Hospital and ATEI Technological University of Athens, Athens, Greece.
Background and aim. Estrogen and progestins have established effects on the gastrointestinal tract and ischemic colitis was related in the past with certain regimens including both hormones. On this basis, we aimed to evaluate a group of postmenopausal women who presented with ischemic colitis after taking hormone replacement therapy (HRT) for the last several months. Method. Postmenopausal women taking conjugated estrogens, conjugated estrogens plus medroxyprogesterone acetate, 17beta-estradiol plus norethisterone and estradiol valerate plus norgestrel are included in the present study. All patients, without a medical history of bowel problems, reported an acute crisis of colitis a few months after the beginning of the treatment. Results. Fasting, parenteral nutrition, intravenous antibiotic treatment with metronidazole and discontinuation of HRT proved successful. Antibiotics were continued after the patients' discharge from the hospital. A second-look colonoscopy, 3 to 4 months after the initial episode, was normal in all cases. Conclusion. Ischemic colitis is a rare complication of HRT that should not be ignored when HRT is prescribed.
Another example is a long term estrogen therapy without progesterone. Despite the fact that estrogen is well known for its facilitative effect on endothelium dependent dilation and NO production, the long term 17beta-estradiol 1mg daily proved to be not very beneficial for NO level. (Long-term effect of estrogen replacement on plasma nitric oxide levels: results from the estrogen in the prevention of atherosclerosis trial (EPAT)., Juliana Hwang, Wendy J Mack, Min Xiang, Alex Sevanian, Roger A Lobo, Howard N Hodis 2005)
The estrogen in the prevention of atherosclerosis trial (EPAT) was a 2-year randomized controlled trial in which unopposed 17beta-estradiol reduced subclinical atherosclerosis progression, measured as change in carotid intima-media thickness (CIMT). This study was conducted to determine whether long-term 17beta-estradiol 1mg daily increased plasma nitric oxide (NO) levels and whether this accounted for atheroprotection in EPAT. Although the on-trial serum estradiol level was significantly higher in the estradiol-treated group (n = 91 subjects) than the placebo group (n = 89 subjects)(mean (S.D.)= 59.0 (31.7) pg/ml versus 14.3 (10.4) pg/ml, p < 0.0001), there was no significant difference in the on-trial plasma NO levels, 18.5 (8.2) microM versus 20.1 (9.3) microM. Correlation between on-trial estradiol level and NO change was -0.22 (p = 0.003) in the total sample (placebo- and estradiol-treated subjects) and -0.21 (p = 0.049) in the estradiol-treated group. Change in NO levels was inversely correlated to change in LDL-cholesterol in the estradiol group (r =-0.23, p = 0.03). An NO response to 17beta-estradiol according to age, time since menopause and baseline CIMT was not found arguing against a possible NO effect in healthy versus diseased endothelium. NO levels were not related to CIMT progression. In this study, we found no evidence for an estrogen-induced effect on plasma total NO levels which unlikely accounted for the mechanism underlying the 17beta-estradiol atheroprotective effect on subclinical atherosclerosis progression.
Along with the endothelium dependent flow-mediated dilation, cardiovascular advantages of menopausal hormone therapy (and the high hormone phase of monthly cycle) was observed also on:
Cardiology, Gachon Medical School, Inchon, South Korea 405-760. kwangk@ghil.com
BACKGROUND: Vascular inflammation plays an important role in the pathogenesis of atherosclerosis. We investigated the effect of hormone replacement therapy (HRT) on vasomotor function and monocyte chemoattractant protein (MCP)-1 levels, an important serological marker of inflammation. METHODS: We administered micronized progesterone (MP) 200 mg for 10 days with conjugated equine estrogen (CEE) 0.625 mg for 25 days and remaining 5 days off cyclically during 2 months to 20 healthy postmenopausal women (PMW). We measured NO bioactivity and plasma levels of MCP-1 before and after HRT in 20 PMW. And we measured plasma levels of MCP-1 in each 20 subjects of premenopausal women, men <50, and men >50 years, respectively. RESULTS: MP combined with CEE significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P<0.001). PMW receiving HRT had lower levels of MCP-1 than those not receiving HRT (121+/-38 versus 146+/-44 pg/ml, P<0.001). In all comparisons, subjects with high estrogen status had significantly lower MCP-1 levels than subjects with low estrogen status (P<0.001 by ANOVA). Premenopausal women had lower levels of MCP-1 than men of a similar age (106+/-14 versus 164+/-40 pg/ml, P<0.001). PMW not receiving HRT had similar levels of MCP-1 compared with men of a similar age (146+/-44 versus 143+/-29 pg/ml, P=0.816). Premenopausal women had markedly lower levels of MCP-1 than PMW not receiving HRT (106+/-14 versus 146+/-44 pg/ml, P=0.001). PMW receiving HRT had similar levels of MCP-1 compared with premenopausal women (121+/-38 versus 106+/-14 pg/ml, P=0.323). CONCLUSION: These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.
Increasing NO by other means such as by nitrite supplementation also have positive effects on cardiovascular system (yes, Viagra, Levitra, or Cialis will work also), in terms of endothelium-dependent dilation, artery stiffness, antioxidant effect, and anti-inflammation.
Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging., Amy L Sindler, Bradley S Fleenor, John W Calvert, Kurt D Marshall, Melanie L Zigler, David J Lefer, Douglas R Seals, 2011
Department of Integrative Physiology, University of Colorado, Boulder, USA. amy.sindler@colorado.edu
We tested the hypothesis that short-term nitrite therapy reverses vascular endothelial dysfunction and large elastic artery stiffening with aging, and reduces arterial oxidative stress and inflammation. Nitrite concentrations were lower (P < 0.05) in arteries, heart, and plasma of old (26-28 month) male C57BL6 control mice, and 3 weeks of sodium nitrite (50 mg L(-1) in drinking water) restored nitrite levels to or above young (4-6 month) controls. Isolated carotid arteries of old control mice had lower acetylcholine (ACh)-induced endothelium-dependent dilation (EDD)(71.7 ± 6.1% vs. 93.0 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (P < 0.05 vs. young), and sodium nitrite restored EDD (95.5 ± 1.6%) by increasing NO bioavailability. 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase (SOD) mimetic, apocynin, a nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, and sepiapterin (exogenous tetrahydrobiopterin) each restored EDD to ACh in old control, but had no effect in old nitrite-supplemented mice. Old control mice had increased aortic pulse wave velocity (478 ± 16 vs. 332 ± 12 AU, P < 0.05 vs. young), which nitrite supplementation lowered (384 ± 27 AU). Nitrotyrosine, superoxide production, and expression of NADPH oxidase were ?100-300% greater and SOD activity was ?50% lower in old control mice (all P < 0.05 vs. young), but were ameliorated by sodium nitrite treatment. Inflammatory cytokines were markedly increased in old control mice (P < 0.05), but reduced to levels of young controls with nitrite supplementation. Short-term nitrite therapy reverses age-associated vascular endothelial dysfunction, large elastic artery stiffness, oxidative stress, and inflammation. Sodium nitrite may be a novel therapy for treating arterial aging in humans.
Clinical Translation of Nitrite Therapy for Cardiovascular Diseases., John W Calvert, David J Lefer, 2009
Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, GA 30030.
The anion nitrite is an oxidative breakdown product of nitric oxide (NO) that has traditionally been viewed as a diagnostic marker of NO formation in biological systems. In this regard, nitrite has long been considered an inert oxidation product of NO metabolism. More recently, this view has changed with the discovery that nitrite represents a physiologically relevant storage reservoir of NO in blood and tissues that can readily be reduced to NO under pathological conditions. This has sparked a renewed interest in the biological role of nitrite and has led to an extensive amount of work investigating its therapeutic potential. As a result, nitrite therapy has now been shown to be cytoprotective in numerous animal models of disease. Given the very robust preclinical data regarding the cytoprotective effects of nitrite therapy it is very logical to consider the clinical translation of nitrite-based therapies. This article will review some of this preclinical data and will discuss the potential use of nitrite therapy as a therapeutic agent for the treatment of cardiovascular diseases including: ischemia-reperfusion injury (i.e. acute myocardial infarction and stroke), hypertension, angiogenesis, and as an adjunctive therapy for transplantation of various organs (i.e. liver and lung).
Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk., Giuseppe M C Rosano, Antonio Aversa, Cristiana Vitale, Andrea Fabbri, Massimo Fini, Giovanni Spera 2005
Since the increased antioxidant activity is part of NO benefits on cardiovascular health, and that part of benefits may be obtained by supplementing antioxidant such as alpha-lipoic acid. It was shown to reduce vascular oxidative stress and inflammation, at least in rats.

Cardiovascular Protective Role Of Progesterone
Many researchers seems to be satisfied by simply demonstrating estrogen's effects on cardiovascular health and treating progesterone as a nuisance that can be potentially detrimental, but has to be tolerated to protect uterus from cancer. Is estrogen alone enough to protect your cardiovascular health? Not really. Actually, it can be detrimental to cardiovascular health in terms of blood clot risk and heart attach risk, even with the safest transdermal estradiol. The progesterone's preventative role against coronary artery spasm induced heart attaches has been known for a long time (The mechanism of coronary artery spasm: roles of oxygen, prostaglandins, sex hormones and smoking., M Karmazyn, M S Manku, D F Horrobin 1979), and its role as a fast acting calcium blocker is well established as reviewed below.
This is particularly important since heart attaches due to coronary artery spasm is said to be a major cause of death in postmenopausal women. It is deadlier than the coronary artery blockade by atherosclerotic plaques and more frequent than cancer death in postmenopause years (Impact of the menopause on the epidemiology and risk factors of coronary artery heart disease in women. G I Gorodeski 1994). Yet progesterone's role is not getting much attention from medical community. Coronary Artery Spasm: A 2009 Update -- Stern and Bayes de Luna or any of its critics (e.g. Letter by Morikawa et al Regarding Article, ''Coronary Artery Spasm: A 2009 Update) does not even mention progesterone therapy as a potential treatment. Apparently, not much became of 1997 article Coronary artery spasm: a hypothesis on prevention by progesterone (I Kanda, M Endo 1997), although progesterone's effects and the underlying mechanism have been know for some time as can be seen in the following articles.

Vascular Effects of Progesterone : Role of Cellular Calcium Regulation. Mario Barbagallo, Ligia J. Dominguez, Giuseppe Licata, Jie Shan, Li Bing, Edward Karpinski, Peter K. T. Pang, Lawrence M. Resnick 2001
Institute of Internal Medicine and Geriatrics (M.B., L.J.D., G.L.), University of Palermo, Palermo, Italy.
-Vascular actions of progesterone have been reported, independently of estrogen, affecting both blood pressure and other aspects of the cardiovascular system. To study possible mechanisms underlying these effects, we examined the effects of P in vivo in intact rats and in vitro in isolated artery and vascular smooth muscle cell preparations. In anesthetized Sprague-Dawley rats, bolus intravenous injections of P (100 μg/kg) significantly decreased pressor responses to norepinephrine (0.3 μg/kg). In vitro, progesterone (10(-8) to 10(-5) mmol/L) produced a significant, dose-dependent relaxation of isolated helical strips, both of rat tail artery precontracted with KCl (60 mmol/L) or arginine vasopressin (3 nmol/L), and of rat aorta precontracted with KCl (60 mmol/L) or norepinephrine  (0.1 μmol/L). In isolated vascular smooth muscle cells, progesterone (5x10(-)(7) mol/L) reversibly inhibited KCl (30 mmol/L)-induced elevation of cytosolic-free calcium by 64.1+/-5.5%(P:<0.05), and in whole-cell patch-clamp experiments, progesterone (5x10(-6) mol/L) reversibly and significantly blunted L-type calcium channel inward current, decreasing peak inward current to 65.7+/-4.3% of the control value (P:<0.05). Our results provide evidence that progesterone is a vasoactive hormone, inhibiting agonist-induced vasoconstriction. The data further suggest that progesterone effects on vascular tissue may, at least in part, be mediated by modulation of the L-type calcium channel current activity and, consequently, of cytosolic-free calcium content.
The effect of progesterone on spontaneous and agonist-evoked contractions of the rat aorta and portal vein. ] M S Mukerji, H L Leathard, H Huddart 2000
Department of Nursing Studies, St. Martin's College, Lancaster, UK.
The mechanisms underlying the suppression of vasocontractility caused by progesterone were investigated by studying changes in the contractile force of rat isolated aorta and portal vein, induced by altering extracellular concentrations of noradrenaline (NA) potassium ions (K+) and calcium ions (Ca2+). In the aorta, progesterone (10 microM) had a general suppressive effect on NA-, Ca2+- and K+-induced contractions. In contrast, in the portal vein a more selective suppression of contractions was observed. Both tonic and phasic components of contractions induced by cumulative addition of Ca2+ to tissues equilibrated in Ca2+-free saline were suppressed. The phasic but not tonic components of contractions induced by NA addition were suppressed. There was no significant effect on tonic contractions induced by elevated (40-120 mM) K+, but a concentration-dependent suppression of the phasic component of contractions was observed during depolarisation with smaller elevations of K+ concentrations (5-20 mM). These results suggest that on the portal vein the suppressive effect of progesterone is due to a potassium channel opening action, whilst on the aorta a different or additional mechanism of suppression exists.
Prompt effect of progesterone on the adrenergic response of smooth muscles. S Morishita 1986
The contractile effects of epinephrine on the uterus and ductus deferens of the rabbit and the ductus deferens of the monkey were inhibited by the preincubation with progesterone (6.4 X 10(-5) M) for 1 or 3 min in Locke-Ringer solution. Epinephrine relaxed the guinea pig uterus and taenia caecum. The relaxant effects were enhanced by preincubation with progesterone. Their effects were in a dose-dependent manner. There was no apparent change in the number and affinity of alpha-adrenergic receptors in the uterus of rabbits and the ductus deferens of guinea pigs during the incubation with progesterone. Progesterone has no direct effect on alpha-adrenergic receptors. All smooth muscles yielded reproducible contractile reactions to Ca2+ when maintained in depolarizing Tyrode's solution containing K+(40 mmol/l). Their concentration-response curves were inhibited by preincubation with progesterone (6.4 X 10(-5) M), and they were shifted to the right in a concentration-dependent manner. Established Ca2+-induced contractions were rapidly relaxed by the addition of progesterone (6.4 X 10(-5) M). It suggests that progesterone directly affects the plasma membrane and inhibits the voltage-dependent Ca2+ channel and then inhibits smooth muscle contraction.
Nongenomic vasodilator action of progesterone on primate coronary arteries.  Richard D Minshall, Dusan Pavcnik, David L Browne, Kent Hermsmeyer 2002
Oregon Regional Primate Research Center, Beaverton 97006, Oregon, USA.
In the present investigation, we test the hypothesis that progesterone can rapidly relax, via a nongenomic mechanism, persistent flow occluding, agonist-activated coronary artery (CA) vasospasm, and hyperreactive vascular muscle cell (VMC) Ca(2+) responses in ovariectomized rhesus monkeys. CA vasospasm, induced by injection of 100 microM serotonin and 1 microM U-46619 (5-HT+U; 1 ml/30 s), resulted in a decrease in CA diameter (phi) from 1.8 +/- 0.2 to 0.3 +/- 0.1 mm at the site of focal constriction. Injection of 100 ng progesterone into the CA significantly relieved the severe vasoconstriction (1.3 +/- 0.2 mm) and reestablished distal flow in 3 min; the preconstriction phi was completely restored in 8.2 +/- 2.6 min (n = 6). Similarly, cell impermeant albumin-conjugated progesterone, but not albumin-conjugated 17 beta-estradiol, decreased 5-HT+U stimulated VMC Ca(2+) responses (250 +/- 34% of basal 30 min after stimulation) back to the prestimulation level (113 +/- 17% of basal) in 25 min (half time = 7 min). The presence of a rapid vasodilator action of progesterone in the primate CA and isolated VMC suggests its benefits in hormone replacement therapy may also include nongenomic vascular relaxant actions.
Ca2+ release mechanism of primate drug-induced coronary vasospasm.  K Miyagawa, J Vidgoff, K Hermsmeyer 1997
Oregon Regional Primate Research Center, Oregon Health Sciences University, Beaverton 97006, USA.
Cellular mechanisms of protection against drug-stimulated coronary vasospasm were studied by multiweek estrogen plus progesterone (P) vs. medroxy-progesterone acetate (MPA) treatments by measuring intracellular Ca2+ and protein kinase C (PKC) signals. Ovariectomized monkeys (OVX) were treated by slow-release implants with either P or MPA for 4 wk added to estradiol-17 beta (E2) begun 2 wk earlier. A third group received E2 for 2 wk and withdrawal of E2 (W; no steroid treatment) during the last 4 wk. OVX coronary artery vascular muscle cells (VMC) in primary culture conditions were labeled by the fluorescent indicators, fluo 3 and hypericin, respectively, to study intracellular Ca2+ and PKC mechanisms of coronary artery hyperre-activity, using digital analysis of single VMC by photon-counting camera. Stimulation by 10 microM serotonin and 100 nM U-46619 (thromboxane A2 mimetic) caused Ca2+ increases (2-5 min) and no PKC activation in VMC from five P-treated monkeys but prolonged (> or = 30 min) increases in both Ca2+ and PKC signals in VMC from six MPA-treated monkeys or seven W-treated monkeys; these P vs. MPA (or W) differences were maintained > or = 14 days. We hypothesize that hyperreactivity in VMC from MPA- or W-treated monkeys results from accelerated prolonged Ca2+ release, with concomitant PKC activation, and that MPA (but not P) negates the coronary vasospasm protective effect of E2.
When you read progesterone research, the important thing to note is the fact that some researchers have been calling progesterone substitute drugs such as medroxyprogesterone acetate (Provera, Amen, Cycrin), and norethindrone acetate (Aygestin, Norlutate), "progesterone" instead of identifying the actual drug used. Consequently, the field of progesterone research has been contaminated and many researchers as well as doctors have come to believe that progesterone may be detrimental to cardiovascular health, as well as a cancer risk. Both are totally false.
One such example is Progesterone abolishes estrogen and/or atorvastatin endothelium dependent vasodilatory effects.(Andre Arpad Faludi, Jose Mendes Aldrighi, Marcelo Chiara Bertolami, Mohamed H Saleh, Renata Alves Silva, Yara Nakamura, Isabela R O Pereira, Dulcineia Saes Parra Abdalla, Jose Antonio Franchini Ramires, Jose Eduardo M R Sousa 2004). Although what they actually used was norethisterone acetate, they are calling it "Progesterone" in the title of the paper.
This double blind randomized placebo controlled study assessed the effects of atorvastatin, estradiol and norethisterone, isolated and in combination, on the lipid profile and on vascular reactivity, in post-menopausal women with hypercholesterolemia and arterial hypertension. Ninety-four women aged 50-65 were selected. All have received dietary counseling (4 weeks), placebo (4 weeks), and drug therapy (12 weeks): 17-beta estradiol 2mg/day (E)(n=17); E + norethisterone acetate 1mg/day (P)(n=18); Atorvastatin 10mg/day (A)(n=20); E + A (n=21) and E + P + A (n=18). All treatment modalities have significantly reduced total cholesterol (TC)(E=8.8%, E + P=10.1%, A=27.9%, A + E=29.4% and E + P + A=35.7%) and LDL-cholesterol (LDL-c) levels (E + P + A=46.6%, E + A=45.9%, A=40.2%, E=20.3%, and E + P=12.1%). As concerns HDL-cholesterol (HDL-c), Groups E and E + A had increases of 15.5% and 13.1%, respectively. The addition of a progesterone compound reduced its concentration (Group E + P=-9.1%, and Group E + P + A=-9.5%). By random, approximately half of the patients in each group were designated to the endothelial function evaluation (brachial artery ultrasound). We observed that in Group A (n=10), in Group E (n=10) and with the association (Group E + A)(n=7), there was a significant increase in the flow-mediated vasodilatation as compared to basal measurements. The addition of a progestin has annulled these benefits. CONCLUSIONS: Atorvastatin has promoted more beneficial effects on TC and LDL-c, whereas estradiol was responsible for an increase in HDL-c. The addition of a progesterone derivative abolished these benefits. Atorvastatin, estradiol or both together improved endothelial function, an effect suppressed by the addition of norethisterone.
Similarly, Effects of exercise training on bone remodeling, insulin-like growth factors, and bone mineral density in postmenopausal women with and without hormone replacement therapy. L A Milliken, et. al., 2003 , states "Any physician prescribed HRT regimen ... estrogen plus progesterone taken orally". There are many hormone combinations that match this description, and it is impossible to know if they used bio-identical or non bio-identical estrogen and progesterone based on this description (judging from the results and given the standard medical practice at the time, "progesterone" was most likely non bio-identical substitute drugs).
Vascular Actions of Estrogens: Functional Implications. (Virginia M. Miller And Sue P. Duckles, 2009) is one of the examples that show how oblivious some researchers are about the differences between real progesterone and progesterone substitute drugs.
The reason why it is important to distinguish the real progesterone from its substitutes is that estrogen + progesterone substitutes does become a risk factor in many ways including but not limited to coronary artery spasm and atherosclerosis.
Cardiovascular disease, the major cause of death in post-menopausal women, can be reduced by replacement of ovarian steroid hormones. To compare medroxyprogesterone with progesterone as the progestin in hormone replacement therapy from the standpoint of coronary artery vasospasm, we treated ovariectomized rhesus monkeys with physiological levels of estradiol-17 beta in combination with medroxyprogesterone or progesterone for four weeks. Coronary vasospasm in response to pathophysiological stimulation without injury showed that progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm. We conclude that medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm.
Department of Pharmacology and Physico-Chemistry of Cellular and Molecular Interactions, College of Pharmacy, Louis Pasteur University, Illkirch, France.
OBJECTIVE:: To examine whether chronic administration of the natural hormone progesterone or a synthetic progestogen, medroxyprogesterone acetate, to ovariectomized rats affects the endothelial control of arterial tone in the isolated mesenteric artery. DESIGN:: Sham-operated rats received a daily subcutaneous injection of solvent (sesame oil), whereas ovariectomized rats received either sesame oil, progesterone (22 mg kg/day), or medroxyprogesterone acetate (22 mg kg/day) for 4 weeks, according to their respective group. RESULTS:: Phenylephrine-induced contractions were significantly increased (about 200% at 10 microM) by N-nitro-L-arginine, a nitric oxide synthase inhibitor, in intact mesenteric arterial rings from the sham-operated but not from the ovariectomized group. The progesterone but not the medroxyprogesterone treatment restored the potentiating effect of N-nitro-L-arginine on phenylephrine-induced contraction (about 180% at 10 microM). Contractions to phenylephrine were not affected by the combination of charybdotoxin plus apamin, two inhibitors of endothelium-derived hyperpolarizing factor-mediated responses, in all groups. Acetylcholine induced endothelium-dependent relaxations, which were partially inhibited by N-nitro-L-arginine and abolished by the combination of N-nitro-L-arginine plus charybdotoxin and apamin, in all groups. Acetylcholine induced similar charybdotoxin and apamin-sensitive hyperpolarizations in intact mesenteric artery segments from all groups. CONCLUSIONS:: Chronic administration of progesterone, but not medroxyprogesterone, to ovarictomized rats restores the endothelium-dependent attenuation of contractile responses to phenylephrine in mesenteric arterial rings through the endothelial formation of nitric oxide. Thus, an enhancement of the protective effect of endothelial cells on the arterial wall might contribute to the beneficial effect of certain progestogen-containing preparations during hormonal treatment.
Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy. t.simoncini@obgyn.med.unipi.it
The conjugated equine estrogens-only arm of the Women's Health Initiative trial, showing a trend toward protection from heart disease as opposed to women receiving also medroxyprogesterone acetate (MPA), strengthens the debate on the cardiovascular effects of progestins. We compared the effects of progesterone (P) or MPA on the synthesis of nitric oxide and on the expression of leukocyte adhesion molecules, characterizing the signaling events recruited by these compounds. Although P significantly increases nitric oxide synthesis via transcriptional and nontranscriptional mechanisms, MPA is devoid of such effects. Moreover, when used together with physiological estradiol (E2) concentrations, P potentiates E2 effects, whereas MPA impairs E2 signaling. These findings are observed both in isolated human endothelial cells as well as in vivo, in ovariectomized rat aortas. A marked difference in the recruitment of MAPK and phosphatidylinositol-3 kinase explains the divergent effects of the two gestagens. In addition, both P and MPA decrease the adhesiveness of endothelial cells for leukocytes when given alone or with estrogen. MPA is more potent than P in inhibiting the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. However, when administered together with physiological amounts of glucocorticoids, MPA (which also binds glucocorticoid receptor) markedly interferes with the hydrocortisone-dependent stabilization of the transcription factor nuclear factor kappaB and with the expression of adhesion molecules, acting as a partial glucocorticoid receptor antagonist. Our findings show significant differences in the signal transduction pathways recruited by P and MPA in endothelial cells, which may have relevant clinical implications.
Departamento de Biologia, Bioquimica y Farmacia, Universidad Nacional del Sur, Bahia Blanca, Argentina.
The rapid non-genomic stimulatory action of progesterone (Pg) and estradiol (E2) on nitric oxide synthase (NOS) activity of endothelium intact aortic rings and its effect on platelet aggregation was investigated. First we measured the effect of the hormones on platelet aggregation when added to rat aortic strips (RAS) incubated in a PRP. RAS induced an antiaggregatory activity, which was enhanced by the presence of the hormones. The inhibitory action induced by the hormones was evoked in a dose dependent manner (10 pM-100 nM). These effects are specific for progesterone and 17-beta-estradiol, since either testosterone and 17-alpha-estradiol were devoid of activity. The hormones induced rapid responses, producing significant inhibition within 1 to 5 minutes of hormonal exposure. The addition of 10(-5) M L-NAME suppressed the antiaggregatory effect of 1 nM E2 or 10 nM Pg. Furthermore, we specifically quantified the NO generation by the 3H-citrulline technique. 10(-8) M E2 induced 2-fold increase of RAS citrulline production, while the increment induced by 10(-7) M Pg was 55% over control. Preincubation with 10(-5) M L-NAME completely suppressed the stimulatory action of 10(-9) M E2 or 10(-8) M Pg, confirming that the antiaggregatory factor released from the aortic tissue was NO. Preincubation with cycloheximide did not block the increment in NO induced by the hormones. In conclusion the present study provides for the first time evidence of acute, non-genomic effects of Pg on rat aorta NOS activity and platelet aggregation in coincidence with the results obtained with estradiol treatment.
Baker Medical Research Institute, Prahran, Melbourne, Australia.
BACKGROUND: The protective functions of oestrogen therapy alone on cardiovascular risk parameters are well established; however, the action of progesterone on vascular parameters in an oestrogen-deprived environment is less clear. OBJECTIVES: To examine the effects of progesterone alone on vascular function and hormone levels in postmenopausal women. DESIGN: In a randomized, double-blind, cross-over design study, 20 healthy postmenopausal women were tested before and after 6 weeks of treatment with micronized progesterone (100 mg/daily) and matching placebo. METHODS: Tests included measurement of sex hormones and gonadatropin levels, lipids and measures of surrogate markers of vascular function including, blood pressure, flow-mediated dilation of the brachial artery, systemic arterial compliance and cutaneous vascular reactivity. RESULTS: The mean (+/- SEM) age of subjects was 56.4 +/- 2.7 years and the average body mass index at the baseline visit was 27.1 +/- 1.0 kg/m2. Progesterone levels increased as a result of progesterone treatment (0.9 +/- 0.2 to 9.5 +/- 2.3 nmol/l, P = 0.001), whereas follicle-stimulating hormone levels decreased (75.1 +/- 11.4 to 67.6 +/- 10.0, P = 0.001). Systemic arterial compliance, flow mediated dilation, cutaneous vascular reactivity, blood pressure, body mass index, plasma levels of cholesterol, lipids and oestrogen were unchanged. CONCLUSIONS: We conclude that progesterone given without oestrogen  does not adversely affect vascular function in postmenopausal women.
Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Regularly menstruating women are relatively protected from cardiovascular disease. Epidemiological and endothelial function studies attribute this protection to estradiol (E(2)), but both progesterone (P) and E(2) are normally present. A range of vascular effects of added progestins have been described, from neutral to detrimental, but the effects of P per se on endothelial function in humans have not been reported. We therefore investigated the acute effects of E(2), P, and E(2) combined with P, on endothelium-dependent and -independent forearm blood flow responses. Using venous occlusion plethysmography, forearm blood flow (FBF) was measured during acute brachial artery infusions, achieving physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P in healthy menopausal women with no cardiovascular disease risk factors. Vehicle or hormones were infused, in random order, on 4 days, 1 week apart. Flow responses were measured during coinfusions of hormone with the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside. Twenty-seven healthy menopausal women were studied, and all had normal baseline endothelial responses. Small ( approximately 15%), statistically nonsignificant increases in endothelium-dependent flow responses were seen after all acute hormone treatments. No impairment in response was seen with P alone or in combination with 17-beta-E(2). In healthy menopausal women without cardiovascular disease risk factors and without baseline defects in endothelial function, acute exposure to physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P produced equivalent endothelium-dependent responses. These data suggest that P does not have detrimental vascular effects in humans.
Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Progesterone induced rapid relaxation of KCl-induced contraction of rat aortic rings. The relaxant effect of progesterone on aortic rings was concentration-dependent (over the range of 10(-10) to 10(-5) M) and partially dependent on the endothelium. Application of a nitric oxide (NO) synthase antagonist N(G)-monomethyl-L-arginine (L-NMMA, 10(-5) M) after progesterone treatment partially inhibited the relaxant effects of progesterone. This suggested that part of the effect was through the production of nitric oxide. Washing out the steroid hormone in the bath solutions could quickly reverse the inhibitory effects of progesterone on phasic tension generation in aortic rings. Five minutes after washout, the tension generation in aortic rings was completely restored. Cultured endothelial cells from rat aorta increased release of NO into culture media in response to a 60-min exposure to progesterone. Aldosterone and dexamethasone were also tested, and failed to relax KCl-induced contraction of aortic rings. These data suggest that the vascular effects of progesterone are not mediated by a genomic action of this steroid, and that the vascular effects are mediated partially through endothelial NO production.
Variations in endothelial function and arterial compliance during the menstrual cycle., M R Williams, R A Westerman, B A Kingwell, J Paige, P A Blombery, K Sudhir, P A Komesaroff, 2001 (there is something funny about the data)
Baker Medical Research Institute, St. Kilda Central, Melbourne, Victoria 8008, Australia.
Female sex hormones have been implicated in the cardioprotection of premenopausal women. However, the cardiovascular actions of these hormones and the effects of their natural fluctuations during the menstrual cycle are not fully understood. We studied changes in vascular function during the menstrual cycle in 15 healthy premenopausal women. Four noninvasive procedures were performed during the early follicular (EF), late follicular (LF), early luteal (EL), and late luteal (LL) phases: flow-mediated dilatation (FMD) of the brachial artery during reactive hyperemia, laser Doppler velocimetry (LDV) with direct current iontophoresis of acetylcholine (ACh) and nitroprusside, whole body arterial compliance (WBAC), and pulse wave velocity. Hormone levels were consistent with predicted cycle phase and showed that all subjects ovulated during the cycle studied. FMD, LDV with ACh, and WBAC varied cyclically, with significant increases from the F to LF phase, sharp falls in the EL phase, and significant recoveries in the LL phase. These changes were most marked for FMD [EF, 8.8 +/- 0.6%(mean +/- SEM); LF, 10.0 +/- 0.7; EL, 4.2 +/- 0.6; LL, 8.6 +/- 0.9] and the LDV response to ACh (EF, 2.7 +/- 0.2 V/min; LF, 3.3 +/- 0.4; EL, 1.8 +/- 0.3; LL, 2.7 +/- 0.4). WBAC changed similarly (EF, 0.58 +/- 0.08 arbitrary units; LF, 0.84 +/- 0.06; EL, 0.65 +/- 0.05; LL, 0.68 +/- 0.06). Sodium nitroprusside-induced vasodilatation decreased significantly from EF to EL, with no other significant difference, and pulse wave velocity did not vary significantly over the four time points. Conductance and resistance artery endothelial reactivity and smooth muscle sensitivity to nitric oxide and arterial compliance are modulated significantly in response to the changing hormonal patterns of the menstrual cycle. These findings emphasize the importance of menstrual phase in the interpretation of data on endothelial function and may provide insights into the mechanisms underlying sex differences in cardiovascular risk and other disease processes in premenopausal women.
Estradiol's benefitial effect on endothelium-dependent dilatation is a well established phenomena, however,  the relation between endothelium-dependent dilatation and coronary artery spasm is not clear.
Flow-mediated, endothelium-dependent dilatation of the brachial arteries is impaired in patients with coronary spastic angina. T Motoyama, H Kawano, K Kugiyama, K Okumura, M Ohgushi, M Yoshimura, O Hirashima, H Yasue 1997
Division of Cardiology, Kumamoto University School of Medicine, Japan.
Coronary spasm is induced by acetylcholine, serotonin, ergonovine, or histamine, all of which cause vasodilation when the endothelium is intact, and is promptly relieved by nitroglycerin, which vasodilates through the direct action on smooth muscle. Endothelial dysfunction is therefore possibly involved in the pathogenesis of coronary artery spasm. The aim of this study was to determine whether endothelium-dependent vasodilation is impaired in the peripheral arteries of patients with coronary spastic angina. Flow-dependent vasodilation of the brachial arteries during reactive hyperemia after the transient arterial occlusion was examined by using the high-resolution ultrasound technique in 35 patients with coronary spastic angina and 35 controls. Flow-dependent vasodilation of the brachial arteries was impaired in patients with coronary spastic angina compared with controls (5.9%+/- 4.2% vs 9.6%+/- 3.4%, p < 0.001) although the percent increase in blood flow during reactive hyperemia was not different between the two groups. The dilator response to nitroglycerin was preserved in patients with coronary spastic angina compared with controls (18.6%+/- 5.1% vs 16.2%+/- 3.9%, p < 0.04). The results indicate that endothelium-dependent vasodilation of the brachial arteries is impaired in patients with coronary spastic angina. Thus endothelial vasomotor dysregulation may also be present in the systemic arteries as well as coronary arteries in patients with coronary spastic angina.
Caucasian patients suffering from coronary vasospastic angina have an intact peripheral endothelium-dependent vasoreactivity. Ali Yilmaz, Matthias Vohringer, Anastasios Athanasiadis, Peter Ong, Rimma Merher, Dieter Ratge, Cornelius Knabbe, Udo Sechtem 2008
Division of Cardiology, Robert-Bosch-Hospital, Stuttgart, Germany.
We sought to evaluate whether Caucasian patients suffering from vasospastic angina have a decreased brachial artery flow-mediated dilation (FMD) like their Japanese counterparts and whether certain serum factors known to be associated with impaired vasomotility or endothelial dysfunction are abnormal. In this prospectively conducted study, 33 subjects presenting with resting angina were identified to suffer from coronary vasospastic angina (coronary spasm group). A control group of 19 subjects with matched cardiovascular risk profiles was defined out of patients admitted to our hospital for evaluation of atypical chest pain. Intracoronary acetylcholine(ACh)-testing for vasospasm was performed in all patients after coronary artery disease (CAD) had been ruled out. Brachial artery FMD was measured using high-resolution ultrasound. There was no significant difference in brachial artery FMD between the coronary spasm and the control group (7.05+/-2.24% vs. 7.12+/-2.50%; p=0.93). The endothelium-independent vasodilator response of the brachial artery to sublingual nitroglycerin did not differ either between the two groups (21.88+/-6.13% vs. 21.48+/-7.38%; p=0.84). Simple and multiple linear regression analysis revealed that only baseline brachial artery diameter was a significant determinant of FMD (p<0.0001). No relationship could be detected between impaired coronary vasomotility and peripheral endothelium-dependent or independent vasodilation in Caucasian patients suffering from coronary vasospastic angina illustrating a further clue for racial differences in the pathophysiology of vasospastic angina.
In fact, the detrimental effect of estrogen alone hormone therapy is not limited to blood clot risk. A heart rate variability study with estrogen alone therapy observed reduced heart rate variability, which is an indicator of coronary artery spasm risk.
Postmenopausal estrogen therapy modulates nocturnal nonlinear heart rate dynamics. Irina Virtanen, Eeva Ekholm, Paivi Polo-Kantola, Heikki Hiekkanen, Heikki Huikuri 2008
OBJECTIVE:: To study the effects of postmenopausal estrogen therapy (ET) on nocturnal nonlinear heart rate variability (HRV). DESIGN:: In this prospective, randomized, double-blind, placebo-controlled study, 71 healthy hysterectomized postmenopausal women received either transdermal estradiol or placebo for 3 months. After a washout period of 1 month, the treatments were reversed. Sleep studies were performed after both treatment periods. One steady-state epoch per night of the awake state, stage 2 (light) non-rapid eye movement (REM) sleep, stage 3-4 (deep) non-REM sleep, also known as slow-wave sleep, and REM sleep was extracted. From the electrocardiogram, nonlinear HRV was analyzed as the fractal scaling exponents alpha1 and alpha2, approximate entropy (ApEn), and the Poincare plot variability coefficients SD1 and SD2. These were correlated to ET use in both different sleep stages and averaged across all sleep stages. RESULTS:: During ET, the nocturnal ApEn decreased from 0.80 +/- 0.01 to 0.74 +/- 0.02 (P < 0.05), the most marked reduction occurring during slow-wave sleep (from 0.77 +/- 0.05 to 0.63 +/- 0.06, P < 0.05). In addition, SD2 decreased in slow-wave sleep and REM sleep during ET (P < 0.05 for both). In light non-REM sleep, alpha1 slightly increased during ET (P < 0.05). CONCLUSIONS:: ET has a slightly but distinctively attenuating effect on some nocturnal nonlinear measures of HRV, especially on complexity of heart rate dynamics. This implies that ET may have potentially deleterious effects on cardiovascular health during sleep.
Progesterone induces endothelium-independent relaxation rather than the endothelium-dependent relaxation estrogen facilitates. It can manifest as attenuation of arterial contraction, which is consistent with its role in prevention of vascular spasm.
Progesterone induces endothelium-independent relaxation of rabbit coronary artery in vitro. C W Jiang, P M Sarrel, D C Lindsay, P A Poole-Wilson, P Collins 1992
Department of Cardiac Medicine, National Heart and Lung Institute, University of London, U.K.
The effect of progesterone on isolated rabbit coronary arteries and its possible mechanism was investigated by measuring changes of isometric tension. Progesterone (1, 3, 10 and 30 microM) induced significant coronary relaxation in K+(30 mM)-, prostaglandin F2 alpha (3 microM)- or Bay K 8644 (1 microM plus 15 mM K+)- precontracted arteries. There was no difference between endothelium-intact and -denuded coronary arteries from both male and female rabbits, precontracted with these three agents. Haemoglobin, indomethacin, methylene blue, glibenclamide or barium chloride did not affect the relaxation. In endothelium-denuded rabbit coronary arteries, progesterone shifted calcium concentration-dependent constrictor-response curves to the right, the maximal contraction was also reduced. The -log ED50s were 3.6 in control, and 3.3 and 2.9 after incubation with progesterone (3 and 30 microM), respectively. Similar results were obtained in rat aorta. We conclude that progesterone induces significant endothelium-independent relaxation in rabbit coronary arteries in vitro, possibly by affecting calcium influx.
Properties of a progesterone-induced relaxation in human placental arteries and veins.  H A Omar, R Ramirez, M Gibson 1995
Department of Pediatrics, West Virginia University, Morgantown 26506.
To study the effects of progesterone on placental vascular tone, we used isolated (1-2 mm in diameter) placental arteries and veins from term uncomplicated pregnancies. These vessels, incubated in Krebs buffer (pH 7.4) under 5% O2-5% CO2 (balance N2, PO2 approximately 35 torr) and precontracted with serotonin were exposed to incremental doses of progesterone (0.01-30 mumol/L) in the presence or absence of endothelium, 10 mumol/L indomethacin (inhibits prostaglandin synthesis), 10 mumol/L methylene blue (a soluble guanylate cyclase inhibitor), 100 mumol/L nitro-L-arginine (inhibits L-arginine metabolism), 1 mmol/L isobutylmethylxanthine (a cAMP phosphodiesterase inhibitor), or 30 mumol/L mifepristone (RU 38486, an antiprogestin). Progesterone elicited an acute dose-dependent relaxation in both arteries and veins that was not altered by removal of the endothelium or pretreatment with indomethacin, nitro-L-arginine, or methylene blue, excluding a role for prostaglandins, L-arginine products, or cGMP in mediating this relaxation. However, isobutylmethylxanthine significantly enhanced the relaxation in response to progesterone, suggesting a role for cAMP. RU 38486 inhibited the relaxation by 50-100%, depending on the progesterone dose, consistent with a role for progesterone receptors. These results suggest that progesterone causes a dose-dependent endothelium-independent relaxation of human placental arteries and veins. This relaxation seems to be mediated by a receptor-activated cAMP mechanism and could be physiologically important in maintaining low resistance and adequate blood flow in the placental circulation.
Progesterone and modulation of endothelium-dependent responses in canine coronary arteries.  V M Miller, P M Vanhoutte 1991
Department of Physiology and Biophysics, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
Chronic treatment with estrogens enhances some endothelium-dependent relaxations. Whether or not progesterone would exert a similar effect is unknown. Experiments were designed to determine the effect of chronic treatment with progesterone on endothelium-dependent responses. Adult female dogs were ovariectomized and pellets containing carrier substance, estrogen, progesterone, or estrogen plus progesterone were implanted subcutaneously. After 14-21 days coronary arteries were removed, cut into rings, and suspended for the measurement of isometric force in organ chambers in the presence of indomethacin. Endothelium-dependent relaxations to ADP, bradykinin, or the calcium ionophore did not differ among groups. However, relaxations to acetylcholine and to the alpha 2-adrenergic agonist BHT-920 were greater in the estrogen-treated group than in the estrogen plus progesterone-treated group. In rings without endothelium, relaxations to nitric oxide and isoproterenol did not differ among groups. However, relaxations of the smooth muscle to ADP were greater in the progesterone-treated group than in the progesterone plus estrogen group. These results suggest that progesterone alone minimally affects endothelium-dependent responses. However, progesterone seems to antagonize the stimulatory effects of estrogen on two endothelium-dependent responses that are associated with pertussis toxin-sensitive guanine nucleotide regulatory proteins and the production of nitric oxide. These studies suggest that a specific receptor/second messenger system can be modulated by female reproductive steroid hormones.
It is obvious that progesterone and estrogen have different roles in vascular function, and are not designed to function alone. The detrimental effect of the imbalance will show up one way or the other.
Differential effects of progesterone and 17beta-estradiol on the Ca(2+) entry induced by thapsigargin and endothelin-1 in in situ endothelial cells., J Y Toshima, K Hirano, J Nishimura, H Nakano, H Kanaide, 2000
The effects of progesterone and 17beta-estradiol on Ca(2+) signaling in in situ endothelial cells were investigated using front-surface fluorometry of fura-2-loaded strips of porcine aortic valve. Progesterone inhibited the thapsigargin-induced sustained [Ca(2+)](i) elevation (IC(50)=33.9 microM, n=4), while 17beta-estradiol added a transient [Ca(2+)](i) elevation. Progesterone and 17beta-estradiol had no significant effect on the thapsigargin-induced [Ca(2+)](i) elevations in the absence of extracellular Ca(2+). A Mn(2+)-induced decline of fluorescent intensity at 360 nm excitation was accelerated by thapsigargin. This acceleration was completely reversed by progesterone, but not by 17beta-estradiol. Progesterone inhibited, and 17beta-estradiol enhanced the endothelin-1 (ET-1)-induced [Ca(2+)](i) elevation, while both had no effect on the ET-1-induced Ca(2+) release observed in the absence of extracellular Ca(2+) or in the pertussis toxin-treated strips. Progesterone and 17beta-estradiol thus had different effects on Ca(2+) signaling, especially on Ca(2+) influx, in endothelial cells.
Another point to note is that lower doses of both estrogen and progesterone were found more beneficial to endothelium functions, which cautions against any study results that used higher doses and did not examine the differential effects of dosage levels.
Different role of endothelium/nitric oxide in 17beta-estradiol- and progesterone-induced relaxation in rat arteries.  H Y Chan, X Yao, S Y Tsang, F L Chan, C W Lau, Y Huang 200

Summary
To the extent estrogen and progesterone influence the endothelium-dependent flow meditated dilation, autonomic nerve system reactivity, atherosclerosis, and vascular spasm, all of which are implicated as cardiovascular health and risk indicators, estrogen and progesterone are deeply involved in cardiovascular health throughout the women's adult life. Young healthy women show endothelium-dependent flow meditated dilation fluctuate coinciding with the menstrual cycle. All measures of cardiovascular health (Blood pressure, endothelium-dependent flow meditated dilation, peak blood flow, plasma NO) are most favorable in high estrogen + progesterone phase. Premenopause women with ischemic cardiovascular risk tend to have more problem when both estrogen and progesterone are low.
Unlike menstrual cycle where the low hormone phase lasts only a week, menopause put women in the lower than low hormone phase indefinitely. The cardiovascular health advantage the pre-menopausal women have over men largely diminishes with menopause. Menopausal hot flushes can be seen as a marker for underlying vascular changes among mid-life, otherwise healthy, menopausal women. Hormone therapy in a form of transdermal estradiol + natural progesterone effectively reduces the cardiovascular health risk of ovarian hormone deficiency without adverse side effects.

It is tragic that the large scale HRT clinical trials conducted as part of Women's Health Initiative in the U.S. used a wrong form of HRT and totally obscured the safe and effective use of real estrogen and progesterone (both in low dose transdermal) and both doctors and the general public are left scared and confused. For reviews, see Hormones: Dos and Don'ts, and Safe Use of Hormones: the Hard Evidence.
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3 comments:

  1. AnonymousJuly 13, 2012 at 1:52 PM

    This is the greatest post I read on this topic. Perhaps Its a research paper. Women suffering from menopausal symptoms should at least read this post once.

    ReplyDelete
  2. Etsuko UedaJuly 14, 2012 at 12:28 AM

    A research paper quality blog is what I am striving for, hence the title. Anything less would be a waste of my time and the readers'.

    ReplyDelete
  3. AnonymousJune 18, 2014 at 7:38 AM

    I would like to thank you from the bottom of my heart no pun intended...active, healthy weight, normal girl went post menopausal early at age 47 and i nearly fell apart. The worst thing was my heart! the PVC's were so intense, my heart would literally stop, then start again and flutter with a pulse, as soon as patch went on, I was cured. BP 120/80 pulse 60 no PVC's. but I am struggling with dosage, I went too high on estrogen and ended up with this terrible non-allergic rhinitis and cough trigger..so I cut my .050 minivelle patch in half!! w 20mg progest cream. So far so good. Heart still staying calm and the cough and sinus issues better. This is the best article I have seen. If I did not ASK and DEMAND estrogen I would have been on 5 other meds, cardiac, anxiety, sleep, etc...PLEASE LADIES GET ESTROGEN IF YOU NEED IT!!!

    ReplyDelete

Before you post your HRT questions, please try what I think safe and effective for at least 3 months: estradiol 0.025~0.050mg/day patch, with 20~40mg/day progesterone cream (about 1000mg progesterone in 2oz cream). You can also add DHEA 5~10mg /day.
That is the only recommendation you will get from me.

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