Dr. Weeks’ Comment: There is always another side of the story and despite a recent critique of using testosterone for men with heart disease, the merits of this anabolic hormone for heart health are worth remembering.
CONSIDERATIONS OF TESTOSTERONE AND HEART DISEASE
| Am J Cardiovasc Drugs. 2005;5(3):141-54. |
Testosterone and atherosclerosis in aging men: purported association and clinical implications.
Jones RD, Nettleship JE, Kapoor D, Jones HT, Channer KS.
Academic Unit of Endocrinology, Division of Genomic Medicine, Hormone & Vascular Biology Group, The University of Sheffield, Sheffield, UK. R.D.Jones@sheffield.ac.uk
Two of the strongest independent risk factors for coronary heart disease (CHD) are increasing age and male sex. Despite a wide variance in CHD mortality between countries, men are consistently twice as likely to die from CHD than their female counterparts. This sex difference has been attributed to a protective effect of female sex hormones, and a deleterious effect of male sex hormones, upon the cardiovascular system. However, little evidence suggests that testosterone exerts cardiovascular harm. In fact, serum levels of testosterone decline with age, and low testosterone is positively associated with other cardiovascular risk factors. Furthermore, testosterone exhibits a number of potential cardioprotective actions. For example, testosterone treatment is reported to reduce serum levels of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, and to increase levels of the anti-inflammatory cytokine IL-10; to reduce vascular cell adhesion molecule (VCAM)-1 expression in aortic endothelial cells; to promote vascular smooth muscle and endothelial cell proliferation; to induce vasodilatation and to improve vascular reactivity, to reduce serum levels of the pro-thrombotic factors plasminogen activator inhibitor (PAI)-1 and fibrinogen; to reduce low-density lipoprotein-cholesterol (LDL-C); to improve insulin sensitivity; and to reduce body mass index and visceral fat mass. These actions of testosterone may confer cardiovascular benefit since testosterone therapy reduces atheroma formation in cholesterol-fed animal models, and reduces myocardial ischemia in men with CHD. Consequently, an alternative hypothesis is that an age-related decline in testosterone contributes to the atherosclerotic process. This is supported by recent findings, which suggest that as many as one in four men with CHD have serum levels of testosterone within the clinically hypogonadal range. Consequently, restoration of serum levels of testosterone via testosterone replacement therapy could offer cardiovascular, as well as other, clinical advantages to these individuals.
| Atherosclerosis. 2005 Apr;179(2):369-73. Epub 2004 Dec 21. |
Sex hormone-binding globulin is a major determinant of the lipid profile: the PRIME study.
Bataille V, Perret B, Evans A, Amouyel P, Arveiler D, Ducimetiere P, Bard JM, Ferrieres J.
INSERM U 558, Faculte de Medecine, Departement d’Epidemiologie, 37 Allees Jules Guesde, 31073 Toulouse cedex, France.
The prevalence of coronary heart disease is much higher in men than in women and sex hormones might play a role in these differences through their influence on the lipid profile. The aim of this cross-sectional study was to study the relationship between hormonal markers (total testosterone (TT), estradiol (E2), sex-hormone-binding globulin (SHBG)) and plasma lipids in a population-based sample. Subjects were 352 men, 50-59 years old, selected in France (Lille, Strasbourg and Toulouse) and Northern-Ireland (Belfast) who had questionnaires and a medical examination at baseline of the PRIME prospective study (1991-1993). Pearson correlation coefficients and Student’s t tests were used to identify factors associated with plasma lipids. Multiple linear regression models were used for multivariate analyses, using triglycerides (TG) (log-transformed) and high density-lipoprotein cholesterol (HDL-C) as dependent variables. SHBG and TT were negatively correlated with TG (p<0.0001 and p<0.05, respectively) and positively correlated with HDL-C (p<0.0001 and p<0.01). E2 was positively correlated with TG (p<0.05). No significant association was found between sex-hormones and LDL-C. In multiple linear regression analyses, SHBG remained independently associated negatively with TG (p<0.01) and positively with HDL-C (p<0.0001) after adjustment for centre of recruitment, age, body mass index, systolic blood pressure, smoking, alcohol intake and physical activity. After further adjustment for insulin, the association between SHBG and HDL-C remained highly significant (p<0.0001). The association between SHBG and TG was weakened but remained also significant. Our results suggest that SHBG might to be a central protein in the hormonal regulation of the lipid profile.
| Eur J Endocrinol. 2005 Feb;152(2):285-91. |
Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina.
Smith AM, English KM, Malkin CJ, Jones RD, Jones TH, Channer KS.
Hormone & Vascular Biology Group, Academic Unit of Endocrinology, Division of Genomic Medicine, The University of Sheffield, Sheffield S10 2RX, UK.
OBJECTIVE: In women, sex hormones cause increased morbidity and mortality in patients with coronary heart disease (CHD) and adversely affect the coagulation profile. We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression, to determine if there is an increased risk of thrombosis. METHODS: Double-blind, randomized, placebo-controlled trial of testosterone in 46 men with chronic stable angina. Measurements of free, total and bioavailable testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH), estradiol, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, tissue plasminogen activator (tPA) and full blood count were made at 0, 6 and 14 weeks. RESULTS: Bioavailable testosterone levels were: 2.58 +/- 0.58 nmol/l at baseline, compared with 3.35 +/- 0.31 nmol/l at week 14 (P < 0.001) after treatment compared with 2.6 +/- 0.18 nmol/l and 2.44 +/- 0.18 nmol/l in the placebo group (P was not significant). There was no change in fibrinogen (3.03 +/- 0.18 g/l at baseline and 3.02 +/- 0.18 g/l at week 14, P = 0.24), tPA activity (26.77 +/- 4.9 Iu/ml and 25.67 +/- 4.4 Iu/ml, P = 0.88) or PAI-1 activity (0.49 +/- 0.85 Iu/ml and 0.36 +/- 0.06 Iu/ml, P = 0.16) with active treatment and no differences between the groups (at week 14, P value 0.98, 0.59 and 0.8 for fibrinogen, PAI-1 and tPA respectively). Haemoglobin concentration did not change over time, in the testosterone group (1.44 +/- 0.02 g/l and 1.45 +/- 0.02 g/l, P = 0.22). CONCLUSION: Physiological testosterone replacement does not adversely affect blood coagulation status.
| J Clin Endocrinol Metab. 2005 May;90(5):2708-11. Epub 2005 Feb 1. |
Is atherosclerotic cardiovascular disease an endocrinological disorder? The estrogen-androgen paradox.
Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Avenue, New York, New York 10019, USA. gbp1@columbia.edu
The strikingly lower incidence of myocardial infarction (MI) in premenopausal women than in men of the same age suggests an important role for sex hormones in the etiology of MI. Supporting such a role are studies, carried out mostly in men, that report abnormalities of sex hormone levels in patients with MI, correlations of sex hormone levels with degree of atherosclerosis and with levels of risk factors for MI, and changes in the levels of risk factors with administration of sex hormones. Studies have also reported a prospective relationship in men of testosterone level with progression of atherosclerosis, accumulation of visceral adipose tissue, and other risk factors for MI. Puzzling, however, is that neither the level of testosterone nor of estrogen was found to be predictive of coronary events in any of the eight prospective studies that have been carried out. Also puzzling is that whereas the gender difference in incidence of MI would suggest that testosterone promotes and/or estrogen prevents MI, the cross- sectional, hormone administration, and prospective studies have suggested that in men testosterone may prevent and estrogen promote MI. These studies have thus revealed an estrogen-androgen paradox: that endogenous sex hormones may relate both to atherosclerotic cardiovascular disease and its risk factors oppositely in women and men. Recently recognized experiments of nature and their knockout mouse models may present another manifestation of this estrogen-androgen paradox and could help resolve these apparent contradictions.
| Biochem Biophys Res Commun. 2005 Mar 4;328(1):312-7. |
Orchiectomy reduces susceptibility to renal ischemic injury: a role for heat shock proteins.
Park KM, Cho HJ, Bonventre JV.
Department of Anatomy and Pain and Neural Injury Research Center, MRC, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea. kmpark@knu.ac.kr
In previous studies we demonstrated that the presence of testosterone, rather than the absence of estrogen, plays a critical role in gender differences in kidney ischemia/reperfusion (I/R) injury. Although molecular chaperones such as heat shock proteins (HSPs) have been implicated as protective agents in the pathophysiology of I/R injury, their roles in gender differences in susceptibility to renal I/R injury remain to be defined. Here we demonstrate that orchiectomy increases the basal and post-ischemic expression of HSP-27 in kidney tubular epithelial cells, but not HSP-72, glucose-regulated protein (GRP)-78 or GRP-94 expression. Orchiectomy prevents the disruption of the actin cytoskeleton and renal functional disorders induced by I/R, when compared with intact male mice or orchiectomized mice treated with dihydrotestosterone, a non-aromatizable isoform of testosterone. Thus, the protection afforded by orchiectomy is associated with increased expression of HSP-27, a heat shock protein important for maintenance of actin cytoskeletal integrity. These findings indicate that testosterone inhibits the heat shock response and may provide a new paradigm for design of therapies for I/R injury.
| Aging Male. 2004 Sep;7(3):197-204. |
Evaluation of sex hormone levels and some metabolic factors in men with coronary atherosclerosis.
Dunajska K, Milewicz A, Szymczak J, Jedrzejuk D, Kuliczkowski W, Salomon P, Nowicki P.
Department of Endocrinology and Diabetology, Wroclaw Medical University, Wroclaw, Poland.
BACKGROUND: Because of the great controversy over the role of androgens in the pathogenesis of atherosclerosis, we investigated the relationship between serum sex hormone levels and angiographically confirmed coronary artery disease in men. MATERIAL AND METHODS: We investigated 86 men aged 40-60 years, 56 with coronary artery disease and 30 healthy men, matched by age, as a control group. Body mass index and waist to hip ratio were calculated and total body fat mass and percentage of abdominal deposit were investigated by dual-energy X-ray absorptiometry (Dpx (+) Lunar, USA). The serum levels of sex hormones and insulin were measured using commercial radioimmunoassay and IRMA (by SHBG) kits (DPC, USA). The serum levels of lipids and glucose were assessed by means of enzymatic methods. RESULTS: Men with coronary artery disease had lower total testosterone levels (17.01+/-6.42 vs. 19.37+/-6.58 nmol/l; p < 0.05), testosterone/estradiol ratio (228.5+/-88.5 vs. 289.8+/-120.1; p < 0.05) and free androgen index (FAI) (59.49+/-14.79 vs. 83.03+/-25.81; p < 0.0001), and higher levels of estrone (49.5+/-27.7 vs. 36.6+/-12.7 pg/ml) than men in the control group. Moreover, men with coronary artery disease were more insulin-resistant than controls and had an atherogenic lipid profile. There was an inverse correlation (p < 0.05) between testosterone level and serum level of glucose (r = -0.29), triglycerides (r= -0.37), body mass index (r= -0.55), waist (r = – 0.43), total body fat mass (r = – 0.3) and fasting insulin resistance index. A significant positive association (p < 0.05) was found between testosterone and the quantitative insulin sensitivity check index and high density lipoprotein cholesterol level in serum (r = 0.26). CONCLUSIONS: Low levels of total testosterone, testosterone/estradiol ratio and free androgen index and higher levels of estrone in men with coronary artery disease appear together with many features of metabolic syndrome and may be involved in the pathogenesis of coronary atherosclerosis.
| Mayo Clin Proc. 2004 Oct;79(10):1284-92. |
Current and future treatment strategies for refractory angina.
Yang EH, Barsness GW, Gersh BJ, Chandrasekaran K, Lerman A.
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.
Patients with refractory angina are not candidates for revascularization and have both class III or IV angina and objective evidence of ischemia despite optimal medical therapy. An estimated 300,000 to 900,000 patients in the United States have refractory angina, and 25,000 to 75,000 new cases are diagnosed each year. This review focuses on treatment strategies for refractory angina and includes the mechanism of action and clinical trial data for each strategy. The pharmacological agents that have been used are ranolazine, ivabradine, nicorandil, L-arginine, testosterone, and estrogen; currently, only L-arginine, testosterone, and estrogen are approved by the Food and Drug Administration. Results with the noninvasive treatments of enhanced external counterpulsation and transcutaneous electrical nerve stimulation are provided. Invasive treatment strategies including spinal cord stimulation, transmyocardial revascularization, percutaneous myocardial revascularization, and gene therapy are also reviewed.
| Heart. 2004 Aug;90(8):871-6. |
Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life.
Malkin CJ, Pugh PJ, Morris PD, Kerry KE, Jones RD, Jones TH, Channer KS.
Department of Cardiology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
BACKGROUND: Low serum testosterone is associated with several cardiovascular risk factors including dyslipidaemia, adverse clotting profiles, obesity, and insulin resistance. Testosterone has been reported to improve symptoms of angina and delay time to ischaemic threshold in unselected men with coronary disease. OBJECTIVE: This randomised single blind placebo controlled crossover study compared testosterone replacement therapy (Sustanon 100) with placebo in 10 men with ischaemic heart disease and hypogonadism. RESULTS: Baseline total testosterone and bioavailable testosterone were respectively 4.2 (0.5) nmol/l and 1.7 (0.4) nmol/l. After a month of testosterone, delta value analysis between testosterone and placebo phase showed that mean (SD) trough testosterone concentrations increased significantly by 4.8 (6.6) nmol/l (total testosterone) (p = 0.05) and 3.8 (4.5) nmol/l (bioavailable testosterone) (p = 0.025), time to 1 mm ST segment depression assessed by Bruce protocol exercise treadmill testing increased by 74 (54) seconds (p = 0.002), and mood scores assessed with validated questionnaires all improved. Compared with placebo, testosterone therapy was also associated with a significant reduction of total cholesterol and serum tumour necrosis factor alpha with delta values of -0.41 (0.54) mmol/l (p = 0.04) and -1.8 (2.4) pg/ml (p = 0.05) respectively. CONCLUSION: Testosterone replacement therapy in hypogonadal men delays time to ischaemia, improves mood, and is associated with potentially beneficial reductions of total cholesterol and serum tumour necrosis factor alpha.
| Coron Artery Dis. 2004 Jun;15(4):199-203. |
Imbalance of sex hormone levels in men with coronary artery disease.
Kajinami K, Takeda K, Takekoshi N, Matsui S, Tsugawa H, Kanemitsu S, Okubo S, Kitayama M, Fukuda A.
Department of Cardiology, Kanazawa Medical University, Uchinada, Japan. kajinami@kanazawa-med.ac.jp
OBJECTIVE: Sex hormones are thought to play a key role in atherogenesis, but the available evidence is inconclusive, partly because of a lack of accuracy in measurement. The aim of the study was to investigate the potential role of sex hormones in coronary atherosclerosis. METHODS: We prospectively applied a simple highly-sensitive method using solid-phase extraction followed by radioimmunoassay. Both phases were carried out using commercially available kits to determine levels of estradiol (E2). We also measured the levels of free testosterone (FT), dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and progesterone in 236 consecutive male patients with angiographically-defined stable coronary artery disease and in 143 disease-free and age-matched controls. RESULTS: The levels of highly-sensitive E2 and FT in patients and controls differed slightly in opposing directions, but neither difference reached statistical significance. However, the ratio of FT to highly-sensitive E2 in patients was significantly higher than in the controls (mean +/- SD; 2.50 +/- 1.89 versus 2.06 +/- 1.14, P = 0.018), and this difference remained significant after adjustments for age and body mass index had been made. Multiple regression analysis revealed that age, the association of diabetes, and the presence of coronary atherosclerosis were significantly and independently associated with the values of the FT/highly-sensitive E2 ratio. Other hormones examined did not differ significantly between the patients and the controls. CONCLUSIONS: Highly-sensitive E2 measurement demonstrated a significant imbalance of FT to E2 in male patients with coronary artery disease, but individual sex hormone levels did not differ between the patients and the controls.
PLANET EARTH, April 9, 2057
A faulty theory on the origin and cause of heart disease, introduced on Planet Earth 100 years prior to this date, has caused the demise of the human race, according to a Pleiadean delegation report. The theory led to food choices that proved lethal to humans over several generations.
“We were surprised at the rapidity of its effects,” said the commission’s chairman, “and the tenacity of the theory. Even when infertility and early death became widespread, humans did not question the validity of the basic assumptions.”
The delegation, which visits Planet Earth once every fifty earth years on fact-finding missions, estimated the decrease in earthling numbers at almost 99 percent. Only pockets of isolated populations and some descendants of impoverished dairy farmers, too poor to purchase supermarket foods, remained.
Proponents of the cholesterol theory maintained that animal fats and cholesterol from animal foods were the cause of heart disease. Vegetable oils gradually replaced animal fats in the human diet as Earth-dwellers sought to lower their blood cholesterol below the levels needed to produce reproductive hormones. The introduction of imitation foods rich in plant-based estrogens, and of plant sterols into commonly eaten foods, exacerbated the antifertility effects.
Humans were also encouraged to take drugs to lower cholesterol levels and these had side effects such as cancer, which contributed to the population decline. And heart disease increased, in spite of rigid adherence to cholesterol-lowering regimes. Low cholesterol levels also contributed to an increase in deaths from suicide and violence. In addition, children experienced growth problems and increasing numbers failed to reach sexual maturity. The investigators cited the lack of protective nutrients found in animal fats as a factor exacerbating all these conditions.
Ironically, a few earthling scientists had warned against the effects of diets based on vegetable oils, the commission found. But these souls were either ignored or persecuted. Over time, mental ability declined, with great numbers of children experiencing learning difficulties and attention deficit disorder. Alzheimer’s and senility increased among the elderly. Humans could no longer make sense of ancestral dietary traditions or of published studies on the role of animal fats in human nutrition.
The real enemy, according to the report, was fear. “Humans were taught to fear the very foods that had made their evolution possible,” said the observers. “They were very gullible and believed the advertisements and pronouncements of those who profited from the sale of vegetable oils and cholesterol-lowering drugs.”
“Even if earthlings can overcome their fear and return to traditional foods,” said the commission, “it will take centuries to repopulate the earth.” The delegation expressed regret at the waste of a fine planet.
CONSIDERATIONS OF TESTOSTERONE AND HEART DISEASE
| Am J Cardiovasc Drugs. 2005;5(3):141-54. |
Testosterone and atherosclerosis in aging men: purported association and clinical implications.
Jones RD, Nettleship JE, Kapoor D, Jones HT, Channer KS.
Academic Unit of Endocrinology, Division of Genomic Medicine, Hormone & Vascular Biology Group, The University of Sheffield, Sheffield, UK. R.D.Jones@sheffield.ac.uk
Two of the strongest independent risk factors for coronary heart disease (CHD) are increasing age and male sex. Despite a wide variance in CHD mortality between countries, men are consistently twice as likely to die from CHD than their female counterparts. This sex difference has been attributed to a protective effect of female sex hormones, and a deleterious effect of male sex hormones, upon the cardiovascular system. However, little evidence suggests that testosterone exerts cardiovascular harm. In fact, serum levels of testosterone decline with age, and low testosterone is positively associated with other cardiovascular risk factors. Furthermore, testosterone exhibits a number of potential cardioprotective actions. For example, testosterone treatment is reported to reduce serum levels of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, and to increase levels of the anti-inflammatory cytokine IL-10; to reduce vascular cell adhesion molecule (VCAM)-1 expression in aortic endothelial cells; to promote vascular smooth muscle and endothelial cell proliferation; to induce vasodilatation and to improve vascular reactivity, to reduce serum levels of the pro-thrombotic factors plasminogen activator inhibitor (PAI)-1 and fibrinogen; to reduce low-density lipoprotein-cholesterol (LDL-C); to improve insulin sensitivity; and to reduce body mass index and visceral fat mass. These actions of testosterone may confer cardiovascular benefit since testosterone therapy reduces atheroma formation in cholesterol-fed animal models, and reduces myocardial ischemia in men with CHD. Consequently, an alternative hypothesis is that an age-related decline in testosterone contributes to the atherosclerotic process. This is supported by recent findings, which suggest that as many as one in four men with CHD have serum levels of testosterone within the clinically hypogonadal range. Consequently, restoration of serum levels of testosterone via testosterone replacement therapy could offer cardiovascular, as well as other, clinical advantages to these individuals.
| Atherosclerosis. 2005 Apr;179(2):369-73. Epub 2004 Dec 21. |
Sex hormone-binding globulin is a major determinant of the lipid profile: the PRIME study.
Bataille V, Perret B, Evans A, Amouyel P, Arveiler D, Ducimetiere P, Bard JM, Ferrieres J.
INSERM U 558, Faculte de Medecine, Departement d’Epidemiologie, 37 Allees Jules Guesde, 31073 Toulouse cedex, France.
The prevalence of coronary heart disease is much higher in men than in women and sex hormones might play a role in these differences through their influence on the lipid profile. The aim of this cross-sectional study was to study the relationship between hormonal markers (total testosterone (TT), estradiol (E2), sex-hormone-binding globulin (SHBG)) and plasma lipids in a population-based sample. Subjects were 352 men, 50-59 years old, selected in France (Lille, Strasbourg and Toulouse) and Northern-Ireland (Belfast) who had questionnaires and a medical examination at baseline of the PRIME prospective study (1991-1993). Pearson correlation coefficients and Student’s t tests were used to identify factors associated with plasma lipids. Multiple linear regression models were used for multivariate analyses, using triglycerides (TG) (log-transformed) and high density-lipoprotein cholesterol (HDL-C) as dependent variables. SHBG and TT were negatively correlated with TG (p<0.0001 and p<0.05, respectively) and positively correlated with HDL-C (p<0.0001 and p<0.01). E2 was positively correlated with TG (p<0.05). No significant association was found between sex-hormones and LDL-C. In multiple linear regression analyses, SHBG remained independently associated negatively with TG (p<0.01) and positively with HDL-C (p<0.0001) after adjustment for centre of recruitment, age, body mass index, systolic blood pressure, smoking, alcohol intake and physical activity. After further adjustment for insulin, the association between SHBG and HDL-C remained highly significant (p<0.0001). The association between SHBG and TG was weakened but remained also significant. Our results suggest that SHBG might to be a central protein in the hormonal regulation of the lipid profile.
| Eur J Endocrinol. 2005 Feb;152(2):285-91. |
Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina.
Smith AM, English KM, Malkin CJ, Jones RD, Jones TH, Channer KS.
Hormone & Vascular Biology Group, Academic Unit of Endocrinology, Division of Genomic Medicine, The University of Sheffield, Sheffield S10 2RX, UK.
OBJECTIVE: In women, sex hormones cause increased morbidity and mortality in patients with coronary heart disease (CHD) and adversely affect the coagulation profile. We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression, to determine if there is an increased risk of thrombosis. METHODS: Double-blind, randomized, placebo-controlled trial of testosterone in 46 men with chronic stable angina. Measurements of free, total and bioavailable testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH), estradiol, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, tissue plasminogen activator (tPA) and full blood count were made at 0, 6 and 14 weeks. RESULTS: Bioavailable testosterone levels were: 2.58 +/- 0.58 nmol/l at baseline, compared with 3.35 +/- 0.31 nmol/l at week 14 (P < 0.001) after treatment compared with 2.6 +/- 0.18 nmol/l and 2.44 +/- 0.18 nmol/l in the placebo group (P was not significant). There was no change in fibrinogen (3.03 +/- 0.18 g/l at baseline and 3.02 +/- 0.18 g/l at week 14, P = 0.24), tPA activity (26.77 +/- 4.9 Iu/ml and 25.67 +/- 4.4 Iu/ml, P = 0.88) or PAI-1 activity (0.49 +/- 0.85 Iu/ml and 0.36 +/- 0.06 Iu/ml, P = 0.16) with active treatment and no differences between the groups (at week 14, P value 0.98, 0.59 and 0.8 for fibrinogen, PAI-1 and tPA respectively). Haemoglobin concentration did not change over time, in the testosterone group (1.44 +/- 0.02 g/l and 1.45 +/- 0.02 g/l, P = 0.22). CONCLUSION: Physiological testosterone replacement does not adversely affect blood coagulation status.
| J Clin Endocrinol Metab. 2005 May;90(5):2708-11. Epub 2005 Feb 1. |
Is atherosclerotic cardiovascular disease an endocrinological disorder? The estrogen-androgen paradox.
Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Avenue, New York, New York 10019, USA. gbp1@columbia.edu
The strikingly lower incidence of myocardial infarction (MI) in premenopausal women than in men of the same age suggests an important role for sex hormones in the etiology of MI. Supporting such a role are studies, carried out mostly in men, that report abnormalities of sex hormone levels in patients with MI, correlations of sex hormone levels with degree of atherosclerosis and with levels of risk factors for MI, and changes in the levels of risk factors with administration of sex hormones. Studies have also reported a prospective relationship in men of testosterone level with progression of atherosclerosis, accumulation of visceral adipose tissue, and other risk factors for MI. Puzzling, however, is that neither the level of testosterone nor of estrogen was found to be predictive of coronary events in any of the eight prospective studies that have been carried out. Also puzzling is that whereas the gender difference in incidence of MI would suggest that testosterone promotes and/or estrogen prevents MI, the cross- sectional, hormone administration, and prospective studies have suggested that in men testosterone may prevent and estrogen promote MI. These studies have thus revealed an estrogen-androgen paradox: that endogenous sex hormones may relate both to atherosclerotic cardiovascular disease and its risk factors oppositely in women and men. Recently recognized experiments of nature and their knockout mouse models may present another manifestation of this estrogen-androgen paradox and could help resolve these apparent contradictions.
| Biochem Biophys Res Commun. 2005 Mar 4;328(1):312-7. |
Orchiectomy reduces susceptibility to renal ischemic injury: a role for heat shock proteins.
Park KM, Cho HJ, Bonventre JV.
Department of Anatomy and Pain and Neural Injury Research Center, MRC, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea. kmpark@knu.ac.kr
In previous studies we demonstrated that the presence of testosterone, rather than the absence of estrogen, plays a critical role in gender differences in kidney ischemia/reperfusion (I/R) injury. Although molecular chaperones such as heat shock proteins (HSPs) have been implicated as protective agents in the pathophysiology of I/R injury, their roles in gender differences in susceptibility to renal I/R injury remain to be defined. Here we demonstrate that orchiectomy increases the basal and post-ischemic expression of HSP-27 in kidney tubular epithelial cells, but not HSP-72, glucose-regulated protein (GRP)-78 or GRP-94 expression. Orchiectomy prevents the disruption of the actin cytoskeleton and renal functional disorders induced by I/R, when compared with intact male mice or orchiectomized mice treated with dihydrotestosterone, a non-aromatizable isoform of testosterone. Thus, the protection afforded by orchiectomy is associated with increased expression of HSP-27, a heat shock protein important for maintenance of actin cytoskeletal integrity. These findings indicate that testosterone inhibits the heat shock response and may provide a new paradigm for design of therapies for I/R injury.
| Aging Male. 2004 Sep;7(3):197-204. |
Evaluation of sex hormone levels and some metabolic factors in men with coronary atherosclerosis.
Dunajska K, Milewicz A, Szymczak J, Jedrzejuk D, Kuliczkowski W, Salomon P, Nowicki P.
Department of Endocrinology and Diabetology, Wroclaw Medical University, Wroclaw, Poland.
BACKGROUND: Because of the great controversy over the role of androgens in the pathogenesis of atherosclerosis, we investigated the relationship between serum sex hormone levels and angiographically confirmed coronary artery disease in men. MATERIAL AND METHODS: We investigated 86 men aged 40-60 years, 56 with coronary artery disease and 30 healthy men, matched by age, as a control group. Body mass index and waist to hip ratio were calculated and total body fat mass and percentage of abdominal deposit were investigated by dual-energy X-ray absorptiometry (Dpx (+) Lunar, USA). The serum levels of sex hormones and insulin were measured using commercial radioimmunoassay and IRMA (by SHBG) kits (DPC, USA). The serum levels of lipids and glucose were assessed by means of enzymatic methods. RESULTS: Men with coronary artery disease had lower total testosterone levels (17.01+/-6.42 vs. 19.37+/-6.58 nmol/l; p < 0.05), testosterone/estradiol ratio (228.5+/-88.5 vs. 289.8+/-120.1; p < 0.05) and free androgen index (FAI) (59.49+/-14.79 vs. 83.03+/-25.81; p < 0.0001), and higher levels of estrone (49.5+/-27.7 vs. 36.6+/-12.7 pg/ml) than men in the control group. Moreover, men with coronary artery disease were more insulin-resistant than controls and had an atherogenic lipid profile. There was an inverse correlation (p < 0.05) between testosterone level and serum level of glucose (r = -0.29), triglycerides (r= -0.37), body mass index (r= -0.55), waist (r = – 0.43), total body fat mass (r = – 0.3) and fasting insulin resistance index. A significant positive association (p < 0.05) was found between testosterone and the quantitative insulin sensitivity check index and high density lipoprotein cholesterol level in serum (r = 0.26). CONCLUSIONS: Low levels of total testosterone, testosterone/estradiol ratio and free androgen index and higher levels of estrone in men with coronary artery disease appear together with many features of metabolic syndrome and may be involved in the pathogenesis of coronary atherosclerosis.
| Mayo Clin Proc. 2004 Oct;79(10):1284-92. |
Current and future treatment strategies for refractory angina.
Yang EH, Barsness GW, Gersh BJ, Chandrasekaran K, Lerman A.
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.
Patients with refractory angina are not candidates for revascularization and have both class III or IV angina and objective evidence of ischemia despite optimal medical therapy. An estimated 300,000 to 900,000 patients in the United States have refractory angina, and 25,000 to 75,000 new cases are diagnosed each year. This review focuses on treatment strategies for refractory angina and includes the mechanism of action and clinical trial data for each strategy. The pharmacological agents that have been used are ranolazine, ivabradine, nicorandil, L-arginine, testosterone, and estrogen; currently, only L-arginine, testosterone, and estrogen are approved by the Food and Drug Administration. Results with the noninvasive treatments of enhanced external counterpulsation and transcutaneous electrical nerve stimulation are provided. Invasive treatment strategies including spinal cord stimulation, transmyocardial revascularization, percutaneous myocardial revascularization, and gene therapy are also reviewed.
| Heart. 2004 Aug;90(8):871-6. |
Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life.
Malkin CJ, Pugh PJ, Morris PD, Kerry KE, Jones RD, Jones TH, Channer KS.
Department of Cardiology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
BACKGROUND: Low serum testosterone is associated with several cardiovascular risk factors including dyslipidaemia, adverse clotting profiles, obesity, and insulin resistance. Testosterone has been reported to improve symptoms of angina and delay time to ischaemic threshold in unselected men with coronary disease. OBJECTIVE: This randomised single blind placebo controlled crossover study compared testosterone replacement therapy (Sustanon 100) with placebo in 10 men with ischaemic heart disease and hypogonadism. RESULTS: Baseline total testosterone and bioavailable testosterone were respectively 4.2 (0.5) nmol/l and 1.7 (0.4) nmol/l. After a month of testosterone, delta value analysis between testosterone and placebo phase showed that mean (SD) trough testosterone concentrations increased significantly by 4.8 (6.6) nmol/l (total testosterone) (p = 0.05) and 3.8 (4.5) nmol/l (bioavailable testosterone) (p = 0.025), time to 1 mm ST segment depression assessed by Bruce protocol exercise treadmill testing increased by 74 (54) seconds (p = 0.002), and mood scores assessed with validated questionnaires all improved. Compared with placebo, testosterone therapy was also associated with a significant reduction of total cholesterol and serum tumour necrosis factor alpha with delta values of -0.41 (0.54) mmol/l (p = 0.04) and -1.8 (2.4) pg/ml (p = 0.05) respectively. CONCLUSION: Testosterone replacement therapy in hypogonadal men delays time to ischaemia, improves mood, and is associated with potentially beneficial reductions of total cholesterol and serum tumour necrosis factor alpha.
| Coron Artery Dis. 2004 Jun;15(4):199-203. |
Imbalance of sex hormone levels in men with coronary artery disease.
Kajinami K, Takeda K, Takekoshi N, Matsui S, Tsugawa H, Kanemitsu S, Okubo S, Kitayama M, Fukuda A.
Department of Cardiology, Kanazawa Medical University, Uchinada, Japan. kajinami@kanazawa-med.ac.jp
OBJECTIVE: Sex hormones are thought to play a key role in atherogenesis, but the available evidence is inconclusive, partly because of a lack of accuracy in measurement. The aim of the study was to investigate the potential role of sex hormones in coronary atherosclerosis. METHODS: We prospectively applied a simple highly-sensitive method using solid-phase extraction followed by radioimmunoassay. Both phases were carried out using commercially available kits to determine levels of estradiol (E2). We also measured the levels of free testosterone (FT), dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and progesterone in 236 consecutive male patients with angiographically-defined stable coronary artery disease and in 143 disease-free and age-matched controls. RESULTS: The levels of highly-sensitive E2 and FT in patients and controls differed slightly in opposing directions, but neither difference reached statistical significance. However, the ratio of FT to highly-sensitive E2 in patients was significantly higher than in the controls (mean +/- SD; 2.50 +/- 1.89 versus 2.06 +/- 1.14, P = 0.018), and this difference remained significant after adjustments for age and body mass index had been made. Multiple regression analysis revealed that age, the association of diabetes, and the presence of coronary atherosclerosis were significantly and independently associated with the values of the FT/highly-sensitive E2 ratio. Other hormones examined did not differ significantly between the patients and the controls. CONCLUSIONS: Highly-sensitive E2 measurement demonstrated a significant imbalance of FT to E2 in male patients with coronary artery disease, but individual sex hormone levels did not differ between the patients and the controls.
PLANET EARTH, April 9, 2057
A faulty theory on the origin and cause of heart disease, introduced on Planet Earth 100 years prior to this date, has caused the demise of the human race, according to a Pleiadean delegation report. The theory led to food choices that proved lethal to humans over several generations.
“We were surprised at the rapidity of its effects,” said the commission’s chairman, “and the tenacity of the theory. Even when infertility and early death became widespread, humans did not question the validity of the basic assumptions.”
The delegation, which visits Planet Earth once every fifty earth years on fact-finding missions, estimated the decrease in earthling numbers at almost 99 percent. Only pockets of isolated populations and some descendants of impoverished dairy farmers, too poor to purchase supermarket foods, remained.
Proponents of the cholesterol theory maintained that animal fats and cholesterol from animal foods were the cause of heart disease. Vegetable oils gradually replaced animal fats in the human diet as Earth-dwellers sought to lower their blood cholesterol below the levels needed to produce reproductive hormones. The introduction of imitation foods rich in plant-based estrogens, and of plant sterols into commonly eaten foods, exacerbated the antifertility effects.
Humans were also encouraged to take drugs to lower cholesterol levels and these had side effects such as cancer, which contributed to the population decline. And heart disease increased, in spite of rigid adherence to cholesterol-lowering regimes. Low cholesterol levels also contributed to an increase in deaths from suicide and violence. In addition, children experienced growth problems and increasing numbers failed to reach sexual maturity. The investigators cited the lack of protective nutrients found in animal fats as a factor exacerbating all these conditions.
Ironically, a few earthling scientists had warned against the effects of diets based on vegetable oils, the commission found. But these souls were either ignored or persecuted. Over time, mental ability declined, with great numbers of children experiencing learning difficulties and attention deficit disorder. Alzheimer’s and senility increased among the elderly. Humans could no longer make sense of ancestral dietary traditions or of published studies on the role of animal fats in human nutrition.
The real enemy, according to the report, was fear. “Humans were taught to fear the very foods that had made their evolution possible,” said the observers. “They were very gullible and believed the advertisements and pronouncements of those who profited from the sale of vegetable oils and cholesterol-lowering drugs.”
“Even if earthlings can overcome their fear and return to traditional foods,” said the commission, “it will take centuries to repopulate the earth.” The delegation expressed regret at the waste of a fine planet.