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1 April 2015Subscribe to our news feed
How well informed are general practitioners and cardiologists about testosterone deficiency and its consequences?
A rapidly growing body of medical research is showing that testosterone deficiency (aka hypogonadism and low-T) is strongly associated with a wide range of detrimental health outcomes1,2, and that testosterone replacement therapy improves those health parameters that are negatively affected by testosterone deficiency.2,3 Therefore, leading testosterone scientists now view testosterone deficiency as a cardiovascular risk factor that contributes to the development of cardiovascular disease.4-7
As general practitioners and cardiologists primarily care for these patients with cardiovascular disease, a survey study was conducted to assess their knowledge, beliefs and clinical practice with respect to testosterone deficiency and cardiovascular health.8
A questionnaire was distributed to 20 cardiologists and 128 family practitioners in British Columbia, Canada. Of the 13 questions, 10 assessed knowledge and beliefs on testosterone deficiency and 3 assessed current practice patterns.8
KEY POINTS
- Most general practitioners and cardiologists believed that hypogonadism is a medical condition (66.7%) and could negatively affect body composition (62%), but a similar majority was unsure whether it was a cardiac risk factor (66.7%).
- While most believed that testosterone replacement therapy could improve exercise tolerance (62%), most were unsure if it was beneficial in cardiac patients.
- Cardiologists were significantly less likely to believe that testosterone deficiency was beneficial in preventing recurrent heart attack (myocardial infarction) and improving oxygen supply to the heart (myocardial perfusion).
- Over half of the respondents (58.8%) said they were unsure whether testosterone deficiency could contribute to low HDL (high-density lipoprotein, the “good” cholesterol) levels.
- The vast majority (88%) of general practitioners and cardiologists did not screen their cardiac patients for testosterone deficiency. If a patient was identified as having hypogonadism, only 23.5% would treat the patient themselves, and 27.5% would refer to an endocrinologist.
What is known
Testosterone deficiency is an acknowledged cardiovascular risk factor among leading hypogonadism researchers.4-7
Studies show that testosterone replacement therapy improves exercise tolerance in both healthy men9 and in cardiac patients.10-12 In fact, cardiac patients are the ones to benefit the most. Several studies shows that in men with known angina by treadmill testing, testosterone replacement therapy significantly increases time to ischemia.10-12 These results are consistent with other studies in humans in which testosterone administration has been shown to induce vasodilation of the coronary13 and brachial arteries.14,15 Testosterone therapy also benefits men with congestive heart failure by significantly improving performance in the 6 minute walk test, incremental shuttle walk test, and/or peak oxygen consumption, and overall exercise capacity, compared to placebo.16-20 No significant adverse cardiovascular events were noted.16-18 Two additional, more recent placebo-controlled trials have confirmed beneficial functional effects of testosterone therapy in men with congestive heart failure.21,22
It is also documented that testosterone deficiency is associated with reduced HDL levels23, and that physiological restoration of testosterone levels with testosterone replacement therapy increases HDL levels, in addition to reducing fasting blood glucose, insulin resistance, triglycerides (blood fats), and waist circumference.24-31
TRT was associated with a significant reduction of fasting plasma glucose, homeostatic model assessment index, triglycerides, and waist circumference. In addition, an increase of high-density lipoprotein cholesterol was also observed.
What this study adds
Despite its high prevalence in cardiac patients, testosterone deficiency is not well-understood by general practitioners and cardiologists; they lack knowledge on its deleterious cardiovascular effects.8
The survey results presented here clearly show that the large majority of primary care physicians and cardiologists need more information about the health consequences of testosterone deficiency, as well as the benefits of testosterone therapy.
The finding that most primary care physicians and cardiologists do not screen their patients for testosterone deficiency is a red flag, as the prevalence of obesity, metabolic syndrome and diabetes is epidemic in today’s society, and it is well documented that testosterone deficiency in men with those conditions is extraordinary common, regardless of age. Specifically, in those men, the prevalence of testosterone deficiency ranges from 35% to almost 80%.32-36
A limitation of this study is that it was a relatively small survey from a Canadian province, and its results may not be the same in other areas of the world. However, other surveys of doctors from countries across the world reported many similarities in their approach to diagnosis and treatment of hypogonadism, and their beliefs about alleged risks (especially prostate and cardiovascular issues).37,38
The results from this survey underscore the importance for men to be pro-active about their own health and specifically request testing for testosterone deficiency if they are having symptoms/signs of hypogonadism.
In a sense, every man, even the young and healthy, should have his testosterone levels checked (plus SHBG, PSA, at a minimum) just to establish his healthy baseline. This is important because relative changes in testosterone levels over time may be a better predictor of impending testosterone deficiency and health deterioration than are the actual levels of total testosterone and/or free or bioavailable testosterone.39
Also, because the testosterone reference range is quite wide, every man needs to find his own optimal testosterone level. The reference range for total spans all the way from approximately 350 to 1200 ng/dL40. This wide range leaves a lot of room for expression of individual variation, i.e. significant decreases in testosterone levels that are still within the reference range. For example, a 50% decrease in testosterone levels will likely negatively impact most men. However, if a man’s healthy optimal baseline is in the upper end of the reference range, let’s say 1000 ng/dL, him reaching 500 mg/dL will not qualify for hypogonadism diagnosis if the current diagnostic criteria are used, which define biochemical hypogonadism as a total testosterone level below 300 ng/dL (US Endocrine Society)41 or below 350 ng/dL (European Association of Urology Guidelines).42
Finding your optimal healthy baseline testosterone level can only be done via regular blood testing, staring early in life. This will provide an invaluable personal benchmark against which to track hormonal changes over time.
References
1. Traish AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids. 2014;88C:106-116.
2. Mesbah Oskui P, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. Journal of the American Heart Association. 2013;2(6):e000272.
3. Traish AM. Outcomes of testosterone therapy in men with testosterone deficiency (TD): Part II. Steroids. 2014.
4. Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur. J. Endocrinol. 2011;165(5):687-701.
5. Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends in endocrinology and metabolism: TEM. 2010;21(8):496-503.
6. Maggio M, Basaria S. Welcoming low testosterone as a cardiovascular risk factor. Int. J. Impot. Res. 2009;21(4):261-264.
7. Ullah MI, Washington T, Kazi M, Tamanna S, Koch CA. Testosterone deficiency as a risk factor for cardiovascular disease. Horm. Metab. Res. 2011;43(3):153-164.
8. Wallis CJ, Brotherhood H, Pommerville PJ. Testosterone deficiency syndrome and cardiovascular health: An assessment of beliefs, knowledge and practice patterns of general practitioners and cardiologists in Victoria, BC. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2014;8(1-2):30-33.
9. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 2010;95(2):639-650.
10. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study. Circulation. 2000;102(16):1906-1911.
11. Webb CM, Adamson DL, de Zeigler D, Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am. J. Cardiol. 1999;83(3):437-439, A439.
12. Rosano GM, Leonardo F, Pagnotta P, et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation. 1999;99(13):1666-1670.
13. Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation. 1999;100(16):1690-1696.
14. Ong PJ, Patrizi G, Chong WC, Webb CM, Hayward CS, Collins P. Testosterone enhances flow-mediated brachial artery reactivity in men with coronary artery disease. Am. J. Cardiol. 2000;85(2):269-272.
15. Kang SM, Jang Y, Kim J, et al. Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease. Am. J. Cardiol. 2002;89(7):862-864.
16. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J. Am. Coll. Cardiol. 2009;54(10):919-927.
17. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur. Heart J. 2006;27(1):57-64.
18. Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure. Heart. 2004;90(4):446-447.
19. Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J. Am. Coll. Cardiol. 2010;56(16):1310-1316.
20. Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-analysis. Circulation. Heart failure. 2012;5(3):315-321.
21. Mirdamadi A, Garakyaraghi M, Pourmoghaddas A, Bahmani A, Mahmoudi H, Gharipour M. Beneficial effects of testosterone therapy on functional capacity, cardiovascular parameters, and quality of life in patients with congestive heart failure. BioMed research international. 2014;2014:392432.
22. Stout M, Tew GA, Doll H, et al. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am. Heart J. 2012;164(6):893-901.
23. Simon D, Charles MA, Nahoul K, et al. Association between plasma total testosterone and cardiovascular risk factors in healthy adult men: The Telecom Study. J. Clin. Endocrinol. Metab. 1997;82(2):682-685.
24. Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int. J. Clin. Pract. 2014;68(3):314-329.
25. Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J. Androl. 2009;30(6):726-733.
26. Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J. Clin. Endocrinol. Metab. 2007;92(10):3844-3853.
27. Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study. . Obes Res Clin Pract 2013.
28. Haider A, Yassin A, Doros G, Saad F. Effects of Long-Term Testosterone Therapy on Patients with “Diabesity”: Results of Observational Studies of Pooled Analyses in Obese Hypogonadal Men with Type 2 Diabetes. International Journal of Endocrinology. 2014:Article ID 683515.
29. Mitkov MD, Aleksandrova IY, Orbetzova MM. Effect of transdermal testosterone or alpha-lipoic acid on erectile dysfunction and quality of life in patients with type 2 diabetes mellitus. Folia Med. (Plovdiv). 2013;55(1):55-63.
30. Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. The journal of sexual medicine. 2014;11(6):1567-1576.
31. Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. The journal of sexual medicine. 2011;8(1):272-283.
32. Caldas AD, Porto AL, Motta LD, Casulari LA. Relationship between insulin and hypogonadism in men with metabolic syndrome. Arq. Bras. Endocrinol. Metabol. 2009;53(8):1005-1011.
33. Laaksonen DE, Niskanen L, Punnonen K, et al. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J. Clin. Endocrinol. Metab. 2005;90(2):712-719.
34. Singh SK, Goyal R, Pratyush DD. Is hypoandrogenemia a component of metabolic syndrome in males? Exp. Clin. Endocrinol. Diabetes. 2011;119(1):30-35.
35. Pellitero S, Olaizola I, Alastrue A, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. 2012;22(12):1835-1842.
36. Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin. Endocrinol. (Oxf). 2012;76(5):665-673.
37. Behre HM, Christin-Maitre S, Morales AM, Tostain J. Transversal European survey on testosterone deficiency diagnosis. The aging male : the official journal of the International Society for the Study of the Aging Male. 2012;15(2):69-77.
38. Gooren LJ, Behre HM. Diagnosing and treating testosterone deficiency in different parts of the world: changes between 2006 and 2010. The aging male : the official journal of the International Society for the Study of the Aging Male. 2012;15(1):22-27.
39. Holm AC, Fredrikson MG, Theodorsson E, et al. Change in testosterone concentrations over time is a better predictor than the actual concentrations for symptoms of late onset hypogonadism. The aging male : the official journal of the International Society for the Study of the Aging Male. 2011;14(4):249-256.
40. Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab. 2011;96(8):2430-2439.
41. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2010;95(6):2536-2559.
42. Dohle GR, Arver S, Bettocchi C, al. e. EAU Guidelines on Male Hypogonadism. European Association of Urology 2012.
2. Mesbah Oskui P, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. Journal of the American Heart Association. 2013;2(6):e000272.
3. Traish AM. Outcomes of testosterone therapy in men with testosterone deficiency (TD): Part II. Steroids. 2014.
4. Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur. J. Endocrinol. 2011;165(5):687-701.
5. Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends in endocrinology and metabolism: TEM. 2010;21(8):496-503.
6. Maggio M, Basaria S. Welcoming low testosterone as a cardiovascular risk factor. Int. J. Impot. Res. 2009;21(4):261-264.
7. Ullah MI, Washington T, Kazi M, Tamanna S, Koch CA. Testosterone deficiency as a risk factor for cardiovascular disease. Horm. Metab. Res. 2011;43(3):153-164.
8. Wallis CJ, Brotherhood H, Pommerville PJ. Testosterone deficiency syndrome and cardiovascular health: An assessment of beliefs, knowledge and practice patterns of general practitioners and cardiologists in Victoria, BC. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2014;8(1-2):30-33.
9. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 2010;95(2):639-650.
10. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study. Circulation. 2000;102(16):1906-1911.
11. Webb CM, Adamson DL, de Zeigler D, Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am. J. Cardiol. 1999;83(3):437-439, A439.
12. Rosano GM, Leonardo F, Pagnotta P, et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation. 1999;99(13):1666-1670.
13. Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation. 1999;100(16):1690-1696.
14. Ong PJ, Patrizi G, Chong WC, Webb CM, Hayward CS, Collins P. Testosterone enhances flow-mediated brachial artery reactivity in men with coronary artery disease. Am. J. Cardiol. 2000;85(2):269-272.
15. Kang SM, Jang Y, Kim J, et al. Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease. Am. J. Cardiol. 2002;89(7):862-864.
16. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J. Am. Coll. Cardiol. 2009;54(10):919-927.
17. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur. Heart J. 2006;27(1):57-64.
18. Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure. Heart. 2004;90(4):446-447.
19. Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J. Am. Coll. Cardiol. 2010;56(16):1310-1316.
20. Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-analysis. Circulation. Heart failure. 2012;5(3):315-321.
21. Mirdamadi A, Garakyaraghi M, Pourmoghaddas A, Bahmani A, Mahmoudi H, Gharipour M. Beneficial effects of testosterone therapy on functional capacity, cardiovascular parameters, and quality of life in patients with congestive heart failure. BioMed research international. 2014;2014:392432.
22. Stout M, Tew GA, Doll H, et al. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am. Heart J. 2012;164(6):893-901.
23. Simon D, Charles MA, Nahoul K, et al. Association between plasma total testosterone and cardiovascular risk factors in healthy adult men: The Telecom Study. J. Clin. Endocrinol. Metab. 1997;82(2):682-685.
24. Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int. J. Clin. Pract. 2014;68(3):314-329.
25. Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J. Androl. 2009;30(6):726-733.
26. Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J. Clin. Endocrinol. Metab. 2007;92(10):3844-3853.
27. Haider A, Saad F, Doros G, Gooren L. Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: an observational study. . Obes Res Clin Pract 2013.
28. Haider A, Yassin A, Doros G, Saad F. Effects of Long-Term Testosterone Therapy on Patients with “Diabesity”: Results of Observational Studies of Pooled Analyses in Obese Hypogonadal Men with Type 2 Diabetes. International Journal of Endocrinology. 2014:Article ID 683515.
29. Mitkov MD, Aleksandrova IY, Orbetzova MM. Effect of transdermal testosterone or alpha-lipoic acid on erectile dysfunction and quality of life in patients with type 2 diabetes mellitus. Folia Med. (Plovdiv). 2013;55(1):55-63.
30. Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. The journal of sexual medicine. 2014;11(6):1567-1576.
31. Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. The journal of sexual medicine. 2011;8(1):272-283.
32. Caldas AD, Porto AL, Motta LD, Casulari LA. Relationship between insulin and hypogonadism in men with metabolic syndrome. Arq. Bras. Endocrinol. Metabol. 2009;53(8):1005-1011.
33. Laaksonen DE, Niskanen L, Punnonen K, et al. The metabolic syndrome and smoking in relation to hypogonadism in middle-aged men: a prospective cohort study. J. Clin. Endocrinol. Metab. 2005;90(2):712-719.
34. Singh SK, Goyal R, Pratyush DD. Is hypoandrogenemia a component of metabolic syndrome in males? Exp. Clin. Endocrinol. Diabetes. 2011;119(1):30-35.
35. Pellitero S, Olaizola I, Alastrue A, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. 2012;22(12):1835-1842.
36. Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin. Endocrinol. (Oxf). 2012;76(5):665-673.
37. Behre HM, Christin-Maitre S, Morales AM, Tostain J. Transversal European survey on testosterone deficiency diagnosis. The aging male : the official journal of the International Society for the Study of the Aging Male. 2012;15(2):69-77.
38. Gooren LJ, Behre HM. Diagnosing and treating testosterone deficiency in different parts of the world: changes between 2006 and 2010. The aging male : the official journal of the International Society for the Study of the Aging Male. 2012;15(1):22-27.
39. Holm AC, Fredrikson MG, Theodorsson E, et al. Change in testosterone concentrations over time is a better predictor than the actual concentrations for symptoms of late onset hypogonadism. The aging male : the official journal of the International Society for the Study of the Aging Male. 2011;14(4):249-256.
40. Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab. 2011;96(8):2430-2439.
41. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2010;95(6):2536-2559.
42. Dohle GR, Arver S, Bettocchi C, al. e. EAU Guidelines on Male Hypogonadism. European Association of Urology 2012.
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Bayer AG This website is intended to provide information to an international audience outside the USA and UK.
Bayer AG This website is intended to provide information to an international audience outside the USA and UK.
Last updated: 2018
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