Male Endocrinology


including diabetes, hypertension, and/or congestive heart failure, an excess of MR activation has been shown to have a negative impact on endothelial function, hence disrupting the physiological balance between vasoconstriction and vasodilatation.70


Such a mechanism may play a role in


the pathogenesis of erectile dysfunction, especially in the aging male, whereas increased cardiovascular risk, hypertension, and diabetes represent precipitating factors contributing to impaired vascular relaxation due to overactivation of the ET-1/endothelin receptor-A (ETA) pathway.71 ETA receptor blockade as well as mineralocorticoid receptor blockade may represent alternative therapeutic approaches for erectile dysfunction associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present.


Conclusions


The endothelium plays a critical role in the physiological function of all vascular beds, maintaining vascular homoeostasis and thus preventing initiation or progression of vascular disease. Any insult or injury to the endothelium may produce pathological states and dysfunction. Synthesis and release of vasodilators from the endothelium, such as NO,


prostaglandin I2 (PGI2), and endothelium-derived hyperpolarizing factor, is integral to the maintenance of physiological function. Endothelial damage due to various insults determines the production of potent


1. Kathir K, Adams MR, Endothelial dysfunction as a predictor of acute coronary syndromes, Semin Vasc Med, 2003;3:355–62.


2. Rosano GM, Androgens and coronary artery disease. A sex-specific effect of sex hormones?, Eur Heart J, 2000;21:868–71.


3. Herrmann J, Lerman A, The endothelium: dysfunction and beyond, J Nucl Cardiol, 2001;8:197–206.


4. Bruzziches R, Aversa A, Phosphodiesterase type 5 inhibitors and endothelial function, Curr Sex Health Rep, 2007;4:157–62.


5. Aversa A, Bruzziches R, Francomano D, et al., Testosterone and phosphodiesterase type-5 inhibitors: new strategy for preventing endothelial damage in internal and sexual medicine?, Ther Adv Urol, 2009;1:179–97.


6. Carlo-Stella C, Di Nicola M, Milani R, et al., Age and irradiation associated loss of bone marrow hematopoietic function in mice is reversed by recombinant human growth hormone, Exp Hematol, 2004;32:171–8.


7. Hill JM, Zalos G, Halcox JP, et al., Circulating endothelial progenitor cells, vascular function, and cardiovascular risk, N Engl J Med, 2003;348:593–600.


8. Vasa M, Fichtlscherer S, Adler K, et al., Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease, Circulation, 2001;103:2885–90.


9. Blankenberg S, Rupprecht HJ, Bickel C, et al., Circulating cell adhesion molecules and death in patients with coronary artery disease, Circulation, 2001;104:1336–42.


10. Witte DR, Broekmans WM, Kardinaal AF, et al., Soluble intercellular adhesion molecule 1 and flow-mediated dilatation are related to the estimated risk of coronary heart disease independently from each other, Atherosclerosis, 2003;170:147–53.


11. Corretti MC, Anderson TJ, Benjamin EJ, et al., Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force, J Am Coll Cardiol, 2002;39:257–65.


12. Anderson TJ, Uehata A, Gerhard MD, et al., Close relation of endothelial function in the human coronary and peripheral circulations, J Am Coll Cardiol, 1995;26:1235–41.


13. Wu WC, Sharma SC, Choudhary G, et al., Flow-mediated vasodilation predicts the presence and extent of coronary artery disease assessed by stress thallium imaging, J Nucl Cardiol, 2005;12:538–44.


14. Yavuz BB, Yavuz B, Sener DD, et al., Advanced age is associated with endothelial dysfunction in healthy elderly subject, Gerontology, 2008;54:153–6.


15. Vita JA, Keaney JF Jr, Endothelial function: a barometer for cardiovascular risk?, Circulation, 2002;106:640–2.


16. Miller VM, Mulvagh SL, Sex steroids and endothelial function: translating basic science to clinical practice, Trends Pharmacol Sci, 2007;28:263–70.


17. Sader MA, Griffiths KA, Skilton MR, et al., Physiological testosterone replacement and arterial endothelial function in men, Clin Endocrinol (Oxf), 2003;59:62–7.


18. Allan CA, McLachlan RI, Age-related changes in testosterone and the role of replacement therapy in older men, Clin Endocrinol (Oxf),


148 2004;60:653–70.


19. Francomano D, Bruzziches R, Natali M, et al., Cardiovascular effect of testosterone replacement therapy in aging male, Acta Biomed, 2010;81(Suppl. 1):101–6.


20. Aversa A, Bruzziches R, Francomano D, et al., Endothelial dysfunction and erectile dysfunction in the aging man, Int J Urol, 2010;17:38–47.


21. Jones TH, Testosterone associations with erectile dysfunction, diabetes, and the metabolic syndrome, Eur Urol, 2007;6:847–57.


22. Hougaku H, Fleg JL, Najjar SS, et al., Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements, Am J Physiol Endocrinol Metab, 2006;290:E234–42.


23. Fukui M, Kitagawa Y, Ose H, et al., Role of endogenous androgen against insulin resistance and atherosclerosis in men with type 2 diabetes, Curr Diabetes Rev, 2007;3:5–31.


24. Rosano GM, Sheiban I, Massaro R, et al., Low testosterone levels are associated with coronary artery disease in male patients with angina, Int J Impot Res, 2007;19:176–82.


25. Akishita M, Hashimoto M, Ohike Y, et al., Low testosterone level is an independent determinant of endothelial dysfunction in men, Hypertens Res, 2007;30:1029–34.


26. Aversa A, Bruzziches R, Spera G, A rationale for the use of testosterone salvage in treatment of men with erectile dysfunction failing phosphodiesterase inhibitors, Endocrinologist, 2005;15:99–105.


27. Hanke H, Lenz C, Hess B, et al., Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall, Circulation, 2001;103:1382–5.


28. Orshal JM, Khalil RA, Gender, sex hormones, and vascular tone, Am J Physiol Regul Integr Comp Physiol, 2004;286:R233–49.


29. Wynne FL, Khalil RA, Testosterone and coronary vascular tone: implications in coronary artery disease, J Endocrinol Invest, 2003;26:181–6.


30. Chou TM, Sudhir K, Hutchison SJ, et al., Testosterone induces dilatation in canine coronary conductance and resistance arteries in vivo, Circulation, 1996;94:2614–9.


31. Littleton-Kearney M, Hurn PD, Testosterone as a modulator of vascular behavior, Biol Res Nurs, 2004;5:276–85.


32. Rosenfeld CR, Chen C, Roy T, Liu X, Estrogen selectively up-regulates eNOS and nNOS in reproductive arteries by transcriptional mechanisms, J Soc Gynecol Investig, 2003;10:205–15.


33. Crews JK, Khalil RA, Antagonistic effects of 17 beta-estradiol, progesterone and testosterone on Ca2+ entry mechanism of coronary vasoconstriction, Arterioscler Thromb Vasc Biol, 1999;19:1034–40.


34. Murphy JG, Khalil RA, Decreased [Ca(2+)](i) during inhibition of coronary smooth muscle contraction by 17beta-estradiol, progesterone, and testosterone, J Pharmacol Exp Ther, 1999;291:44–52.


35. Marin R, Escrig A, Abreu P, Mas M, Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes, Biol Reprod, 1999;61:1012–6.


36. Mäkinen J, Järvisalo MJ, Pöllänen P, et al., Increased carotid atherosclerosis in andropausal middle-aged men, J Am Coll Cardiol,


vasoconstrictors—such as ET-1, thromboxane-A2, and angiotensin-II— that contribute to vascular disease and increase the risk of morbidity and mortality in aging males with CAD. Considerable evidence now suggests that steroid hormones modulate endothelial function in all vascular beds and that their deficiencies promote endothelial dysfunction. Androgens and estrogens produce specific and marked biological effects on endothelial function, as demonstrated by the changes in the endothelial markers of function and dysfunction. Low testosterone and DHT are associated with ultrastructural damage of the aortic endothelium. Also, endothelial dysfunction in men is associated with low plasma testosterone levels, independent of other risk factors, suggesting a protective effect of testosterone on the endothelium. Several studies have corroborated that DHEA and the mineralocorticoid system play a crucial role in CVD, but extensive investigation is necessary to elucidate the mechanisms underlying the vascular effects of MR activation. These observations point to the clinical relevance of steroid hormones in vascular health and to treating patients with hormonal deficiencies with appropriate levels of physiological hormone formulations. Better understanding of the role of steroid hormones in regulating endothelial function is critical for translation of the basic research into treatment of patients with metabolic syndrome, vascular disease, and erectile dysfunction. n


2005;45:1603–8.


37. Malkin CJ, Pugh PJ, Jones RD, et al., Testosterone as a protective factor against atherosclerosis—immunomodulation and influence upon plaque development and stability, J Endocrinol, 2003;178:373–80.


38. Malkin CJ, Pugh PJ, Jones RD, et al., The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men, J Clin Endocrinol Metab, 2004;89:3313–8.


39. Sharpe RM, The roles of oestrogen in the male, Trends Endocrinol Metab, 1998;9:371–7.


40. Lakshman KM, Kaplan B, Travison TG, et al., The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men, J Clin Endocrinol Metab, 2010;95:3955–64.


41. Orwoll E, Lambert LC, Marshall LM, et al., Testosterone and estradiol among older men, J Clin Endocrinol Metab, 2006;91:1336–44.


42. Araujo AB, Travison TG, Leder BZ, et al., Correlations between serum testosterone, estradiol, and sex hormone-binding globulin and bone mineral density in a diverse sample of men, J Clin Endocrinol Metab, 2008;93:2135–41.


43. Gonzales RJ, Walker BR, Kanagy NL, 17β-Estradiol increases nitric oxide-dependent dilation in rat pulmonary arteries and thoracic aorta, Am J Physiol Lung Cell Mol Physiol, 2001;280:L555–64.


44. Sudhir K, Chou TM, Messina LM, et al., Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene, Lancet, 1997;349:1146–7.


45. Lew R, Komesaroff P, Williams M, et al., Endogenous estrogens influence endothelial function in young men, Circ Res, 2003;93:1127–33.


46. Ceccatelli S, Grandison L, Scott RE, et al., Estradiol regulation of nitric oxide synthase mRNAs in rat hypothalamus, Neuroendocrinology, 1996;64:357–63.


47. Nakamura J, Savinov A, Lu Q, Brodie A, Estrogen regulates vascular endothelial growth/permeability factor expression in 7,12- dimethylbenz(a)anthracene-induced rat mammary tumors, Endocrinology, 1996;137:5589–96.


48. Shi J, Simpkins JW, 17 beta-Estradiol modulation of glucose transporter 1 expression in blood-brain barrier, Am J Physiol, 1997;272:E1016–E1022.


49. Shi J, Zhang YQ, Simpkins JW, Effects of 17beta-estradiol on glucose transporter 1 expression and endothelial cell survival following focal ischemia in the rats, Exp Brain Res, 1997;117:200–6.


50. Prevot V, Croix D, Rialas CM, et al., Estradiol coupling to endothelial nitric oxide stimulates gonadotropin-releasing hormone release from rat median eminence via a membrane receptor, Endocrinology, 1999;140:652–9.


51. Ochoa AL, Mitchner NA, Paynter CD, et al., Vascular endothelial growth factor in the rat pituitary: differential distribution and regulation by estrogen, J Endocrinol, 2000;165:483–92.


52. McNeill AM, Zhang C, Stanczyk FZ, et al., Estrogen increases endothelial nitric oxide synthase via estrogen receptors in rat cerebral blood vessels: effect preserved after concurrent treatment with medroxyprogesterone acetate or progesterone, Stroke, 2002;33:1685–91.


US ENDOCRINOLOGY


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84