Non-reproductive system effects of progesterone and its non-selective antagonists mifepristone
Keywords:progesterone, mifepristone, cardiovascular system, arrhythmia
Analysis of the data of progesterone effect on cardiovascular system, bone and muscle function, and nervous system were presented in the paper. Possible effects of progesterone activity inhibition are discussed. Physiological progesterone concentration characterized by its protective effect on cardiovascular system. It was demonstrated in the literature that progesterone significantly influence repolarization process in cardiomyocytes and shorten QT interval. At the same time QT-interval prolongation is a strong marker of the risk of arrhythmia.
Also, the hormone decreases apoptosis of cardiomyocytes and increase NO production. Different effects of progesterone on lipid metabolism are described in the paper. Data concerning progesterone influence on central nervous system and its ability to regulate human behavior and influence on the risk of depression and cognitive disorders are given in this review. Progesterone protection effects in patient survived stork are known now. Anabolic effect of the hormone and its ability to increase muscle mass are highly important to maintain women health.
Analysis of the data of both branch and clinical studies suggests that the drug interacts with the progesterone receptor and glucocorticoid and less with the androgen receptors (to testosterone). The data showed lack evidence of safety profile for long-term use of mifepristone, the duration of most clinical trials do not exceed 6 months, and more often presented in a dose of 5–10 mg per day. Also, two clinical cases of arrhythmia onset during long-term therapy with mifepristone due to leiomyoma are given to illustrate possible side effects. Without a doubt, scientific data about the safety of long-term use of mifepristone demonstrate the necessity of randomized clinical trials to study possible side effects of the drug on cardiovascular system, bone, muscles and nerves system as well as its metabolic effects.
- Ablewska, U., Jankowski, K., Rzewuska, E., et al. “A levels of endogenous gonadal hormones and their relationship with selected coronary artery disease risk factors among young women post myocardial infarction.” Acta Biochim Pol 58.3 (2011): 385–9.
- Arbo, B.D., Bennetti, F., Ribeiro, M.F. “Astrocytes as a target for neuroprotection: Modulation by progesterone and dehydroepiandrosterone.” Prog Neurobiol 144 (2016): 27–47. DOI: 10.1016/j.pneurobio.2016.03.010
- Archer, D.F. “Drosperinon and estradiol: a new option for the postmenopausal women.” Climacteric 10.1 (2007): 3–10.
- Armanini, D., Bordin, L., Donà, G., et al. “Polycystic ovary syndrome: Implications of measurement of plasma aldosterone, renin activity and progesterone.” Steroids 77.6 (2012): 655–8.
- Bagaria, M., Suneja, A, Vaid, N.B., et al. “Low-dose mifepristone in treatment of uterine leiomyoma: a randomised double-blind placebo-controlled clinical trial.” Aust N Z J Obstet Gynaecol 49.1 (2009): 77–83. DOI: 10.1111/j.1479-828X.2008.00931.x
- Barsheshet, A., Dotsenko, O., Goldenberg, I. “Genotype-specific risk stratification and management of patients with long QT syndrome.” Ann Noninvasive Electrocardiol 18.6 (2013): 499–509. DOI: 10.1111/anec.12117
- Benagiano, G., Bastianelli, C., Farris, M., Brosens, I. “Selective progesterone receptor modulators: an update.” Expert Opin Pharmacother 15.10 (2014): 1403–15. DOI: 10.1517/14656566.2014.914494
- Boschitsch, E., Mayerhofer, S., Magometschnigg, D. “Hypertension in women: the role of progesterone and aldosterone.” Climacteric 13.4 (2010): 307–13.
- Brown, M.S., Ho, Y.K., Goldstein, J.L. “The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters.” J Biol Chem 255.19 (1980): 9344–52.
- Butler, J.D., Blanchette-Mackie, J., Goldin, E., et al. “Progesterone blocks cholesterol translocation from lysosomes.” J Biol Chem 267.33 (1992): 23797–805.
- Chai, W., Hofland, J., Jansen, P.M., et al. “Steroidogenesis vs. steroid uptake in the heart: do corticosteroids mediate effects via cardiacmineralocorticoid receptors?” J Hypertens 28.5 (2010): 1044–53. DOI: 10.1097/HJH.0b013e328335c381
- Cheng, J., Su, D., Ma, X., Li, H. “Concurrent supplement of estradiol and progesterone reduces the cardiac sensitivity to D,L-sotalol-induced arrhythmias in ovariectomized rabbits.” J Cardiovasc Pharmacol Ther 17.2 (2012): 208–14. DOI: 10.1177/1074248411418972
- Cheng, J., Zhang, J., Ma, X., Su, D. “Frequency-dependent acceleration of cardiac repolarization by progesterone underlying its cardiac protection against drug-induced proarrhythmic effects in female rabbits.” Eur J Pharmacol 689.13 (2012): 172–8. DOI: 10.1016/j.ejphar.2012.05.052
- Cheng, W., Lau, O.D., Abumrad, N.A. “Two antiatherogenic effects of progesterone on human macrophages; inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids.” J Clin Endocrinol Metab 84.1 (1999): 265–71.
- Ciato, D., Mumbach, A.G., Paez-Pereda, M., Stalla, G.K. “Currently used and investigational drugs for Cushing´s disease.” Expert Opin Investig Drugs 26.1 (2017): 75–84. DOI: 10.1080/13543784.2017.1266338
- Cohan, P. “Mifepristone Accelerates HPA Axis Recovery in Secondary Adrenal Insufficiency.” Case Rep Endocrinol (2016): 4709597. DOI: 10.1155/2016/4709597
- Creemers, S.G., Hofland, L.J., Lamberts, S.W., Feelders, R.A. “Cushing’s syndrome: an update on current pharmacotherapy and future directions.” Expert Opin Pharmacother 16.12 (2015): 1829-44. DOI: 10.1517/14656566.2015.1061995
- Day, D.S., Gozansky, W.S., Bell, C., Kohrt, W.M. “Acute sex hormone suppression reduces skeletal muscle sympathetic nerve activity.” Clin Auton Res 21.5 (2011): 339–45. DOI: 10.1007/s10286-011-0127-5
- Dhote, V.V., Balaraman, R. “Gender specific effect of progesterone on myocardial ischemia/ reperfusion injury in rats.” Life Sci 81.3 (2007): 188–97.
- Eisinger, S.H., Bonfiglio, T., Fiscella, K., et al. “Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas.” J Minim Invasive Gynecol 12.3 (2005): 227–33.
- Eisinger, S.H., Meldrum, S., Fiscella, K., et al. “Low-dose mifepristone for uterine leiomyomata.” Obstet Gynecol 101.2 (2003): 243–50.
- Ekenros, L., Papoutsi, Z., Fridén, C., et al. “Expression of sex steroid hormone receptors in human skeletal muscle during the menstrual cycle.” Acta Physiol (Oxf) (2016). DOI: 10.1111/apha.12757
- Feiteiro, J., Mariana, M., Verde, I., Cairrao, E. “Genomic and Nongenomic Effects of Mifepristone at the Cardiovascular Level: A Review.” Reprod Sci (2016). PII: 1933719116671002
- Funder, J.W. “Why are mineralocorticoid receptors so nonselective?” Curr Hypertens Rep 9.2 (2007): 112–216.
- Gaignard, P., Fréchou, M., Schumacher, M., et al. “Progesterone reduces brain mitochondrial dysfunction after transient focal ischemia in male and female mice.” J Cereb Blood Flow Metab 36.3 (2016): 562–8. DOI: 10.1177/0271678X15610338
- Genazzani, A.R., Mannella, P., Simoncini, T. “Drosperinon and its antialdosteron proprieties.” Climacteric 10.1 (2007): 11–18.
- Gibson, C.L., Bath P.M. “Feasibility of progesterone treatment for ischaemic stroke.” J Cereb Blood Flow Metab 36.3 (2016): 487–91. DOI: 10.1177/0271678X15616782
- Girdler, S.S., Klatzkin, R. “Neurosteroids in the context of stress: implications for depressive disorders.” Pharmacol Ther 116.1 (2007): 125–39. DOI:10.1016/j.pharmthera.2007.05.006
- Guennoun, R., Labombarda, F., Gonzalez Deniselle, M.C., et al. “Progesterone and allopregnanolone in the central nervous system: response to injury and implication for neuroprotection.” J Steroid Biochem Mol Biol 146 (2015): 48–61. DOI: 10.1016/j.jsbmb.2014.09.001
- Herzog, R., Zendedel, A., Lammerding, L., et al. “Impact of 17beta-estradiol and progesterone on inflammatory and apoptotic microRNA expression after ischemia in a rat model.” J Steroid Biochem Mol Biol (2016). DOI: 10.1016/j.jsbmb.2016.11.018
- Howland, R.H. “Mifepristone as a therapeutic agent in psychiatry.” J Psychosoc Nurs Ment Health Serv 51.6 (2013): 11–4.
- Ingegno, M.D., Money, S.R., Thelmo, W., et al. “Progesterone receptors in the human heart and great vessels.” Lab Invest 59.3 (1988): 353–6.
- Jiang, C., Zuo, F., Wang, Y., et al. “Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke.” Mol Neurobiol (2016). DOI: 10.1007/s12035-015-9651-y
- Kadish, A.H., Greenland, P., Limacher, M.C., et al. “Estrogen and progestin use and the QT interval in postmenopausal women.” Ann Noninvasive Electrocardiol 9.4 (2004): 366–74.
- Kapur, A., Angomchanu, R., Dey, M. “Efficacy of Use of Long-Term, Low-Dose Mifepristone for the Treatment of Fibroids.” J Obstet Gynaecol India 66.1 (2016): 494–8. DOI: 10.1007/s13224-016-0861-7
- Kuebler, J.F., Jarrar, D., Bland, K., et al. “Progesterone administration after trauma and hemorrhagic shock improves cardiovascular responses.” Crit Care Med 31.6 (2003): 1786–93.
- Kuznetsova, N.V., Palchikova, N.A., Selyatitskaya, V.G., Kuzminova, O.I. “Effect of Mifepristone on Corticosteroid Production in Vitro by Adrenal Glands of Rats with Streptozotocin Diabetes.” Bull Exp Biol Med 162.3 (2017): 327–30. DOI: 10.1007/s10517-017-3607-3
- Lobo, R.A., Davis, S.R., de Villiers, T.J., et al. “Prevention of diseases after menopause.” Climacteric 17.5 (2014): 540–56.
- Losert, W., Casals-Stenzel, J., Buse, M. “Progestogens with antimineralocorticoid activity.” Arzneimittelforschung 35.2 (1985): 459–71.
- Metherall, J.E., Waugh, K., Li, H. “Progesterone inhibits cholesterol biosynthesis in cultured cells. Accumulation of cholesterol precursors.“ J Biol Chem 271.5 (1996): 2627–33.
- Minshall, R.D., Pavcnik, D., Browne, D.L., Hermsmeyer, K. “Nongenomic vasodilator action of progesterone on primate coronary arteries.” J Appl Physiol 92.2 (2002): 701–8.
- Morrissy, S., Xu, B., Aguilar, D., et al. “Inhibition of Apoptosis by Progesterone in Cardiomyocytes.” Aging Cell 9.5 (2010): 799–809.
- Nakagawa, M., Ooie, T., Takahashi, N., et al. “Influence of menstrual cycle on QT interval dynamics.” Pacing Clin Electrophysiol 29.6 (2006): 607–13.
- Nakamura, H., Kurokawa, J., Bai, C.X., et al. “Progesterone regulates cardiac repolarization through a nongenomic pathway: an in vitro patch-clamp and computational modeling study.” Circulation 116.25 (2007): 2913–22.
- Odening, K.E., Choi, B.R., Liu, G.X., et al. “Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective.” Heart Rhythm 9.5 (2012): 823–32. DOI: 10.1016/j.hrthm.2012.01.009
- Oelkers, W. “Drospirenone – a new progestogen with antimineralocorticoid activity, resembling natural progesterone.” Eur J Contracept Reprod Health Care 5.3 (2000): 17–24.
- Perez-Alvarez, M.J., Wandosell, F. “Stroke and Neuroinflamation: Role of Sexual Hormones.” Curr Pharm Des 22.10 (2016): 1334–49.
- Riad, F.S., Davis, A.M., Moranville, M.P., Beshai, J.F. “Drug-Induced QTc Prolongation.” Am J Cardiol 119.2 (2017): 280–3. DOI: 10.1016/j.amjcard.2016.09.041
- Rodriguez, I., Kilborn, M.J., Liu, X.K., et al. “Drug-induced QT prolongation in women during the menstrual cycle.” JAMA 285.10 (2000): 1322–6.
- Rudolph, L.M., Cornil, C.A., Mittelman-Smith, M.A., et al. “Actions of Steroids: New Neurotransmitters.” J Neurosci 36.45 (2016): 11449–58.
- Salem, J.E., Alexandre, J., Bachelot, A., Funck-Brentano, C. “Influence of steroid hormones on ventricular repolarization.” Pharmacol Ther (2016). DOI: 10.1016/j.pharmthera.2016.07.005
- Shannon, C.S., Winikoff, B., Hausknecht, R., et al. “Multicenter trial of a simplified mifepristone medical abortion regimen.” Obstet Gynecol 105.2 (2005): 345–51.
- Smith, G.I., Yoshino, J., Reeds, D.N., et al. “Testosterone and progesterone, but not estradiol, stimulate muscle protein synthesis in postmenopausal women.” J Clin Endocrinol Metab 99.1 (2014): 256–65. DOI: 10.1210/jc.2013-2835
- Stein, D.G. “Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials.” Brain Inj 29.11 (2015): 1259–72.
- Wenner, M.M., Stachenfeld, N.S. “Blood pressure and water regulation: understanding sex hormone effects within and between men and women.” J Physiol 590.23 (2012): 5949–61.
- Wittnich, C., Tan, L., Wallen, J., Belanger, M. “Sex differences in myocardial metabolism and cardiac function: an emerging concept.“ Pflugers Arch 465.5 (2013): 719–29. DOI: 10.1007/s00424-013-1232-1
- Xiao, Z.L., Cao, W., Biancani, P., Behar, J. “Nongenomic effects of progesterone on the contraction of muscle cells from the guinea pig colon.” Am J Physiol Gastrointest Liver Physiol 290.5 (2006): G1008–15.
- Yang, X., Zhang, W., Chen, Y., et al. “Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression: the dual pathophysiological roles of progesterone.” Biol Chem 291.29 (2016): 15108–18. DOI: 10.1074/jbc.M116.726737
- Yousuf, S., Atif, F., Sayeed, I., et al. “Neuroprotection by progesterone after transient cerebral ischemia in stroke-prone spontaneously hypertensive rats.” Horm Behav 84 (2016): 29–40. DOI: 10.1016/j.yhbeh.2016.06.002
- Johanssen, S., Allolio, B. “Mifepristone (RU 486) in Cushing’s syndrome.” Eur J Endocrinol 157.5 (2007): 561–9.
- Cadepond, F., Ulmann, A., Baulieu, E.E. “RU486 (mifepristone): mechanisms of action and clinical uses.” Annu Rev Med 48 (1997): 129–56.
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