Published Jul 5, 2013

Fuzhou Wang  


Events in cerebral vessel have long been considered as a leading cause of disability in postmenopausal women with the physiological changes in expression and secretion of sex hormones. Hormone replacement therapy (HRT) emerged as a supplementary therapeutic strategy for them with the potential risk of cerebrovascular accidents. Epidemiological and genetic data showed that an interrelationship exists between hormone replacement and cerebrovascular disorders. Many animal experiments and clinical observations produced different results: these varied from positive to negative. Furthermore, recent studies could not identify the particular hormone, estrogen or progesterone that is more beneficial than the other. Here we summarize the two hormones’ effects on cerebrovascular diseases; associated epidemiological and genetic evidences; and the real status of the benefits and risks of HRT as well. We further hypothesize that whatever effects of HRT on brain vessel, hormone receptor expression, density, sensitivity and function may undergo alteration to varying extents, i.e. receptor plasticity gives rise to the receptor remodeling in postmenopausal older women, this may terminally produce the unwelcome effects.



Cerebrovascular Disease, Hormone Replacement Therapy, Estrogen, Progesterone, Inflammation, Lipopolysaccharide

Supporting Agencies

This work is supported by the National Natural Scientific Foundation of China (NSFC, 30901397, 81271242); Nanjing Medical University Grant for Science & Technology Development (08NMUZ-033); Nanjing Municipal Young Scientist Grant (201208009); and Nanjing Municipal Developmental Key Grant of Medical Science (ZKX10018).

1. Burke D, Wissel J, Donnan GA. Pathophysiology of spasticity in stroke. Neurology 2013; 80: S20-6.

2. Chen PH, Gao S, Wang YJ, Xu AD, Li YS, Wang D. Classifying Ischemic Stroke, from TOAST to CISS. CNS Neurosci Ther 2012;18: 452-6.

3. Norrving B, Kissela B. The global burden of stroke and need for a continuum of care. Neurology 2013;80: S5-12.

4. Della-Morte D, Guadagni F, Palmirotta R, Testa G, Caso V, Paciaroni M, Abete P, Rengo F, Ferroni P, Sacco RL, Rundek T. Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments. Pharmacogenomics 2012; 13: 595-613.

5. Yamamoto Y, Craggs L, Baumann M, Kalimo H, Kalaria RN. Review: molecular genetics and pathology of hereditary small vessel diseases of the brain. Neuropathol Appl Neurobiol 2011; 37: 94-113.

6. Arboleda-Velasquez JF, Manent J, Lee JH, Tikka S, Ospina C, Vanderburg CR, Frosch MP, Rodríguez-Falcón M, Villen J, Gygi S, Lopera F, Kalimo H, Moskowitz MA, Ayata C, Louvi A, Artavanis-Tsakonas S. Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci USA 2011; 108: E128-35.

7. Romão EA, Lourenço CM, Júnior WM, Rolfs A, Muñoz V, Vieira Neto OM, Dantas M, Silva GE, Costa RS. What lies beneath: Fabry nephropathy in a female patient with severe cerebrovascular disease. Clin Nephrol 2013; 79: 330-4.

8. Parlakis SG, Phillips PC, Dimauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: a distinctive clinical syndrome. Ann Neurol 1984; 16: 481-8.

9. Flanagan JM, Sheehan V, Linder H, Howard TA, Wang YD, Hoppe CC, Aygun B, Adams RJ, Neale GA, Ware RE. Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia. Blood 2013; 121: 3237-45.

10. DiCocco JM, Fabian TC, Emmett KP, Magnotti LJ, Zarzaur BL, Khan N, Kelly JM, Croce MA. Functional outcomes following blunt cerebrovascular injury. J Trauma Acute Care Surg 2013; 74: 955-60.

11. Unsworth CA. Selection for rehabilitation: acute care discharge patterns for stroke and orthopaedic patients. Int J Rehabil Res 2001; 24: 103-14.

12. Collin C, Wade DT, Davis S, Horne V. The Barthel ADL Inndex: a reliability study. Int Disabil Stud 1988; 10: 61-3.

13. Dimyan MA, Cohen LG. Neuroplasticity in the context of motor rehabilitation after stroke. Nat Rev Neurol 2011; 7: 76-85.

14. Gross BA, Du R. Cerebrovascular neurosurgery 2011. J Clin Neurosci 2012; 19: 1344-7.

15. Debert CT, Ide K, Poulin MJ. Effects of estrogen and progesterone on cerebrovascular responses to euoxic hypercapnia in women. Climacteric 2012; 15: 621-31.

16. Sayeed I, Guo Q, Hoffman SW, Stein DG. Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion. Ann Emerg Med 2006; 47: 381-9.

17. Cerrantes M, Gonzalez-Vidal MD, Ruelas R, Escobar A, Moralí G. Neuroprotective effects of progesterone on damage elicited by acute global cerebral ischemia in neurons of the caudate nucleus. Arch Med Res 2002; 33: 6-14.

18. Krause DN, Duckles SP, Pelligrino DA. Influence of sex steroid hormones on cerebrovascular function. J Appl Physiol 2006; 101: 1252-61.

19. Gibson CL, Murphy SP. Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice. J Cereb Blood Flow Metab 2004; 24: 805-13.

20. Murphy SJ, Littleton-Kearney MT, Hurn PD. Progesterone administration during reperfusion, but not preischemia alone, reduces injury in ovariectomized rats. J Cereb Blood Flow Metab 2002; 22: 1181-8.

21. Murphy SJ, Traystman RJ, Hurn PD. Progesterone exacerbates striatal stroke injury in progesterone-deficient female animals. Stroke 2000; 31: 1173-8.

22. Burkman RT. Hormone replacement therapy. Current controversies. Minerva Ginecol 2003; 55: 107-16.

23. Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update 2006; 12: 169-78.

24. Herson PS, Koerner IP, Hurn PD. Sex, sex steroids, and brain injury. Semin Reprod Med 2009; 27: 229-39.

25. Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma 2000; 17: 367-88.

26. Patkar S, Farr TD, Cooper E, Dowell FJ, Carswell HV. Differential vasoactive effects of oestrogen, oestrogen receptor agonists and selective oestrogen receptor modulators in rat middle cerebral artery. Neurosci Res 2011; 71: 78-84.

27. Cimarosti H, Siqueira IR, Zamin LL, Nassif M, Balk R, Frozza R, Dalmaz C, Netto CA, Salbego C. Neuroprotection and protein damage prevention by estradiol replacement in rat hippocampal slices exposed to oxygen-glucose deprivation. Neurochem Res 2005; 30: 583-9.

28. Sumino H, Ichikawa S, Kasama S, Kumakura H, Takayama Y, Sakamaki T, Kurabayashi M. . Effect of transdermal hormone replacement therapy on carotid artery wall thickness and levels of vascular inflammatory markers in postmenopausal women. Hypertens Res 2005; 28: 579-84.

29. Gordon KB, Macrae IM, Carswell HVO. Effects of 17beta-oestradiol on cerebral ischaemic damage and lipid peroxidation. Brain Res 2005; 1036: 155-62.

30. Yong Y, Xie HJ, Zhang YF, Yang QD, Liao DF, Yang HL, Yan PK, Liu ZJ. 17beta-estradiol potentiates ischemia–reperfusion injury in diabetic ovariectomized female rats. Brain Res 2005; 1054: 192-9.

31. Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 2009; 30: 201-11.

32. Stein DG. Brain damage, sex hormones and recovery: a new role for progesterone and estrogen? Trends Neurosci 2001; 24: 386-91.

33. Moralí G, Letechipía-Vallejo G, López-Loeza E, Montes P, Hernández-Morales L, Cervantes M. Post-ischemic administration of progesterone in rats exerts neuroprotective effects on the hippocampus. Neurosci Lett 2005; 382: 286-90.

34. Gibson CL, Constantin D, Prior MJW, Bath PM, Murphy SP. Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia. Exp Neurol 2005; 193: 522-30.

35. Thomas T, Rhodin J, Clark L, Garces A. Progestins initiate adverse events of menopausal estrogen therapy. Climacteric 2003; 6: 293-301.

36. Pelligrino DA, Galea E. Estrogen and cerebrovascular physiology and pathophysiology. Jpn J Pharmacol 2001; 86: 137-58.

37. Singh M, Simpkins JW, Simpkins JW, Bimonte-Nelson HA, Bimonte-Nelson HA, Brinton RD, Brinton RD. Window of opportunity for estrogen and progestin intervention in brain aging and Alzheimer's disease. Brain Res 2013; 1514: 1-2.

38. Stork S, von Schacky C, Angerer P. The effect of 17beta-estradiol on endothelial and inflammatory markers in postmenopausal women: a randomized controlled trial. Atherosclerosis 2002; 165: 301-7.

39. Losem-Heinrichs E, Görg B, Redecker C, Schleicher A, Witte OW, Zilles K, Bidmon HJ. 1alpha,25-Dihydroxy-vitamin D3 in combination with 17beta-estradiol lowers the cortical expression of heat shock protein-27 following experimentally induced focal cortical ischemia in rats. Arch Biochem Biophys 2005; 439: 70-9.

40. Xing D, Miller A, Novak L, Schleicher A, Witte OW, Zilles K, Bidmon HJ. Estradiol and progestins differentially modulate leukocyte infiltration after vascular injury. Circulation 2004; 109: 234-41.

41. Liu R, Wen Y, Perez E, Wang X, Day AL, Simpkins JW, Yang SH. 17beta-Estradiol attenuates blood–brain barrier disruption induced by cerebral ischemia–reperfusion injury in female rats. Brain Res 2005; 1060: 55-61.

42. Sunday L, Tran MM, Krause DN, Duckles SP. Estrogen and progesterones differentially modulate vascular proinflammatory factors. Am J Physiol Endocrinol Metab 2006; 291: E261-7.

43. Pan Y, Acharya AB, Patrick PH, Patrick PH, Oliver D, Morley JE. Effect of testosterone on functional recovery in a castrate male rat stroke model. Brain Res 2005; 1043: 195-204.

44. Brass LM. Hormone replacement therapy and stroke clinical trials review. Stroke 2004; Suppl I: 2644-7.

45. Bath PMW, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. Br Med J 2005; 330: 342-5.

46. Li C, Engstrom G, Hedblad B, Berglund G, Janzon L. Risk of stroke and hormone replacement therapy. A prospective cohort study. Maturitas 2006; 54: 11-8.

47. de Lecinana MA, Egido JA, Fernandez C, Martínez-Vila E, Santos S, Morales A, Martínez E, Pareja A, Alvarez-Sabín J, Casado I; PIVE Study Investigators of the Stroke Project of the Spanish Cerebrovascular Diseases Study Group. Risk of ischemic stroke and lifetime estrogen exposure. Neurology 2007; 68: 33-8.

48. Heikkinen J, Vaheri R, Timonen U. A 10-year follow-up of postmenopausal women on long-term continuous combined hormone replacement therapy: Update of safety and quality-of-life findings. J Br Menopause Soc 2006; 12: 115-25.

49. Couzin J. The great estrogen conundrum. Science 2003; 302: 1136-8.

50. Wickelgren I. Brain researchers try to salvage estrogen treatment. Science 2003; 302: 1138-9.
How to Cite
Wang, F. (2013). The Hormone Replacement Therapy in Cerebrovascular Diseases: Is the Receptor Remodeled?. Science Insights, 1(1), 9-15. https://doi.org/10.15354/si.13.re001