Robert M Levin1,2*,
Catherine Schuler1, Robert E Leggett1
1Stratton VA Medical Center, Albany, NY, USA
2Albany College of Pharmacy and Health
Sciences, Albany, NY, USA
*Corresponding
author: Robert
M Levin, Senior Research Career Scientist, Stratton VA Medical Center, Albany,
NY 12208, USA. Tel: +1-5183690173; Email: Robert.levin2@va.gov
Received Date: 20 September, 2018; Accepted Date: 05 October, 2018; Published
Date: 10 October, 2018
Citation: Levin RM, Schuler C, Leggett RE (2018) Cyclical Estrogen as a Major Etiology of Interstitial Cystitis: A Theory and Review. J Urol Ren Dis 2018: 1125. DOI: 10.29011/2575-7903.001125
1. Abstract
Interstitial Cystitis / Pelvic Bladder Syndrome (IC/PBS) is a lower urinary tract dysfunction characterized by urgency, frequency, and pain upon bladder distension. Although there is no widely accepted etiology of IC, most researchers and clinicians believe it involves the breakdown of the mucosal permeability barrier and the penetration of solutes from the urine into the bladder mucosa and muscle, causing sensory neuro-inflammation and other cellular and sub-cellular pathologies resulting in IC/PBS. Our hypothesis is: Cyclical Estrogen is a Major Etiological factor of Interstitial Cystitis / Pelvic Bladder Syndrome: The menstrual cycle is characterized by cyclical changes in circulating estrogen. We completed two rabbit studies in which circulating estrogen was cycled between low estrogen (following ovariectomy) and high estrogen (following implantation of slow-release estrogen tablet). Circulating estrogen concentrations were cycled at two-week intervals (mimicking the menstrual cycle) for 4 complete cycles; ending either after a low estrogen period or after a high estrogen period. These rabbit studies on the effect of cyclical estrogen demonstrate that during low estrogen periods, blood flow, PO2, and blood vessel density decrease; mucosa thickness decreases, mucosal and smooth muscle hypoxia increase; free radical generation and oxidative stress increase; and the volume fraction of smooth muscle / collagen decreases. During high estrogen periods all responses to low estrogen return back to or toward normal. This time frame would make it very likely that these same changes occur in women during the normal menstrual cycle; which provides direct support of our hypothesis. Additional support comes from several clinical papers that show: 1) Estrogen variations during the menstrual cycle significantly affect bladder pain in IC/PBS patients. 2) On a cellular level, estrogen directly modulates pain mechanisms. And 3) if one suppresses circulating estrogen, or increases circulating estrogen continually, IC/PBS pain symptoms are relieved but return when cyclical estrogen is restored.
Although the above studies provide direct support that cyclical estrogen has marked cyclical effects on bladder smooth muscle and mucosal blood flow, nerve density, oxidative stress, hypoxia, and structure (including hypertrophy, hyperplasia, apoptosis, and smooth muscle / collagen ratios). At this time there is no direct evidence that the pain associated with IC/PBS is directly related to either low or high estrogen periods.
2. Keywords: Bladder; Estrogen; Interstitial Cystitis; Ischemia; Oxidative Stress; Painful Bladder Syndrom; Rabbits; Reperfusion
Figure 1: Schematic of the
menstrual cycle showing the circulating estrogen, uteral hypertrophy,
follicular and luteal phases, this figure is a modified free clip-art schematic
Figure 2: Effect of cyclic
estrogen on compliance and volume fraction of smooth muscle: Each bar is the
mean +/- SEM of 4 rabbits. Ovx = ovariectomy; Ovx + E = ovariectomy plus
continuous estrogen; Cyclic – E = cyclical estrogen ending at the end of a low
estrogen period. Cyclic + E = cyclical estrogen ending at the end of a high
estrogen period. * = Significantly different from control; x = significantly
different.
Figure 3: Effect of cyclic
estrogen on blood flow and blood vessel density: Each bar is the mean +/- SEM
of 4 rabbits. * = Significantly different from control; x = significantly
different from Ovx; ** = significantly different from Ovx + E; xx =
significantly different from Cyclic – E; p < 0.05.
Figure 4: Effect of cyclic
estrogen on the Oxidative Stress Products: Each bar is the mean +/- SEM of 4
rabbits. * = Significantly different from control; x = significantly different
from Ovx; ** = significantly different from Ovx + E; xx = significantly
different from Cyclic – E; p < 0.05.
Figure 5: Effect of cyclic
estrogen on in
vitro contractile responses: Each bar is the mean +/- SEM of 4
rabbits. * = Significantly different from control; x = significantly different
from Ovx; ** = significantly different from Ovx + E; xx = significantly
different from Cyclic – E; p < 0.05.
1. Patnaik SS, Lagana AS, Vitale SG, Butticè S, Noventa M, et al. (2017) Etiology, pathophysiology and biomarkers of interstitial cystitis/painful bladder syndrome. Archives of gynecology and obstetrics 295: 1341-1359.
2. Kim HJ (2016) Update on the Pathology and Diagnosis of Interstitial Cystitis/Bladder Pain Syndrome: A Review. International neurourology journal 20: 13-17.
3. Offiah I, McMahon SB, O'Reilly BA (2013) Interstitial cystitis/bladder pain syndrome: diagnosis and management. International urogynecology journal 24: 1243-1256.
4. McLennan MT (2014) Interstitial cystitis: epidemiology, pathophysiology, and clinical presentation. Obstetrics and gynecology clinics of North America 41: 385-395.
5. Parsons M, Toozs-Hobson P (2005) The investigation and management of interstitial cystitis. The journal of the British Menopause Society 11: 132-139.
6. Vesela R, Aronsson P, Andersson M, Wsol V, Tobin G (2012) The potential of non-adrenergic, non-cholinergic targets in the treatment of interstitial cystitis/painful bladder syndrome. J Physiol Pharmacol 63: 209-216.
7. Hunter C, Dave N, Diwan S, Deer T (2013) Neuromodulation of pelvic visceral pain: review of the literature and case series of potential novel targets for treatment. Pain Pract 13: 3-17.
8. Adams K, Denman MA (2011) Bladder pain syndrome: a review. Female Pelvic Med Reconstr Surg 17: 279-289.
9. Mahmoud MS (2011) Bladder pain syndrome/interstitial cystitis: a reappraisal for the clinician. J Reprod Med 56: 405-409.
10. Teichman JM, Moldwin R (2007) The role of the bladder surface in interstitial cystitis/painful bladder syndrome. Can J Urol 14: 3599-3607.
11. Parsons CL, Greene RA, Chung M, Stanford EJ, Singh G (2005) Abnormal urinary potassium metabolism in patients with interstitial cystitis. J Urol 173: 1182-1185.
12. Davis NF, Brady CM, Creagh T (2014) Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and evidence-based treatment options. European journal of obstetrics, gynecology, and reproductive biology 175: 30-37.
13. Tirlapur SA, Kuhrt K, Chaliha C, Ball E, Meads C, et al. (2013) The 'evil twin syndrome' in chronic pelvic pain: a systematic review of prevalence studies of bladder pain syndrome and endometriosis. Int J Surg 11: 233-237.
14. Portman DJ, Gass ML, Vulvovaginal Atrophy Terminology Consensus Conference P (2014) Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause 21: 1063-1068.
15. Portman DJ, Gass ML, Vulvovaginal Atrophy Terminology Consensus Conference P (2014) Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. The journal of sexual medicine 11: 2865-2872.
16. Nappi RE, Davis SR (2012) The use of hormone therapy for the maintenance of urogynecological and sexual health post WHI. Climacteric: the journal of the International Menopause Society 15: 267-274.
17. Gardella B, Iacobone AD, Porru D, Musacchi V, Dominoni M, et al. (2015) Effect of local estrogen therapy (LET) on urinary and sexual symptoms in premenopausal women with interstitial cystitis/bladder pain syndrome (IC/BPS). Gynecological endocrinology: the official journal of the International Society of Gynecological Endocrinology 31: 828-832.
18. Gardella B, Porru D, Nappi RE, Dacco MD, Chiesa A, et al. (2011) Interstitial cystitis is associated with vulvodynia and sexual dysfunction--a case-control study. The journal of sexual medicine 8: 1726-1734.
19. Powell-Boone T, Ness TJ, Cannon R, Lloyd LK, Weigent DA, et al. (2005) Menstrual cycle affects bladder pain sensation in subjects with interstitial cystitis. The Journal of urology 174: 1832-1836.
20. Caruso S, Cianci S, Vitale SG, Matarazzo MG, Amore FF, et al. (2017) Effects of ultralow topical estriol dose on vaginal health and quality of life in postmenopausal women who underwent surgical treatment for pelvic organ prolapse. Menopause 24: 900-907.
21. Malone L, Schuler C, Leggett RE, Levin RM (2014) Effect of estrogen and ovariectomy on response of the female rabbit urinary bladder to two forms of in vitro oxidative stress. International urogynecology journal 25: 791-798.
22. Juan YS, Mannikarottu A, Kogan BA, Leggett RE, Whitbeck C, et al. (2008) The effect of low-dose estrogen therapy on ovariectomized female rabbit bladder. Urology 71: 1209-1213.
23. Lin AD, Levin RM, Kogan BA, Whitbeck C, Leggett RE, et al. (2006) Alteration of contractile and regulatory proteins in estrogen-induced hypertrophy of female rabbit bladder. Urology 68: 1139-1143.
24. Lin AD, Mannikarottu A, Kogan BA, Whitbeck C, Chichester P, et al. (2006) Estrogen induces angiogenesis of the female rabbit bladder. The Journal of endocrinology 190: 241-246.
25. Aikawa K, Sugino T, Matsumoto S, Chichester P, Whitbeck C, et al. (2003) The effect of ovariectomy and estradiol on rabbit bladder smooth muscle contraction and morphology. The Journal of urology 170: 634-637.
26. Lin WY, Radu F, Schuler C, Leggett RE, Mannikarottu A, et al. (2008) The effect of ovariectomy and oestrogen therapy on the free fatty acid content, endogenous lipase activity, and phospholipid content of the rabbit urinary bladder. BJU international 102: 885-889.
27. Imamov O, Yakimchuk K, Morani A, Schwend T, Wada-Hiraike O, et al. (2007) Estrogen receptor beta-deficient female mice develop a bladder phenotype resembling human interstitial cystitis. Proc Natl Acad Sci U S A 104: 9806-9809.
28. Stein PC, Ha TJ, Parsons CL (2001) Estrogenic regulation of HSP90 kD synthesis in rat urinary bladder. Urol Res 29: 338-344.
29. Hypolite JA, Longhurst PA, Gong C, Briscoe J, Wein AJ, et al. (1993) Metabolic studies on rabbit bladder smooth muscle and mucosa. Molecular and cellular biochemistry 125: 35-42.
30. Levin RM, Haugaard N, Hypolite JA, Wein AJ, Buttyan R (1999) Metabolic factors influencing lower urinary tract function. Experimental physiology 84: 171-194.
31. Chughtai B, Mannikarott A, Levin RM, Chichester P, Schuler C, et al. (2008) Ischemic Etiology of Incontinence in Women: A Theory and a Review. The Open Urology and Nephrology Journal 1: 1-8.
32. Parsons CL (1996) Interstitial cystitis. Int J Urol 3: 415-420.
33. Parsons CL (2002) Interstitial cystitis: epidemiology and clinical presentation. Clin Obstet Gynecol 45: 242-249.
34. Parsons CL, Boychuk D, Jones S, Hurst R, Callahan H (1990) Bladder surface glycosaminoglycans: an epithelial permeability barrier. The Journal of urology 143: 139-142.
35. Nickel JC, Downey J, Morales A, Emerson L, Clark J (1998) Relative efficacy of various exogenous glycosaminoglycans in providing a bladder surface permeability barrier. J Urol 160: 612-614.
36. Lilly JD, Parsons CL (1990) Bladder surface glycosaminoglycans is a human epithelial permeability barrier. Surgery, gynecology & obstetrics 171: 493-496.
37. Ruggieri MR, Hanno PM, Levin RM (1985) Further characterization of bacterial adherence to urinary bladder mucosa: comparison with adherence to anion exchange resin. The Journal of urology 134: 1019-1023.
38. Ruggieri MR, Hanno PM, Levin RM (1987) Reduction of bacterial adherence to catheter surface with heparin. The Journal of urology 138: 423-426.
39. Ruggieri MR, Hanno PM, Samadzadeh S, Johnson EW, Levin RM (1986) Heparin inhibition of increased bacterial adherence following overdistension, ischemia and partial outlet obstruction of the rabbit urinary bladder. The Journal of urology 136: 132-135.
40. Parsons CL (1994) The therapeutic role of sulfated polysaccharides in the urinary bladder. Urol Clin North Am 21: 93-100.
41. Zderic SA LRM, Wein AJ (1996) Voiding Function and Dysfunction: A Relevant Anatomy, Physiology, and Pharmacology, and molecular biology. In: J. Y. Gillenwater JTG, S. S. Howards and J. D. Duckett, ed. Adult and Pediatric Urology. Chicago: Mosby Year Book Medical Publishers 1996: 1159-1219.
42. Jost SP, Gosling JA, Dixon JS (1990) The fine structure of Brunn's nests in human bladder urothelium. J Submicrosc Cytol Pathol 22: 203-210.
43. Hossler FE, Monson FC (1995) Microvasculature of the rabbit urinary bladder. Anat Rec 243: 438-448.
44. Hohlbrugger G, Lentsch P (1985) Intravesical ions, osmolality and pH influence the volume pressure response in the normal rat bladder, and this is more pronounced after DMSO exposure. Eur Urol 11: 127-130.
45. Moldwin RM, Sant GR (2002) Interstitial cystitis: a pathophysiology and treatment update. Clin Obstet Gynecol 45: 259-272.
46. Hanno P, Levin RM, Monson FC, Teuscher C, Zhou ZZ, et al. (1990) Diagnosis of interstitial cystitis. The Journal of urology 143: 278-281.
47. Sant GR (2002) Etiology, pathogenesis, and diagnosis of interstitial cystitis. Rev Urol 1: S9-S15.
48. Sant GR, Hanno PM (2001) Interstitial cystitis: current issues and controversies in diagnosis. Urology 57: 82-88.
49. Ruggieri MR, Hanno PM, Levin RM (1984) The effects of heparin on the adherence of five species of urinary tract pathogens to urinary bladder mucosa. Urological research 12: 199-203.
50. Monson FC, Wein AJ, McKenna BA, Whitmore K, Levin RM (1991) Indigocarmine as a quantitative indicator of urothelial integrity. The Journal of urology 145: 842-845.
51. Tammela T, Wein AJ, Monson FC, Levin RM (1993) Urothelial permeability of the isolated whole bladder. Neurourology and urodynamics 12: 39-47.
52. Irwin P, Galloway NT (1993) Impaired bladder perfusion in interstitial cystitis: a study of blood supply using laser Doppler flowmetry. J Urol 149: 890-892.
53. Pontari MA, Hanno PM, Ruggieri MR (1999) Comparison of bladder blood flow in patients with and without interstitial cystitis. J Urol 162: 330-334.
54. Lin AT, Chen MT, Yang CH, Chang LS (1995) Blood flow of the urinary bladder: effects of outlet obstruction and correlation with bioenergetic metabolism. Neurourol Urodyn 14: 285-292.
55. Bajory Z, Hutter J, Krombach F, Messmer K (2002) Microcirculation of the urinary bladder in a rat model of ischemia-reperfusion-induced cystitis. Urology 60: 1136-1140.
56. Kozlowski R, Siroky MB, Krane RJ, Azadzoi KM (2002) Regulation of blood flow and microcirculation resistance in rabbit bladder. J Urol 168: 1608-1614.
57. Batra S, Bjellin L, Sjogren C, Iosif S, Widmark E (1986) Increases in blood flow of the female rabbit urethra following low dose estrogens. J Urol 136: 1360-1362.
58. Batra S, Bjellin L, Iosif S, Martensson L, Sjogren C (1985) Effect of oestrogen and progesterone on the blood flow in the lower urinary tract of the rabbit. Acta Physiol Scand 123: 191-194.
59. Parekh MH, Chichester P, Lobel RW, Aikawa K, Levin RM (2004) Effects of castration on female rabbit bladder physiology and morphology. Urology 64: 1048-1051.
60. Badger WJ, Whitbeck C, Kogan B, Chichester P, Levin RM (2006) The immediate effect of castration on female rabbit bladder blood flow and tissue oxygenation. Urologia internationalis 76: 264-268.
61. Mannikarottu A, Kogan, B, Levin, R (2005) Ischemic etiology of obstructive bladder dysfunction: A review. Recent Res. Devel. Mol. Cell Biochem 2: 15-34.
62. Rehfuss A, Schuler C, Maxemous C, Leggett RE, Levin RM (2010) Cyclical estrogen and free radical damage to the rabbit urinary bladder. International urogynecology journal 21: 489-494.
63. Li S, Hydery T, Juan Y, Lin WY, Kogan B, et al. (2009) The effect of 2- and 4-week ovariectomy on female rabbit urinary bladder function. Urology 74: 691-696.
64. Fitzpatrick B, Schuler C, Leggett RE, Levin RM (2012) Nitrotyrosine Density of Rabbit Urinary Bladder Muscle and Mucosa Measured via Western Blotting and 96-Well Plate Analysis. ISRN urology 2012.
65. Juan YS, Lin WY, Kalorin C, Kogan BA, Levin RM, et al. (2007) The effect of partial bladder outlet obstruction on carbonyl and nitrotyrosine distribution in rabbit bladder. Urology 70: 1249-1253.
66. Juan YS, Mannikarottu A, Schuler C, Lin WY, Huang CH, et al. (2008) The immediate effect of nitric oxide on the rabbit bladder after ovariectomy. Nitric oxide: biology and chemistry19: 289-294.
67. Nichol P, Lee L, Parekh MH, Levin RM, Hass MA (2001) The effects of ovariectomy on and prostaglandin levels in the rabbit urinary bladder. Urology 57: 112.
68. Chuang SM, Long CY, Lin RJ, Liu KM, Levin RM, et al. (2013) Protective effects of estrogen on ischemia/reperfusion-induced bladder dysfunction in female rabbits. Menopause 20: 209-217.
69. Onal B, Levin RM, Kogan BA, Guven A, Leggett RE, et al. (2007) Novel alterations in superoxide dismutase and catalase activities in the female rabbit bladder subjected to hormonal manipulations. International urology and nephrology 39: 1049-1054.
70. Levin RM, O'Connor LJ, Leggett RE, Whitbeck C, Chichester P (2003) Focal hypoxia of the obstructed rabbit bladder wall correlates with intermediate decompensation. Neurourology and urodynamics 22: 156-163.
71. Levin RM, Whitmore K, Monson FC, Witkowski BA, Ruggieri M (1990) Trypan blue as an indicator of urothelial integrity. Neurourol Urodyn 9: 269-280.
72. Hass MA, Nichol P, Lee L, Levin RM (2009) Estrogen modulates permeability and prostaglandin levels in the rabbit urinary bladder. Prostaglandins, leukotrienes, and essential fatty acids 80: 125-129.
73. Slayden OD (2014) Cyclic remodeling of the nonhuman primate endometrium: a model for understanding endometrial receptivity. Seminars in reproductive medicine 32: 385-391.
74. Maybin JA, Critchley HO (2015) Menstrual physiology: implications for endometrial pathology and beyond. Human reproduction update 21: 748-761.
75. Lucan L, Stamatian F, Lucan V, Tabaran AF (2013) Cell proliferation and apoptosis in urinary bladder urothelium of rats following ovariectomy and chronic estrogen replacement therapy. Clujul medical 86: 27-30.
76. Yu Y, Shen Z, Zhou X, Chen S (2009) Effects of steroid hormones on morphology and vascular endothelial growth factor expression in female bladder. Urology 73: 1210-1217.
77. Palmieri K, Mannikarottu AS, Chichester P, Kogan B, Leggett RE, et al. (2007) The effects of cyclical oestrogen on bladder and urethral structure and function. BJU international 99: 171-176.
78. Sadler KE, Stratton JM, Kolber BJ (2014) Urinary bladder distention evoked visceromotor responses as a model for bladder pain in mice. Journal of visualized experiments 2014.
79. Erickson DR, Davies MF (1998) Interstitial cystitis. International urogynecology journal and pelvic floor dysfunction 9: 174-183.
80. Akiyama Y, Homma Y, Maeda D (2018) Pathology and terminology of interstitial cystitis/bladder pain syndrome: A review. Histology and histopathology 2018: 18028.
81. Champaneria R, D'Andrea RM, Latthe PM (2016) Hormonal contraception and pelvic floor function: a systematic review. International urogynecology journal 27: 709-722.
82. Juan YS, Chuang SM, Kogan BA, Mannikarottu A, Huang CH, et al. (2009) Effect of ischemia/reperfusion on bladder nerve and detrusor cell damage. International urology and nephrology 41: 513-521.
83. Bratslavsky G, Kogan BA, Matsumoto S, Aslan AR, Levin RM (2003) Reperfusion injury of the rat bladder is worse than ischemia. The Journal of urology 170: 2086-2090.
84. Greenland JE, Hvistendahl JJ, Andersen H, et al. (2000) The effect of bladder outlet obstruction on tissue oxygen tension and blood flow in the pig bladder. BJU international 85: 1109-1114.
85. Warren JW, Clauw DJ, Wesselmann U, Langenberg PW, Howard FM, et al. (2011) Sexuality and reproductive risk factors for interstitial cystitis/painful bladder syndrome in women. Urology 77: 570-575.
86. Lin WY, Mannikarottu A, Li S, Juan YS, Schuler C, et al. (2011) Correlation of in vivo bladder blood flow measurements with tissue hypoxia. World journal of urology 29: 165-170.
87. Greenland JE, Brading AF (2001) The effect of bladder outflow obstruction on detrusor blood flow changes during the voiding cycle in conscious pigs. The Journal of urology 165: 245-248.
88. Levin RM, Schuler C, Leggett RE, Callaghan C, Maknuru S (2013) Partial outlet obstruction in rabbits: duration versus severity. International journal of urology: official journal of the Japanese Urological Association 20: 107-114.
89. Callaghan CM, Johnson A, Neumann P, Leggett RE, Schuler C, et al. (2013) The effect of partial outlet obstruction on calpain and phospholipase-2 activities: analyzed by severity and duration. Molecular and cellular biochemistry 381: 217-220.
90. Chaban V (2015) Visceral pain modulation in female primary afferent sensory neurons. Current trends in neurology 9: 111-114.
91. Lentz GM, Bavendam T, Stenchever MA, Miller JL, Smalldridge J (2002) Hormonal manipulation in women with chronic, cyclic irritable bladder symptoms and pelvic pain. American journal of obstetrics and gynecology 186: 1268-1271.
review article