SUMÁRIO
PERI-MENOPAUSA
4. MATERIAIS E MÉTODOS
7.2. Efeito dos andrógenos na bexiga e uretra de ratas OVX Na bexiga urinária:
§ As contrações induzidas pelo carbacol e EFS foram significativamente reduzidas pela OVX comparado com o grupo Sham;
§ A testosterona restaurou as alterações funcionais observadas na bexiga urinária; § A flutamida alterou significativamente os efeitos protetores da testosterona;
§ Na bexiga urinária, a OVX não modificou a resposta contrátil ao cloreto de cálcio, mas, a pré-incubação de testosterona aumentou significativamente a resposta contrátil ao cloreto de cálcio;
§ A testosterona per se não induz relaxamento na musculatura lisa detrusora e a mesma não modifica o relaxamento da bexiga pela ativação dos receptores β-adrenérgicos. § Não houve diferença significativa na expressão gênica dos receptores muscarínicos (M2/
M3), L-VOCC, AR e 5α-redutase entre os grupos.
§ Os níveis de mRNA do receptor β3-adrenérgico estão reduzidos na OVX e o receptor
GPRC6A e a aromatase não foi detectado na musculatura lisa vesical.
Na uretra:
§ As contrações induzidas pela fenilefrina e CaCl2 foram aumentadas no grupo OVX;
§ A testosterona restaurou as alterações funcionais observadas na uretra; § A flutamida alterou significativamente os efeitos protetores da testosterona; § A testosterona reduziu a hipercontratilidade uretral pelo CaCl2;
§ A OVX não alterou o relaxamento mediado pelo SNP;
§ A testosterona per se não induz relaxamento, porem a pré-incubação do andrógeno potencializa o relaxamento do SNP;
§ Os níveis de mRNA do AR, 5α-redutase, nNOS e L-VOCC aumentaram significativamente na OVX;
§ O receptor α1A-adrenérgico e o receptor GPRC6A e a aromatase não foram detectados
8. CONCLUSÃO
Concluímos que os andrógenos promovem um padrão distinto de resposta em condições fisiológicas e de OVX. Em condições fisiológicas, os andrógenos (testosterona e 5α-DHT) reduzem a contração induzida pelo carbacol e EFS, e no tecido uretral aumenta a contratilidade à fenilefrina. Além disso, a testosterona não interferiu com o influxo de cálcio extracelular através de L-VOCC na bexiga e uretra, excluindo estes canais como alvo da testosterona na condição fisiológica. Esses resultados sugerem que os andrógenos desempenham papel importante na manutenção da continência urinária.
Na OVX há redução da contratilidade vesical e aumento da contratilidade uretral, e a testosterona reverte estas alterações, trazendo-a próximas dos valores das ratas Sham. De fato, a testosterona reduziu a hipercontratilidade uretral induzida pelo CaCl2, agindo de modo similar
aos inibidores de L-VOCC e potencializa o relaxamento mediado pelo óxido nítrico. Esses resultados sugerem que a testosterona inibe a entrada de cálcio extracelular restabelecendo as respostas funcionais próximas ao controle e melhora a abertura uretral para o correto esvaziamento da bexiga.
Dessa forma, compreendendo o mecanismo de ação dos andrógenos no trato urinário inferior permitirá sugerir a reposição com andrógenos como alternativa terapêutica para as complicações urológicas na pós-menopausa.
9.
REFERÊNCIAS
1. Mitchell E, Woods N. Correlates of urinary incontinence during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women’s Health Study. Climateric. 2013; 16: 653-62.
2. Malheiros ESA, Costa CMB, Muniz da Silva DS, Dias CLL, Brito LGO, Pinto-Neto AM et
al. Climacteric syndrome in a Northeastern Brazilian city: a household survey. Rev Bras
Ginecol Obstet. 2014; 36(4): 163-9.
3. Baber RJ, Panay N, Fenton A, IMS Writing Group. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climateric. 2016; 19(2): 109-50.
4. Sassarini J, Lumsden MA. Oestrogen replacement in postmenopausal women. Age and Ageing. 2015; 44:551-58. 2013; 9:216-27.
5. Castelo-Branco C, Blümel JE, Chedraui P, Calle A, Bocanera R, Depiano E et al. Age at menopause in Latin America. Menopause. 2006; 13(4): 706-12.
6. Williams RE, Levine KB, Kalilani L, Lewis J, Clark RV. Menopause-specific questionnaire assessment in US population-based study shows negative impact on health-related quality of life. Maturitas. 2009; 62:153-59.
7. Gandhi J, Chen A, Dagur G, Suh Y, Smith N, Cali B et al. Genitourinary syndrome of menopause: an review of clinical manifestations, pathophysiology, etiology, evaluation, and management. Am J Obstet Gynecol. 2016; 215(6): 704-11.
8. Portman DJ, Gass ML, Vulvovaginal Atrophy Terminology Consensus Conference Panel. 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. 2014; 21: 1063-68.
9. Simon JA, Goldstein I, Kim NN, Davis SR, Kellogg-Spadt S, Lowenstein L et al. The role of androgens in the treatment of genitourinary syndrome of menopause (GSM): International Society for the Study of Women’s Sexual Health (ISSWSH) expert consensus panel review. Menopause. 2018; 25 (7): 837-47.
10. Robinson D, Cardozo L, Milsom I, Pons ME, Kirby M, Koelbl H et al. Oestrogens and overactive bladder. Neurourol Urodyn. 2014; 33(7):1086-91.
11. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U et al. The Standardization of Terminology of Lower Urinary Tract Function: Report from the Standardization Sub- committee of the International Continence Society. Neurourol and Urodyn. 2002; 21(2):167- 78.
12. Kim HK, Kang SY, Chung YJ, Kim JH, Kim MR. The Recent Review of the Genitourinary Syndrome of Menopause. J Menopausal Med. 2015; 21(2):65-71.
13. DiBonaventura M, Luo X, Moffatt M, Bushmakin AG, Kumar M, Bobula J. The Association Between Vulvovaginal Atrophy Symptoms and Quality of Life Among Postmenopausal Women in the United States and Western Europe. J Women Health (Larchmt). 2015; 24 (9): 713-22.
14. Krychman ML. Declining sexuality at midlife. Menopause. 2017; 24 (4): 358-59.
15. Dinç A. Menopause and urinary incontinence. Chapter 31. Recent studies in health sciences. ST Kliment Ohridski university press. 2019.
16. Andersson KE, Wein AJ. Anatomy, physiology and pharmacology of the Lower Urinary Tract. C. R. Chapple et al. (eds.), Urologic Principles and Practice, Springer Specialist Surgery Series. 2020; 97-117.
17. Andersson KE. Purinergic signalling in the urinary bladder. Auton Neurosci; 2015, 191: 78- 81.
18. Andersson KE, Wein AJ. Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence. Pharmacol Rev. 2004; 56(4):581-631.
19. Zhang X, Alwaal A, Lin G, Li H, Zaid UB, Wang G et al. Urethral musculature and innervation in the female rat. Neurourol Urodyn. 2016; 35: 382-89.
20. Gabella G, Uvelius B. Urinary bladder of rat: fine structure of normal and hypertrophic musculature. Cell Tissue Res. 1990; 262 (1), 67–79.
21. Brading AF, Teramoto N, Dass N, Mccoy R. Scandinavian Journal of Urology and Nephrology Morphological and Physiological Characteristics of Urethral Circular and Longitudinal Smooth Muscle Morphological and Physiological Characteristics of Urethral Circular and Longitudinal Smooth Muscle. Scand J Urol Nephrol Suppl. 2001; 35207(207):12– 18.
22. de Groat WC, Yoshimura N. Anatomy and physiology of the lower urinary tract. Handb Clin Neurol. 2015; 130: 61-108.
23. Jung J, Ahn HK, Huh Y. Clinical and functional anatomy of the urethral sphincter. Int Neurourol J. 2012; 16(3): 102-6.
24. Merril L, Gonzalez EJ, Girard BM, Vizzard MA. Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol; 2016, 13: 193-204.
25. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci, 2008, 9(6): 453-466.
26. Wang P, Luthin GA, Ruggieri MR. Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J Pharmacol Exp Ther; 1995, 273(2): 959-966.
27. Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev; 2004, 84: 935-986.
28. Leiria LO, Mónica FZ, Carvalho FD, Claudino MA, Franco-Penteado CF, Schenka A et al. Functional, morphological and molecular characterization of bladder dysfunction in streptozotocin-induced diabetic mice: evidence of a role for L- type voltage-operated Ca2+ channels. Br J Pharmacol; 2011, 163(6): 1276-1288.
29. Sui G, Fry CH, Montgomery B, Roberts M, Wu R, Wu C. Purinergic and muscarinic modulation of ATP release from the urothelium and its paracrine actions. Am J Physiol Ren Physiol; 2014a/b, 306(3): F286-F298.
30. Yamaguchi O, Chapple CR. Beta3-adrenoceptors in urinary bladder. Neurourol Urodyn; 2007, 26(6): 752-756.
31. Tanaka Y, Horinouchi T, Koike K. New insights into β-adrenoceptors in smooth muscle: Distribution of receptor subtypes and molecular mechanisms triggering muscle relaxation. Clin Exp Pharmacol Physiol; 2005, 32(7): 503-514.
32. Petkov GV. Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology. Am J Physiol Regul Integr Comp Physiol; 2014, 307: R571–R584. 33. Alexandre EC, de Oliveira MG, Campos R, Kiguti LR. How important is the α1 adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of α1 adrenoceptor to urethral contractility. Am J Physiol Renal Physiol; 2017, 312(6): F1026-F1034. 34. Michel MC, Vrydag W. α1- α2 and β-adrenoceptors in the urinary bladder, urethra and
prostate. Br J Pharmacol; 2006, 147 Suppl 2: S88-119.
35. Persson K, Igawa Y, Mattiasson A, Andersson KE. Effects of inhibition of the L- arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro. Br J Pharmacol; 1992, 107 (1): 178-184.
36. Burnett AL. Nitric oxide control of lower genitourinary tract functions: a review. Urol; 1995, 45(6): 1071-1083.
37. Gao Y. The multiple actions of NO. Pflugers Archiv – Eur J Physiol; 2010, 459(6): 829- 839.
38. Kyle BD. Ions channels of the mammalian urethra. Channels; 2014, 8(5): 393-401.
39. Andersson KE, Persson K. Nitric oxide synthase and nitric oxide-mediated effects in lower urinary tract smooth muscles. World J Urol. 1994;12(5):274–80.
40. Fleischmann N, Christ G, Sclafani T, Melman A. The effect of ovariectomy and long-term estrogen replacement on bladder structure and function in the rat. J Urol; 2002, 168: 1265– 1268.
41. Sartori MG, Feldner PC, Jarmy-Di Bella ZI, Aquino Castro R, Baracat EC, Rodrigues de Lima G et al. Sexual steroids in urogynecology. Climateric; 2011, 14(1): 5-14.
42. Dantas AP, Scivoletto R, Fortes ZB, Nigro D, Carvalho MC. Influence of female sex hormones on endothelium-derived vasoconstrictor prostanoid generation in microvessels of spontaneously hypertensive rats. Hypertension; 1999, 34 (4 Pt 2): 914-9.
43. Dantas AP, Franco MdoC, Tostes RC, Fortes ZB, Costa SG, Nigro D et al. Relative contribution of estrogen withdrawal and gonadotropins increase secondary to ovariectomy on prostaglandin generation in mesenteric microvessels. J Cardiovasc Pharmacol; 2004, 43(1): 48- 55.
44. Costas TJ, Ceravolo GS, dos Santos RA, de Oliveira MA, Araújo PX, Gianquinto LR et al. Association of testosterone with estrogen abolishes the beneficial effects of estrogen treatment by increasing ROS generation in aorta endothelial cells. Am J Physiol Heart Circ Physiol; 2015, 308(7): H723-32.
45. Castardo-de-Paula JC, de Campos BH, Amorim EDT, da Silva RV, de Faria CC, Higachi L et al. Cardiovascular risk and the effect of nitric oxide synthase inhibition in female rats: The role of estrogen. Exp Gerontol; 2017, 28(97): 38- 48
46. Yiloren T, Ercan F, Tarcan T. Exogenous Testosterone and Estrogen Affect Bladder Tissue Contractility and Histomorphology Differently in Rat Ovariectomy Model. J Sex Med; 2011, 8 (6): 1626-1637.
47. Ramos Filho AC, Faria JA, Calmasini FB, Teixeira SA, Mónica FT, Muscará MN et al. The renin–angiotensin system plays a major role in voiding dysfunction of ovariectomized rats. Life Sci; 2013, 93(22): 820-829.
48. Bonilla-Becerra SM, de Oliveira MG, Calmasini FB, Rojas-Moscoso JA, Zanesco A, Antunes E. Micturition dysfunction in four-month old ovariectomized rats: Effects of testosterone replacement. Life Sci; 2017, 179: 120-129.
49. Dambros M, Rodrigues Palma PC, Mandarim-de-Lacerda CA, Miyaoka R, Rodrigues Netto Jr N. The effect of ovariectomy and estradiol replacement on collagen and elastic fibers in the bladder of rats. Int Urogynecol J; 2003, 14: 108–112.
50. Diep N, Constantinou CE. Age dependent response to exogenous estrogen on micturition, contractility and cholinergic receptors of the rat bladder. Life Sci; 1999, 64(23): PL 279-89. 51. Abrams P, Andersson KE. Muscarinic receptor antagonists for overactive bladder. BJU Int; 2007, 100(5): 987-1006.
52. Mónica FZ, Antunes E. Stimulators and activators of soluble guanylate cyclase for urogenital disorders. Nat Rev Urol; 2017, Nov 14: 1-12.
53. Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T et al. Effect of (R)-2-(2- aminothiazol-4-yl)-4'-{2-[(2- hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther; 2007, 321(2): 642-7.
54. Torimoto K, Matsushita C, Yamada A, Goto D, Matsumoto Y, Hosokawa Y et al. Clinical efficacy and safety of mirabegron and imidafenacin in women with overactive bladder: A randomized crossover study (The MICRO Study). Neurourol Urodyn; 2016, 36(4): 1097- 1103.
55. Kuo HC, Lee KS, Na Y, Sood R, Nakaji S, Kubota Y et al. Results of a randomized, double- blind, parallel-group, placebo- and active-controlled, multicenter study of mirabegron, a β3- adrenoceptor agonist, in patients with overactive bladder in Asia. Neurourol Urodyn; 2015, 34(7): 685-92.
56. Serati M, Leone Roberti Maggiore U, Sorice P, Cantaluppi S, Finazzi Agrò E, Ghezzi F et al. Is mirabegron equally as effective when used as first- or second-line therapy in women with overactive bladder?. Int Urogynecol J; 2017, 28(7): 1033-1039.
57. Pinkerton JV. Hormone Therapy for Postmenopausal Women. N Engl J Med. 2020; 382 (5): 446-55.
58. Villier TJ, Pines A, Panay N, Gambacciani M, Archer DF, Baber RJ et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric; 2013, 16 (3): 316-337.
59. Traish AM, Vignozzi L, Simon JA, Goldstein I, Kim NN. Role of Androgens in Female Genitourinary Tissue Structure and Function: Implications in the Genitourinary Syndrome of Menopause. Sex Med Rev, 2019; 4: 558-571.
60. Kim HK, Kang SY, Chung YJ, Kim JH, Kim MR. The Recent Review of the Genitourinary Syndrome of Menopause. J Menopausal Med; 2015, 21(2):65-71.
61. Shifren JL, Davis SR. Androgens in postmenopausal women: a review. Menopause; 2017, 24(8): 970-979.
62. Glaser R, Dimitrakakis C. Testosterone therapy in women: myths and misconceptions. Maturitas; 2013, 74 (3): 230-4.
63. Simpson ER, Davis SR. Minireview: aromatase and the regulation of estrogen biosynthesis- some new perspectives. Endocrinology; 2001, 142(11): 4589-94.
64. Davis SR, Worsley R. Androgen treatment of postmenopausal women. J Steroid Biochem Mol Biol; 2014, 142: 107-114.
65. Pretorius E, Arlt W, Storbeck KH. A new dawn for androgens: Novel lessons from 11- oxygenated C19 steroids. Mol Cell Endocrinol; 2017, 441: 76-85.
66. Lucas-herald AK, Alves-lopes R, Montezano AC, Ahmed SF, Touyz RM. Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications. Clin Sci (Lond); 2017, 131(13): 1405-1418.
67. Pihlajamaa, P, Sahu B, Jänne OA. Determinants of receptor- and tissue-specific actions in androgen signaling. Endocr Rev; 2015, 36 (4): 357–384.
68. Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Mol Cell Endocrinol; 1996, 120: 51–57.
69. Bennett NC, Gardiner RA, Hooper JD, Johnson DW, Gobe GC. Molecular cell biology of androgen receptor signaling. Int J Biochem Cell Biol. 2010; 42 (6): 813-27.
70. Loy CJ, Sim KS, Yong EL. Filamin-A fragment localizes to the nucleus to regu-late androgen receptor and coactivator functions. Proc Natl Acad Sci U S A. 2003; 100(8): 4562– 7.
71. Dixit KCS, Wu J, Smith LB, Hadoke PWF, Wu FCW et al. Androgens and coronary artery disease. Chapter 16, 2015 In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, Koch C, McLachlan R, New M, Rebar R, Singer F, Vinik A, Weickert MO (Eds.), Endotext, [Internet]. MDText.com.
72. Tostes RC, Carneiro FS, Carvalho MHC, Reckelhoff JF. Reactive oxygen species: players in the cardiovascular effects of testosterone. Am J Physiol Regul Integr Comp Physiol; 2016, 310: R1–R14.
73. Son BK, Akishita M, Iijima K, Ogawa S, Maemura K, Yu J et al. Androgen receptor- dependent transactivation of growth arrest-specific gene 6 mediates inhibitory effects of testosterone on vascular calcification. J Biol Chem; 2010, 285: 7537–7544.
74. Alves-Lopes R, Neves KB, Silva MB, Olivon VC, Ruginsk SG, Antunes-Rodrigues J et al. Functional and structural changes in internal pudendal arteries underlie erectile dysfunction induced by androgen deprivation. Asian J Androl; 2016, 18: 1-7.
75. Levin ER, Hammes SR. Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol; 2016, 17(12): 783-797.
76. Kouloumenta V, Hatziefthimiou A, Paraskeva E, Gourgoulianis K, Molyvdas PA. Non- genomic effect of testosterone on airway smooth muscle. Br J Phamacol; 2006, 149: 1083-1091. 77. Pi M, Parril AL, Quarles D. GPRC6A mediates the non-genomic effects of steroids. J Biol Chem; 2010, 285(51): 39953- 64
78. Asuthkar S, Elustondo PA, Demirkhanyan L, Sun X, Baskaran P, Velpula KK et al. The TRPM8 protein is a testosterone receptor: I Biochemical evidence for direct TRPM8- testosterone interactions. J Biol Chem; 2015, 290(5): 2659-2669.
79. Asuthkar S, Demirkhanyan L, Sun X, Elustondo PA, Krishnan V, Baskaran P et al. The TRPM8 protein is a testosterone receptor: II Functional evidence for an ionotropic effect of testosterone on TRPM8. J Biol Chem; 2015, 290(5): 2670-2688.
80. Perusquía M, Greenway CD, Perkins LM, Stallone JN. Systemic hypotensive effects of testosterone are androgen structure-specific and neuronal nitric oxide synthase-dependent. Am J Physiol Regul Integr Comp Physiol; 2015, 309(2): R189-95.
81. Perusquía M, Stallone JN. Do androgens play a beneficial role in the regulation of vascular tone? Nongenomic vascular effects of testosterone metabolites. Am J Physiol Heart Circ Physiol; 2010, 29(5): H1301-7.
82. Hristov KL, Parajuli SP, Provence A, Petkov GV. Testosterone decreases urinary bladder smooth muscle excitability via novel signaling mechanism involving direct activation of the BK channels. Am J Physiol Renal Physiol; 2016, 311(6): F1253-F1259.
83. Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Mol Cell Endocrinol; 1996, 120: 51–57.
84. Pelletier G. Localization of androgen and estrogen receptors in rat and primate tissues. Histol Histopathol; 2000, 15 (4): 1261-70.
85. Rosenzweig BA, Parminder SB, Lynn B, Moran C, Marcovici L, Prins GS. Location and Concentration of Estrogen, Progesterone, and Androgen Receptors in the Bladder and Urethra of the Rabbit. Neurourol and Urodyn; 1995, 14(1):87- 96.
86. Miyamoto H, Yao JL, Chaux A, Zheng Y, Hsu I, Izumi K et al. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int; 2012, 109(11): 1716-26.
87. Inoue S, Mizushima T, Miyamoto H. Role of the androgen receptor in urothelial cancer. Mol Cell Endocrinol; 2017, pii: S0303-7207(17): 30348-9.
88. Li P, Chen J, Miyamoto H. Androgen Receptor Signaling in Bladder Cancer. Cancers (Basel); 2017, 9(2) pii: E20.
89. Hsu JW, Hsu I, Xu D, Miyamoto H, Liang L, Wu XR et al. Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor. Am J Pathol; 2013, 182(5): 1811-20.
90. Maróstica E, Avellar MC, Porto CS. Effects of testosterone on muscarinic acetylcholine receptors in the rat epididymis. Life Sci. 2005, 77(6): 656-69.
91. Anderson GF, Navarro SP. The response of autonomic receptors to castration and testosterone in the urinary bladder of the rabbit. J Urol; 1988, 140
92. Davey DA. Androgens in women before and after the menopause and post bilateral oophorectomy: clinical effects and indications for testosterone therapy. Womens Health (Lond); 2012, 8(4): 437-46.
93. Davis SR, Moreau M, Kroll R, Bouchard C, Panay N, Gass M et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med; 2008, 359 (19): 2005-17. 94. Panay N, Al-Azzawi F, Bouchard C, Davis SR, Eden J, Lodhi I et al. Testosterone treatment of HSDD in naturally menopausal women: The ADORE Study. Climacteric; 2010, 13 (2): 121- 31.
95. Pardini D. Hormone replacement therapy in menopause. Arq Bras Endocrinol Metab. 2014; 58 (2): 172-81.
96. Chapple CR, Wein AJ, Abrams P, Dmochowski RR, Giuliano F, Kaplan SA et al. Lower urinary tract symptoms revisited: a broader clinical perspective. Eur Urol. 2008; 54(3): 563-9. 97. Ho MH, Bathia NN, Bashin S. Anabolic effects of androgens on muscles of female pelvic floor and lower urinary tract. Curr Opin Obstet Gynecol. 2004; 16 (5): 405-9
98. Traish AM, Gooren LJ. Safety of physiological testosterone therapy in women: lessons from female-to-male transsexuals (FMT) treated with pharmacological testosterone therapy. J Sex Med. 2010; 7 (11): 3758-64.
99. Borell M. Organotherapy and the emergence of reproductive endocrinology. J Hist Biol. 1985; 18: 1-30.
100. Biglia N, Maffei S, Lello S, Nappi RE. Tibolone in postmenopausal women: a review based on recent randomised controlled clinical trials. Gynecol Endocrinol; 2010, 26: 804-14. 101. Nappi RE, Cucinella L. Advances in pharmacotherapy for treating female sexual dysfunction. Expert Opin Pharmacother; 2015, 16: 875-87.
102. Labrie F, Bélanger A, Pelletier G, Martel C, Archer DF, Utian WH. Science of intracrinology in postmenopausal women. Menopause. 2017; 24 (6): 702-12.
103. Labrie F, Archer DF, Koltun W, et al., VVA Prasterone Research Group. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause; 2016, 23: 243-56.
104. Terra DG, de Lima EM, do Nascimento AM, Brasil GA, Filete PF, Kalil IC et al. Low dose of methyltestosterone in ovariectomised rats improves baroreflex sensitivity without geno- and cytotoxicity. Fundam Clin Pharmacol; 2016, 30(4): 316-26.
105. Dalpiaz PL, Lamas AZ, Caliman IF, Ribeiro RF Jr, Abreu GR, Moyses MR et al. Sex hormones promote opposite effects on ACE and ACE2 activity, hypertrophy and cardiac contractility in spontaneously hypertensive rats. PLoS One; 2015, 10(5): e0127515.
106. Glaser R, York AD, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas; 2011, 68(4): 355-61. 107. André DM, Calixto MC, Sollon C, Alexandre EC, Leiria LO, Tobar N, et al. Therapy with resveratrol attenuates obesity-associated allergic airway inflammation in mice. Int immunopharmacol. 2016; 38: 298-05.
108. Oliveira MG, Alexandre EC, Bonilla-Becerra SM, Bertollotto GM, Justo AFO, Mónica FZ, et al. Autonomic dysregulation at multiple site is implicated in age-associated underactive bladder in female mice. Neurourol Urodyn. 2019; 38: 1212-21.
109. Robinson D, Cardozo L. Overactive bladder: diagnosis and management. Maturitas. 2012; 71 (2): 188-93.
110. Salmi S, Santti R, Gustafsson JA, Mákela S. Co-localization of androgen receptor with estrogen receptor b in the lower urinary tract of the male rat. J Urology, 2001; 166: 674-7. 111. Keast JR. The autonomic nerve supply of male sex organ – an importance target of circulating androgens. Behavl Brain Res, 1999; 105: 81-92.
112. Zitzmann M. Testosterone and the brain. Aging Male. 2006; 9 (4): 195-9.
113. Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol; 2011, 165 (5): 675-85.
114. Kullmann FA, Daugherty SL, de Groat WC, Birder LA. Bladder smooth muscle strip contractility as a method to evaluate lower urinary tract pharmacology. J Vis Exp; 2014, 90: e51807.
115. Perusquía M, Flores-Soto E, Sommer B, Campuzano-González E, Martínez-Villa I, Martínez-Banderas AI, Montaño LM. Testosterone-induced relaxation involves L-type and store-operated Ca2+ channels blockade, and PGE2 in guinea pig airway smooth muscle. Pflugers Arch; 2015, 467 (4): 767-77.
116. Kouloumenta V, Hatziefthimiou A, Paraskeva E, Gourgoulianis K, Molyvdas PA. Non- genomic effect of testosterone on airway smooth muscle. Br J Pharmacol; 2006, 149 (8): 1083- 91.
117. Gao W, Kim J, Dalton JT. Pharmacokinetics and Pharmacodynamics of nonsteroidal androgens receptor ligands. Pharm Res. 2006; 23: 1641-1658.
118. Fernandes VS, Barahona MV, Recio P, Martínez-Sáenz, Ribeiro ASF, Contreras C et al. Mechanisms involved in testosterone-induced relaxation to the pig urinary bladder neck. Steroids. 2012; 77: 394-402.
119. Rahman F, Christian HC. Non-classical actions of testosterone: an uptade. Trends Endocrinol Metab; 2007, 10: 371-8.
120. Bennett NC, Gardiner RA, Hooper JD, Johnson DW, Gobe GC. Molecular cell biology of