Investigative and Clinical Urology

The Korean Urological Association (대한비뇨의학회)
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The Effects of Estrogen on Neuronal Nitric Oxide Synthase Expression, Endothelial Nitric Oxide Synthase Expression and Vascular Endothelial Growth Factor Expression and on the Histologic Composition of Rat Uterus and Vagina

백서의 질과 자궁에서 nNOS, eNOS 및 VEGF의 발현 및 조직학적 변화에 에스트로겐이 미치는 영향

Park, Sung-Woo;Lee, Young-Jin;Lee, Jeong-Zoo
박성우;이영진;이정주

  • Published : 20060100
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Abstract

Purpose: As suggested by many investigators, the cause of age-related female sexual dysfunction is the decline of serum estrogen. We investigated the effects of estrogen on the nitric oxide synthase(NOS) and vascular endothelial growth factor(VEGF) expressions and the histologic composition in the uterus and proximal and distal vagina of rats. Materials and Methods: Forty-five mature female Sprague-Dawley rats were randomly divided into three groups; the control group(C), the oophorectomy group(O), and the estrogen replacement group(E). The expression rates of neuronal NOS(nNOS), endothelial NOS(eNOS), VEGF and the changes of the collagen component in the uterus and proximal and distal vaginal tissues were investigated by immunohistochemical staining and Masson's trichrom staining. Results: The expression rate of NOS was highest in the proximal vagina, and this was followed by the portion of the vagina distal to the uterus. The nNOS and eNOS expression rates were significantly decreased in the uterus and the proximal vagina of the E group(p<0.05), and they were increased in the uterus and proximal vagina of the O group(p<0.05). However, the VEGF expression rate was increased in only the uterus of E group. In all tissues, the collagen component was significantly decreased in the E group, while it was increased in the O group(p<0.05). Conclusions: These data suggest that estrogen downregulates nNOS and eNOS. In addition, estrogen deficiency induces collagen synthesis and it decreases the content of smooth muscle in the uterus and vagina, resulting in structural relaxation difficulty.

Keywords

References

  1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281: 537-44 https://doi.org/10.1001/jama.281.6.537
  2. Bachmann GA. Sexual function in the perimenopause. Obstet Gynecol Clin North Am 1993;20:379-89
  3. Berman JR, McCarthy MM, Kyprianou N. Effect of estrogen withdrawal on nitric oxide synthase expression and apoptosis in the rat vagina. Urology 1998;51:650-6 https://doi.org/10.1016/S0090-4295(97)00683-3
  4. Zavara P, Sioufi R, Schipper HM, Begin LR, Brock GB. Nitric oxide mediated erectile activity is a testosterone dependent event: a rat erection model. Int J Impot Res 1995;7:209-19
  5. Gross SS, Wolin MS. Nitric oxide: pathophysiological mechanisms. Annu Rev Physiol 1995;57:737-69 https://doi.org/10.1146/annurev.ph.57.030195.003513
  6. Marthol H, Hilz MJ. Female sexual dysfunction: a systematic overview of classification, pathophysiology, diagnosis and treatment. Fortschr Neurol Psychiatr 2004;72:121-35 https://doi.org/10.1055/s-2004-818357
  7. Semmens JP, Semmens EC. Sexual function and the menopause. Clin Obstet Gynecol 1984;27:717-23 https://doi.org/10.1097/00003081-198409000-00019
  8. Levin RJ. The physiology of sexual function in women. Clin Obstet Gynaecol 1980;7:213-52
  9. Coope J. Hormonal and non-hormonal interventions for menopausal symptoms. Maturitas 1996;23:159-68 https://doi.org/10.1016/0378-5122(95)00971-X
  10. Myers LS, Morokoff PJ. Physiological and subjective sexual arousal in pre- and postmenopausal women and postmenopausal women taking replacedment therapy. Psychophysiology 1986;23:283-92 https://doi.org/10.1111/j.1469-8986.1986.tb00633.x
  11. Dennerstein L, Dudley EC, Hopper JL, Burger H. Sexuality, hormones and the menopausal transition. Maturitas 1997;26: 83-93 https://doi.org/10.1016/S0378-5122(96)01093-6
  12. Verkauf BS, Von Thron J, O'Brien WF. Clitoral size in normal women. Obstet Gynecol 1992;80:41-4
  13. Yoon HN, Chung WS, Park YY, Shim BS, Han WS, Kwon SW. Effects of estrogen on nitric oxide synthase and histological composition in the rabbit clitoris and vagina. Int J Impot Res 2001;13:205-11 https://doi.org/10.1038/sj.ijir.3900687
  14. Baram DA. Sexuality and sexual function. In: Berek JS, Adaxhi EY, Hillard PA, editors. Novak's gynecology. 12th ed. Baltimore: Williams and Wilkins; 1996;279-98
  15. Tarcan T, Park K, Goldstein I, Maio G, Fassina A, Krane RJ, et al. Histomorphometric analysis of age-related structural changes in human clitoral-cavernosal tissue. J Urol 1999;161: 940-4 https://doi.org/10.1016/S0022-5347(01)61825-1
  16. Sarrel PM. Ovarian hormones and vaginal blood flow: using laser Doppler velocimetry to measure effects in a clinical trial of post-menopausal women. Int J Impot Res 1998;10(Suppl 2):S91-3
  17. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science 1992;257:401-3 https://doi.org/10.1126/science.1378650
  18. Naftolin F, MacLusky NJ, Leranth CZ, Sakamoto HS, Garcia- Segura LM. The cellular effects of estrogens on neuroendocrine tissues. J Steroid Biochem 1988;30:195-207 https://doi.org/10.1016/0022-4731(88)90093-3
  19. Hoyle CH, Stones RW, Robson T, Whitley K, Burnstock G. Innervation of vasculature and microvasculature of the human vagina by NOS and neuropeptide-containing nerves. J Anat 1996;188:633-44
  20. Hyder SM, Nawaz Z, Chiappetta C, Stancel GM. Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Res 2000;60:3183-90
  21. Heryanto B, Lipson KE, Rogers PA. Effect of angiogenesis inhibitors on oestrogen-mediated endometrial endothelial cell proliferation in the ovariectomized mouse. Reproduction 2003; 125:337-46 https://doi.org/10.1530/rep.0.1250337
  22. Batra S, Al-Hijji J. Characterization of nitric oxide synthase activity in rabbit uterus and vagina: down regulation by estrogen. Life Sci 1998;62:2093-100 https://doi.org/10.1016/S0024-3205(98)00184-2
  23. Al-Hijji J, Larsson I, Batra S. Effect of ovarian steroids on nitric oxide synthase in the rat uterus, cervix and vagina. Life Sci 2001;69:1133-42 https://doi.org/10.1016/S0024-3205(01)01204-8
  24. Kang JS, Lee BJ, Ahn B, Kim DJ, Nam SY, Yun YW, et al. Expression of estrogen receptor alpha and beta in the uterus and vagina of immature rats treated with 17-ethinyl estradiol. J Vet Med Sci 2003;65:1293-7 https://doi.org/10.1292/jvms.65.1293
  25. Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev 2002;23:665-86 https://doi.org/10.1210/er.2001-0045
  26. Molero L, Garcia-Duran M, Diaz-Recasens J, Rico L, Casado S, Lopez-Farre A. Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: regulation by estrogen. Cardiovasc Res 2002;56: 43-51 https://doi.org/10.1016/S0008-6363(02)00505-9
  27. Traish AM, Kim NN, Huang YH, Min K, Munarriz R, Goldstein I. Sex steroid hormones differentially regulate nitric oxide synthase and arginase activities in the proximal and distal rabbit vagina. Int J Impot Res 2003;15:397-404 https://doi.org/10.1038/sj.ijir.3901097