Localization of the Androgen-Synthesizing Enzymes, Androgen Receptor, and Sex Steroids in the Vagina: Possible Implications for the Treatment of Postmenopausal Sexual Dysfunction

Journal of Sexual Medicine

Volumn 11, Issue 8, 2014, Pages 1949-1961

  Bertin, Jonathan ^a   Dury, Alain Y ^a   Ouellet, Johanne ^a   Pelletier, Georges ^b   Labrie, Fernand ^a  

^a Endoceutics Inc   (Canada)

^b LAVAL UNIVERSITY   (Canada)

Author keywords

Androgens; DHEA; Sexual dysfunction; Vagina; Vulvovaginal atrophy

Indexed keywords

17 BETA DEHYDROGENASE 3; ANDROGEN RECEPTOR; PRASTERONE; SEX HORMONE; STEROID; STEROID 5ALPHA REDUCTASE 1; STEROID 5ALPHA REDUCTASE 2; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BASEMENT MEMBRANE; BLOOD VESSEL WALL; ENZYME LOCALIZATION; FEMALE; HORMONE DETERMINATION; IMMUNOFLUORESCENCE; IMMUNOHISTOCHEMISTRY; LAMINA PROPRIA; MACACA FASCICULARIS; NERVE FIBER; NONHUMAN; NUCLEOTIDE SEQUENCE; POSTMENOPAUSE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SEXUAL DYSFUNCTION; SQUAMOUS EPITHELIUM; VAGINA EPITHELIUM; VAGINAL LUBRICATION;

ANDROGENS; DHEA; SEXUAL DYSFUNCTION; VAGINA; VULVOVAGINAL ATROPHY;

17-HYDROXYSTEROID DEHYDROGENASES; 3-OXO-5-ALPHA-STEROID 4-DEHYDROGENASE; ANDROGENS; ANIMALS; DEHYDROEPIANDROSTERONE; FEMALE; MACACA FASCICULARIS; POSTMENOPAUSE; RECEPTORS, ANDROGEN; SEXUAL DYSFUNCTION, PHYSIOLOGICAL; TANDEM MASS SPECTROMETRY; VAGINA;

EID: 84905037935     PISSN: 17436095     EISSN: 17436109     Source Type: Journal    
DOI: 10.1111/jsm.12589     Document Type: Article

References (68)

1. Berman JR, Berman L, Goldstein I. Female sexual dysfunction: Incidence, pathophysiology, evaluation, and treatment options. Urology 1999;54:385-391.
2. Berman JR, Berman LA, Werbin TJ, Goldstein I. Female sexual dysfunction: Anatomy, physiology, evaluation and treatment options. Curr Opin Urol 1999;9:563-568.
3. Bachmann GA, Schaefers M, Uddin A, Utian WH. Microdose transdermal estrogen therapy for relief of vulvovaginal symptoms in postmenopausal women. Menopause 2009;16:877-882.
4. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002;137:805-813.
5. Labrie F, Labrie C. DHEA and intracrinology at menopause, a positive choice for evolution of the human species. Climacteric 2013;16:205-213.
6. Labrie F, Martel C, Balser J. Wide distribution of the serum dehydroepiandrosterone and sex steroid levels in postmenopausal women: Role of the ovary? Menopause 2011;18:30-43.
7. Labrie F. DHEA after menopause-Sole source of sex steroids and potential sex steroid deficiency treatment. Menopause Manag 2010;19:14-24.
8. Labrie F, Cusan L, Gomez JL, Côté I, Bérubé R, Bélanger P, Martel C, Labrie C. Effect of intravaginal DHEA on Serum DHEA and eleven of its metabolites in postmenopausal women. J Steroid Biochem Mol Biol 2008;111:178-194.
9. Labrie F, Cusan L, Gomez JL, Côté I, Bérubé R, Bélanger P, Martel C, Labrie C. Corrigendum to: Effect of intravaginal DHEA on serum DHEA and eleven of its metabolites in postmenopausal women. J Steroid Biochem Mol Biol 2008;112:169.
10. Labrie F, Martel C, Berube R, Cote I, Labrie C, Cusan L, Gomez JL. Intravaginal prasterone (DHEA) provides local action without clinically significant changes in serum concentrations of estrogens or androgens. J Steroid Biochem Mol Biol 2013;138:359-367.
11. Osborn M, Hawton K, Gath D. Sexual dysfunction among middle aged women in the community. Br Med J (Clin Res Ed) 1988;296:959-962.
12. Avis NE, Stellato R, Crawford S, Johannes C, Longcope C. Is there an association between menopause status and sexual functioning? Menopause 2000;7:297-309.
13. Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril 2001;76:456-460.
14. Leiblum SR, Koochaki PE, Rodenberg CA, Barton IP, Rosen RC. Hypoactive sexual desire disorder in postmenopausal women: US results from the Women's International Study of Health and Sexuality (WISHeS). Menopause 2006;13:46-56.
15. Spira A, Bajos N, Ducot B. Trends in sexual behavior. Analyse des Comportements Sexuels en France Investigators. Sex Transm Dis 1994;21:S14-18.
16. Burwell SR, Case LD, Kaelin C, Avis NE. Sexual problems in younger women after breast cancer surgery. J Clin Oncol 2006;24:2815-2821.
17. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: Prevalence and predictors. JAMA 1999;281:537-544.
18. Hammerstein J. [Sense and nonsense of hormone determinations in gynecology and obstetrics. Secondary amenorrhea, androgenization, sterility]. Gynakol Rundsch 1981;21:78-85.
19. Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, Huebler D, Oettel M, Ernst M, Schulte HM, Allolio B. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;341:1013-1020.
20. Arlt W, Callies F, Allolio B. DHEA replacement in women with adrenal insufficiency-Pharmacokinetics, bioconversion and clinical effects on well-being, sexuality and cognition. Endocr Res 2000;26:505-511.
21. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: A prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom Med 1985;47:339-351.
22. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côté I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J. Effect on intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause 2009;16:923-931.
23. Labrie F. Intracrinology. Mol Cell Endocrinol 1991;78:C113-118.
24. Labrie F, Luu-The V, Bélanger A, Lin S-X, Simard J, Labrie C. Is DHEA a hormone? Starling review. J Endocrinol 2005;187:169-196.
25. Labrie F, Luu-The V, Labrie C, Bélanger A, Simard J, Lin S-X, Pelletier G. Endocrine and intracrine sources of androgens in women: Inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev 2003;24:152-182.
26. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côté I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J. Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy. Menopause 2009;16:907-922.
27. Hickey M, Davis SR, Sturdee DW. Treatment of menopausal symptoms: What shall we do now? Lancet 2005;366:409-421.
28. Berman JR, Almeida FG, Jolin J, Raz S, Chaudhuri G, Gonzalez-Cadavid NF. Correlation of androgen receptors, aromatase, and 5-alpha reductase in the human vagina with menopausal status. Fertil Steril 2003;79:925-931.
29. Lephart ED, Mathews D, Noble JF, Ojeda SR. The vaginal epithelium of immature rats metabolizes androgens through an aromatase-like reaction: Changes during the time of puberty. Biol Reprod 1989;40:259-267.
30. Lange CA, Gioeli D, Hammes SR, Marker PC. Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. Annu Rev Physiol 2006;69:171-199.
31. Heinlein CA, Chang C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol 2002;16:2181-2187.
32. Hamasaki N, Tomoda A, Harasaki H, Minakami S. Accumulation of phosphoenolpyruvate in red cells incubated with the phosphate ester in an acidified isotonic sucrose medium. J Biochem 1977;81:1505-1509.
33. Kennedy TG, Armstrong DT. Induction of vaginal mucification in rats with testosterone and 17beta-hydroxy-5alpha-androstan-3-one. Steroids 1976;27:423-430.
34. Berger L, El-Alfy M, Martel C, Labrie F. Effects of dehydroepiandrosterone, Premarin and Acolbifene on histomorphology and sex steroid receptors in the rat vagina. J Steroid Biochem Mol Biol 2005;96:201-215.
35. Pelletier G, Ouellet J, Martel C, Labrie F. Effects of ovariectomy and dehydroepiandrosterone (DHEA) on vaginal wall thickness and innervation. J Sex Med 2012;9:2525-2533.
36. Pelletier G, Ouellet J, Martel C, Labrie F. Androgenic action of dehydroepiandrosterone (DHEA) on nerve density in the ovariectomized rat vagina. J Sex Med 2013;10:1908-1914.
37. Zhao G, Lu L, Luu-The V, Fan Z, Labrie F, Pelletier G. Expression of 5α-reductase type 1 in breast cancer and adjacent non-malignant tissue: An immunohistochemical study. Horm Mol Biol Clin Investig 2010;3:411-415.
38. Luu-The V, Paquet N, Calvo E, Cumps J. Improved real-time RT-PCR method for high-throughput measurements using second derivative calculation and double correction. Biotechniques 2005;38:287-293.
39. Warrington JA, Nair A, Mahadevappa M, Tsyganskaya M. Comparison of human adult and fetal expression and identification of 535 housekeeping/maintenance genes. Physiol Genomics 2000;2:143-147.
40. Bélanger B, Bélanger A, Labrie F, Dupont A, Cusan L, Monfette G. Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: Unique importance of extratesticular androgens in men. J Steroid Biochem 1989;32:695-698.
41. Liu H, Bellemare V, Labrie F, Luu-The V. Molecular characterization of the cynomolgus monkey Macaca fascicularis steroidogenic enzymes belonging to the aldo-keto reductase family. J Steroid Biochem Mol Biol 2007;104:75-80.
42. Blanchard PG, Luu-The V. Differential androgen and estrogen substrates specificity in the mouse and primates type 12 17beta-hydroxysteroid dehydrogenase. J Endocrinol 2007;194:449-455.
43. Brotto LA, Petkau AJ, Labrie F, Basson R. Predictors of sexual desire disorders in women. J Sex Med 2011;8:742-753.
44. Bolour S, Braunstein G. Testosterone therapy in women: A review. Int J Impot Res 2005;17:399-408.
45. Traish AM, Kim SW, Stankovic M, Goldstein I, Kim NN. Testosterone increases blood flow and expression of androgen and estrogen receptors in the rat vagina. J Sex Med 2007;4:609-619.
46. Giuliano F, Pfaus J, Srilatha B, Hedlund P, Hisasue S, Marson L, Wallen K. Experimental models for the study of female and male sexual function. J Sex Med 2010;7:2970-2995.
47. Bachmann GA. A new option for managing urogenital atrophy in postmenopausal women. Contemp Obstet Gynecol 1997;42:13-28.
48. Gerich JE. Metabolic effects of long-term somatostatin infusion in man. Metabolism 1976;25:1505-1507.
49. Hodgins MB, Spike RC, Mackie RM, MacLean AB. An immunohistochemical study of androgen, oestrogen and progesterone receptors in the vulva and vagina. Br J Obstet Gynaecol 1998;105:216-222.
50. Traish AM, Kim N, Min K, Munarriz R, Goldstein I. Role of androgens in female genital sexual arousal: Receptor expression, structure, and function. Fertil Steril 2002;77(4 suppl):S11-18.
51. Narvekar N, Lakha F, Critchley HO, Glasier AF, Williams AR, Leminen R, Heikinheimo O, Kelly RW, Baird DT. Changes in vaginal morphology, steroid receptor and natural antimicrobial content following treatment with low-dose mifepristone. Contraception 2007;75:271-280.
52. Zumoff B, Rosenfeld R, Strain GW, Levin J, Fukushima DK. Sex differences in the twenty-four hour mean plasma concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) and the DHEA to DHEAS ratio in normal adults. J Clin Endocrinol Metab 1980;51:330-333.
53. Zumoff B, Strain GW, Miller LK, Rosner W. Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab 1995;80:1429-1430.
54. Labrie F, Bélanger A, Bélanger P, Bérubé R, Martel C, Cusan L, Gomez JL, Candas B, Castiel I, Chaussade V, Deloche C, Leclaire J. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol 2006;99:182-188.
55. Tuiten A, Laan E, Panhuysen G, Everaerd W, de Haan E, Koppeschaar H, Vroon P. Discrepancies between genital responses and subjective sexual function during testosterone substitution in women with hypothalamic amenorrhea. Psychosom Med 1996;58:234-241.
56. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-688.
57. Avruch J, Leone GR, Martin DB. Identification and subcellular distribution of adipocyte peptides and phosphopeptides. J Biol Chem 1976;251:1505-1510.
58. Opelz G, Terasaki PI. Decreased transplant survival rate of shared and nonshared machine-preserved cadaver kidneys. Transplant Proc 1977;9:1505-1512.
59. Labrie F, Luu-The V, Lin S-X, Simard J, Labrie C, El-Alfy M, Pelletier G, Bélanger A. Intracrinology: Role of the family of 17b-hydroxysteroid dehydrogenases in human physiology and disease. J Mol Endocrinol 2000;25:1-16.
60. Luu-The V, Pelletier G, Labrie F. Quantitative appreciation of steroidogenic gene expression in mouse tissues: New roles for type 2 5alpha-reductase, 20alpha-hydroxysteroid dehydrogenase and estrogen sulfotransferase. J Steroid Biochem Mol Biol 2005;93:269-276.
61. Ezrailson EG, Hanley HG, Hartley CJ, Lewis RM, Entman ML, Schwartz A. Studies on the mechanism of an antibiotic ionophore, R02-2985 (X537A) in the conscious chronically instrumented dog: Involvement of the prostaglandin synthetic pathway. Cardiovasc Res 1982;16:670-674.
62. Berkley KJ, Robbins A, Sato Y. Functional differences between afferent fibers in the hypogastric and pelvic nerves innervating female reproductive organs in the rat. J Neurophysiol 1993;69:533-544.
63. Pessina MA, Hoyt RF Jr, Goldstein I, Traish AM. Differential effects of estradiol, progesterone, and testosterone on vaginal structural integrity. Endocrinology 2006;147:61-69.
64. Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 2003;79:1341-1352.
65. Gonzalez M, Viafara G, Caba F, Molina E. Sexual function, menopause and hormone replacement therapy (HRT). Maturitas 2004;48:411-420.
66. Long CY, Liu CM, Hsu SC, Wu CH, Wang CL, Tsai EM. A randomized comparative study of the effects of oral and topical estrogen therapy on the vaginal vascularization and sexual function in hysterectomized postmenopausal women. Menopause 2006;13:737-743.
67. Raghunandan C, Agrawal S, Dubey P, Choudhury M, Jain A. A comparative study of the effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in postmenopausal women. J Sex Med 2010;7:1284-1290.
68. Baldassarre M, Perrone AM, Giannone FA, Armillotta F, Battaglia C, Costantino A, Venturoli S, Meriggiola MC. Androgen receptor expression in the human vagina under different physiological and treatment conditions. Int J Impot Res 2013;25:7-11.