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Intracrinología: la falta de DHEA

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Céline Bouchard

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Intracrinología: la falta de DHEA

  1. 1. Céline Bouchard, MD, FRCSC Québec, Canada Jornadas nacionales HM Gabinete Velázquez Actualizaciones en Ginecología y Obstetricia Novotel Madrid Center, Madrid, 22 de febrero de 2019 Intracrinology - Healthy and Sex Steroid- Deprived Vagina – From Preclinical to Clinical Characteristics
  2. 2. Intracrinology • Local synthesis and degradation of steroids represent the way tissues can control hormone levels and exposure in the local microenvironment. • Pathways that generate, deactivate steroids in peripheral tissues and ultimately control steroid exposure in a tissue-specific manner. • Recent technological advances in steroid profiling together with an improved knowledge of intracrine enzymes create today unprecedented opportunities to expand our understanding of intracrinology. 2
  3. 3. 3 Steroidogenesis Starting from cholesterol
  4. 4. DHEA and intracrinology: unique mechanism • DHEA: inactive precursor originating from the adrenals –Prohormone with no effect by itself –Produced in human and some primates –No negative feedback by ACTH • The blood levels decreases with age –Peak at 30 years and 60% less around menopause 4
  5. 5. The decrease in DHEA availability is the main cause of menopausal symptoms, including VVA and GSM 5Labrie et al., Menopause 18: 30-43, 2011.
  6. 6. DHEA and intracrinology: unique mechanism • Transformation is exerted at different levels and at specific ratios of estrogens and androgens, depending upon the cell type • No transformation in the human uterus • Inactivated at their site of synthesis before being released –minimal leakage or no leakage of the active sex steroids into the circulation 6
  7. 7. 71. Labrie, Mol. Cell. Endocrinol. 78, C113-118, 1991; 2. Labrie et al., Menopause 24, 702-712, 2017 Intracrinology step by step First step: Intracellular synthesis of estradiol and testosterone from circulating inactive DHEA (prasterone) followed by their intracellular action in the same cells1-2 Peripheral tissue cell DHEA (Endogenous from the adrenals or exogenous (Prasterone) Aromatase Testosterone Estradiol AR: Androgen receptor ER: Estrogen receptor ARER
  8. 8. 81. Labrie, Mol. Cell. Endocrinol. 78, C113-118, 1991; 2. Labrie et al., Menopause 24, 702-712, 2017 Intracrinology step by step Peripheral tissue cell DHEA (Endogenous from the adrenals or exogenous (Prasterone) Aromatase Testosterone Estradiol ARER Second step: Intracellular inactivation of the estrogens and androgens (sulfonation or glucuronidation)1 Consequence: Mainly inactive metabolites appear in the blood2-4, minimizing systemic exposure Local inactivation Inactive metabolites released in the circulation
  9. 9. Vulvovaginal Atrophy (VVA) • VVA affects – 50% of postmenopausal women from 50 to 60 years – 72% of women 70 years and older • 1/3 will engage conversation with HCP • 25% are not affected: – Difference in DHEA levels between women – Difference in intracellular DHEA transformation – Difference in tissue sensitivity to DHEA • It thus becomes important to study the effects of DHEA, not only estradiol and testosterone, in animal models Labrie F. et al., Horm Mol Biol Clin Invest 2010;4(1):499-507 9
  10. 10. Healthy Vagina 1. Epithelium – Protection against infection (microbiome, immune response) – Comfort: length, width, strength. 2. Lamina propria mainly made of collagen and vessels and nerves ending – Elasticity and vaginal engorgement during sexual activity – Lubrication during arousal 3. Muscularis: 2 muscular layers – Circular and longitudinal: contraction Nerves present in the lamina propria and muscularis are essential for the sexual response 1 0 Epithelium Lamina propria Muscularis Dury A.Y. et al., unpublished data. Masson’s trichrome stain from 68 year old post-menopausal woman’s vagina (post-mortem) 100 µm
  11. 11. Modified from Johnston SL. Geriatrics & Aging 2002;5(7):9-15. 1. Labrie et al., J. Ster. Biochem. Mol. Biol. 99, 182-188, 2006 1- Lack of both estrogens and androgens. DHEA has decreased at least by 60% on average at time of menopause1 2- Ovaries produce no estrogen Vaginal environment 1- Adrenals produce DHEA 2- Ovaries produce estrogen Before menopause After menopause 11
  12. 12. Effect of Estrogens on Vaginal Tissue • Increase of vaginal thickness associated with: –Decrease of parabasal cells and increase in superficial cells –Lowering of pH –Increase in vaginal secretions • Animal1 models –Decrease in compactness of collagen fibers in lamina propria on rats and rabbits –No effect of estrogens on nerve endings in lamina propria2 –50% positive effect on muscularis layer 1 Labrie et al. Menopause,Vol. 24 No 6 , 2017 2 Pelletier et al. J. Sex Med. 10, 1908-1914, 2013 12
  13. 13. Estradiol on Vaginal Collagen Metabolism in Women with Stress Incontinence • Prospective double-blind placebo controlled trial with estradiol valerate 2mg x 6 months – Periurethral biopsy before and after treatment for collagen content analysis • 49 women: 26 on estrogen 23 on placebo • Results – Estrogen decreases • Total collagen 44% versus 35.8 % P= 0.0054 • Mature cross-links decreases 1/3 P= 0.0009 • Advanced glycation end-products decreases by 1/2 P= 0.0009 • Conclusion – Estrogen has a profound negative effect on pelvic collagen metabolism, stimulating collagen degradation via increased proteinase activity Jackson S et al., BJOG Vol 109 p 339-344 2002 13
  14. 14. WHI (E) Results on Urinary Incontinence (UI) • 23,296 women with urinary symptoms at baseline and at 1 year in estrogen alone arm – Stress UI: RR: 2.15 95% CI 1.77-2.62 – Urge UI: RR: 1.32 95% CI 1.10-1.50 – Combined UI: RR: 1.79 95% 95% CI 1.26-2.53 • Conclusion – Conjugated equine estrogen alone arm: • Increased the risk of UI among continent women • Worsened the characteristics of UI among symptomatic women after 1 year • Corroboration with Edwall et all: 54 women with Stress UI – Estrogen decreased total collagen content, stimulated pelvic collagen degradation following administration to post-menopausal women Hendrix SL et al. JAMA 2005;293(8):935-948 Edwall et all. Neurourol Urodynam.200726:410-415 14
  15. 15. Systemic and Topical Hormone Therapies (Estrogens alone) Reduce Vaginal Innervation Density in Postmenopausal Women Griebling TL et al. Menopause 2012;19(6):630-635 15 Systemic Estrogens: 6 subjects Topical Estrogens: 5 subjects No HT: 9 subjects PGP: Pan-neuronal marker TH: Noradrenergic sympathetic fibers VIP: Cholinergic pelvic parasympathetic innervation NANC: non-adrenergic & non-cholinergic
  16. 16. Preclinical Observations of Androgenic Activities of DHEA in the Vagina of Animal Model 16
  17. 17. The androgenic action of DHEA is exerted on the 3 layers of the animal vagina • Increases thickness of the epithelium1,2,3,4,5,6,7,8 • Increases density of collagen fibers and thickness in the second layer (lamina propria)4,7 and nerve endings density by 60% • Stimulates muscular third layer7,8,9 and, specifically nerve endings9,10 • DHEA increases vaginal weight, an effect 50% related to estrogens and 50% due to androgens1 • DHEA increases androgen receptor density in the three layers1 1. Huggins et al., J. Exp. Med. 100, 225-243, 1954; 2. Ladinsky et al., J. Endocrinol 41, 161-169, 1968; 3. Mehrotra and Karkun, Indian J. Exp. Biol. 11, 1-6, 1973; 4. Kennedy and Armstrong, Steroids 27, 423-440, 1976; 5. Mori et al., Proc. Soc. Exp. Biol. Med. 199, 466-469, 1992; 6. Sourla et al., J. Ster. Bioch. Mol. Biol. 66, 137-149, 1998; 7. Berger et al., J. Ster. Bioch. Mol. Biol. 96, 201-215, 2005; 8. Berger et al., J. Ster. Bioch. Mol. Biol. 109, 67-80, 2008; 9. Pelletier et al., J. Sex Med. 9, 2525-2533, 2012; 10. Pelletier et al., J. Sex Med. 10, 1908-1914, 2013 17
  18. 18. Effect of the Androgenic Component of DHEA on Nerve Endings in the Rat Vagina DENSITY OF PGP 9.5 FIBERS 68%57% Pelletier, Ouellet et al., J Sex Med 10,1908-1914,2013. 18
  19. 19. Berger et al., J. Ster. Biochem. Mol. Biol. 96, 201-215, 2005 Estrogens + Androgens Estrogens + Androgens Estrogens + Androgens OVX + DHEA OVX + DHEA + ACOLBIFENE The androgenic and estrogenic action of DHEA in the animal vagina 19
  20. 20. Cynomolgus Monkey • Animal model closest to the human • Steroidogenic enzymes responsible for estradiol and testosterone formation from DHEA are present: –In the superficial layer of the stratified squamous epithelium –In blood vessel walls –In muscular fibers of the vagina • Androgen receptors present in the 3 layers of the vagina Bertin J. et al., Am J Obstet Gynecol 2014;211:e1-e9 20
  21. 21. Effect of androgens on women’s vagina: what do we know? • Very few data • Edwall et all: 54 women with stress UI • Serum testosterone may reflect an inhibitory effect of androgens on collagen degradation in urogenital tissue in SUI • Berman et all: • Androgen receptors (AR) are found in vaginal mucosa, lamina propria, smooth muscle and vascular endothelium. Expression was greater in lamina propria – Conclusion: androgens may play a role in regulating vaginal smooth muscle and vaginal blood flow • Baldassarre et al: • AR exist in the epithelium and stroma of the human vagina. Testosterone administration increased AR expression in both the mucosa and stroma • Increased AR may prepare the organ for sexual intercourse • Testosterone augment sensation and blood flow in the vagina1 21 Berman J et all. Fertil Steril 2003;79:925-31 1 Bodour et all Int J Impot Res 2005;17:399-408 Traish AM et allSex Med Rev 2018;6:558-571 Edwall et all. Neurourol Urodynam2007;26:410-415 Baldasarre et all Int J Impot Res 2013;52;7-11
  22. 22. 22 Pre-clinical data suggest that androgens and oestrogens have both overlapping and distinct roles in maintaining vaginal health1–3 The role of androgens in female genitourinary tissues is based predominantly on data from animal studies1 1. Traish AM et al. Sex Med Rev 2018 Apr 6. Oct;6(4):558-571. 2. Labrie F et al. Menopause 2017;24(4):452–61. 3. Goldstein I et al. Sex Med 2013;1(2):44–53. 4. Berger et al, J. Ster. Biochem. Mol. Biol. 96, 201-215, 2005 Stimulation of the surface area of the nerve ending of rat vaginas appears to be exclusively androgenic2 Testosterone, independently from oestradiol, has been shown to modulate vaginal wall contractility in rats3 Oestrogen stimulates glycogen production by vaginal epithelium. Epithelial cells are shed into lumen. Glycogen is hydrolysed to glucose and metabolised by Lactobacilli into lactic acid, which maintains pH at 3.5–4.53 Adapted from Traish AM et al, 2018, Labrie F et al, 2017 and Goldstein I et al, 2013. ANDROGENIC area of action COMPLEMENTARY effects of androgens and estrogens ESTROGENIC area of action Vaginal nerve area and density2 Vaginal wall contractility3 Increase in collagen compactness4 Vaginal pH3Vaginal epithelium, lamina propria and muscularis2 Vaginal perfusion1 DHEA also stimulates collagen fiber compactness of the lamina propria (second layer)—an effect essentially due to an androgenic effect
  23. 23. Female Sexual Function Index (FSFI) Intrarosa ® • All 6 domains of the FSFI questionnaire, namely desire, arousal, lubrication, orgasm, and pain were improved with DHEA (374 subjects) vs placebo (180 subjects) – Desire: 49 % increase; p= 0.0105 – Arousal: 56.8% increase; p= 0.0022 – Lubrication: 36.1% increase; p= 0.0005 – Orgasm: 33% increase; p= 0.047 – Satisfaction: 48.3% increase; p= 0.0012 – Pain: 41.3% improvement; p= 0.006 Labrie F. et al., J Sex Med 2015;12:2401-2402 23
  24. 24. Arousal / lubrication Sensitive fibers Desire Arousal / sensation Orgasm Prasterone-(androgenic) 24
  25. 25. Conclusion • DHEA makes estrogens and androgens intracellularly in the three layers of the vagina • DHEA has an exclusive androgenic action in the nerve endings possibly responsible for the positive effects of intravaginal DHEA on sexual dysfunction in women • With intravaginal DHEA, the serum levels of estradiol and testosterone always remain within normal values for postmenopausal women 25
  26. 26. TAKE HOME MESSAGE • The healthy vagina needs both androgens and estrogens to act on the 3 layers to mimic nature • A local therapy with both hormonal effects should be the appropriate therapy –Up to now, only Intrarosa® responds to this criteria • The sexual response needs adequate nerve response which is essentially of an androgenic nature 26

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