New Pharmacology Compounds for Female Sexual
Transcript of New Pharmacology Compounds for Female Sexual
New PharmacologyCompounds for Female Sexual Dysfunction:
Peripheral Agents
www.sandiegosexualmedicine.com
Irwin Goldstein MDDirector, Sexual Medicine, Alvarado Hospital, San Diego, CaliforniaClinical Professor of Surgery, University of California, San DiegoEditor-in-Chief, The Journal of Sexual MedicineInterim Editor-in-Chief, Sexual Medicine Reviews
Pharmacology:
branch of medicine and biology concerned with study of drug action where a drug can be broadly defined as any man-made, natural, or endogenous (within the cell) molecule which exerts a biochemical and/or physiological effect on the cell, tissue, organ, or organism
Sexual Pharmacology
Peripherally – Acting Hormones Vestibular and Vaginal Estradiol Vestibular and Vaginal Estradiol and TestosteroneIntravaginal DHEA
Peripherally – Acting Non-HormonesVasodilatorVasoconstrictorSkeletal Muscle RelaxantsPain ManagementOther
Sexual Pharmacology – Peripheral Agents
Genitourinary Syndrome of Menopause
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
Members of the consensus conference agreed that the term genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing, and publicly aceptable term than vulvovaginal atrophy.
JSM in print
• 45% post-menopausal & currently or previously experienced Vulvo-Vaginal Atrophy VVA/GSM sx
• 4% attributed sx to GSM/VVA; • 63% failed to recognize GSM/VVA as chronic• 75% stated vaginal atrophy had negative impact• Trend away from oral, - toward topical hormones• Safety concerns, lack of MD recommendation
major reasons for discontinuing or not using
Santoro N, Korni J. Sex Med 2009;6:2133‐2142.Nappi RE, Kokot‐Kierepa M. Climacteric 2012; Early Online 1‐9.
Vulvo-Vaginal Atrophy - Genito-Urinary Syndrome of Menopause
Local Vaginal Estrogen
• Much lower doses of estrogen applied vaginally are effective with minimal elevation of serum estradiol levels
• In one study, use of local vaginal cream was associated with better symptom relief than oral dose, even with lower systemic levels seen
Long CY, Liu CM, Hsu SC et al Menopause 2006;13:737-743. Tsai CC, Semmens JP, Semmens EC et al Br J HospMed1993;49:799-808.
Vaginal estrogen receptors are dependent in part on estradiol – inverse relationship compared to the uterus
Hormonal Treatment with Local Peripherally –Acting Estradiol
Differential Effects of Estradiol, Progesterone, andハTestosterone on Vaginal Structural Integrity
Monica A. Pessina, Richard F. Hoyt, Jr., Irwin Goldstein, and Abdulmaged M. TraishEndocrinology 147(1):61-69, 2005
Differential Effects of Estradiol, Progesterone, andハTestosterone on Vaginal Structural Integrity
Monica A. Pessina, Richard F. Hoyt, Jr., Irwin Goldstein, and Abdulmaged M. TraishEndocrinology 147(1):61-69, 2005
Peripherally – Acting Hormones Vestibular and Vaginal Estradiol Vestibular and Vaginal Estradiol and TestosteroneIntravaginal DHEA
Peripherally – Acting Non-HormonesVasodilatorVasoconstrictorSkeletal Muscle RelaxantsPain ManagementOther
Sexual Pharmacology – Peripheral Agents
Glands of Littre
Positive External Controls for AR
Prostate sections
Hormonally Mediated Provoked Vestibulodynia
Vulvoscopy 10/5/12 Vulvoscopy 1/18/13
Most commonly caused by hormonal contraceptives (may not resolve just by stopping OCPs.)Other causes include: menopause, oophorectomy, hormonal control of endometriosis or hirsutism, breast-feeding, infertility treatments, treatment of breast cancer
Hormonally Mediated Provoked Vestibulodynia
Burrows LJ, Goldstein AT. Vulvodynia. J Sex Med 2008;5:5-15.
Diffuse vestibular tenderness of the entirevestibule
Ostia of glands are frequently erythematous
The vestibule may have a diffuse pallor with superimposed erythema
Low estradiol, low free testosterone, very high SHBG
Hormonally Mediated Provoked Vestibulodynia
Burrows LJ, Goldstein AT. Vulvodynia. J Sex Med 2008;5:5-15.
Treatment: Stop hormonal
contraceptivesSystemic testosterone
– ideal calculated free testosterone 0.8 ng/dl
Local to vestibule estradiol 0.02%/testosterone 0.1% in methylcellulose BID
Expect no improvement for 6 weeks, 30-40% by 12 weeks
Burrows LJ, Goldstein AT. Vulvodynia. J Sex Med 2008;5:5-15.
Hormonally Mediated Provoked Vestibulodynia
Peripherally – Acting Hormones Vestibular and Vaginal Estradiol Vestibular and Vaginal Estradiol and TestosteroneIntravaginal DHEA
Peripherally – Acting Non-HormonesVasodilatorVasoconstrictorSkeletal Muscle RelaxantsPain ManagementOther
Sexual Pharmacology – Peripheral Agents
INTRAVAGINAL DHEA
216 post-menopausal women with vaginal atrophy(ITT Population)
0.0% (Placebo; n=53)
0.25% (3.25 mg DHEA; n=53)
0.5% (6.5 mg DHEA; n=56)
1.0 % (13 mg DHEA; n=54)
Daily intravaginal application of one ovule for 12 weeks
0
70
80
0% 0.25% 0.5% 1.0%DHEA dose
%Day 12 weeks4 "8 "12 "
PARABASAL CELLS
60
NSp=0.83
p<0.0001
p<0.0001
p<0.0001VS PLACEBO
VS PLACEBO
VS PLACEBO
40
50
30
20
10
Labrie et al., Menopause 16, 907-922, 2009
0
70
0.5% DHEA
Day 112 weeks
60
vs baseline NS
p=0.83
vs placebo
p<0.0001
40
50
30
20
10
% parabasal cells
vs baseline NS
p=0.194
vs placebop<0.0001
0
8
10
6
2
4
% superficial cells
4
6
7
5
vs baselinep=0.0002
pH
0
1
2
3
vs placebop<0.0001
vs baselinep=0.0033
Pain at sexual activity
Placebo 0.5% DHEA Placebo 0.5% DHEA Placebo 0.5% DHEA
vs placebo
p<0.0001
Placebo
Labrie et al., Menopause 16, 907-922, 2009
ENDOMETRIUMThe enzymes required to
transform DHEA into estrogens are absent in the endometrium
DHEA Vaginal changes
Desire – Arousal – Orgasm – Pleasure
Immunohistochemical staining of the fibers in the rat vagina
ISSWSH 2012- FL250112 33
INTACT OVX OVX + DHEA
E: EpitheliumLP: Lamina Propria (or Stroma)M: Muscle
: Stained TH fibers
LP
LPLP
M
M M
E
E
E
Peripherally – Acting Hormones Vestibular and Vaginal Estradiol Vestibular and Vaginal Estradiol and TestosteroneIntravaginal DHEA
Peripherally – Acting Non-HormonesVasodilatorVasoconstrictorSkeletal Muscle RelaxantsPain ManagementOther
Sexual Pharmacology – Peripheral Agents
Baseline state
Arousedstate
Baseline state
Arousedstate
Metabolic Syndrome
Arterial occlusive pathology in the ilio-hypogastric-pudendal arterial bed
vaginal lubrication vaginal wall pressuresvaginal length/widthclitoral blood flow
Pelvic genitalia
Park K, Goldstein I, Andry C, Siroky MB, Krane RJ, Azadzoi KM. Vasculogenic female sexual dysfunction: the hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency. Int J Impot Res. 1997 Mar;9(1):27-37.
Tarcan T, Park K, Goldstein I, Maio G, Fassina A, Krane RJ, Azadzoi KM. Histomorphometric analysis of age-related structural changes in human clitoral cavernosal tissue. J Urol. 1999 Mar;161(3):940-4.
2012
Based on limited current data, there appears to be an association between female sexual health and vascular risk factors (hypertension, hyperlipidemia, metabolic syndrome/obesity, diabetes, and coronary heart disease). More research is needed