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