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Testosterone Therapy for Testosterone Therapy for Hypoactive Sexual Desire Hypoactive Sexual Desire DisorderDisorder


IntroductionIntroduction

Rationale for use

Combination estrogen-testosterone therapy

Testosterone use in women– Therapies available and under investigation

– Dosing/administration issues

– Clinical trials of testosterone use in women

– Managing side effects

Patient selection


Rationale for Testosterone TherapyRationale for Testosterone Therapy

Testosterone levels in women decline with aging– Women in their 40s have approximately one-half the level of

women in their 20s

Women who undergo oophorectomy experience dramatic decreases in the level of testosterone

– Level of testosterone decreases to one half of those prior to surgery

Zumoff B, et al. J Clin Endocrinol Metab. 1995;80:1429-1430.Judd HL, et al. J Clin Endocrinol Metab. 1974;39:1020-1024.


Rationale for Testosterone Therapy (cont’d)Rationale for Testosterone Therapy (cont’d)

Testosterone has been linked to sexual desire and coital frequency in menopausal women

Accumulating data indicate that testosterone therapy increases sexual function, including sexual desire, in postmenopausal women

McCoy NL, et al. Maturitas. 1985;7:203-210.Shifren JL, et al. N Engl J Med. 2000;343:682-688.Lobo RA, et al. Fertil Steril. 2003;79:1341-1352.


Combination Estrogen-Combination Estrogen-Testosterone TherapyTestosterone Therapy


Impact of Estrogen Deficiency Impact of Estrogen Deficiency on Sexual Functionon Sexual Function

Changes in urogenital anatomy– Shortening and loss of elasticity of the vagina

– Diminished secretions

– Increased pH

– Thinning of vaginal epithelial layers

Reduced blood flow

Reduced nerve transmission and discharge

Sleep disruption

Mood alterations

Sarrel PM. Obstet Gynecol. 1990;75:26S-30S.Bachmann GA, et al. Menopause. 2004;11:120-130.


Low Estrogen Is Associated With Low Estrogen Is Associated With Increased Prevalence of Sexual ProblemsIncreased Prevalence of Sexual Problems

Sarrel PM. J Womens Health Gend Based Med. 2000;9:S25-S32.Sarrel PM. Obstet Gynecol. 1990;75:26S-30S.

Per

cen

tag

e o

f W

om

en

Rep

ort

ing

Pro

ble

ms

0

10

20

30

40

50

60

70

VaginalDryness

Bothered byProblem

Dyspareunia(Intensity)

Pain WithPenetration

Burning

<50 pg/mL estradiol

>50 pg/mL estradiol

N=93; significance not reported.


Simon J, et al. Menopause. 1999;6:138-146.

N=93; *P≤0.05

EE=esterified estrogens; MT=methyltestosterone

Placebo Low-Dose EE

High-Dose EE

Low-Dose EE + MT

High-Dose EE + MT

Postplacebo run-in period

Month 1

Month 3

*

*

*

* *

**

*

Efecto de Terapia con Estrógenos and Estrógenos-Efecto de Terapia con Estrógenos and Estrógenos-Andrógenos sobre Síntomas menopaúsicosAndrógenos sobre Síntomas menopaúsicos


Testosterone Use in WomenTestosterone Use in Women


Testosterone Therapies Available Testosterone Therapies Available and Under Investigationand Under Investigation*

Oral– Methyltestosterone– Testosterone undecanoate

Intramuscular– Testosterone propionate– Testosterone cypionate– Testosterone enanthate

Subcutaneous (implant)– Testosterone propionate

pellets– Testosterone crystalline

pellets

Transdermal– Transdermal testosterone

patch– Testosterone gel– Testosterone emulsion– Testosterone spray

Other– Testosterone-containing

vaginal ring– Sublingual testosterone in

propylene glycol

* Not approved by US Food and Drug Administration for use in women.


Estrógenos y Enantato de Testosterona: Estrógenos y Enantato de Testosterona: Deseo sexualDeseo sexual

Sherwin BB, et al. Psychosom Med. 1987;49:397-409.

SemanasB 1 2 3 4

Estrógeno + TEControl

EstrógenoInyeccion

1

2

3

0

4

5N

ivel

es

med

ios

de

Des

eo

S

exu

al

N=65; TE=testosterona enantato


Davis SR, et al. Maturitas. 1995;21:227-236.

Estrogen

Estrogen + testosterone

Libido

Activity

Satisfaction

Pleasure

Fantasy

Orgasm

Relevancy

5 6 7 8 9 10Sexuality Score

(Means of 6, 12, 18, and 24 Months)

Summary Statistics

N=34

Estradiol and Testosterone Implants:Estradiol and Testosterone Implants:Sexual FunctionSexual Function


EE EE+MT Treatment difference

Total Testosterone (ng/dL)

Baseline

Change from baseline (mean serum concentration)

20.8 1.1

-0.1 7.4

18.9 8.4

-3.7 6.8 P=0.02

Bioavailable Testosterone (pg/mL)

Baseline

Change from baseline (mean serum concentration)

3.1 2.7

-0.3 2.4

2.7 1.5

2.0 2.0 P<0.010

Lobo RA, et al. Fertil Steril. 2003;79:1341-1352.


Estrogen and Methyltestosterone:Estrogen and Methyltestosterone:Effect on Testosterone Levels Effect on Testosterone Levels

N = 111 N = 107



*P<0.02 vs baseline

*

EE+MT (n = 107)

0

0.3

0.6

0.9

4 8 12 16

Study Week

Mea

n C

han

ge EE (n = 111)

Estrogen and Methyltestosterone:Estrogen and Methyltestosterone:Sexual DesireSexual Desire



Estrogen and Methyltestosterone:Estrogen and Methyltestosterone: Frequency of Interest/Desire Frequency of Interest/Desire


*P<0.02 vs baseline; †P<0.01 vs baselineStudy Week

EE+MT (n = 107)

EE (n = 111)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

4 8 12 16

Mea

n C

han

ge

*

† †



Estrogen and Methyltestosterone: Estrogen and Methyltestosterone: Sexual FunctioningSexual Functioning

Sarrel PM, et al. J Reprod Med. 1998;43:847-856.

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

Sensationand Desire

Sensation Desire Frequency VaginalChanges

EEEE+MT

Ch

an

ge

in R

aw

Sco

re F

rom

P

revi

ou

s H

orm

on

e T

he

rap

y

*

*

†

N=20; *P<0.01; †P≤0.05 EE=esterified estrogens; MT=methyltestosterone


Estrogen and Testosterone Patch: Estrogen and Testosterone Patch: Free and Bioavailable Testosterone LevelsFree and Bioavailable Testosterone Levels

Shifren JL, et al. N Engl J Med. 2000;343:682-688.

N=75; *P<0.001 for comparison with placebo

Endocrine Sciences normal range for cycling women

Placebo

Regimen (+CEE) 0

Regimen (+CEE)

1 2 3 4 5 6 7 8

Fre

e T

(p

g/m

L)

*

*

0

2

4

6

8

10

12

14

Bio

ava

ilab

le T

(n

g/d

L)

*

*

Baseline 300 mcg150 mcg

CEE=conjugated equine estrogens; T=testosterone



Baseline

300 mcg

150 mcg

Placebo

Thoughts/Desires

Frequency Pleasure/Orgasm

Problems

Per

cen

tag

e o

f N

orm

ativ

e M

ean

40

50

60

70

80

90

100

110

120

*

*

Arousal


Oral Estrogen and Testosterone Patch: Oral Estrogen and Testosterone Patch: Sexual FunctionSexual Function


Oral Estrogen and Testosterone Patch: Oral Estrogen and Testosterone Patch: Effect on Sexual Function Effect on Sexual Function

Author (Year) Population (N)

Treatment(Dose)

Outcome(at 24 Weeks)

Braunstein (2003)

SM, HSDD (N=447)

T patch (150, 300, 450 mcg/d)

Placebo patch

Desire Activity

Davis (2003) SM, HSDD (N=77)

T patch (300 mcg/d) Placebo patch

Desire Activity

Braunstein GD, et al. In: Program and abstracts of the 14th annual meeting of the North American Menopause Society; September 17-20, 2003; Miami Beach, Fla. Abstract 60.Davis S, et al. Fertil Steril. 2003;80(suppl 3):76.

SM=surgically menopausal; HSDD=hypoactive sexual desire disorder; T=testosterone


Oral Estrogen and Testosterone Patch: Oral Estrogen and Testosterone Patch: Effect on Sexual Function (cont’d)Effect on Sexual Function (cont’d)

Author (Year) Population (N)

Treatment(Dose)

Outcome(at 24 Weeks)

Simon (2004)

SM, HSDD (N=562)


Desire Activity

Buster (2004)

SM, HSDD (N=533)


Desire Activity

Simon JA, et al. Obstet Gynecol. 2004;103(suppl):64S.Buster J, et al. In: Program and abstracts of the 86th annual meeting of the Endocrine Society; June 16-19, 2004; New Orleans, La. Abstract OR44-6.

SM=surgically menopausal; HSDD=hypoactive sexual desire disorder; T=testosterone


Floter A, et al. Climacteric. 2002;5:357-65.

N=50; EV-estradiol valerate; TU-testosterone undecanoate*P<0.05 vs EV at 24 weeks

Estrogen and Testosterone Undecanoate: Estrogen and Testosterone Undecanoate: Sexual FunctionSexual Function

0

2

4

6

Mc

Co

y S

ex S

cale

Sc

ore

(M

ean

)

* EV

Baseline

**

EV + TU

Enjoyment of Sex

Satisfaction With Frequency of Sex

Interest in Sex


Potential Side Effects With Testosterone Potential Side Effects With Testosterone TherapiesTherapies

Hirsutism

Acne

Voice deepening

Alopecia

Liver toxicity

Negative effects on lipoproteins

Clitoromegaly


Side Effects in Studies With Side Effects in Studies With Testosterone Therapies Testosterone Therapies

Few side effects are reported in studies

Increased doses are associated with– Facial hair

– Acne/oily skin

Oral preparations– Decreases in high-density lipoprotein

• Not seen with transdermal preparations



0.0

0.5

1.0

1.5

2.0

2.5

Hirsutism

(Lorenzo Scale)

Acne

(Palatsi Scale)

Facial Depilation

(Times/Month)

Me

an

Sc

ore

(S

EM

)

Baseline 300 mcg

*

150 mcgPlacebo


Estrogen and Testosterone Patch: SafetyEstrogen and Testosterone Patch: Safety


Estrogen and Methyltestosterone: Safety Estrogen and Methyltestosterone: Safety

EE EE+MT

Hirsutism score

(Lorenzo scale)

Baseline score

Change from baseline at week 162.3 2.5

0.0 1.9

2.9 3.3

-0.4 2.2

Acne score

(Palatsi scale)

Baseline score

Change from baseline at week 160.1 0.4

0.2 0.5

0.2 0.5

0.1 0.5




Patient Selection Patient Selection

Testosterone therapy, in conjunction with estrogen therapy, may be indicated in women with:

– Surgical menopause

– Decreased libido

– Diminished sense of well-being

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