“Terapia ormonale

sostitutiva in menopausa”

Prof. Cesare Battaglia

Menopause occurs when the ovarian

follicular pool is functionally

exhausted (Age/POF) or by surgical

removal of both ovaries

Differences in genetics, BMI, and body habitus may influence the estrogen and

androgen levels in post-menopause

The hypoestrogenic state may

affect estrogen target tissues

adversely including the brain,

skeleton, and skin as well as

the cardiovascular and

genitourinary systems

The concentrations and functions of

hormone receptors vary in these organs

and systems

Menopause occurs when the ovarian follicular pool

is functionally exhausted (Age/POF) or by surgical

removal of both ovaries

Differences in genetics, BMI, and body habitus may influence the estrogen and

androgen levels in post-menopause

The frequency and

severity of menopausal

symptoms and the

reaction of target tissues

to estrogen deficiency

significantly vary among

women

Women > 50 years

> 1.5 billion in 2030

12.5 / 60 millions (>20%)

Hormonal treatment (HT) of climacteric complaints is effective in

many women and may improve their quality of life

During the past years a prodigious amount of researches has taken place regarding advances in

postmenopausal women’s health, and it is reflected by equally extensive medical publications

In the early days of HRT it was believed that a woman could maintain her femininity and health

almost eternally by using estrogens

Traditionally, hormone

replacement therapy (HRT) has

been offered to aging women

Alleviation of vasomotor symptoms

Prevention of osteoporosis and fractures

Management of urogenital atrophy

Reduction of colon cancer

•Dementia

•Age-related macular degeneration

•Osteoarthritis

??? ???

1. Menopausal symptoms are tolerable

2. I don’t like taking medication

1. Weight gain

2. Breast tenderness or enlargement

3. Water retention/puffiness

4. Decrease in sex drive

5. Fear of endometrial/breast cancer

1. Physician didn’t think I needed them

2. Physician never brought this up

Patients convincements

Fear/side effects

Physician’s suggestions

Better compliants

1. Hystory of

hysterectomy

2. High level of education

3. High income

4. Previous OC users

HRT

48

41

28

25

USA UK Italy Thai

% HRT users

in 1990

During the past yrs a prodigious amount of researches has taken place

regarding advances in postmenopausal women’s health, and it is

reflected by equally extensive medical publications

Women Health Initiative

(JAMA, 2002)

Million Women Study

(Lancet, 2003)

???

• PATOLOGIE CARDIOVASCOLARI ( RR= 1.29)

•ICTUS (RR = 1.41)

•EMBOLIE POLMONARI ( RR = 2.13)

•CANCRO DELLA MAMMELLA ( RR = 1.26)

Pre WHI

(1990)

Post WHI

~ - 40%

HR

T i

n t

he

Worl

d

0

20

40

60

80

100

<6 mths 6-12

mths

12-18

mths

18-24

mths

>24 mths

Mean duration of the continous use of HRT (%)

6.7 %

1. Menopausal symptoms are now tolerable

2. I don’t like taking medication

1. Weight gain

2. Breast tenderness or enlargement

3. Water retention/puffiness

4. Decrease in sex drive

5. Fear of developing endometrial/breast cancer

1. Physician didn’t think I needed them

2. Physician never brought this up

Patients convincements

Fear/side effects

Physician’s suggestions

• Physician didn’t think I needed them

• Physician never brought this up

GynecologistG.P.

20%80%

Questionnaire: 52 specific questions with multiple answers

Menopause HRT

•GP (n°)

•Age (Yrs)

•Sex M vs F

(%)

1.287 136

47.5 48.2

77/23 67/33

Gynecol (n°)

Age (Yrs)

Sex M vs F (%)

Emilia-Romagna 2004-2008

Doc/Menopause/HRT

0

25

50

Decrease Increase Unchang ?

<E2 and Endometrial Ca

All data are expressed as %

*0

25

50

Decrease Increase Unchang ?

Gyn GP

<E2 and Breast Ca

*

Doc/Menopause/HRT

All data are expressed as %

0

25

50

75

Reduce Increase Unchang ?

Gyn GP

HRT and Endometrial Ca ?

0

25

50

Reduce Increase Unchang ?

HRT and Breast Ca ?

Doc/Menopause/HRT

0

25

50

75

<1 yr <5 yrs <10 yrs >10 yrs ?

Gyn GP

How long HRT ?

Doc/Menopause/HRT

1. Although Doctors correctly answered to many

questions, important cultural and comportamental errors

rose

2. The Experts need to better interact with GP and

General Gynecologyst

3. Formative and Informative meetings have to increase

and improve

4. It is mandatory that Doctors are not only informed by

Media and Industries

1. Menopausal symptoms are tolerable

2. I don’t like taking medication

1. Weight gain

2. Breast tenderness or enlargement

3. Water retention/puffiness

4. Decrease in sex drive

5. Fear of endometrial/breast cancer

1. Physician didn’t think I needed them

2. Physician never brought this up

Patients convincements

Fear/side effects

Physician’s suggestions

Better compliants

1. Hystory of

hysterectomy

2. High level of education

3. High income

4. Previous OC users

HRT

DROSPIRENONE

Is derived from spironolactone and

is, essentially, an

antimineralcorticoid progestin. In

addition, it has some

antiandrogenic actions.

In rats, the antimineralcorticoid activity was associated with reduction in

sodium and water retention due to partial suppression of the renin-

angiotensin-aldosterone system

Drospirenone has been associated with weight loss rather than weight gain

as observed in other HRT.

In a small randomised study in postmenopausal women with hypertension

treated with enalapril, Drospirenone produced an additive antihypertensive

effect.

Estranes:

-1,6

-1,2

-0,8

-0,4

0

0,4

0,8

1,2

Estradiol Angeliq

1 3 6 12 Mths

Kg

0

25

50

75

100

Abdom bloating Breast tendern Swelling of extrem

Improvement in severity of somatic

symptoms 6 mths after a HRT

switch

Weight modifications

0

20

40

60

80

Pre 8 12 16 Wks

Placebo EE+DRSP 1mg

EE+DRSP 2 mg EE+DRSP 3 mg

HOT FLASHES AND THERAPY

n°

N=15 N=15

0

40

80

120

160

Dia Mean Sys

Ang Act

8-24 h

mm

Hg6 Mths

0

40

80

120

160

Dia Mean Sys

Ang Act

24-8 h

mm

Hg

0

2

4

>140 >90 >140 >90 >120 >8024 h 8-24 h 24-8 h

%

mmHg

6 Mths Blood Pressure

Wake-up: 116±2 mmHg vs 120±3 mmHg; p=0.067

Ang

Act

34

36

38

40

42

44

Pre 30" 60" 120"

Act Ang

mm

Brachial Artery Flow-mediated

Vasodilation

Time Cuff-release

Normal flow-mediated vasodilation is approximately >10% using the

upper-arm occlusion technique

6 Mths

1

2

3

4

5

Pre 30" 60" 120"

Act Ang

PI

Brachial Artery Flow-mediated

Vasodilation

Time Cuff-release

The decreased vascular compliance may be attributable to nonenzymatic glycation of elastin and collagen in the tunica

6 Mths

1

1,5

2

Ang Act

PI

Ophthalmic Artery

Doppler Analysis

6 Mths

Traditionally, hormone

replacement therapy (HRT) has

been offered to aging women

Alleviation of vasomotor symptoms

Prevention of osteoporosis and fractures

Management of urogenital atrophy

Reduction of colon cancer

•Dementia

•Age-related macular degeneration

•Osteoarthritis

??? ???

POST-VOID URINE VOLUME

V= AxBxCx0.523

VOCAL

Sono AVC

Fattori organici

Il crollo degli estrogeni e degli androgeni possono: a) influenzare negativamente

il desiderio e la risposta sessuale; b) indurre atrofia dell’epitelio vaginale con

obliterazione dei fornici e delle pliche vaginali e conseguente accorciamento

della vagina (maggiore tendenza alle infezioni)

Fattori psicologico-culturali

La cessazione delle mestruazioni e la perdita della fertilità sono vissute dalla

donna come segnali di “definitivo” invecchiamento. Pertanto il sesso, di

esclusiva pertinenza ed interesse “giovanile” va assolutamente evitato

Frequenza

e Piacere

Sessuale

2-D Ultrasonography

H.E. O’Connell, J Urol 2005

• Less Expensive and time-consuming

•Equally accurate

•Noninvasive technique

Linear array transducer was placed

on the upper part of the vulva

3-D Ultrasonography

•Less Expensive and time-consuming

•Equally accurate

•Noninvasive technique

DOPPLER US and CLITORAL BLOOD FLOW

The Clitoris is highly vascularized, and many vessels branch out in each

clitoral artery structure

Color flow images of the dorsal clitoral

artery were sampled, in a longitudinal

plane, on the outer surface of the clitoral

body

The course of the

artery was always

detectable in the

clitoral

neurovascular

bundle

DOPPLER US and CLITORAL BLOOD FLOW

The Clitoris is highly vascularized, and many vessels branch out in each

clitoral artery structure

Color flow images of the dorsal clitoral artery were sampled, in a longitudinal

plane, on the outer surface of the clitoral body

Clitoral Artery

Clitoral Vascularization at Menopause: the role of HT

1.2

1.6

2.0

18-25 yrs >50 yrs

p<0.001

Dyspareunia was present

in 57% of >1 yr

menopausal womem

Clitoral Artery

1.2

1.6

2.0

18-25 yrs Angeliq

Clitoral Vascularization at Menopause: the role of HT

0

20

40

60

MFSQ Part MFSQ Sex

Pre Post

<0.001

0.002

Dyspareunia significantly decreased

after 6 mths HT

Estrogens restore normal vaginal pH as well as

thickness and revascularize the epithelium.

Furthermore, they positively affect the Vaginal

Maturation Index (increase of superficial cells

and decrease of parabasal cells) and alleviate the

subjective symptoms of atrophy (dryness,

irritation, pruritis, urinary urgency and

dyspareunia)

Angeliq and

Clitoral Body Volume evidenced no significant differences between Groups I and II patients neither at baseline (061

0.52 mL vs. 0.65 0.38 mL) nor at the end of the study (0.64 0.55 mL vs. 0.62 0.53 mL). The resistances registered at

the level of the Dorsal Clitoral Artery did not show any differences between Group I and Group II before (1.75 0.44

vs. 1.64 0.35) and after the 3-month treatment (1.79 0.43 vs.1.65 0.29).

Genistein 45 mg/day

Labium Major

Labium Minus

Vaginal Introitus

Clitoral

Hood

A

B

L Maj

L Min

L Min

Clitoral Hood

Introitus

Labia Majora

Intro

itus

Labia Minora

C

La

bia

Min

ora

Labia Minora Vascularization

• Valutare se il calo della libido causa problemi

• Valutazione della componente psico-sociale

• Malattie croniche

• Depressione

• Anamnesi ginecologica completa

• Esame obiettivo ginecologico

• Biochimica: tiroide, anemia, PRL, profilo estrogenico

e androgenico

Management delle pazienticon calo della libido

• E vaginali -atrofia, lubrificazione

• E o EP sistemici alleviano i disturbi menopausali uro-ginecologici ma non agiscono

sulla libido

• P non benefici sfera sessuale

• T aumenta la libido, l’eccitazione e la risposta orgasmica

Approccio terapeutico

Total satisfying sexual activity at 24 weeks in

the preceding 7 days

Increased desire at 24

weeks

Donne in postmenopausa chirurgica in HRT

Donne in postmenopausa naturale

in HRT

• Tp cognitivo-comportamentale mancano studi controllati e

randomizzati

• DHEA non ci sono evidenze di efficacia

• Raloxifene non ha effetti sulla sfera sessuale

• Tibolone possibile alternativa a E+T ma servono ulteriori dati

• Flibanserin 100 mg/gg (5-HT1A agonista/5-HT2A antagonista) migliora

HSDD

• Mirtazapina (antagonista R 5HT e α2-adrenergici) migliora HSDD

nelle donne depresse ma può far nascere nuovi problemi sessuali

• Bupropione (inibitore della ricaptazione di NA e D) migliora libido,

eccitazione e orgasmo

• Bremelanotide (agonista R melanocortina) migliora desiderio e

eccitazione in donne in pre-menopausa

Ci sono alternative alla terapiaandrogenica?

Donne in

premenopausa con

HSDD

50 mg/gg

Flibanserin a tutte

Flibanserin: open label phase (sett 0-24) R Nappi

“Terapia ormonale sostitutiva in menopausa”

Prof Cesare Battaglia

Conclusions

Hormonal treatment (HT) of climacteric complaints has a low cost

and is effective in many women and may improve their quality of

life:

• Alleviation of vasomotor symptoms

• Prevention of osteoporosis and fractures

• Management of urogenital atrophy

Alternative methods as Laser Theraphy