ORMONI E ORMONI E FERTILITA’

“L’evoluzione dell’ HRT”

Cesare Battaglia, Arianna Cianciosi

The Menopausal Transition begins at age 47 and takes about 4 yrs. It is unchanged during the centuries, but enviromental factors (i.e.

smoking) may alter the ovarian aging process

~ 51 yrs

~ 4 yrs

Premenopause

Progressive loss of functional follicles pool

The perimenopausal transition begins in the mid- late thirties and is related to a

granulosa cells compromise(Barri, 2000)

The granulosa cells have a reduced function indicated by decreased mitosis and increased

apoptosis(Seifer and Naftolin, 1996)

(spontaneous ovulation <5% and pregnancies ~ 0%)

Menopause occurs when the ovarian follicular pool is functionally

exhausted(Age/POF) or by surgical removal of both ovaries

The hypoestrogenic state may affect estrogen target tissues

adverselyincluding the brain, adverselyincluding 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

Differences in genetics, BMI, and body habitus may influence the estrogen and androgen levels in post-menopause

Menopause occurs when the ovarian follicular pool is functionally exhausted (Age/POF) or by surgical

removal of both ovaries

The frequency and severityof menopausal

symptoms and the

Differences in genetics, BMI, and body habitus may influence the estrogen and androgen levels in post-menopause

symptoms and the reaction of target tissues

to estrogen deficiency significantly vary among

women

Hot flushes

Sweat (nocturnal)

Anxiety

Sleep disturbances (chronic or transient):

Anxiety

Panic attack

Fatigue

Irritability

Inability to concentrate

Difficulty falling asleep

Early awakening

Trouble to resume sleep

Irregular sleep schedule

Libido

Vaginal lubrication

Premenstrual syndrome

Dispareunia

Vaginism

Genitourinary effects:

Incontinence

Nocturia

Vulvovaginal atrophy

After LMP there is a worsening of the premenopausal

symptomsFrontal cortex:

Cognition, Memory, Planning behavioral

Parietal cortex: Perception, Attention

Occipital cortex: visionTemporal cortex: Recognition, Memory

Cerebellum: motor coordination

Hypothalamus: Reproduction, Sexual

behavior, Thermoregulation, Feeding behavior

Hippocampus: short term memory

Amigdala: Emotion

After LMP there is a worsening of the premenopausal

symptoms

Thermoregulation

Serotonine

Feeding behavioir

Serotonine

Depressed mood

Serotonine

Noradrenaline

DOPA

β-endorphin

Noradrenaline

DOPA

β-endorphin

NPY

Noradrenaline

DOPA

GH reduction = 20-50% decrease in muscle mass

Initial increase of body fat followed by a 20% decrease

GH and Age

The anabolic effect of replacing GH can result in stimulated muscle development and strenght, a loss

of fat, and an increase in bone

mass.

Prl: no significant variations. Sometimes it is possible to observe a slight decrease

Thyroid: no significant variations in TSH values. With age there is an increase of thyroid disorders related to autoimmune diseases

Variable findings have been reported in regard the changes in circulating

androgens in relation to the FMP. However, the possible hirsutism may related to the

increased FAI

Adrenal gland and age

Cortisol unchange until advanced age. Then, because a higher nocturnal rhytmcity, there is a progressive increase with a further increase of sleep

disturbance and hypertension

DHEA

The data on enhancing insulin sensitivity and immune function, as well as quality of life, sex, mood and cognition are inconsistent. In addition, the correlation between elevated DHEA-S levels and better cardiovascular

survival, observed in men, was not found in women.

After 40ty % of women with coronary occlusions

% of plaque index of >3

C

V% of plaque index of >3

% of the intima media thickness (IMT)

V

D

HDL-C

LDL

Dyslipidemia

Triglycerides

HDL/triglycerides

3-7-fold Increased relative risk of CAD

Women > 50 years

> 1.5 billion in 2030

12.5 / 60 millions (>20%)

Hormonal treatment (HRT) 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

•Reduction of cardiovascular risk•Reduction of cardiovascular risk

•Prevention of osteoporosis and fractures

•Management of urogenital atrophy

•Reduction of colon cancer

•Dementia

•Age-related macular degeneration??? ???

% HRT users

4825

<15 % in 1990

41

28

USA UK Italy Thai

15

Women Health Initiative (JAMA, 2002)

Million Women Study (Lancet, 2003)

The picture of omnipotent and safe HRT was tarnished among physicians and mass media

RISCHI E BENEFICI DELL’HRT

• PATOLOGIE CARDIOVASCOLARI ( RR= 1.29)

•ICTUS (RR = 1.41)

•EMBOLIE POLMONARI ( RR = 2.13)

MAGGIORE INCIDENZA DI

•CANCRO DELLA MAMMELLA ( RR = 1.26)

MINORE INCIDENZA DI

•CANCRO DEL COLON -RETTO ( RR = 0.63)

•CANCRO DELL’ENDOMETRIO ( RR = 0.83)

•FRATTURE DA OSTEOPOROSI (RR = 0.66)

MA…IN QUESTO STUDIO CI SONO STATI

SOSTANZIALI ERRORI METODOLOGICI :

WHI

Età media 63.2 aaEtà media 63.2 aa

89% ha iniziato HRT dopo i 55 aa

BMI medio 28.5 (34% >30)

7% affetta da patologie cardiovascolari

37.5 % in terapia antipertensiva

19% usava aspirina come antiaggregante

41

25

48 15

Italy USA UK Thai

Pre WHI (1990-1995)

40

60

80

100

Mean duration of the continous use of HRT (%)

369

Post WHI~ - 40%

0

20

<6 mths 6-12mths

12-18mths

18-24mths

>24 mths

25

15

36

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

Patients convincements

Fear/side effects

3. Water retention/puffiness

4. Decrease in sex drive

5. Fear of developing endometrial/breast cancer becauseMedia

1. Physician didn’t think I needed them

2. Physician never brought this up

Physician’s suggestions

Although HT may improve a woman’s quality of life, each woman has a unique risk profile that might lead to more, or less, benefit

from HT.

Patient preferencesas well as evidence from medical research may influence management decisions

As a result

A standard treatment applied to all A standard treatment applied to all menopausal women will not necessarily meet

the needs of many individual women.

Health-care providers should, therefore, consider the balance between the benefits and risks of treatmentfor individual patient

and likelihood of adherence to the prescribed regimenbefore drawing conclusions or recommending HT

Progesterone or a progestin prevents the overproliferation of the endometrial tissue, but the degree of this effect depends upon its antiestrogenic properties and the dose and duration of treatment

In the last decades many speculations were provided on the role of ESTROGENS in HRT. As regards PROGESTINS, there was a general consensus that they are more or less similar and play a minor role in HRT. This oversimplification could

not have been further from the truth.

Proliferative

Secretive

Administration of progesterone/progestin for 12-14 dys/mth induces secretory/atrophic transformation of the endometrium

The effects of progestins are related to interaction not only with

Progesterone Receptors (PR) Estrogen Receptors (ER)

but also with:

Androgen receptors (AR)Glucocort Receptors (GR)Minercort Receptors (MR)

Which Progestins are New?By convention the older progestins are divided into three generations:

•Ist: Noretynodrel, Nortestosterone, 17-Hydroxyprogesterone derivatives

•IInd : Norgestrel and Levonorgestrel

•IIIrd : Levonorgestrel derivatives (Desogestrel, Gestodene, Norgestimate)

Most of the progestins in these 3 generations were derived from testosterone

Several New Progestins have been synthesized in the last decade for use in HRTs

The new progestins may be defined as a 4th generation: they were designed to bind very specifically to PR, and to exert no androgenic, estrogenic, or glucocorticoid adverse effects

• Pregnanes:Nestorone Progestational and antigonadotropinic

Nomegestrol AcetateAntigonadotropinic

Trimegestone Progestational

•Estranes: Dienogest Antiandrogenic

Drospirenone Antimineralcorticoid/Antiandrogenic

DROSPIRENONE

Is derived from spironolactone and is, essentially, an

antimineralcorticoid progestin. In addition, it has some

antiandrogenic actions.

Estranes:

antiandrogenic actions.

In rats, the antimineralcorticoid activity was associated with reduction in sodium and water retentiondue to partial suppression of the renin-

angiotensin-aldosterone system

Drospirenone has been associated with weight lossrather 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.

Estrogens

In those women who become hypertensive while taking

ethinylestradiol, thecompensatory fall in reninis incomplete, leading to large

aldosterone

Weight

Blood Pressure

incomplete, leading to large increases in the levels of plasma

renin activity, angiotensin II, aldosterone and blood pressure.

Natural progesterone is a strong aldosterone antagonist that acts on the mineralcorticoid receptors to prevent

sodium retention.

-1,6

-1,2

-0,8

-0,4

0

0,4

0,8

1,2

Estradiol Angeliq

KgWeight modifications

Estradiol Angeliq

1 3 6 12 Mths

0

25

50

75

100

Abdom bloating Breast tendern Swelling of extrem

Improvement in severity of somatic symptoms 6 mths after a HRT

switch

Drospirenonedoes not antagonize the benificial effect of estradiol on lipids. Angeliq® is

associated with favorable effects associated with favorable effects on total-cholesterol and LDL and has neutral effects with respect to

HDL-cholesterol

A dose-dependent effect in hypertensive w

omen

dependent effect in hypertensive wom

en

40

60

80

HOT FLASHES AND THERAPY

n°

0

20

40

Pre 8 12 16 Wks

Placebo EE+DRSP 1mgEE+DRSP 2 mg EE+DRSP 3 mg

80

100

%

Clinical efficacy for induction of complete amenorrhea/absence of spotting

60

3 6 12 wks

EE+DRSP 1mg EE+DRSP 2 mg EE+DRSP 3 mg

%

No cases of endometrial hyperplasia or carcinoma. 85-92% of women had an inactive/atrophic endoemtrium

Age >50 (51-56)

BMI <30 (22.5-27.5)

Multiparae (2-3)

Basal: before therapy

N=15 N=15No: dyslipidemia/diabetes/hypertension/

gynecological disorders

Drosp 2 mg + estr 1 mgNoretist Ac 0.5+ estr 1 mg

After 6 mths

Drosp 2 mg + estr 1 mgNoretist Ac 0.5+ estr 1 mg

40

80

120

160

Blood Pressure 24 H

Basal

0Dia Mean Sys

0

40

80

120

160

Dia Mean Sys

Ang Act

24-8 h

0

40

80

120

160

Dia Mean Sys

Ang Act

8-24 h

mm

Hg

mm

Hg

40

80

120

160Blood Pressure 24 H

6 Mths

0Dia Mean Sys

0

40

80

120

160

Dia Mean Sys

Angt Act

8-24 h

mm

Hg

0

40

80

120

160

Dia Mean Sys

Ang Act

24-8 h

mm

Hg

2

4

%

Basal Blood Pressure

0

2

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

mmHg

Wake-up: 118±4 mmHg vs 121±4 mmHg; p=0.058

Ang

Act

2

4

%

6 Mths Blood Pressure

0

2

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

mmHg

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

Ang

Act

Endothelial dysfunction is present in the earliest stage of vascular diseases

Dysfunctional endothelium can be identified by

reduced vasodilation or

vasoconstriction

Vasodilating

•Nitric Oxide

•Prostacyclin

•Bradykinin

•Hyperpolarizing Factor

Contracting

•Endothelin

•Thromboxane

•Angiotensin

equilibrium

40

42

44

Brachial Artery Flow -mediated Vasodilation

Normal flow-mediated vasodilation is approximately >10% using the upper-arm occlusion technique

Basal

34

36

38

40

Pre 30" 60" 120"

Act Ang

mm

Time Cuff-release

40

42

44

Brachial Artery Flow -mediated Vasodilation

Normal flow-mediated vasodilation is approximately >10% using the upper-arm occlusion technique

6 Mths

34

36

38

40

Pre 30" 60" 120"

Act Ang

mm

Time Cuff-release

4

5

Brachial Artery Flow -mediated Vasodilation

Basal

1

2

3

Pre 30" 60" 120"

Act Ang

PI

Time Cuff-release

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

4

5

Brachial Artery Flow -mediated Vasodilation

6 Mths

1

2

3

Pre 30" 60" 120"

Act Ang

PI

Time Cuff-release

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

2

Ophthalmic Artery

Doppler Analysis

1

1,5

Ang Act

PIBasal

2

Ophthalmic Artery

Doppler Analysis

1

1,5

Ang Act

PI6 Mths

Although no differences were found in HRT users

it would seem prudent to

CONCLUSIONS

it would seem prudent to reccomend lifestyle modifications (i.e. smoking, physical inactivity,

salt loading, job or marital/familial stress), particularly for obese

women