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MENOPAUSE

PHYSIOLOGY OF MENSTRUATION
The female has a fixed number of gamets for
her reproductive life.
7 million oogonia at 20 weeks gestatation
700 000 at the time of birth
400 000 by puberty
100 000 by 30 35 years of age

PHYSIOLOGY OF MENSTRUATION
AND MENOPAUSE
Relative changes in FSH
as a Function of Life Stages

Life Stages
Chidhood

FSH (mIU/mL)
<4

Reproductive years

6 10

Perimenopause

14 24

Menopause

> 30

PHYSIOLOGY OF MENSTRUATION
AND MENOPAUSE

A women ovulates approximately 400 oocytes


during her reproductive years.

During the reproductive cycle, a cohort of oocytes


is stimulated to begin maturation, but only 1 or 2
complete the process and are ovulated.

Menopause occurs when the residual follicles are


refractory to elevated concentration of FSH.

PERIMENOPAUSE
The period of 5 to 10 years before the menopause.
Symptoms:
Increasingly inefficient reproductive functions

Increasing of the FSH level


Decreases the frequency of ovulation

PHYSIOLOGY OF MENSTRUATION
AND MENOPAUSE
Steroid Hormone Serum Concentrations
Premenopausal
Women

Postmenopausal
Women

Postoophorectomy

Testosterone
(ng/dl)

325
(200 600)

230

110

Androstendione
(ng/dl)

1500
(500 - 3000)

800 900

800 900

Estrone
(pg/ml)

30 200

25 30

30

Estradiol
(pg/ml)

35 - 500

10 - 15

15 - 20

Hormone

MENOPAUSE
The permanent cessation of menses
The mean age of women at menopause is 51
years
Approximately 4% of women undergo a
natural menopause befor 40 year of age
premature ovarian failure.

MENOPAUSE
Menopause is a physiologic process,
however, the consequences of ovarian
failure can diminish a womans quality of
life and can predispose her to osteoporosis
and increased risk of cardiovascular
disease.

PHYSIOLOGY OF MENSTRUATION
AND MENOPAUSE

The postmenopausal ovary produces


testosterone and androstendione
primarily from stromal and hilar
cells

PHYSIOLOGY OF MENSTRUATION
AND MENOPAUSE
The major source of postmenopausal
estrogens is adrenal androgens,
particulary androstendione, which
undergoes aromatization by
peripherial tissues to estrone.

MENOPAUSE
1.

2.

CATEGORIES OF SYMPTOMS:
Vasomotor disturbances:
hot flushes, night sweats, palpitations headaches,
muscle aches
Organ atrophy:
- vaginal dryness, atrophy, dyspareunia
- urinary incontinence, dysuria, infections
- brest atrophy
- skin dryness and thinning, brittle nails

MENOPAUSE
3.

4.
5.

CATEGORIES OF SYMPTOMS:
Changes in mood and libido:
anxiety, insomnia, depression, irritability,
inability to concentrate, lack of energy
Accelerated bone mineral loss leading to
osteoporosis (long term)
Coronary artery disease (long term)

HORMONAL REPLACEMENT
THERAPY
The indication for HRT:

the treatment of climacteric symptoms

prevention of postmenopausal diseases


with individually tailored approach based
also on an individual risk-benefit score

HORMONAL REPLACEMENT
THERAPY
Types

of oestrogens

NATURAL
17-oestradiol
Oestradiol valerate
Oestrone piperazine
sulphat
Conjugated equine
oestrogens
Oestriol

SYNTHETIC
Ethinyloestradiol
Mestranol
Diethylstilboestrol
Dienoestrol

HORMONAL REPLACEMENT
THERAPY
Routes of estrogens administration

Oral
Transdermal
Intranasal
Transbucal
Transvaginal
Intravenous
Intramuscular

HORMONAL REPLACEMENT
THERAPY
Estrogens administration modes

Long-term high doses administartion

Pulsatile administartion

HORMONAL REPLACEMENT
THERAPY
Mechanism of estrogen action

Two different intracellular estrogen receptor


proteins: ER and ER
Different expression of ER and ER in different
target tissues and in different stages of
developement
Different binding affinity between the two
receptors for 17-estradiol, androgen metabolites,
phytoestrogens and estrogen agonist/antagonist

New possibilities in HRT


Different distribution of ER receptors in the
different target organs enabled to had
developed the group of selective estrogen
receptor modulators (SERM)
(Raloxifen)

HORMONAL REPLACEMENT
THERAPY
Estro
gens estrogens produce fewer metabolic
The natural
side effects than synthetic
Synthetic estrogens with a steroid structure (i.e.
ethinyl estradiol) are most frequenty used in
oral contarception
Conjugated equine estrogens in use mostly in USA
Native human estrogens (i.e. 17-estradiol) or
estradiol valerate mostly in use in Europe

RISK FACTORS OF ATHEROSCLEROSIS AND


CIRCULATORY SYSTEM DISEASES AND THE
RESPONSE TO THE ESTROGEN REPLACEMENT
THERAPY
Postmenopause
physiology

Estrogen supplementation
Oral
TTS

Arterial resistance
Uterine artery
Carotid artery

Estrogen influence on serum lipid level


according to routs of administration
Postmenopause
physiology
Total cholesterol
HDL
LDL
VLDL
Triglyceride

Oral TTS

0/

RISK FACTORS OF ATHEROSCLEROSIS AND


CIRCULATORY SYSTEM DISEASES AND THE
RESPONSE TO THE ESTROGEN REPLACEMENT
THERAPY
Postmenopause
physiology
HDL2

Ch-LDL

Triglyceride

Renine substrates

Blood preassure

Insulin basal level

Prostacycline

Procoagulant factors VII & X

Estrogene supplementation
Oral
TTS

0/
0/
0/
0/

0/

0/

ESTROGEN INFLUENCE ON
CARBOHYDRATE METABOLISM
Transdermal E2 administration decreases the basal
insulin level and increases insulin clearanse, when
administrated orally does not influence insulin turnover
E2 decreases insulin resistance, conjugated E interacts
equivocally
E2 is necessary, among others, to support pancreatic
insulin secretion

ESTROGEN REPLACEMENT
BENEFITS IN BONES
Estrogen therapy given for at least 5
years early in the climacteric period
reduces subsequent hip and Colles
fracture by 50% and vertebral fractures
by up to 90%.
Consensus Development Conference, Copenhagen, 1990

RISK FACTORS FOR


OSTEOPOROSIS
MAJOR:
Low bone density
High rate of bone loss
OTHER:
Genetic
Environmental
Lifestyle
Hormonal factors
Other diseases

RISK FACTORS FOR


OSTEOPOROSIS

GENETIC:
European or Asian race
Slender build
Previous osteoporotic fracture
Family history of osteoporosis
ENVIRONMENTAL:
Low exposure to sunlight

RISK FACTORS FOR


OSTEOPOROSIS

LIFESTYLE:
Low dietary calcium intake
Smoking
Chronic alcohol consumption
Sedentary lifestyle
HORMONAL FACTORS:
Early menopause
Nulliparity

RISK FACTORS FOR


OSTEOPOROSIS

OTHER DISEASES:
Liver disorders
Thyrotoxicosis
Hyperparathyroidism
Chronic debilitating illness
Prolonged immobility
Oral corticosteroid therapy
Postgastrectomy malabsorption states

HORMONAL REPLACEMENT
THERAPY
Types

of progestogens

19-Nortestosterone
Derivatives

Norethisteron acetate
Norethisteron
Levonorgestrel
Desogestrel
Gestodene
Lynestrol
Ethynodiol diacetate
Norgestimat

17-Hydroxyprogesterone
Derivatives

Medroxyprogesterone
acetate
Dydrogesterone
Megestrol acetate
Cyptoterone acetate
Medrogestone

HORMONAL REPLACEMENT
THERAPY
Progestogens

All progestogens are able to induce


secretory phase in the estrogen-primed
endometrium
Depending on their derivation they may
have androgenic and/or estrogenic effects
or antiandrogenic and/or antiestrogenic
effects

HORMONAL REPLACEMENT THERAPY


Biological activity of progestogens
Progestogen

Progestogenic
effect

Androgenic
effect

Estrogenic
effect

Antiestrogenic
effect

Progesteron

Dydrogesteron

Medroxyprogest
eron acetate

++

Cyproterone
acetate

++

Norethinodron

++

++

Levonorgestrel

+++

+++

++

Norgestimate

+++

++

Desogestrel

+++

++

Gestodene

+++

++

++

HORMONAL REPLACEMENT
THERAPY
Progestogens

According to their chemical structure,


progestogens have different effects on lipid
and carbohydrate metabolism
Progestogens may induce some adverse
metabolic effects to estrogens

HORMONAL REPLACEMENT
THERAPY
Adverse effects of HRT
(thromboembolism, coronary artery disease,
brest and endometrial cancer)
are higly related to the drugs, dosage, regimen or
route of administration used, and to duration
of use

CONTRAINDICATIONS TO HRT

Pregnancy
Lactation
Severe disturbances of liver functions
Jaundice or persistent itching during previous
pregnancy
Previous or existing liver tumours
Estrogendepended tumors of uterus, ovaries or brest
or suspicion of such tumours

CONTRAINDICATIONS TO HRT

Endometriosis
Existing or previous thromboembolic
processes
Severe diabetes mellitus with vascular
changes
Sickle-cell anaemia
Disturbances of lipo-metabolism

CONTRAINDICATIONS TO HRT

A history of herpes of pregnancy


Otosclerosis with deterioration during
pregnancy

REASONS FOR IMMEDIATE


DISCONTINUATION OF HRT

Occurrence for the first time of migrainous


headaches
More frequent occurrence of unusually
severe headaches
Sudden perceptual disorders
(vision or hearing)
First signs of thrombophlebitis or
thromboembolic symptoms

REASONS FOR IMMEDIATE


DISCONTINUATION OF HRT

Pain and tightness in chest


Impending operation (six weeks beforhand)
Immobilization
Onset of jaundice
Onset of hepatitis
Generalized pruritis

REASONS FOR IMMEDIATE


DISCONTINUATION OF HRT

Increase in epileptic seizures


Significant rise in blood pressure
Pregnancy

What to do when, because of


contraindications, the patient is not
suitable for HRT?

Taking nutritional advice to ensure balanced diet


with adequate calcium intake
Stopping smoking, and limiting alcohol
consumption
Exercising regularly to help maintain helthy
bones
Learning yoga or relaxation techniques to help
cope with hot flushes, anxiety or irritability