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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 FSH (mIU/mL)Chidhood < 4

Reproductive years 6 – 10

Perimenopause 14 – 24

Menopause > 30


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


Hormone Premenopausal Women

Postmenopausal Women

Postoopho-rectomy

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

Steroid Hormone Serum Concentrations

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”.

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„Menopause is a physiologic process, however, the consequences of ovarian failure can diminish a woman’s quality of life and can predispose her to osteoporosis and increased risk of cardiovascular disease.”


The postmenopausal ovary produces testosterone and androstendione primarily from stromal and hilar cells


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

MENOPAUSECATEGORIES OF SYMPTOMS:

1. Vasomotor disturbances: hot flushes, night sweats, palpitations headaches, muscle aches

2. Organ atrophy:- vaginal dryness, atrophy, dyspareunia - urinary incontinence, dysuria, infections- brest atrophy- skin dryness and thinning, brittle nails

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CATEGORIES OF SYMPTOMS:3. Changes in mood and libido:

anxiety, insomnia, depression, irritability, inability to concentrate, lack of energy

4. Accelerated bone mineral loss leading to osteoporosis (long term)

5. 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 THERAPYTypes of oestrogens

NATURAL 17-oestradiol Oestradiol valerate Oestrone piperazine

sulphat Conjugated equine

oestrogens Oestriol

SYNTHETIC Ethinyloestradiol Mestranol Diethylstilboestrol Dienoestrol

HORMONAL REPLACEMENT THERAPYRoutes of estrogens administration

Oral Transdermal Intranasal Transbucal Transvaginal Intravenous Intramuscular

HORMONAL REPLACEMENT THERAPYEstrogens administration modes

Long-term high doses administartion

Pulsatile administartion

HORMONAL REPLACEMENT THERAPYMechanism 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 THERAPYEstrogens

The natural estrogens produce fewer metabolic

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 Estrogen supplementation

physiology Oral TTS

Arterial resistance

Uterine artery Carotid artery

Estrogen influence on serum lipid level according to routs of administration

Postmenopause

Oral TTS

Total cholesterol HDL LDL VLDL Triglyceride 0/

physiology

RISK FACTORS OF ATHEROSCLEROSIS AND CIRCULATORY SYSTEM DISEASES AND THE

RESPONSE TO THE ESTROGEN REPLACEMENT THERAPY

Postmenopause Estrogene supplementation physiology Oral TTS

HDL2 Ch-LDL Triglyceride Renine substrates 0/Blood preassure 0/ 0/Insulin basal level 0/ Prostacycline 0/

Procoagulant factors VII & X 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 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

ESTROGEN REPLACEMENT BENEFITS IN BONES

RISK FACTORS FOR OSTEOPOROSIS

MAJOR:Low bone densityHigh rate of bone loss

OTHER:GeneticEnvironmentalLifestyleHormonal factorsOther diseases


GENETIC: European or Asian race Slender build Previous osteoporotic fracture Family history of osteoporosis

ENVIRONMENTAL: Low exposure to sunlight


LIFESTYLE: Low dietary calcium intake Smoking Chronic alcohol consumption Sedentary lifestyle

HORMONAL FACTORS: Early menopause Nulliparity


OTHER DISEASES:

Liver disorders

Thyrotoxicosis

Hyperparathyroidism

Chronic debilitating illness

Prolonged immobility

Oral corticosteroid therapy

Postgastrectomy malabsorption states

HORMONAL REPLACEMENT THERAPYTypes 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 THERAPYProgestogens

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 THERAPYBiological activity of progestogens

Progestogen Progestogenic effect

Androgenic effect

Estrogenic effect

Antiestrogenic effect

Progesteron + _ +

Dydrogesteron + _ +

Medroxyprogesteron acetate

++ _ +

Cyproterone acetate

++ _ +

Norethinodron ++ ++ + ++

Levonorgestrel +++ +++ ++

Norgestimate +++ + ++

Desogestrel +++ + ++

Gestodene +++ + ++

HORMONAL REPLACEMENT THERAPYProgestogens

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


Endometriosis Existing or previous thromboembolic

processes Severe diabetes mellitus with vascular

changes Sickle-cell anaemia Disturbances of lipo-metabolism


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


Pain and tightness in chest Impending operation (six weeks beforhand) Immobilization Onset of jaundice Onset of hepatitis Generalized pruritis


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

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