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 Reproductive years Perimenopause Menopause FSH (mIU/mL) < 4 6 – 10 14 – 24 > 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 Hormone Testosterone (ng/dl) Androstendione (ng/dl) Estrone (pg/ml) Estradiol (pg/ml) Premenopausal Women 325 (200 – 600) 1500 (500 - 3000) 30 – 200 Postmenopausal Women 230 800 – 900 25 – 30 Postoopho rectomy 110 800 – 900 30 35 - 500 10 - 15 15 - 20

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 woman’s quality of life and can predispose her to osteoporosis and increased disease.” risk of cardiovascular

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 .

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MENOPAUSE

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

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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 Ty

pes 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 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 Arterial resistance

Postmenopause physiology

Uterine artery Carotid artery  

E strogen supplementation Oral TTS

   

Estrogen influence on serum lipid level according to routs of administration

Total cholesterol HDL LDL VLDL Triglyceride Postmenopause physiology     

Oral

    

0/



TTS

    

RISK FACTORS OF ATHEROSCLEROSIS AND CIRCULATORY SYSTEM DISEASES AND THE RESPONSE TO THE ESTROGEN REPLACEMENT THERAPY HDL2 Ch-LDL Triglyceride Renine substrates Blood preassure Insulin basal level Prostacycline

Postmenopause physiology

       Procoagulant factors VII & X

Estrogene supplementation Oral TTS

        0/  0/  0/  0/  0/    0/  

ESTROGEN INFLUENCE ON CARBOHYDRATE METABOLISM • Transdermal E 2 administration decreases the basal insulin level and increases insulin clearanse, when administrated orally does not influence insulin turnover • E 2 decreases insulin resistance, conjugated E interacts equivocally • E 2 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    Family history of osteoporosis ENVIRONMENTAL:  Slender build Previous osteoporotic fracture 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 Ty

pes 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 Progesteron Dydrogesteron Medroxyprogest eron acetate Cyproterone acetate Norethinodron Progestogenic effect

+ + ++ ++

Levonorgestrel Norgestimate Desogestrel Gestodene

++ +++ +++ +++ +++

Androgenic effect

_ _ _ _ ++ +++ + + +

Estrogenic effect

+

Antiestrogenic effect

+ + + + ++ ++ ++ ++ ++

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