PATHOPHYSILOGY OF PATHOPHYSILOGY OF CLIMACTERIUMCLIMACTERIUM

DefinitionDefinitionss

MenopauseMenopause

PremenopausePremenopause

PostmenopausePostmenopause

PerimenopausePerimenopause

LAST MENSTRUAL PERIODLAST MENSTRUAL PERIOD

-4 -3 -2 -1 0 1 2 3 4 5 6 -4 -3 -2 -1 0 1 2 3 4 5 6

PREMENOPAUSEPREMENOPAUSE POSTMENOPAUSEPOSTMENOPAUSE

PERIMENOPAUSEPERIMENOPAUSE

PremenopausePremenopause

beginning - 45,1 years (39-51 )beginning - 45,1 years (39-51 )

mean time of duration 4 years (2-8 )mean time of duration 4 years (2-8 )

Treolar i wsp. ( study of 2700 Treolar i wsp. ( study of 2700 patients) patients)

Massachussets Women’s Health StudyMassachussets Women’s Health Study

median of the premenopausal median of the premenopausal period began 47,5 yearsperiod began 47,5 years

10% had no irregular ble10% had no irregular bleeedingding

Mean age of the menopause Mean age of the menopause occuring occuring

50,2 50,2 +/- 3,9+/- 3,9 years years

0

20

40

60

80

100

1850 1900 1950 2000

ŚR. CZAS ŻYCIA WIEK MENOPAUZY

FACTORS FLOWING IN ACCELERATE FACTORS FLOWING IN ACCELERATE OF MENOPAUSE OCCURINGOF MENOPAUSE OCCURING

Social and economical factors Social and economical factors MountainlifeMountainlife Smoking !!!Smoking !!! Lost of one ovary in reproductive ageLost of one ovary in reproductive age Multiple hyperstimulationsMultiple hyperstimulations Genetic factorsGenetic factors

FACTORS RETARDING OF FACTORS RETARDING OF MENOPAUSE OCCURINGMENOPAUSE OCCURING

Early menarche Early menarche Oral contraceptive Oral contraceptive Genetic factorsGenetic factors

HORMONAL CHANGESHORMONAL CHANGESpremenopausal periodpremenopausal period

FSH growthFSH growth Absence of LH pulsationAbsence of LH pulsation DecreaseDecrease level level of inhibin of inhibin Normal or even Normal or even sometimes sometimes increase increase

level level of E2 solidification of E2 solidification Decrease of progesteronDecrease of progesteron

Decline number of oocytes

decrease of inhibin production

FSHgrowth

first small increase of E2 and then decrease level of E2

HORMONAL CHANGESHORMONAL CHANGESpostmenopausal periodpostmenopausal period

High levels of FSH i LHHigh levels of FSH i LH Low level of E2Low level of E2 Comparatively growth E1Comparatively growth E1 LLess androgen levelsess androgen levels

AnrostendionAnrostendion

TestosteronTestosteron

DHEA i DHEASDHEA i DHEAS

70 - 80% 70 - 80% of womenof women have have symptoms because of symptoms because of

hypoestrogenism hypoestrogenism

SymptomsSymptoms

EarlyEarly vasomotorvasomotor somatic somatic pspsyycchical hical atrophicatrophic urinary incontinanceurinary incontinance

LateLate CVDCVD osteoporosisosteoporosis changes in central nervous systemchanges in central nervous system

SymptomsSymptoms

Vasomotor symptomsVasomotor symptomsHot flushesHot flushesDrenching sweatDrenching sweatNocturnal sweatNocturnal sweat

Somatic symptomsSomatic symptomsHeadache , dizzinessHeadache , dizzinessesesHard palpitatingHard palpitatingWeight gainWeight gainSleep disorderSleep disorderConstipationsConstipations

Psychical symptomsPsychical symptomsIrritabilityIrritabilityDepressionDepressionAttempts of weepingAttempts of weeping

Hot flushesHot flushes

They are the subjective sensation of intense They are the subjective sensation of intense warmth of the upper body and range warmth of the upper body and range duration from 30 seconds to 5 minutes. duration from 30 seconds to 5 minutes.

They frequently follow a prodrome of They frequently follow a prodrome of palpations or sensation of presure within palpations or sensation of presure within the headthe head

They usually end in sweating and cold They usually end in sweating and cold senasation senasation

The frequency varies from several per year The frequency varies from several per year to many per dayto many per day

Hot flushesHot flushes

Are result of withdrawal of Are result of withdrawal of estrogens in postmenopause , not estrogens in postmenopause , not from hypoestrogenism from hypoestrogenism per seper se

The loss of estrogen may cause a The loss of estrogen may cause a hypothalamic thermoregulatory hypothalamic thermoregulatory instabilisation instabilisation

They accompanyThey accompany natural, surgical natural, surgical and „medical” menopauseand „medical” menopause

Other reasons for hot Other reasons for hot flushesflushes

Carcinoid Carcinoid tumortumor LeukaemiaLeukaemia PheochromocytomaPheochromocytoma Thyroid diseases Thyroid diseases (thyreotoxicosis)(thyreotoxicosis) Stress Stress Psychosomatic disorders Psychosomatic disorders Drugs (nitroglicerine, nifedipine, Drugs (nitroglicerine, nifedipine,

vancomycin, corticotropin - releasing vancomycin, corticotropin - releasing hormone)hormone)

Atrophic symptomsAtrophic symptoms

Atrophic vaginitis Atrophic vaginitis Atrophic changes at external Atrophic changes at external

genitalsgenitals Urinary stress incontinence Urinary stress incontinence Detrusor overactivityDetrusor overactivity Atrophic urethritis and trigonitisAtrophic urethritis and trigonitis

Cardiovascular system and Cardiovascular system and estradiol influencingestradiol influencing

E2 has beneficial action on lipoprotein E2 has beneficial action on lipoprotein levelslevels

There is evidence that estrogens act There is evidence that estrogens act directly to promote vasodilatation ( the directly to promote vasodilatation ( the binding of estrogens to endothelial binding of estrogens to endothelial estrogen receptors could stimulate the estrogen receptors could stimulate the release of nitric oxide)release of nitric oxide)

Estrogens increasing levels of prostacyclin Estrogens increasing levels of prostacyclin and decreasing the levels of thromboxaneand decreasing the levels of thromboxane

Lipid metabolism Lipid metabolism disordersdisorders

LDL cholesterolLDL cholesterol and TG and TG levelslevels growth growth

Not big decrease of HDL cholesterol Not big decrease of HDL cholesterol levelslevels

Carbohydrate metabolism Carbohydrate metabolism disordersdisorders

We oftener observedWe oftener observed

HyperinsulinemiaHyperinsulinemia

Cellular insulin resistanceCellular insulin resistance

Diabetes IIDiabetes II

ESTROGENS CAN ACT ASESTROGENS CAN ACT AS

ANTIOXIDANT FACTORSANTIOXIDANT FACTORS

CARDIOVASCULAR DISEASESCARDIOVASCULAR DISEASES

PREMENOPAUSAL WOMEN APPEAR TO PREMENOPAUSAL WOMEN APPEAR TO BE PROTECTED AGAINST CVD BY BE PROTECTED AGAINST CVD BY THEIR TYPICALLY LOWER LDL LEVELS THEIR TYPICALLY LOWER LDL LEVELS AND HIGHER HDL LEVELS, COMPARED AND HIGHER HDL LEVELS, COMPARED WITH MEN IN THE SAME AGE WITH MEN IN THE SAME AGE

SYNDROM XSYNDROM X

Symptoms of coronary diseaseSymptoms of coronary disease Positive exercise testPositive exercise test Normal coronarogramNormal coronarogram

Kemp 1973 rokKemp 1973 rok

Postmenopausal osteoporosisPostmenopausal osteoporosis

Progressive reduction in bone mass Progressive reduction in bone mass in the first years after menopausein the first years after menopause

Most frequent fracturesMost frequent fracturesDistal radius 55 yearsDistal radius 55 years

Vertebral bodies 65 yearsVertebral bodies 65 years

Famoral neck 75 yearsFamoral neck 75 years

Postmenopausal osteoporosisPostmenopausal osteoporosis

Additional risk factorsAdditional risk factorsCigarettesCigarettes, , coffee, alcoholcoffee, alcohol

Low calcium and vit. D3 consumptionLow calcium and vit. D3 consumption

Low body mass indexLow body mass index

SedentarySedentary

High protein or phosphate dietsHigh protein or phosphate diets

Family history Family history

Postmenopausal Postmenopausal osteoporosisosteoporosis

DiagnosticDiagnosticMethod of choice: QDR (quantitive Method of choice: QDR (quantitive digital radiography)digital radiography)Excellent precision ( 1-2%)Excellent precision ( 1-2%)Lower radiation exposure than Lower radiation exposure than tomographytomographyMore precision method than ultrasound More precision method than ultrasound densitometry densitometry

Estrogens and CNSEstrogens and CNS

Facilitate to build the synapsesFacilitate to build the synapses Antioxidant peculiarities Antioxidant peculiarities Accelerate the blood flow in CNS Accelerate the blood flow in CNS Escalate metabolism in CNSEscalate metabolism in CNS Have positive influence on protein Have positive influence on protein

metabolism witch are connected with metabolism witch are connected with

Alzheimer DiseaseAlzheimer Disease ( (amyloidamyloid))

Alzheimer diseaseAlzheimer disease

more frequent at women than menmore frequent at women than men symptoms at women are more symptoms at women are more

severe severe hypoestrogenism is one of the most hypoestrogenism is one of the most

important factors involve in important factors involve in pathogenesispathogenesis

estrogen treatment relieving estrogen treatment relieving symptoms of these diseasesymptoms of these disease

Fertility in premenopausal periodFertility in premenopausal period

FSH > 20 IU/L oraz LH > 30 IU/LFSH > 20 IU/L oraz LH > 30 IU/L

IUDIUD

oral contraceptives with the lowest oral contraceptives with the lowest estrogen solidificationestrogen solidification

Benefits of OC use in the Benefits of OC use in the premenopausal periodpremenopausal period

frequency of endometrial cancerfrequency of endometrial cancer

frequency of ovarian cancerfrequency of ovarian cancer

mineral bone mass mineral bone mass

better control of bleedingbetter control of bleeding

PRACTICAL RECOMENDATIONS PRACTICAL RECOMENDATIONS

FOR HRT IN THE PRE AND FOR HRT IN THE PRE AND

POSTEMENOPAUSEPOSTEMENOPAUSE. .

Expert Workshop, February Expert Workshop, February 20042004

Teatment in the Teatment in the climacterium periodclimacterium period

ONLY WHEN THERE ARE ONLY WHEN THERE ARE INDICATIONS TO THE INDICATIONS TO THE

TREATMENTTREATMENT

Indications for HRTIndications for HRT

menopausal symptoms (autonomic menopausal symptoms (autonomic disturbances such as hot flushes, disturbances such as hot flushes, sweating, insomia, palpitations etc)sweating, insomia, palpitations etc)

atrophic changes in the urogenital atrophic changes in the urogenital tract and their consequences (EG tract and their consequences (EG vaginal dryness, dyspareunia , vaginal dryness, dyspareunia , urinary friquency )urinary friquency )

Indications for HRTIndications for HRT

Prevention and treatment of Prevention and treatment of postmenopausal osteoporosis postmenopausal osteoporosis

estrogens prevent postmenopausal bone loss estrogens prevent postmenopausal bone loss and reduce fracture riskand reduce fracture risk in symptomatic women treated with HRT , the in symptomatic women treated with HRT , the effect of bone mass is major additional benefiteffect of bone mass is major additional benefit

Premature menopause ( is associated Premature menopause ( is associated with ana accelerated risk of osteoporosis with ana accelerated risk of osteoporosis and probably coronary heart disease)and probably coronary heart disease)

Teatment in the climacterium Teatment in the climacterium periodperiod

estrogens with estrogens with progestogensprogestogens ( in ( in women in the intact uterus )women in the intact uterus )

only after total or subtotal only after total or subtotal hysterectomy estrogens alonehysterectomy estrogens alone

Initiation of treatment Initiation of treatment

Perimenopause Perimenopause progestogens, if menstrual disturbances progestogens, if menstrual disturbances are the main symptoms are the main symptoms HRT , if vasomotor symptoms have begun HRT , if vasomotor symptoms have begun or cycle regulation is neededor cycle regulation is needed OC (preferebly low dose) , if OC (preferebly low dose) , if contraception is also neededcontraception is also needed

Postmenopause – early initiation of Postmenopause – early initiation of HRT in symptomatic patients is HRT in symptomatic patients is major importancemajor importance

PRINCIPLE OF USE THE LOWEST PRINCIPLE OF USE THE LOWEST

EFFECTIVE DOSEEFFECTIVE DOSE

HRT DOSE RECOMENDATIONHRT DOSE RECOMENDATION

0,5-1 mg 17B-estradiol0,5-1 mg 17B-estradiol 0,3-45 mg conjugated equine 0,3-45 mg conjugated equine

estrogens estrogens 25-37,5 ug transdermal estradiol25-37,5 ug transdermal estradiol 0,5 estradiol gel0,5 estradiol gel 150 ug intranasal estradiol150 ug intranasal estradiol

( only in about 10% of patients higher ( only in about 10% of patients higher dose may be required)dose may be required)

DURATION OF DURATION OF TREATMENTTREATMENT

Indication, dose and type of HRT Indication, dose and type of HRT should be re-evaluated annuallyshould be re-evaluated annually

To relieve menopausal symptoms 2-3 To relieve menopausal symptoms 2-3 yearsyears

For the prevention or treatment For the prevention or treatment osteoporosis only long-term therapy is osteoporosis only long-term therapy is effective ( HRT may be initial option and effective ( HRT may be initial option and then could be followed by SERMs or then could be followed by SERMs or biphosphonatesbiphosphonates

To relieve symptoms of urogenital To relieve symptoms of urogenital atrophy –long-term topical treatmentatrophy –long-term topical treatment

DURATION OF TREATMENTDURATION OF TREATMENT

individually individually depend on symptomsdepend on symptoms no longer then 5-6 yearsno longer then 5-6 years exceptionally after 60 exceptionally after 60

ROUTES OF ROUTES OF ADMINISRTRATIONADMINISRTRATION

Oral Oral Non-oral (lack of the first-pass effect on the Non-oral (lack of the first-pass effect on the

liver ) ,may be preferable in women withliver ) ,may be preferable in women withHypertrigliceridemiaHypertrigliceridemia

Liver diseasesLiver diseases

Migraine headachesMigraine headaches

Increased risk of venous thrombosisIncreased risk of venous thrombosis

Vaginal estrogens for women with Vaginal estrogens for women with urogenital symptoms aloneurogenital symptoms alone

MONITORING TREATMENTMONITORING TREATMENT

Pretreatment assessment should Pretreatment assessment should include:include:

History and physical examinationHistory and physical examination WeightWeight Blood preasureBlood preasure

MammographyMammography Vaginal ultrasoundVaginal ultrasound Bone mineral densityBone mineral density

CONTRAINDICATIONSCONTRAINDICATIONS

Current, pass or suspected breast cancerCurrent, pass or suspected breast cancer Known or suspected estrogen-dependent Known or suspected estrogen-dependent

malignant tumorsmalignant tumors Undiagnosed genital bleedingUndiagnosed genital bleeding Untreated endometrial hyperplasiaUntreated endometrial hyperplasia Previous or current venous thromboembolismPrevious or current venous thromboembolism Active or recent arterial thromboembolic diseaseActive or recent arterial thromboembolic disease Untreated hypertensionUntreated hypertension Active liver diseaseActive liver disease Porphyria Porphyria Known hypersensivity to the active substances Known hypersensivity to the active substances

or to any of the excipiens or to any of the excipiens

Estrogen-progestin therapyEstrogen-progestin therapy

Sequence ( with bleeding)Sequence ( with bleeding)

continuouslycontinuously

cyclicallycyclically

Continuous without bleedingContinuous without bleeding

Sequence - continuouslySequence - continuously

28 days of estrogens28 days of estrogens10-12 days progestins10-12 days progestins

bleedingbleeding

Sequence - cyclicallySequence - cyclically

21 days of estrogens21 days of estrogens

10-12 days progestins10-12 days progestins

bleedingbleeding

ContinuousContinuous

28 days of estrogens28 days of estrogens

28 days progestins28 days progestins

HRT AND BREAST HRT AND BREAST CANCERCANCER

There is small increase in the incidence of There is small increase in the incidence of breast cancer in women onbreast cancer in women on long-term HRT long-term HRT with with estrogens or estrogen/progestogen combinationestrogens or estrogen/progestogen combination

There is no definite evidence of any differences There is no definite evidence of any differences between the various estrogens and between the various estrogens and progestogens in terms of their effect on the risk progestogens in terms of their effect on the risk of breast cancerof breast cancer

Tibolone also increased the riskTibolone also increased the risk The increased risk returns to the never-user of The increased risk returns to the never-user of

HRT after 5 years of discontinuation of HRT after 5 years of discontinuation of treatmenttreatment

Breast cancer associated with HRT have better Breast cancer associated with HRT have better prognosis prognosis

Low-dose vaginal estrogen treatment has not Low-dose vaginal estrogen treatment has not been reported to increase breast cancer riskbeen reported to increase breast cancer risk

HRT AND CARDIOVASCULAR HRT AND CARDIOVASCULAR RISKRISK HRT increases the risk of venous thromboembolic HRT increases the risk of venous thromboembolic

diseasesdiseases There is reported small increased risk for ischemic There is reported small increased risk for ischemic

stroke (WHI)stroke (WHI) Epidemiological results suggest a relationship Epidemiological results suggest a relationship

between estrogen dose and risk for between estrogen dose and risk for thromboembolic events and stroke, a decrese in thromboembolic events and stroke, a decrese in dose results decrease in the respective riskdose results decrease in the respective risk

HRT should not be used for secondary prevention HRT should not be used for secondary prevention of CVDof CVD

Estrogens may have favorable effect on the Estrogens may have favorable effect on the arteries if HRT is initiated soon after menopause arteries if HRT is initiated soon after menopause BUT !! Currently primary prevention of coronary BUT !! Currently primary prevention of coronary heart disease in not an indication for HRTheart disease in not an indication for HRT

BenefitsBenefits

osteoporosis preventionosteoporosis prevention vasomotor symptoms liquidationvasomotor symptoms liquidation atrophic symptoms liquidationatrophic symptoms liquidation decrease incidence of colon cancerdecrease incidence of colon cancer primary prevention of CVD ?primary prevention of CVD ?