HRT Current Concepts

8/13/2019 HRT Current Concepts

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HORMONE REPLACEMENT

THERAPY

EVIDENCE BASEDPRACTICE


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HIERARCHY OF EVIDENCECLINICAL EXPERIENCE

EXPERT OPINION, CONSENSUS OPINION

BASIC RESEARCH

TEST TUBE, ANIMAL, HUMAN PHYSIOLOGY

OBSERVATIONAL STUDIES

COHORT AND CASE-CONTROL STUDIES

INDIVIDUAL RCT

META-ANLAYSIS OF RCTs

SYSTEMATIC REVIEW OF RCTs


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MENOPAUSE

Permanent cessation of menstruationdue to loss of ovarian follicular function

Lack of ovarian hormonesDiagnosed retrospectively after 12months of amenorrhoea

Average age of menopause in Indiaranges from 43.5 to 48.5 yrs

Two decades of life in menopausal state


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PROBLEM IN INDIA

Life expectancy - 61 yrs

Women in menopausal age (50-59 yrs)

- 36 millionsRegional variation

by age 40

In Kerala - 8.2% menopausal

In AP - 37.6% menopausal

by age 50

In Kerala - 53% menopausal

In AP - 83% menopausal


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REACTION TO MENOPAUSE

A welcome change -

No bleeding and no risk of pregnancy

Relatively clean state and hence can attendreligious and social functions

Less psychological symptoms - joint family support

Low-fat, high calorie diet

Diet rich in soya products, milk productsAdequate exercise

gnorance is a bliss


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DEFINITIONS

Premenopause - Two yrs before cessationof periods

Perimenopause - 5 yrs before and 1 yr

after menopausePostmenopause - dates from final

menstrual period

Induced menopause - chemotherapy,radiotherapy or surgery

Climacteric - 2 yrs before and 5 yrs aftermenopause


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VASOMOTOR SYMPTOMS

Experienced by 50-75% womenOnly 25% suffer physical distress

Hot flushes & night sweats

Sudden, transient sensation rangingfrom warmth to intense heat thatspreads over the body, particularly onchest, face, and head. Accompanied by

flushing and perspiration, followed by achill

Lasts for 3-6 mins

Not very common in Indian women


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ENDOCRINOLOGY OF

VASOMOTOR SYMPTOMS

Estrogen influences thermoregulatory,

neural and vascular functionNo association with LH surge, episodicGnRH release.

Sudden decrease in estrogen levels

More marked in surgical menopause


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GENITAL SYMPTOMS

Dryness of vagina

Vaginal irritation

Vaginal dischargeRecurrent infections

Vulvovaginal pruritis

DyspareuniaPost-coital bleeding

Genital prolapse


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URINARY SYMPTOMS

Frequency

UrgencyNocturia

SUI

Urge incontinence

Recurrent UTI


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PSYCHOLOGICAL SYMPTOMS

Sustained change of mood

Inability to enjoy oneself

Presence of depressive thought processSexual dysfunction

Increased irritability

Reduced memory


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BONE AND OSTEOPOROSIS

ER- receptors in bone tissue

Postmenopausal osteoporosis - low

bone mass & micro architecturaldeterioration of bone tissue due toincreased bone resorption - increasedfracture risk

Indians have poor skeletal health

High prevalence of osteoporosis


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EVALUATION FOR

POSTMENOPAUSAL OSTEOPOROSISAll women over 65 yrs of age

Younger postmenopausal patients with

high risk factors Prior fracture

Tobacco use

Weight loss

Low body weight

Patients on long term glucocorticoid therapy

Suspicion of osteoporosis on plain X-Ray


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EVALUATION FOR

POSTMENOPAUSAL OSTEOPOROSISDXA Scan for Bone Mineral Density

Dual energy X-Ray absorptiometry of the hip and

spineFor every 1-SD decrease in age-adjusted BMD, the RR of fractureincreases by 2 fold

Consider pharmacotherapy for patientswith low BMD


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LONG TERM GENITAL EFECTS

Genital atrophy

Senile vulvovaginitisUV prolapse

Dyspareunia

Recurrent infections


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EFFECT ON

CARDIOVASCULAR SYSTEMCardioprotective role of estrogens iscontroversial

EPRT favourably affects lipid profileIt lowers LDL and raises HDL

But it increases triglycerides

It reduces antithrombin III & protein S(prothrombotic)

It increases levels of CRP - anindependent predictor of CAD


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EFFECT ON

CARDIOVASCULAR SYSTEM

Epidemiological and Observationalstudies have shown 35.5% reduction ofcardiovascular events inpostmenopausal women on traditionalHRT

Current evidence contrary to this(WHI trial, HERS I, HERS II)


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MISCELLANEOUS LONG

TERM EFFECTSSarcopenia

Age related Lens opacities

Menopausal gingivostomatitisThe reduction of collagen causesthinning of skin and wrinkling

The incidence of thinning of skin andwrinkling reduces by 30% in women ontraditional HRT


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WHY TREAT ?

MEDICALIZATION OF NORMALPHYSIOLOGICAL PROCESS

CHANGE OF LIFESTYLE DIETARY CHANGES

EXERCISE

REASSURANCE

MEDITATION

TREATMENT IMPROVES QUALITY OFLIFE


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THE IDEAL HRT

TREATS MENOPAUSAL SYMPTOMS

BENEFICIAL EFFECT ONCARDIOVASCULAR SYSTEM

LOW INCIDENCE OF BREASTTENDERNESS, NO INCREASE OF CABREAST

NO ENDOMETRIAL PROLIFERATIONTREATS VAGINAL ATROPHY

PREVENTS MENOPAUSAL BONE LOSS


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ESTROGENS

Premarin, Conjugated estrogens 0.625mg tab

Premarin cream (conjugated estrogen)

Evalon cream (Estriol succinate) 1 mg/gProgynova (Estradiol Valerate)

1 mg, 2 mg tab

Estraderm skin patch, self adhesivetransdermal. 0.75, 1.5, 3 mg

E 2 gel (estradiol 0.06% w/w)

Sandrena gel (estradiol 1 mg / satchet)


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PROGESTERONES

Deviry (medroxy progesterone acetate)2.5 mg, 10 mg tab

Regesterone ( Norethindrone acetate)1 mg, 5 mg tab

Microgest, Puregest (Micronised naturalprogesterone) 100 mg, 200 mg, 400 mg

tab


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TRADITIONAL HRT

NEED BASED CLASSIFICATION OF HRT

THERAPEUTIC/SYMPTOM RELIEF HRT

SHORT TERM. 2-3 YRSPREVENTIVE HRT

SHORT TERM UPTO 5 YRS

LONG TERM > 5 YRS


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TRADITIONAL HRT

Absence of uterus - continuos estrogenreplacement therapy (ERT)

In presence of uterus (EPRT)

SEPRT (addition of progesterones for 12-14 dayseach month)

Cyclic (estrogen D 1-25, progesterone D 12-25)

continuos (estrogen continuos, progesterone

D 12-25)

CCEPRT

Incidence of invasive carcinoma endometrium may

be increased


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TRADITIONAL HRT

HRT relayed treatment

HRT multimodal therapy

HRT with bisphosphonates and calcium HRT with antioxidants, micronutrients,

multivitamins, calcium


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PRE TREATMENT EVALUATION

Routine Physical Examination

Height

Weight

BP

Breast Examination

Pelvic Examination


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PRE TREATMENT EVALUATION

Routine Screening Examination

Mammography

TVS

Lipid Profile

LFT

Pap Smear


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CONTRA-INDICATIONS

Active endometrial and gynaecologicalhormone dependant cancers

Active breast cancer and estrogen progestogenreceptor positive cancers

Known or suspected pregnancy

Undiagnosed, abnormal vaginal bleeding

Severe active liver disease with

impaired/abnormal liver functionAcute vascular thrombosis

Estrogen dependent venous thrombosis

Inherent increased risk of thromboembolism


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CONTRA-INDICATIONS

Migraine headaches,

Superficial thrombophlebitisStrong family history of breast cancer

Uterine fibroids

EndometriosisGallbladder disease


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SIDE EFFECTS - ESTROGENS

Leg pain

Breast tenderness

HeadacheBloating

Nausea

DyspepsiaVaginal discharge


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SIDE EFFECTS

PROGESTOGENS - PHYSICALAcne

Bloating

BackacheBreast tenderness

Headache

DizzinessGreasy skin

Fatigue

Weight gain


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SIDE EFFECTS

PROGESTOGENS - PSYCHOLOGICALAnxiety

Confusion

DepressionForgetfulness

Irritability

Panic attacks

Poor concentration

Restlessness

Poor sleep


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ANDROGENS

Tab Testosterone undecanoate 40mg/day

Oral Micronised Testosterone 2.5mg/day

Gels, creams, transdermal matrixpatches


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ANDROGENS- INDICATIONS

Premenopausally oophorectomizedwomen, who continue to suffer from

decreased libido or reduced energylevels despite full dose ERT

Women who have not experienced reliefof vasomotor symptoms despite

maximally tolerated estrogen doseNatural menopause with unsatisfactorysexual function, especially loss of libido


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ANDROGENS

Maximum duration 6-9 mths

No long term studiesTibolone can be an alternative


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DESIGNER ESTROGENS

SERMS

RALOXIFENE

ORMILOXIFENEGONADOMIMETIC

TIBOLONE

PHYTO-ESTROGENS

ISOFLAVONES

LIGNANS

COUMESTROL


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THE IDEAL SERM

SITE ESTROGEN RALOXIFENE IDEAL SERM

BONE + + +

BREAST + _ _

UTERUS + _ _

CHD RISK + + +

VTE RISK + + _

MENOPAUSAL

SYMPTOMS

+ _ +

UROGENITAL

ATROPHY

+ ? +


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RALOXIFENE

Dose - 60 mg/day

Does not improve the vasomotorsymptoms of menopause, as well as the

symptoms of urogenital atrophyOsteoporosis prevention

Approved by USFDA for prevention and treatmentof osteoporosis in menopausal women

MORE trial (Multiple Outcomes of Raloxifene)

Increases bone mineral density

Reduced incidence of fracture


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RALOXIFENE

Effect on CVS

Favourable effect on lipid profile

RUTH trial (Raloxifene use for the heart), resultsexpected by 2005.

Reduction in cardiovascular risk

Effect on Endometrium

No stimulatory effect

Does not increase risk of endometrial hyperplasia


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RALOXIFENE

Effect on breast

Does not increase frequency of breast pain andtenderness

Reduces incidence of ER-positive breast tumours

Long term effects on breast not known

Contra-indicated for premenopausal

womenPrecipitate severe menopausalsymptoms


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TIBOLONE

Dose - 2.5 mg/day

Estrogenic, progestogenic and

androgenic activityTissue specific pharmacologic effects

Metabolites

-4 tibolone

3-OH tibolone

3-OH tibolone


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TIBOLONE - clinical use

Treatment of menopausal symptoms,both vasomotor and psychological

Beneficial effect on vaginal epithelium

Significant increase in Karyopyknoticindex

Reversal of atrophic vaginitis, reductionof vaginal dryness

Improvement of libido

Reduction of dyspareunia


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Effect on Bone Exerts estrogenic effects on bone

Effective in prevention and treatment ofosteoporosis

Increases bone mass

Prevents bone loss

Reduces the incidence of fractures

Effect on breast anti-estrogenic

Does not increase incidence of cancer breast

No long term trials


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Effect on Endometrium

No endometrial hyperplasia

No effect on endometriosis Does not increase fibroid size

No adverse effect on liver and renalfunction

No adverse effect on coagulation

Increases level of antithrombin III


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TIBOLONE - SIDE EFFECTS

Vaginal bleeding

Breast pain

HeadacheWeight gain

Edema

RashDepression


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PHYTOESTROGENS

Isoflavones - Soy

Dietary source

Soy

Lentils

Beans Legumes

Lignans - Flaxseed

Dietary source

Cereals

Fruits

Plant cell wall

Flaxseed oil


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PHYTOESTROGENS

Coumestans - Red Clover

Dietary source

Bean spouts

Sunflower seeds

Red clover

Weak estrogens. ER binding less than1% of estradiol

300 plants possess estrogenic activity


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PHYTOESTROGENS

Use of phytoestrogens associated with alower incidence of breast, endometrial,and colorectal cancer

Inhibitory effect on human cancer cellline

Decrease the intensity and frequency ofvasomotor symptoms

Placebo controlled trial suggest thatdaily intake of 60 gm/day soy protein isuseful in alleviating vasomotor

symptoms


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PHYTOESTROGENS

Does not alter the psychologicalsymptoms of menopause

Does not reduce symptoms of vaginalatrophy

Clinical trials have shown that theincidence of cardiovascular disease is

reduced

Favourable effect on lipid profile


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PHYTOESTROGENS

Prevention of osteoporosis iscontroversial. Data lacking

Dose - 40 mg isoflavone dailySide effects:-

acidity

abdominal cramping

constipation

allergic reaction


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HERBS

Turmeric

Cumin (jeera)

Saunf

Methi

Cardamom

Cinnamon

SaffronGinger

Ginseng


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BISPHOPHONATES

Antiresorptive drugs

Suppress bone resorption

improve bone mass reduce fracture risk

Alendronate

For prevention 5 mg/day or 35 mg/week

For treatment 10 mg/day or 70 mg/week

Double blind randomised, placebo controlled trialshave shown efficacy in increasing bone mass andreducing fracture incidence


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BISPHOPHONATES

The effect lasts for 2 years afterstopping the drug

Can be used safely for 7 years

Can be combined with HRT

Given along with calcium and Vit D


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CALCITONIN

Not enough evidence

Trials have shown some increase in

bone densityAvailable as inj 100 U s/c per day orNasal spray 200 U/day


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MICRONUTRIENTS &

ANTIOXIDANTSMicronutrients & antioxidants havedefinite beneficial effect on oxidativestress of menopausal women

Existing evidence supports increasedrequirement for Vitamins E, A, C andselenium. Recent evidence for increase

requirement of B1 and B6 is alsoaccumulating


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MICRONUTRIENTS &

ANTIOXIDANTS

A balanced diet with 59 servings offruits & vegetables can provide all themicronutrients & antioxidants

Heart and Estrogen/Progestin


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Heart and Estrogen/ProgestinReplacement Study (HERS I)

(JAMA 1998) Secondary prevention of coronary heart

disease

Included only women with a prior

history of CVD Average age - 67 years

Duration of the follow-up was 4.1 yearsamong 2763 women

Randomized to 0.625 mg of CEE plus 2.5mg of MPA, to placebo

Evaluate effects of HRT on fatal &

nonfatal CAD


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Mean Change in LDL, HDL and TriglycerideLevels by One Year

HERS

JAMA 1998: 280: 605-613

% change from baselineto year one

15

10

5

0

oestrogen-progestin

placebo

LDL-C HDL-C Triglycerides

-5

-10

-15

-20


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Incidence of Non Fatal MI and CHD DeathHERS

JAMA 1998: 280: 605-613

Incidence (%)

15

10

5

00 1 2 3 4 5

Follow-up (years)

oestrogen-progestinplacebo


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Despite improving the lipid

profile in women with CHD,

HRT did not improve theirsurvival


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HERS II RESULTS

(2002)The HERS II study reconfirms the absence of

secondary cardioprotection. However it

demonstrates no overall increased cardiac risk

with long term use.

Extension of HERS I study

Follow up of 6.8 yrs


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HRT & CA BREAST

Meta-analysis published in Lancet 1997

52,705 patients of breast cancer and

108,411 women without breast cancerwere evaluated retrospectively

Ever users for > 5 yrs had a relative riskof 1.35 and risk increased with increasing

duration of use

Collaborative Group on Hormonal Factors in Breast Cancer. Lancet; 1997; 350: 1047


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What was the WHI (The

Womens Health InitiativeStudy) all about?

JAMA, July 17, 2002 -- Vol 288, No. 3


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Objective

Assess the major health benefits and risks of the most commonly used

combined hormone

Design

First randomized placebo controlled primary prevention trial with oral

estrogen- progestin

Patient Population

16,608 postmenopausal women with intact uterus aged from 50 -79Interventions

0. 625mg Premarin & 2.5mg Provera (PremPro)

Main Outcomes

Coronary heart disease (nonfatal myocardial infarction and CHD death)Invasive breast cancer

Planned Duration

8. 5 years, however, stopped at 5.2 years on 31 Mar 2002

JAMA, July 17, 2002 -- Vol 288, N


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WHI TRIAL


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Monitored outcomesCoronary Heart Disease (CHD)Invasive Breast CancerStroke

Pulmonary Embolism (PE)Endometrial CancerColorectal CancerHip Fracture

Death due to other causesRisk ratio

calculated for

each condition

WHI TRIAL


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KAPLAN MEIER ESTIMATES


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CHD EVENTS

Relative risk - 1.29

Additional cases per 10,000 women/yr-7

Higher in the first yearWith another peak at year 5

Beneficial effect seen in year 6


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STROKE



Risk appeared during the 2nd

year and persistedthrough to 5thyear

Beneficial effect seen in the 6th year


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BREAST CANCER

Relative risk -


Significant risk after first 4 years.

Highest in the 5thyear .

Risk seemed to decline in the 6thyear.

Higher in women with prior use of hormones

No increase in in-situ form of breast cancer

Probably hastened detection of small existing

cancers


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PULMONARY EMBOLISM



Greatest in first 2 yearsWith a second peak at year 5

Beneficial effect seen in year 6.


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COLORECTAL CANCER


Less cases per 10,000 women/yr - 6

Beneficial effect seen in year 6.


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HIP FRACTURES


Less cases per 10,000 women/yr - 5


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ALL CAUSE MORTALITY

NOT INCREASED


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WHY DID THE TRIAL STOP ?

ESTROGEN - PROGESTIN ARM

crossed global index of 19/10,000

RISKS

CHD > 7

STROKES > 8

BREAST CANCER > 8

PE > 8

BENEFITS

COLORECTAL CA < 6

HIP FRACTURES < 5

RISK - BENEFIT ANALYSIS

~ 19 additional risks per 10,000 patient years


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ESTROGEN ONLY ARM

DID NOT REACH A RISK -

BENEFIT LEVEL OF CONCERN

HENCE CONTINUING

STUDY CONCLUDES ON 31 MAR 2005


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LIMITATIONS OF WHI TRIAL

The trial tested only one drug regimen and inone fixed dose only

The findings should not be extrapolated toother forms of therapy like tibolone, SERMs,phytoestrogens etc

The trial did not differentiate between the

effects of estrogen and the MPAThe results of this trial do not necessarilyapply to other routes of administration


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LIMITATIONS OF WHI TRIAL

The long term effects have not really beenassessed because of stopping the trial early

Some of the women participating in the trialhad either been past or current HRT userswith a family history of breast cancer

The mean age of women in this trial was 63.3

years. This is an older age group than theone which usually seeks HRT for symptomrelief


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HRT & CA OVARY

Short term Estrogen-Progestin only

replacement therapy does not increase risk of

ovarian cancer in women.

Women on Estrogen only (unopposedestrogen) therapy, particularly for 10 years ormore were at significant risk of ovariancancer.

Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer.

JAMA, July 17, 2002 Vol288, No3, 334-431


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ASYMPTOMATIC

MENOPAUSAL WOMEN

NO TREATMENT

S O C O S


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SYMPTOMATIC MENOPAUSAL

WOMENVASOMOTOR SYMPTOMS - TREAT

ONLY PSYCHOLOGICAL SYMPTOMS

- DO NOT TREAT CHANGE OF LIFE STYLE

DIETARY CHANGES

EXERCISE

MEDITATION



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WOMENHYSTERECTOMIZED PATIENT

ONLY ESTROGEN (ERT) 0.625 mg PREMARINDAILY

INTACT UTERUS

COMBINED ESTROGEN-PROGESTERONEREPLACEMENT THERAPY

0.625 mg PREMARIN + 2.5 mg DEVIRY DAILY 0.625 mg PREMARIN DAILY + 10 mg DEVIRY FOR

12 DAYS IN A MONTH

HOW LONG ?


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HOW LONG ?

ERT - Results awaited (Mar 2005)

More than 10 yrs - RR of Ca Ovary 2.0

EPRT

2 Years

Definitely not more than 4 years Taper off over 4 weeks ( every alternate day)

Stop during winter months

The increase in cardiac events in the first year inthe WHI trial could well be because the trial wasdealing with a mean age group of women whowere 63.3 years of age. Hence this data need notnecessarily apply to women in their 50s.


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HOW LONG ?

EPRT In the WHI trial the risk of pulmonary embolism is

greatest in the first 2 years and the risk of strokeappears in the 2ndyear. The women considering

HRT would need to be counseled regarding theseissues

If symptoms persist after withdrawal, consider:

Change of life style

Tibolone Phytoestrogens

Herbal treatment


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DO NOT START ERT/EPRT IN

THE SIXTH DECADE OF LIFEONWARDS


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DO NOT GIVE HRT FOR

PRIMARY OR SECONDARYCARDIOPREVENTION

OSTEOPREVENTIONTREATMENT OF OSTEOPOROSIS

PATIENT HESITANT FOR


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ERT/EPRTTIBOLONE

Effective in alleviating symptoms

Androgenic effects

No need for adding progestogens

Vaginal bleeding, depression

Costly

Long term randomised studies lacking



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ERT/EPRTPHYTOESTROGENS

Till further evidence is available, the use ofextracted phytoestrogen preparations cannot be

propagated. However consumption of naturalwhole food with high content of phytoestrogens isa good alternative until more scientific data isavailable

Do not alleviate psychological symptoms Do not improve urogenital symptoms

POSTMEONOPAUSAL


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POSTMEONOPAUSAL

OSTEOPOROSISPHARMACOTHERAPY FOR:-

TREATMENT OF OSTEOPOROSIS

PREVENTION OF OSTEOPOROSIS

BMD WITH T-SCORE < 2.0

BMD WITH T-SCORE < 1.0 WITH RISK

FACTORS OF OSTEOPOROSIS

POSTMEONOPAUSAL


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POSTMEONOPAUSAL

OSTEOPOROSISTAB ALENDRONATE

For prevention - 5 mg/day or 35 mg/week

For treatment - 10 mg/day or 70 mg/week

For 7-9 years

TAB RALOXIFENE

Dose 60 mg/day

Suitable in patients interested in breast cancer riskreduction

Does not alleviate menopausal symptoms

POSTMEONOPAUSAL


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POSTMEONOPAUSAL

OSTEOPOROSISTIBOLONE

Dose 2.5 mg/day

If patient has associated menopausal symptoms

ALL PATIENTS WITH LOW BMD GIVE:-

TAB CALCIUM 1200 mg - 1500 mg DAILY

TAB VIT D 400 IU - 800 IU DAILY

ONGOING IMPORTANT


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ONGOING IMPORTANTTRIALS

WHI- ESTROGEN ONLY ARM

WISDOM- Women International Studyof Long Duration Estrogen afterMenopause

RUTH- Raloxifene use for the Heart

MORE- Multiple outcomes of Raloxifene

evaluation

You do not heal old age


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You protect itYou promote itYou extend it Sir James Ross


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Documents

HRT Current Concepts