HORMONE REPLACEMENT THERAPY

EVIDENCE BASED PRACTICE

HIERARCHY OF EVIDENCE
CLINICAL 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 menstruation due to loss of ovarian follicular function Lack of ovarian hormones Diagnosed retrospectively after 12 months of amenorrhoea Average age of menopause in India ranges 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 millions Regional 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 attend religious and social functions Less psychological symptoms - joint family support Low-fat, high calorie diet Diet rich in soya products, milk products Adequate exercise

Ignorance is a bliss
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DEFINITIONS
Premenopause - Two yrs before cessation of periods Perimenopause - 5 yrs before and 1 yr after menopause Postmenopause - dates from final menstrual period Induced menopause - chemotherapy, radiotherapy or surgery Climacteric - 2 yrs before and 5 yrs after menopause
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VASOMOTOR SYMPTOMS
Experienced by 50-75% women Only 25% suffer physical distress Hot flushes & night sweats Sudden, transient sensation ranging from warmth to intense heat that spreads over the body, particularly on chest, face, and head. Accompanied by flushing and perspiration, followed by a chill 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 function No association with LH surge, episodic GnRH release. Sudden decrease in estrogen levels More marked in surgical menopause

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GENITAL SYMPTOMS

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Dryness of vagina Vaginal irritation Vaginal discharge Recurrent infections Vulvovaginal pruritis Dyspareunia Post-coital bleeding Genital prolapse

URINARY SYMPTOMS
Frequency Urgency Nocturia SUI Urge incontinence Recurrent UTI

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PSYCHOLOGICAL SYMPTOMS
Sustained change of mood Inability to enjoy oneself Presence of depressive thought process Sexual dysfunction Increased irritability Reduced memory

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BONE AND OSTEOPOROSIS

ER- receptors in bone tissue Postmenopausal osteoporosis - low bone mass & micro architectural deterioration of bone tissue due to increased bone resorption - increased fracture risk Indians have poor skeletal health High prevalence of osteoporosis
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EVALUATION FOR POSTMENOPAUSAL OSTEOPOROSIS

All women over 65 yrs of age Younger postmenopausal patients with high risk factors

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Prior fracture Tobacco use Weight loss Low body weight Patients on long term glucocorticoid therapy Suspicion of osteoporosis on plain X-Ray

EVALUATION FOR POSTMENOPAUSAL OSTEOPOROSIS

DXA Scan for Bone Mineral Density
Dual energy X-Ray absorptiometry of the hip and spine

For every 1-SD decrease in ageadjusted BMD, the RR of fracture increases by 2 fold Consider pharmacotherapy for patients with low BMD
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LONG TERM GENITAL EFECTS

Genital atrophy Senile vulvovaginitis UV prolapse Dyspareunia Recurrent infections

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EFFECT ON CARDIOVASCULAR SYSTEM

Cardioprotective role of estrogens is controversial EPRT favourably affects lipid profile It lowers LDL and raises HDL But it increases triglycerides It reduces antithrombin III & protein S (prothrombotic) It increases levels of CRP - an independent predictor of CAD

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EFFECT ON CARDIOVASCULAR SYSTEM

Epidemiological and Observational studies have shown 35.5% reduction of cardiovascular events in postmenopausal women on traditional HRT Current evidence contrary to this (WHI trial, HERS I, HERS II)
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MISCELLANEOUS LONG TERM EFFECTS

Sarcopenia Age related Lens opacities Menopausal gingivostomatitis The reduction of collagen causes thinning of skin and wrinkling The incidence of thinning of skin and wrinkling reduces by 30% in women on traditional HRT
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WHY TREAT ?
MEDICALIZATION OF NORMAL PHYSIOLOGICAL PROCESS
CHANGE OF LIFESTYLE DIETARY CHANGES EXERCISE REASSURANCE MEDITATION

TREATMENT IMPROVES QUALITY OF LIFE

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THE IDEAL HRT

TREATS MENOPAUSAL SYMPTOMS BENEFICIAL EFFECT ON CARDIOVASCULAR SYSTEM LOW INCIDENCE OF BREAST TENDERNESS, NO INCREASE OF CA BREAST NO ENDOMETRIAL PROLIFERATION TREATS VAGINAL ATROPHY PREVENTS MENOPAUSAL BONE LOSS
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ESTROGENS
Premarin, Conjugated estrogens 0.625 mg tab Premarin cream (conjugated estrogen) Evalon cream (Estriol succinate) 1 mg/g Progynova (Estradiol Valerate) 1 mg, 2 mg tab Estraderm skin patch, self adhesive transdermal. 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 natural progesterone) 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 YRS

PREVENTIVE HRT
SHORT TERM LONG TERM UPTO 5 YRS > 5 YRS

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TRADITIONAL HRT
Absence of uterus - continuos estrogen replacement therapy (ERT) In presence of uterus (EPRT)
SEPRT (addition of progesterones for 12-14 days each 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 gynaecological hormone dependant cancers Active breast cancer and estrogen progestogen receptor positive cancers Known or suspected pregnancy Undiagnosed, abnormal vaginal bleeding Severe active liver disease with impaired/abnormal liver function Acute vascular thrombosis Estrogen dependent venous thrombosis Inherent increased risk of thromboembolism
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CONTRA-INDICATIONS

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Migraine headaches, Superficial thrombophlebitis Strong family history of breast cancer Uterine fibroids Endometriosis Gallbladder disease

SIDE EFFECTS - ESTROGENS

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Leg pain Breast tenderness Headache Bloating Nausea Dyspepsia Vaginal discharge

SIDE EFFECTS PROGESTOGENS - PHYSICAL

Acne Bloating Backache Breast tenderness Headache Dizziness Greasy skin Fatigue Weight gain

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SIDE EFFECTS PROGESTOGENS - PSYCHOLOGICAL

Anxiety Confusion Depression Forgetfulness Irritability Panic attacks Poor concentration Restlessness Poor sleep

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ANDROGENS
Tab Testosterone undecanoate 40 mg/day Oral Micronised Testosterone 2.5 mg/day Gels, creams, transdermal matrix patches

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ANDROGENS- INDICATIONS
Premenopausally oophorectomized women, who continue to suffer from decreased libido or reduced energy levels despite full dose ERT Women who have not experienced relief of vasomotor symptoms despite maximally tolerated estrogen dose Natural menopause with unsatisfactory sexual function, especially loss of libido
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ANDROGENS
Maximum duration 6-9 mths No long term studies Tibolone can be an alternative

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DESIGNER ESTROGENS
SERMS
RALOXIFENE ORMILOXIFENE

GONADOMIMETIC
TIBOLONE

PHYTO-ESTROGENS
ISOFLAVONES LIGNANS COUMESTROL
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THE IDEAL SERM

SITE BONE BREAST UTERUS CHD RISK VTE RISK MENOPAUSAL SYMPTOMS UROGENITAL ATROPHY
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ESTROGEN + + + + + + +

RALOXIFENE + _ _ + + _ ?

IDEAL SERM + _ _ + _ + +

RALOXIFENE
Dose - 60 mg/day Does not improve the vasomotor symptoms of menopause, as well as the symptoms of urogenital atrophy Osteoporosis prevention
Approved by USFDA for prevention and treatment of 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), results expected 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 and tenderness Reduces incidence of ER-positive breast tumours Long term effects on breast not known

Contra-indicated for premenopausal women Precipitate severe menopausal symptoms

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TIBOLONE
Dose - 2.5 mg/day Estrogenic, progestogenic and androgenic activity Tissue 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 Karyopyknotic index Reversal of atrophic vaginitis, reduction of vaginal dryness Improvement of libido Reduction of dyspareunia
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TIBOLONE - clinical use

Effect on Bone
Exerts estrogenic effects on bone Effective in prevention and treatment of osteoporosis 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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TIBOLONE - clinical use

Effect on Endometrium
No endometrial hyperplasia No effect on endometriosis Does not increase fibroid size

No adverse effect on liver and renal function No adverse effect on coagulation Increases level of antithrombin III
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TIBOLONE - SIDE EFFECTS

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Vaginal bleeding Breast pain Headache Weight gain Edema Rash Depression

PHYTOESTROGENS
Isoflavones Dietary source Soy Lentils Beans Legumes

Soy

Lignans

Flaxseed

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Dietary source Cereals Fruits Plant cell wall Flaxseed oil

PHYTOESTROGENS
Coumestans
Dietary source Bean spouts Sunflower seeds Red clover

- Red Clover

Weak estrogens. ER binding less than 1% of estradiol 300 plants possess estrogenic activity
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PHYTOESTROGENS
Use of phytoestrogens associated with a lower incidence of breast, endometrial, and colorectal cancer Inhibitory effect on human cancer cell line Decrease the intensity and frequency of vasomotor symptoms Placebo controlled trial suggest that daily intake of 60 gm/day soy protein is useful in alleviating vasomotor symptoms

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PHYTOESTROGENS
Does not alter the psychological symptoms of menopause Does not reduce symptoms of vaginal atrophy Clinical trials have shown that the incidence of cardiovascular disease is reduced Favourable effect on lipid profile
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PHYTOESTROGENS
Prevention of osteoporosis is controversial. Data lacking Dose - 40 mg isoflavone daily Side effects:
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acidity abdominal cramping constipation allergic reaction

HERBS

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Turmeric Cumin (jeera) Saunf Methi Cardamom Cinnamon Saffron Ginger Ginseng

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 trials have shown efficacy in increasing bone mass and reducing fracture incidence

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BISPHOPHONATES
The effect lasts for 2 years after stopping 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 density Available as inj 100 U s/c per day or Nasal spray 200 U/day

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MICRONUTRIENTS & ANTIOXIDANTS

Micronutrients & antioxidants have definite beneficial effect on oxidative stress of menopausal women Existing evidence supports increased requirement for Vitamins E, A, C and selenium. Recent evidence for increase requirement of B1 and B6 is also accumulating
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MICRONUTRIENTS & ANTIOXIDANTS

A balanced diet with 59 servings of fruits & vegetables can provide all the micronutrients & antioxidants

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Heart and Estrogen/Progestin Replacement Study (HERS I)

(JAMA 1998)

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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 years among 2763 women Randomized to 0.625 mg of CEE plus 2.5 mg of MPA, to placebo Evaluate effects of HRT on fatal & nonfatal CAD

Mean Change in LDL, HDL and Triglyceride Levels by One Year HERS
% change from baseline to year one 15 10 5 0 -5 -10 -15 -20 LDL-C
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oestrogen-progestin placebo

HDL-C

Triglycerides JAMA 1998: 280: 605-613

Incidence of Non Fatal MI and CHD Death HERS

Incidence (%) 15 oestrogen-progestin placebo

10

0 0 1 3 2 Follow-up (years) 4 5

JAMA 1998: 280: 605-613

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Despite improving the lipid profile in women with CHD, HRT did not improve their survival

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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 cancer were evaluated retrospectively Ever users for > 5 yrs had a relative risk of 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 Initiative Study) 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 post- menopausal women with intact uterus aged from 50 -79 Interventions 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, No spsk

WHI TRIAL

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WHI TRIAL
Monitored outcomes

Coronary Heart Disease (CHD) Invasive Breast Cancer Stroke Pulmonary Embolism (PE) Endometrial Cancer Colorectal Cancer Hip Fracture Death due to other causes

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Risk ratio calculated for each condition

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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 year With another peak at year 5 Beneficial effect seen in year 6

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STROKE
Relative risk - 1.41 Additional cases per 10,000 women/yr-8 Risk appeared during the 2nd year and persisted through to 5th year Beneficial effect seen in the 6th year

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BREAST CANCER
Relative risk Additional cases per 10,000 women/yr-8 Significant risk after first 4 years. Highest in the 5th year . Risk seemed to decline in the 6th year. Higher in women with prior use of hormones

No increase in in-situ form of breast cancer

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Probably hastened detection of small existing cancers

PULMONARY EMBOLISM
Relative risk - 2.11 Additional cases per 10,000 women/yr-8 Greatest in first 2 years With a second peak at year 5 Beneficial effect seen in year 6.

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COLORECTAL CANCER
Relative risk - 0.63 Less cases per 10,000 women/yr - 6 Beneficial effect seen in year 6.

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HIP FRACTURES
Relative risk - 0.66 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

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~ 19 additional risks per 10,000 patient years

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 in one fixed dose only The findings should not be extrapolated to other forms of therapy like tibolone, SERMs, phytoestrogens etc The trial did not differentiate between the effects of estrogen and the MPA The results of this trial do not necessarily apply to other routes of administration
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LIMITATIONS OF WHI TRIAL

The long term effects have not really been assessed because of stopping the trial early Some of the women participating in the trial had either been past or current HRT users with 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 the one which usually seeks HRT for symptom relief
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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 (unopposed estrogen) therapy, particularly for 10 years or more were at significant risk of ovarian cancer.
Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer. JAMA, July 17, 2002 Vol288, No3, 334-431 spsk

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ASYMPTOMATIC MENOPAUSAL WOMEN

NO TREATMENT
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SYMPTOMATIC MENOPAUSAL WOMEN

VASOMOTOR SYMPTOMS - TREAT ONLY PSYCHOLOGICAL SYMPTOMS - DO NOT TREAT
CHANGE OF LIFE STYLE DIETARY CHANGES EXERCISE MEDITATION

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SYMPTOMATIC MENOPAUSAL WOMEN

HYSTERECTOMIZED PATIENT
ONLY ESTROGEN (ERT) 0.625 mg PREMARIN DAILY

INTACT UTERUS
COMBINED ESTROGEN-PROGESTERONE REPLACEMENT THERAPY 0.625 mg PREMARIN + 2.5 mg DEVIRY DAILY 0.625 mg PREMARIN DAILY + 10 mg DEVIRY FOR 12 DAYS IN A MONTH
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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 in the WHI trial could well be because the trial was dealing with a mean age group of women who were 63.3 years of age. Hence this data need not necessarily 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 stroke appears in the 2nd year. The women considering HRT would need to be counseled regarding these issues 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 LIFE ONWARDS

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DO NOT GIVE HRT FOR

PRIMARY OR SECONDARY CARDIOPREVENTION OSTEOPREVENTION TREATMENT OF OSTEOPOROSIS

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PATIENT HESITANT FOR ERT/EPRT

TIBOLONE
Effective in alleviating symptoms Androgenic effects No need for adding progestogens Vaginal bleeding, depression Costly Long term randomised studies lacking

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PATIENT HESITANT FOR ERT/EPRT

PHYTOESTROGENS
Till further evidence is available, the use of extracted phytoestrogen preparations cannot be propagated. However consumption of natural whole food with high content of phytoestrogens is a good alternative until more scientific data is available Do not alleviate psychological symptoms Do not improve urogenital symptoms
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POSTMEONOPAUSAL OSTEOPOROSIS
PHARMACOTHERAPY FOR: TREATMENT OF OSTEOPOROSIS PREVENTION OF OSTEOPOROSIS BMD WITH T-SCORE < 2.0 BMD WITH T-SCORE < 1.0 WITH RISK FACTORS OF OSTEOPOROSIS

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POSTMEONOPAUSAL OSTEOPOROSIS
TAB 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 risk reduction Does not alleviate menopausal symptoms
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POSTMEONOPAUSAL OSTEOPOROSIS
TIBOLONE
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

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ONGOING IMPORTANT TRIALS

WHI - ESTROGEN ONLY ARM WISDOM - Women International Study of Long Duration Estrogen after Menopause RUTH - Raloxifene use for the Heart MORE - Multiple outcomes of Raloxifene evaluation

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 You do not heal old age You protect it; You promote it;

You extend it. Sir James Ross

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