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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
‫٭‬ One third 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
‫٭‬ Disturbed sleep-irritability-depression
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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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Anatomical Changes
‫٭‬ Atrophy of genital organs
– ovary,
– fallopian tubes,
– Uterus,
– Cervix,
– vagina,
– labia
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GENITAL SYMPTOMS
‫٭‬ Dryness of vagina
‫٭‬ Vaginal irritation
‫٭‬ Vaginal discharge
‫٭‬ Recurrent infections
‫٭‬ Vulvovaginal pruritis
‫٭‬ Dyspareunia
‫٭‬ Post-coital bleeding
‫٭‬ Genital prolapse
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URINARY SYMPTOMS
(Urethral Syndrome)
‫٭‬ 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
‫٭‬ 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
– 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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Pathophysiology
‫٭‬ Balance between osteoblastic and
osteoclastic activity
‫٭‬ Accelerated bone loss after menopause
due to lack of estrogen
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Bone Formation & Bone resorption
Normal Osteoporosis
- BAD CELLS - GOOD CELLS
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EVALUATION FOR
POSTMENOPAUSAL OSTEOPOROSIS
‫٭‬ DEXA Scan for Bone Mineral Density
– Dual energy X-Ray absorptiometry of the hip and
spine
‫٭‬ For every 1-SD decrease in age-
adjusted 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
‫٭‬ Estrogen favourably affects lipid profile
‫٭‬ It lowers LDL and raises HDL
‫٭‬ Estrogen deficiency may lead to
atherosclerosis,IHD,MI
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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
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MISCELLANEOUS LONG
TERM EFFECTS
‫٭‬ 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
‫٭‬ Alzheimer disease
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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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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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Management of Menopause
‫٭‬ Counseling-Pregnancy and cancer
phobia
‫٭‬ Thorough clinical examination
‫٭‬ Contraceptive advice
‫٭‬ Diet
‫٭‬ Exercises
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Hormone Replacement therapy
‫٭‬ Estrogen
‫٭‬ Progesterone
‫٭‬ Androgens
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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
‫٭‬ Absence of uterus - continuos estrogen
replacement therapy (ERT)
‫٭‬ In presence of uterus (EPRT)
– 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)
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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
‫٭‬ Migraine headaches,
‫٭‬ Superficial thrombophlebitis
‫٭‬ Strong family history of breast cancer
‫٭‬ Uterine fibroids
‫٭‬ Endometriosis
‫٭‬ Gallbladder disease
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SIDE EFFECTS - ESTROGENS
‫٭‬ Leg pain
‫٭‬ Breast tenderness
‫٭‬ Headache
‫٭‬ Bloating
‫٭‬ Nausea
‫٭‬ Dyspepsia
‫٭‬ Vaginal discharge
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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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Other Drugs
‫٭‬ SERMS
– RALOXIFENE
– ORMILOXIFENE
‫٭‬ 19 nortestosterone derivative
– TIBOLONE
‫٭‬ PHYTO-ESTROGENS
– ISOFLAVONES
– LIGNANS
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Other Drugs
‫٭‬ Biphosphonates
‫٭‬ Herbs
‫٭‬ Micronutrients and antioxidants
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RALOXIFENE
‫٭‬ Dose - 60 mg/day
‫٭‬ Does not improve the vasomotor
symptoms of menopause, as well as the
symptoms of urogenital atrophy
‫٭‬ Important in 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
– 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
Side Effects-Hot Flushes
Contraindications-Venous thrombosis,hepatic
dysfunction
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TIBOLONE
‫٭‬ Dose - 2.5 mg/day
‫٭‬ Estrogenic, progestogenic and
androgenic activity
‫٭‬ Tissue specific pharmacologic effects
‫٭‬ Metabolites
– Δ-4 tibolone
– 3α-OH tibolone
– 3β-OH tibolone
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TIBOLONE - clinical use
‫٭‬ Treatment of menopausal symptoms,
both vasomotor and psychological
‫٭‬ Beneficial effect on vaginal epithelium
‫٭‬ 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
– ? 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
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TIBOLONE - SIDE EFFECTS
‫٭‬ Vaginal bleeding
‫٭‬ Breast pain
‫٭‬ Headache
‫٭‬ Weight gain
‫٭‬ Edema
‫٭‬ Rash
‫٭‬ Depression
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PHYTOESTROGENS
‫٭‬ Isoflavones - Soya
– 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 sprouts
• Sunflower seeds
• 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:-
– acidity
– abdominal cramping
– constipation
– allergic reaction
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HERBS
‫٭‬ Turmeric
‫٭‬ Cumin (jeera)
‫٭‬ Saunf
‫٭‬ Methi
‫٭‬ Cardamom
‫٭‬ Cinnamon
‫٭‬ Saffron
‫٭‬ Ginger
‫٭‬ 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 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 5–9 servings of
fruits & vegetables can provide all the
micronutrients & antioxidants
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‫٭‬ Menopause is ……….
not a pause,
…..It’s beginning of new
Life…………
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To be
continued
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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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Heart and Estrogen/Progestin
Replacement 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 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
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Mean Change in LDL, HDL and Triglyceride
Levels by One Year
HERS
JAMA 1998: 280: 605-613
% change from baseline
to 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 Death
HERS
JAMA 1998: 280: 605-613
Incidence (%)
15
10
5
0
0 1 2 3 4 5
Follow-up (years)
oestrogen-progestin
placebo
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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
Women’s 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
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WHI TRIAL
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• Monitored outcomes
– Coronary Heart Disease (CHD)
– Invasive Breast Cancer
– Stroke
– Pulmonary Embolism (PE)
– Endometrial Cancer
– Colorectal Cancer
– Hip Fracture
– Death due to other causes
Risk 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 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
‫٭‬ Probably hastened detection of small existing
cancers
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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
~ 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 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
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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
spsk
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
spsk
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
spsk
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
spsk
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
spsk
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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HRT& Menopause.ppt

  • 1. spsk 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 ‫٭‬ One third of life in menopausal state
  • 2. spsk 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
  • 3. spsk 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
  • 4. spsk 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
  • 5. spsk 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 ‫٭‬ Disturbed sleep-irritability-depression
  • 6. spsk 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
  • 7. spsk Anatomical Changes ‫٭‬ Atrophy of genital organs – ovary, – fallopian tubes, – Uterus, – Cervix, – vagina, – labia
  • 8. spsk GENITAL SYMPTOMS ‫٭‬ Dryness of vagina ‫٭‬ Vaginal irritation ‫٭‬ Vaginal discharge ‫٭‬ Recurrent infections ‫٭‬ Vulvovaginal pruritis ‫٭‬ Dyspareunia ‫٭‬ Post-coital bleeding ‫٭‬ Genital prolapse
  • 9. spsk URINARY SYMPTOMS (Urethral Syndrome) ‫٭‬ Frequency ‫٭‬ Urgency ‫٭‬ Nocturia ‫٭‬ SUI ‫٭‬ Urge incontinence ‫٭‬ Recurrent UTI
  • 10. spsk PSYCHOLOGICAL SYMPTOMS ‫٭‬ Sustained change of mood ‫٭‬ Inability to enjoy oneself ‫٭‬ Presence of depressive thought process ‫٭‬ Sexual dysfunction ‫٭‬ Increased irritability ‫٭‬ Reduced memory
  • 11. spsk BONE AND OSTEOPOROSIS ‫٭‬ 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
  • 12. spsk EVALUATION FOR POSTMENOPAUSAL OSTEOPOROSIS ‫٭‬ All 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
  • 13. spsk Pathophysiology ‫٭‬ Balance between osteoblastic and osteoclastic activity ‫٭‬ Accelerated bone loss after menopause due to lack of estrogen
  • 14. spsk Bone Formation & Bone resorption Normal Osteoporosis - BAD CELLS - GOOD CELLS
  • 15. spsk EVALUATION FOR POSTMENOPAUSAL OSTEOPOROSIS ‫٭‬ DEXA Scan for Bone Mineral Density – Dual energy X-Ray absorptiometry of the hip and spine ‫٭‬ For every 1-SD decrease in age- adjusted BMD, the RR of fracture increases by 2 fold ‫٭‬ Consider pharmacotherapy for patients with low BMD
  • 16. spsk LONG TERM GENITAL EFECTS ‫٭‬ Genital atrophy ‫٭‬ Senile vulvovaginitis ‫٭‬ UV prolapse ‫٭‬ Dyspareunia ‫٭‬ Recurrent infections
  • 17. spsk EFFECT ON CARDIOVASCULAR SYSTEM ‫٭‬ Cardioprotective role of estrogens ‫٭‬ Estrogen favourably affects lipid profile ‫٭‬ It lowers LDL and raises HDL ‫٭‬ Estrogen deficiency may lead to atherosclerosis,IHD,MI
  • 18. spsk EFFECT ON CARDIOVASCULAR SYSTEM ‫٭‬ Epidemiological and Observational studies have shown 35.5% reduction of cardiovascular events in postmenopausal women on traditional HRT
  • 19. spsk MISCELLANEOUS LONG TERM EFFECTS ‫٭‬ 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 ‫٭‬ Alzheimer disease
  • 20. spsk WHY TREAT ? ‫٭‬ MEDICALIZATION OF NORMAL PHYSIOLOGICAL PROCESS – CHANGE OF LIFESTYLE – DIETARY CHANGES – EXERCISE – REASSURANCE – MEDITATION ‫٭‬ TREATMENT IMPROVES QUALITY OF LIFE
  • 21. spsk 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
  • 22. spsk PRE TREATMENT EVALUATION ‫٭‬ Routine Physical Examination – Height – Weight – BP – Breast Examination – Pelvic Examination
  • 23. spsk PRE TREATMENT EVALUATION ‫٭‬ Routine Screening Examination – Mammography – TVS – Lipid Profile – LFT – Pap Smear
  • 24. spsk Management of Menopause ‫٭‬ Counseling-Pregnancy and cancer phobia ‫٭‬ Thorough clinical examination ‫٭‬ Contraceptive advice ‫٭‬ Diet ‫٭‬ Exercises
  • 25. spsk Hormone Replacement therapy ‫٭‬ Estrogen ‫٭‬ Progesterone ‫٭‬ Androgens
  • 26. spsk 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)
  • 27. spsk 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
  • 28. spsk TRADITIONAL HRT ‫٭‬ Absence of uterus - continuos estrogen replacement therapy (ERT) ‫٭‬ In presence of uterus (EPRT) – 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)
  • 29. spsk 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
  • 30. spsk CONTRA-INDICATIONS ‫٭‬ Migraine headaches, ‫٭‬ Superficial thrombophlebitis ‫٭‬ Strong family history of breast cancer ‫٭‬ Uterine fibroids ‫٭‬ Endometriosis ‫٭‬ Gallbladder disease
  • 31. spsk SIDE EFFECTS - ESTROGENS ‫٭‬ Leg pain ‫٭‬ Breast tenderness ‫٭‬ Headache ‫٭‬ Bloating ‫٭‬ Nausea ‫٭‬ Dyspepsia ‫٭‬ Vaginal discharge
  • 32. spsk SIDE EFFECTS PROGESTOGENS - PHYSICAL ‫٭‬ Acne ‫٭‬ Bloating ‫٭‬ Backache ‫٭‬ Breast tenderness ‫٭‬ Headache ‫٭‬ Dizziness ‫٭‬ Greasy skin ‫٭‬ Fatigue ‫٭‬ Weight gain
  • 33. spsk SIDE EFFECTS PROGESTOGENS - PSYCHOLOGICAL ‫٭‬ Anxiety ‫٭‬ Confusion ‫٭‬ Depression ‫٭‬ Forgetfulness ‫٭‬ Irritability ‫٭‬ Panic attacks ‫٭‬ Poor concentration ‫٭‬ Restlessness ‫٭‬ Poor sleep
  • 34. spsk ANDROGENS ‫٭‬ Tab Testosterone undecanoate 40 mg/day ‫٭‬ Oral Micronised Testosterone 2.5 mg/day ‫٭‬ Gels, creams, transdermal matrix patches
  • 35. spsk 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
  • 36. spsk ANDROGENS ‫٭‬ Maximum duration 6-9 mths ‫٭‬ No long term studies ‫٭‬ Tibolone can be an alternative
  • 37. spsk Other Drugs ‫٭‬ SERMS – RALOXIFENE – ORMILOXIFENE ‫٭‬ 19 nortestosterone derivative – TIBOLONE ‫٭‬ PHYTO-ESTROGENS – ISOFLAVONES – LIGNANS
  • 38. spsk Other Drugs ‫٭‬ Biphosphonates ‫٭‬ Herbs ‫٭‬ Micronutrients and antioxidants
  • 39. spsk RALOXIFENE ‫٭‬ Dose - 60 mg/day ‫٭‬ Does not improve the vasomotor symptoms of menopause, as well as the symptoms of urogenital atrophy ‫٭‬ Important in 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
  • 40. spsk RALOXIFENE ‫٭‬ Effect on CVS – Favourable effect on lipid profile – Reduction in cardiovascular risk ‫٭‬ Effect on Endometrium – No stimulatory effect – Does not increase risk of endometrial hyperplasia
  • 41. spsk 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 Side Effects-Hot Flushes Contraindications-Venous thrombosis,hepatic dysfunction
  • 42. spsk TIBOLONE ‫٭‬ Dose - 2.5 mg/day ‫٭‬ Estrogenic, progestogenic and androgenic activity ‫٭‬ Tissue specific pharmacologic effects ‫٭‬ Metabolites – Δ-4 tibolone – 3α-OH tibolone – 3β-OH tibolone
  • 43. spsk TIBOLONE - clinical use ‫٭‬ Treatment of menopausal symptoms, both vasomotor and psychological ‫٭‬ Beneficial effect on vaginal epithelium ‫٭‬ Reversal of atrophic vaginitis, reduction of vaginal dryness ‫٭‬ Improvement of libido ‫٭‬ Reduction of dyspareunia
  • 44. spsk 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 – ? increase incidence of cancer breast – No long term trials
  • 45. spsk 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
  • 46. spsk TIBOLONE - SIDE EFFECTS ‫٭‬ Vaginal bleeding ‫٭‬ Breast pain ‫٭‬ Headache ‫٭‬ Weight gain ‫٭‬ Edema ‫٭‬ Rash ‫٭‬ Depression
  • 47. spsk PHYTOESTROGENS ‫٭‬ Isoflavones - Soya – Dietary source • Soy • Lentils • Beans • Legumes ‫٭‬ Lignans - Flaxseed – Dietary source • Cereals • Fruits • Plant cell wall • Flaxseed oil
  • 48. spsk PHYTOESTROGENS ‫٭‬ Coumestans - Red Clover – Dietary source • Bean sprouts • Sunflower seeds • Red clover ‫٭‬ Weak estrogens. ER binding less than 1% of estradiol ‫٭‬ 300 plants possess estrogenic activity
  • 49. spsk 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
  • 50. spsk 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
  • 51. spsk PHYTOESTROGENS ‫٭‬ Prevention of osteoporosis is controversial. Data lacking ‫٭‬ Dose - 40 mg isoflavone daily ‫٭‬ Side effects:- – acidity – abdominal cramping – constipation – allergic reaction
  • 52. spsk HERBS ‫٭‬ Turmeric ‫٭‬ Cumin (jeera) ‫٭‬ Saunf ‫٭‬ Methi ‫٭‬ Cardamom ‫٭‬ Cinnamon ‫٭‬ Saffron ‫٭‬ Ginger ‫٭‬ Ginseng
  • 53. spsk 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
  • 54. spsk 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
  • 55. spsk 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
  • 56. spsk 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
  • 57. spsk MICRONUTRIENTS & ANTIOXIDANTS ‫٭‬ A balanced diet with 5–9 servings of fruits & vegetables can provide all the micronutrients & antioxidants
  • 58. spsk ‫٭‬ Menopause is ………. not a pause, …..It’s beginning of new Life…………
  • 60. spsk “ You do not heal old age You protect it; You promote it; You extend it.” Sir James Ross
  • 61. spsk
  • 62. spsk Heart and Estrogen/Progestin Replacement 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 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
  • 63. spsk Mean Change in LDL, HDL and Triglyceride Levels by One Year HERS JAMA 1998: 280: 605-613 % change from baseline to year one 15 10 5 0 oestrogen-progestin placebo LDL-C HDL-C Triglycerides -5 -10 -15 -20
  • 64. spsk Incidence of Non Fatal MI and CHD Death HERS JAMA 1998: 280: 605-613 Incidence (%) 15 10 5 0 0 1 2 3 4 5 Follow-up (years) oestrogen-progestin placebo
  • 65. spsk Despite improving the lipid profile in women with CHD, HRT did not improve their survival
  • 66. spsk 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
  • 67. spsk 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
  • 68. spsk
  • 69. spsk What was the “ WHI (The Women’s Health Initiative Study)” all about? JAMA, July 17, 2002 -- Vol 288, No. 3
  • 70. spsk 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
  • 72. spsk • Monitored outcomes – Coronary Heart Disease (CHD) – Invasive Breast Cancer – Stroke – Pulmonary Embolism (PE) – Endometrial Cancer – Colorectal Cancer – Hip Fracture – Death due to other causes Risk ratio calculated for each condition WHI TRIAL
  • 73. spsk
  • 75. spsk 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
  • 76. spsk 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
  • 77. spsk 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 ‫٭‬ Probably hastened detection of small existing cancers
  • 78. spsk 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.
  • 79. spsk COLORECTAL CANCER ‫٭‬ Relative risk - 0.63 ‫٭‬ Less cases per 10,000 women/yr - 6 ‫٭‬ Beneficial effect seen in year 6.
  • 80. spsk HIP FRACTURES ‫٭‬ Relative risk - 0.66 ‫٭‬ Less cases per 10,000 women/yr - 5
  • 82. spsk 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
  • 83. spsk ESTROGEN ONLY ARM DID NOT REACH A RISK - BENEFIT LEVEL OF CONCERN HENCE CONTINUING STUDY CONCLUDES ON 31 MAR 2005
  • 84. spsk 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
  • 85. spsk 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
  • 86. spsk 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
  • 87. spsk
  • 89. spsk SYMPTOMATIC MENOPAUSAL WOMEN ‫٭‬ VASOMOTOR SYMPTOMS - TREAT ‫٭‬ ONLY PSYCHOLOGICAL SYMPTOMS - DO NOT TREAT – CHANGE OF LIFE STYLE – DIETARY CHANGES – EXERCISE – MEDITATION
  • 90. spsk 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
  • 91. spsk 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.
  • 92. spsk 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
  • 93. spsk DO NOT START ERT/EPRT IN THE SIXTH DECADE OF LIFE ONWARDS
  • 94. spsk DO NOT GIVE HRT FOR ‫٭‬ PRIMARY OR SECONDARY CARDIOPREVENTION ‫٭‬ OSTEOPREVENTION ‫٭‬ TREATMENT OF OSTEOPOROSIS
  • 95. spsk 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
  • 96. spsk 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
  • 97. spsk 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
  • 98. spsk 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
  • 99. spsk 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
  • 100. spsk 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