2. INTRODUCTION
With medical advancements , average life expectancy has increased,and most women can
now expect to live at least one third of their lives in the menopause.
Importantly, menopausal transition and the years of life spent in the postmenopausal state
bring with them issues related to both quality of life and disease prevention and
management.
3. MENOPAUSE
GREEK: Menos; Month, Pausis; cessation
Menopause is that point in time when permanent cessation of menstruation occurs following loss of
ovarian activity.
The clinical diagnosis is confirmed following stoppage of menstruation for twelve consecutive months
without any other pathology. So, it is a retrospective diagnosis.
However , if a women bleeds after a gap of 6 months is considered to have post menopausal bleeding and
should be thoroughly investigated.
4. AGE OF MENOPAUSE
Genetically determined
Not related to age of menarche
Average age of menopause -
western women – 51 years
Indian women – 46.2 years ( PAN survey by IMS)
5. RISK FACTORS FOR EARLIER MENOPAUSE :
Smoking (upto 2 years)
Nulliparous
Hystrectomy
Fragile X carrier
Autoimmune disorder
Exposure to chemo/radiotherapy
6. TERMINOLOGIES ASSOCIATED
Premature Menopause: defined as spontaneous menopause occurring 2 SD in years
before the mean estimated age for the reference population.
It is clinically defined as secondary ammenorhea for atleast three months with
raised FSH levels (more than or equal to 40 IU on 2 occasions done 1 month apart),
raised FSH to LH ratio and low E2 in women less than 40 years of age.
Estimated incidence is 1%.
Menopausal transition: refers to the years prior to menopause that encompass the
change from normal ovulatory cycles to cessation of menses. Begins with menstrual cycle
irregularities and extends 1 year after permanent cessation of menses. (average age at
its onset is 47 yrs and spans to 4-7 years.)
Postmenopause: years following the 1 year after complete cessation of menstruation.
7. STAGES OF MENOPAUSE (by Dr Behram
Anklesaria)
STAGE 1 STAGE 2 STAGE 2B STAGE 3
Roughly 2 yrs
before the
menopause
Early
(premenopausal
symptoms)
Stage 2A
Vasomotor
instability and
urethral
syndrome
Insert space i.e.
up tp 5 yrs after
menopause
Intermediate
(postmenopausal
symptoms)
Atrophic
changes
Lifetime
Late
(postmenopausal
complications)
3A: Residual
changes
1A
Vasomotor
instability
2B Late
Psychosomatic
symptoms
3B: ischemic
heart disease
1B
Early
psychosomatic
symtoms
3C:Very late
complications,
Eg Alzeimers
disease
8. STRAWS CLASSIFICATION (Staging of reproductive aging workshop)
- This criteria describes the changes that encompass the transition from reproductive life to postmenopause.
9. PHYSIOLOGY OF MENOPAUSE
( 20 WEEKS) ----> 6-7 million oocytes
At birth -----> 2 million primordial follicles
At puberty -----> 4,00,000 primary oocytes (rest become atretic)
During entire reproductive period some 400 are likely to ovulate.
The degeneration starts in intrauterine life and continuous throughout childhood and childbearing
period.
There is depletion of ovarian follicles secondary to apoptosis and programmed cell death.
Menopause occurs when the no of remaining follicles falls below a critical threshold of about 1,000,
regardless of age.
In an average women, continuing follicular depletion and declining fertility begin at the age of 37- 38 years
and menopause follows approx. 13 years later.
12. HORMONAL CHANGES
Reduced quantity of aging follicles
Cessation of ovarian activity
Decreased estrogen & Inhibin B ( a granulosa cell product that exerts
negative feedback over FSH secretion by pitutary gland)
Increased FSH &Lh
Levels of FSH and LH increase throughout the later stages of the
Climacteric and reach a peak 2 to 3 years after the menopause
FSH may rise as much as 10-20 times & LH rises 3-4 times.
13. - Decrease in AMH ( produced by small ovarian follicles)
-Decrease in androstenedione , DHEA and DHEAS ( Declining
markedly during aging )
-Testosterone production decreases 25% after menopause.
15. LEVELS OF HORMONES IN MENOPAUSAL WOMEN:-
Estradiol:5-25 pg/ml
Oestrone:20-70 pg/ml(more in obese)
FSH:>40 mIU/ml
E2/E1<1 (=1 in premenopause)
AMH- Undetectable(<1 ng/ml)
Inhibin B-<15 pg/ml
16.
17. ANATOMICAL CHANGES
OVARIES -shrink in size (2x1.5x1cm)
8ml in volume
thinning of cortex
increase in medullary component
FALLOPIAN TUBES- muscles atrophy
Cilia disappear
UTERUS-smaller with atrophy of muscles
The ratio of body to cervix reverts to 1:1
VAGINA - no glycogen
Dordeline bacillus absent
Maturation index(parabasal, intermediate, superficial cells);10/85/5.
18. SYMPTOMS OF MENOPAUSE
MENSTRUAL PATTERN SEXUAL DISTURBANCES
Shorter cycles Decreased libido
longer cycles dyspareunia
Irregular bleeding Vaginal dryness
VASOMOTOR SYMPTOMS SOMATIC SYMPTOMS
Hot flushes Headache
Sleep disturbances Dizziness
Night sweats Palpitations
PSHYCOLOGICAL SYMPTOMS breast enlargement
Depression joint pains
Irritability OTHERS
Mood swings weight gain
Poor memory dry/itchy skin
19. SYMPTOMS ACC TO DURATION
ACUTE; Hot flushes
Night sweats
Headaces
Panic attacks
Mood swings
Indecisiveness
Cramps
Irregular periods
Insomnia
Irritability
Difficulty with concentration
INTERMEDIATE SYMPTOMS;
Vaginal dryness
Dyspareunia
Reduced libido
Thinning skin/hair
Skin formication
Urethral syndrome
Genital prolapse
Weight gain
LONG TERM CONSEQUENCES;
Cardiovascular disease
Osteoporosis
Cerebrovascular disease
Alzheimers disease
20. 1. MENSTRUAL DISTURBANCES
It occurs in three ways:-
• Sudden cessation of menstruation
• Gradual decrease in amount of blood loss
• Gradual increase in spacing of periods until they cease.
Abnormal uterine bleeding (AUB) is common, and it is found
that menses were irregular in more than one half of all women
in this transition.
Anovulation is the most common cause of erratic bleeding
during menopausal transition
21. 2. VASOMOTOR SYMPTOMS
The most common and the most noticeable symptoms are the
HOT FLUSHES AND SWEATING.
HOT FLUSHES are the waves of vasodilation affecting the face
and the neck and these last for 2-5 minutes each.
PHASES OF VASOMOTOR SYMPTOMS; Increase in core body
temperatur---increase in peripheral temperature---Diaphores---
Fall in temperature.
22. PATHOPHYSIOLOGY OF VASOMOTOR SYMPTOMS
Hot flushes are definitely brought by decline in estrogen,however not all hot flushes are due
to estrogen deficiency
Estrogen withdrawl is associated with decreased blood serotonin levels,which is followed by
upregulation of serotonin receptors in hypothalamus.Activation of specific serotonin
receptors has been shown to mediate heat loss.
In addition to estrogen,the altered neurotransmitters concentration may create a narrow
thermoregulatory zone and lowered sweating threshold.Norepinephrine is primary
neurotransmitter responsible for lowering the thermoregulatory set point and triggering the
heat loss mechanisms associated with hot flushes.Plasma levels of NE metabolites are
increased before and after hot flushes.
23. TREATMENT
1)Lifestyle modifications:
Avoid triggering factors
Dec. stress by meditation, yoga, massage, paced
breathing ,etc.
Keep cool &ambient temperature.
Exercise-Dec hot flushes in 50%.
Layered clothing.
2)Placebo:20-50%dec. in hot flushes after 4wk of treatment.
24. 3) Pharmacological therapy
Antidepressants e.g. SNRI(Venlafaxine-37.5 mg/day for 1
week followed by 75 mg/day)
Paroxetine-10 mg/day and then increase to 20 mg/day
Fluoxetine-20 mg/day
Clonidine (alpha agonist)-50-75 mcg bd
Gabapentin(GABA analogue)-300mg/day and increase to
900mg/day in divided doses
Propranolol
Evening primrose oil
Veralapride
Cetrizine
multivitamins like Vit B,C and E
Dietary phytoestrogens and
herbal remedies
4)Hormonal therapy
25. 3. OSTEOPOROSIS
Osteoporosis is as skeletal disorder that progressively reduces
bone mass and strength and leads to increased fracture risks.
It can be defined as decrease in bone mass exceeding 2.5 SD
below the mean for young adults.
CHANGES IN THE MICROSTRUCTURE OF BONE IN POSTMENOPAUSAL
WOMEN :-
• Increase in the cortical porosity
• Decrease in bone mass
• Disturbed trabecular architecture
• Decrease in cortical thickness
• Lower mineral content of bone
26. RISK FACTORS FOR OSTEOPOROSIS
NON MODIFIABLE ASSOCIATED MEDICAL
CONDITIONS
Age Hyperthyroidism
race Hyperparathyroidism
Early menopause Chronic renal disease
family history Prolonged steroid therapy
Prolonged amenorrhea
MODIFIABLE
Inadequate intake of vitamin D and calcium
Low body weight
smoking
excess alcohol intake
sedentary lifestyle
27. • MOST COMMON FRACTURES ASSOCIATED ARE:-
Vertebral
femoral neck
wrist
OSTEOPOROSIS IS CATEGORIZED INTO TWO TYPES BASED ON ETIOLOGY:-
1. Primary osteoporosis
2. Secondary osteoporosis
PRIMARY OSTEOPOROSIS:- Refers to bone loss associated with aging and
menopausal estrogen deficiency.
• Fall in the estrogen level after menopause leads to loss of regulatory
effect on bone resorption leading to imbalance between bone resorption
and bone formation.
29. INVESTIGATIONS
DEXA (Dual X-Ray absorptiometry) –
• Used to determine Bone mineral density ,which is used to asses fracture
risk.it can be used to diagnose osteoporosis and identify women who
would benefit from therapeutic intervention.
• BMD is reported as absolute density (gm/mineral/cm2)and in relation to
two norms.
1. T SCORE:- is the standard deviation above or below the mean for a 70
year old women.
2. Z SCORE:- is the standard deviation variance above or below the mean
for a woman of similar age.
30. • Evaluation of BMD by DEXA is recommended for all women
aged 65 and older, regardless of risk factors and for
younger postmenopausal women with one or more risk
factors
Quantitative usg
Quantitative CT
31. • FRAX:-
An online fracture risk assessment, provides the 10 year
probability of major osteoporosis fracture for an
individual women.
FRAX helps us to identify women with low BMD (score
between -1 to -2.5) who will benefit from
pharmacological treatment.
• Women should be counselled to alter modifiable risk
factors as an important step in the prevention of
osteoporosis and fracture.
32. PREVENTION AND TREATMENT OF OSTEOPOROSIS
1.CALCIUM
• Essential for good bone health
• Recommended intakes
(from diet and supplements):
– Peri-menopause - 1000 mg/d
– Post-menopause - 1500 mg/d
– Should be taken in divided doses
• Calcium therapy alone is not enough to prevent fracture. Vitamin D is necessary for
calcium absorption.
CALCIUM SUPPLEMENTS-
• Limit 500 mg calcium at one time from food and/or supplements
• Spread calcium sources throughout the day
• Start supplements with 500 mg calcium daily for about a week, gradually adding more
to reduce side effects
• Absorption of calcium is decreased when taken with foods rich in fires and fat, Iron,
zinc, spinach, coffee, alcohol and antacid
33. 2. VITAMIN D
• Important to maintain bone health
• Most recommend intake of 400-600IU/day
• Deficiency due to limited sun exposure / use of sunscreen
• Food sources not adequate
• May be more important than calcium
MANAGEMENT OF VITAMIN D DEFICIENCY
• Cholecalciferol (vitamin D3) tablet or powder 60,000 IU/once a week for eight
weeks preferably with milk or
• One IM injection of 6,00,000 IU is given to correct the deficiency (not to be
repeated before three months and may be given after confirmation of persisting low
levels of vitamin D )
• Maintenance therapy(from natural sources or supplements) is advised after
correction of the deficiency.
34.
35.
36. PHARMACOLOGICAL TREATMENT
In postmenopausal female with T-score<=2.5
With osteoporotic, vertebral #(no BMD reqd.)
Osteopenia with risk factor.
Premature menopause- HT till age of her natural menopause
Include:
1. Hormone therapy
2. BISPHOSPONATES – DRUG OF CHOICE
Prevents bone loss by enhancing osteoclast apoptosis and inhibiting bone resorption.
It is best reserved for postmenopausal women.
In relatively young postmenopausal women hormone therapy may be preferentially
considered as a first line approach for osteoporosis prevention and fracture risk
reduction.
37. Zolidronate: I/V 5mg over 15 min once a yr.
Alendronate: 10 mg daily, 70 mg weekly
Risedronate: 5 mg daily, 35 mg weekly, 150 mg monthly
Ibandronate: 2.5 mg daily, 150 mg monthly,
3mg I/V 3 monthly
3. TIBOLONE- selective tissue estrogenic activity regulator
2.5 mg od
38. • SERMS:
selective estrogen receptor modulators, having agonist effect on bones.
Raloxifene-60 mg OD,
bazedoxifene-20 mg OD
CALCITONIN:
Regulates plasma calcium by inhibiting bone resorption
nasal spray or s/c injections.
PARATHYROID HORMONE:
increases bone formation
Teliparatide.-20 mcg s/c
39. • DENOSUMAB –
60 mg s/c every 6 months
Monoclonal antibody against RANK-L. prevents RANK mediated activation of
osteoclasts.
After discontinuation of denosumab, however bone loss begins immediately.
FLOURIDE –
potent stimulator of bone formation.
Treatment recommended for no longer than 4 years to avoid toxic
accumulation of fluoride in bones.
25 mg bd
STRONTIUM RANELATE-
Acts through uncoupling and rebalancing of the bone turn over in favour of
net bone formation.
2 gm in water BT
Teriparatide and fluoride are only 2 drugs that stimulate osteoclasts to form bone
40. 4. CARDIOVASCULAR CHANGES
The atherosclerotic cardiovascular diseases remains the leading cause of death in women
older than 50 years.
It accounts for approx. 40% of deaths in comparison to 5% due to breast cancer.
In premenopausal women, the cardiovascular protection is mainly attributed to the
greater HDL levels which is a effect of estrogen.
The atherogenic lipid profile associated with abdominal adiposity is also partly mediated
through insulin and estrogen
So,the risk of CVD rises exponentially for women as they enter menopause as estrogen
levels declines along with the effects of aging ( decrease in clotting factors, fibrinogen,
plasminogen activator inhibitor-1 and factor 8) leading to hypercoaguable state.
• This becomes vitally important for women in menstrual transition as preventive measures
can significantly improve the mortality.
41. 5.CNS CHANGES
SLEEP DYSFUNCTION AND FATIGUE:- Decrease in sleep quantity, frequent awakenings
associated with hot flushes, insomnia, sleep disordered breathing.
COGNITIVE DYSFUNCTION:- It is the most common concern of menopausal and aging women.
Alzhemier’s disease is the most common form of dementia and women are at greater risk.
PSYCHOSOCIAL CHANGES:- Increase risk of depressive symptoms during MT. The risk of
developing a major depressive disorder is 1.9 times higher in women. It has been suggested
that hormone fluctuation in the earlier MT are responsible for the affective instability.
so, screening for depression is prudent for women in this transition.
42. 6. SEXUAL CHANGES
Loss of libido
Dyspareunia
Organic dysfunction( 86% reported no orgasm after menopause)
7. BREAST CHANGES
Mainly due to hormonal withdrawl:- reduction in the volume and tissue density due
to reduction in the breast proliferation.
Breast cancer is the major health concern for menopausal women. So, regular
screening mammography starting at the age 40 is indicated to reduce the risk of
death due to breast cancer.
43. 8. GENITOURINARY SYMPTOMS
MENOPAUSE SOCIETY adopted this term to encompass the signs
and symptoms that effect genitourinary symptoms after
menopause.
Estrogen receptors have been identified in vulva, vagina,
bladder, urethra, pelvic floor musculature. These structures thus
show a similar hormonal responsiveness and are susceptible to
estrogen deprivation.
44. VULVOVAGINAL CHANGES:- Estrogen deficiency leads to
• Loss of vaginal collagen,adipose tissue and ability to retain water
• Vaginal walls shrink,rugae flatten and vagina attain smooth dilated pink appearance
• Vaginal ph becomes alkaline >4.5 , leading to less hospitable to lactobacilli and
more susceptible to infections.
• Bacterial vaginosis ranges from 23 to 38% in post menopausal women and rates
increased with age.
• Candida species were noted in 5 to 6% of these women and it decline with age.
Vaginal atrophy leads to vaginal dryness,itching,irritation,dyspareunia,with
prevelance of around 10 to 50% during MT.
UROGENITAL CHANGES:- It includes dysuria, urgency, urethral prolapse and
recurrent UTI’s.
45. OTHER CHANGES ATTRIBUTABLE TO MENOPAUSE ARE:-
WEIGHT GAIN :- common complain during MT
associated with fat deposition in abdomen ,
increased visceral fat and fat redistribution
which can lead to insulin resistance and subsequent DM and CVS diseases
DERMATOLOGICAL CHANGES:- Hyperpigmentation, itching, wrinkles particularly due to aging.
Hormonal changes leads to -> reduced thickness due to low collagen content
diminished sebaceous gland secretion
loss of elasticity
Purse string wrinkles around the mouth and crew feet around the eyes.
DENTAL CHANGES:- Due to decreased estrogen levels:-
atrophy of buccal epithelium
loss of alveolar bone
increased cavities
46. DIAGNOSIS OF MENOPAUSE AND PATIENT EVALUATION
Cessation of periods for 12 consecutive months.
Includes complete medical history, physical examination and laboratory studies.
Risk factors for common problems like obesity, osteoporosis , diabetes, cancers are
assessed and managed.
Counselling regarding diet, exercise, alcohol moderation and smoking cessation is
done.
Psychosocial wellbeing is assessed (depression,anxiety, sexual functions)
Thorough general physical examination is performed
• Height
• Weight
• Waist circumference
• BMI
47. • The diagnosis of MT can be made with age appropriate symptoms and careful
physical examination.
(hot flushes, menstrual irregularities, vaginal dryness etc.)
If ovarian failure develops before age of 40 years, it is usually pathologic.so,
the causes of premature ovarian failure should be ruled out. (as discussed
earlier)
BIOCHEMICAL TESTS AND HORMONE LEVELS
An increase in FSH LEVELS MORE THAN 40 IU/ML
Estrogen levels may be normal, elevated or low depending on stage of MT.
At menopause estrogen levels are extremely low or indetectable.
48. ESTROGEN MATURATION INDEX
Inexpensive, less often used to evaluate hormonal influence in women.
Specimen is collected during vaginal speculum examination, and at same time cervical
cancer screening is performed.
Cells are suspended in small amount of saline smeared to the slide and fixed with 95%
ethanol spray fixative.
The index report is read from left to right and refers to the percentage of parabasal,
intermediate and superficial squamous cells with total sum of 100%.
SUPERFICIAL – ESTROGEN EFFECT
INTERMEDIATE – PROGESTRONE EFFECT
BASAL- POSTMENOPAUSAL WOMEN
Parabasal/intermediate/superficial – 100/0/0 in postmenopausal women/postpartum
SO,the clinical goals during MT are to optimize women’s health and well being before
and after the transition.
50. HORMONE REPLACEMENT THERAPY
• Not for all
• A suitable candidate is chosen for the HRT after weighing
out benefit risk analysis
• HRT is optimised according to the patient’s symptoms
• Before initiating HRT, a women is thoroughly evaluated
including history, examination and investigations.
51. ASSESSMENT
Detailed History
Evaluate women’s need
Evaluation of women’s individual risk factor
Assess general condition of patient
55. ESTROGEN
Three major naturally occuring circulating estrogens in
women:
• Estrone E1 - low potent (menopause)
• Estradiol E2 - most potent (reproductive phase)
• Estriol E3 - least potent (pregnancy)
• Estetrol E4 - low potency estrogen
present during pregnancy, produced from fetal liver
56. Effect of estrogen on end organs
PHYSIOLOGICAL EFFECT EXCESS
UTERUS- smooth muscle growth leads to fibroid
ENDOMETRIUM- proliferation of endometrium endometrial malignancy
CERVICAL MUCOUS- copious, watery, thin, spinnbarket
BONES- bone mineralisation, closure of epiphysis
BREAST TISSUE- proliferation of ducts breast carcinoma
LIPID PROFILE- increase in HDL
decrease in LDL
increase in TGs (CARDIOPROTECTIVE)
COAGULATION- procoagulant effect venous thromboembolism
increase clotting factors 2,7,8,9 mainly stroke
increase plasma fibrinogen hypercoaguabe state
decrease antithrombin 3
(inhibitor of coagulation)
57. ESTROGEN RECEPTORS
• ER α is expressed: Liver
• ER β is expressed most highly in: Lungs, kidney, bladder,
intestines
• Many cells express both ER α and ER β, which can form
either homo or heterodimers: CNS, blood vessels, bone,
heart, breast, ovary, uterus, testes, prostate
58. Natural Estrogens Used For Menopausal HT
• 17 beta estradiol
• Estradiol valerate
• Conjugated equine estrogens
• Estriol
Synthetic estrogens
NOT USED IN MENOPAUSAL HORMONE THERAPY
• Ethinyl estradiol
• 750-1000 times more potent than natural estrogens
• Enhances hepatic effects which increases synthesis of clotting factors, angiotensin,
SHBG
Used in perimenopause, premature menopause
59. ESTROGEN THERAPY (ORAL)
1. CONJUGATED EQUINE ESTROGEN:-
Lowest dose is 0.3 mg per day. It is usually used as 0.625 mg per
day.
2. ESTRADIOL:-
0.5 mg is the lowest dose. 1mg is usually given daily.
60. PROGESTRONE
Involved in female menstrual cycle, supports pregnancy, and
embryogenesis in the womb
• Progesterone is not measurable in menopausal women
Progesterone is used in HT at menopause to prevents
endometrial hyperplasia & endometrial cancer
62. PROGESTRONE THERAPY
1. MEDROXY PROGESTRONE ACETATE:-
2.5 mg daily in the continuous treatment or 5 mg daily for 10-12 days in month in
cyclical regimen.
2. MICRONISED PROGESTRONE:-
100 mg daily in the continuous treatment or 200 mg for 10-12 days in month in
cyclical regimen.
3. NORETHINDRONE ACETATE :-
0.5 mg to 1 mg in continuous regimen or 1 mg in cyclical regimen.
4. 2 mg DROSPERINONE
5. 2 mg DIENOGEST
It can be administered orally with estrogen as sequential or continuous regimen.
It can be administered vaginally
64. COMBINED THERAPY
Drosperinone used in the dose of 2 mg daily with 30 microgm estradiol.
Levonorgestrel {mirena} releases 20 microgm daily can be used with
estrogen
Conjugated ethinyl estradiol {0.625 mg} with MPA {5mg} 28 pills
It can be used in continuous sequential manner.
The first 14 pills contains only estrogen and the next 14 pills contains
combined therapy.
The Mirena is now licensed for use with Oestrogen only HT for 4
years. The advantage is that it can be used in younger women to
induce a no-bleed regimen.
65. METHODS OF DELIVERY
Regimen Ostrogen Progestrone
Estrogen only Everyday N0t given
Cyclic sequential 1st-25th day 13th -25th
day/month
Cyclic combined 1st- 25th day 1st- 25th day
Continuous sequential Everday 13 TO 25TH day per
month
Continuous long
sequential cycle
Everyday 14 days every 3-6
months
Continuous
combined
Everyday Everyday
66. Regimen used
For hysterectomised patients For women with intact uterus
-> only continuous estrogen is used ->both estrogen and proestrone used to
prevent endometrial hyperplasia and
cancer.
If the hysterectomy was subtotal, then may need to use progestogens as well (some
endometrium may be left behind)
If the hysterectomy was for endometriosis, then progestogens continuously along
with oestrogen should be used at least initially
HT is prescribed in the lowest dose possible for the shortest period of time.
Current guidelines recommend reevaluation of the need for HT at 6-12 months.
67. ROUTES OF ADMINISTRATION
HOW?
ORALLY TRANSDERMAL INTRANASAL
>ESTROGEN >PATCH faster action
>PROGESTRONE >GELS Not very popular since it causes
>COMBINED THERAPY >CREAMS nasal pruritis.
>VAGINAL RINGS
>SUBDERMAL ESTRADIOL IMPLANTS
68. TRANSDERMAL
PATCH-> It contains 3.2 mg estradiol , releases 50 microgm in 24 hrs and is changed
twice weekly.
Comb packs contains estradiol with LNG and is changed weekly.
GELS-> It also contains 17 beta estradiol and is applied topically to the affected areas.
SUBDERMAL IMPLANTS-> Three types containing 25,50, 100 mg estradiol are available.
Inserted subdermally in the anterior abdominal wall.
especially suited for hysterectomised patients.
• In selected cases, testosterone implants are done for loss of libido cases.
69. VAGINAL ADMINISTRATION OF ESTROGEN
It is a very low dose method of estrogen therapy.
Used for vulvovaginal atrophy.
VAGINAL RINGS [FEMRINGS} -> 0.1 mg per day inserted for 90 days.
ESTRING- 55 mm diameter rings contains 2 mg estradiol with release rate of
75mcg for 90 days.
VAGIFEM – it contains 10 mcg or 25mcg estradiol tablets kept daily for 2 weeks
followed by twice weekly.
VAGINAL CREAMS -> Either contains CEE 1.25 MG Estrogen daily or estradiol cream
1.25 mg daily.
Provides minimal or no systemic side effects.
70. ORAL VS TRANSDERMAL ESTROGEN
Transdermal route of estrogen administration be preferentially considered if
decision for initiating HT is made after weighing out risk benefit ratio in the
following patients:-
Obese women with metabolic syndrome
Smokers
History of deep venous thrombosis
Tobacco users
Hypertriglyceridemia
Reason being
Avoid first pass metabolism
Less effect on clotting factors
No effect or less effect on
Decreases triglyceride levels
Less or minimal effects on inflammation, coagulation and insulin senstivity
71. The potential benefits of androgen treatment include
improvement in psychological well being and increase in sexuality motivated behaviour
Increase in libido
AVAILABLE AS:-
Testosterone undecanoate {orally}
Sublingual micronized testosterone
Intramuscular injections
Subcutaneous implants
Transdermal preparations
Only testosterone formulation approved for exclusive use in female population in US is a
combination of esterified estrogen with methyltestosterone [2.5 mg or 1.5 mg]
DEHYDROEPIANDROSTERONE (DHEA)
Intravaginal DHEA in a dose of 0.5% demonstrated a significal improvement in symptoms of
vaginal atrophy
ROLE OF ANDROGENS
72. SERMS selective estrogen receptor modulators
1.RALOXIFENE-
• Raloxifene is the first of a benzothiophene series of antiestrogens to be labelled a SERM
Tissue selectivity
• Agonist - Bone - Lipid Metabolism
• Antagonist - Uterine Endometrium - Breast Tissue
Approved for Treatment & Prevention of post – Menopausal osteoporosis
Not for symptom control
Recommended dosage is Raloxifene 60 mg once daily, which may be administered any time of
day without regard to meals
75. BAZEDOXIFENE
It is a SERM combined with CEE for treatment of vasomotor symptoms.
This combination is a tissue selective estrogen complex , acts antagonist in uterus
tissue to prevent endometrial hyperplasia
When combine with CEE , it reduces bone mass density loss and incidence of hot
flushes
OSPEMIFENE
It is a SERM being primarily used for treatment of dryness of vulva and vagina in
adose of 60 mg/ day
According to the posthoc analysis of safety data ,it is reassuring in terms of effect
on breast , endometrium, and bone,
vasomotor symptoms can however worsen.
76. TIBOLONE
It is STEAR(selective tissue estrogenic activity regulator)
It is a synthetic gonadomimetic containing oestrogen, progestogens and androgens
Approved for vasomotor symptoms and osteoporosis
The risk:benefit ratio similar to HT in women under 60, but over 60 increased risk of stroke
Slightly increased risk for endometrial cancer
Less risk of breast cancer compared with CCT but increased over Estrogen only HT
May help libido due to androgen content
Approved in 90 countries to treat menopausal symptoms and in 45 countries for osteoporosis
Not recommended within 1 year of menopause because of risk of irregular vaginal bleeding
77. Specific Indications:
• Mood & libido
• Adverse effects with conventional HRT
• Older women
• Family history of breast cancer
• History of endometriosis, fibroids
• Add back therapy with GnRH analogues
Dosage:
• 2.5 mg single daily dose orally
• 1.25 mg equally effective
78. ADVERSE EFFECTS OF TIBOLONE
• Nausea & weight gain
• No change in HDL level
• Increases risk of recurrence in breast cancer survivor
CONTRAINDICATIONS OF TIBOLONE
• Undiagnosed genital bleeding
• Women over 60 years, women with risk factors for stroke, e.g. Hypertension, smoking,
diabetes and atrial fibrillation
• Known past or suspected breast cancer known or suspected estrogen dependent malignant
tumor, endometrial hyperplasia
• Previous or current venous thromboembolism (VTE) [deep vein thrombosis (DVT), pulmonary
embolism], known thrombophilic disorders (e.g. Protein C, protein S or antithrombin
deficiency)
• History of arterial thromboembolic disease [e.g. angina, myocardial infarction, stroke or •
Transient ischemic attack (TIA)],
acute liver disease or with abnormal liver function tests, porphyria
79. INDICATIONS OF HT
WHO TO GIVE?
Relief of severe vasomotor symptoms
Urogenital symptoms
Osteoporosis
Prevention of atrophy -> epithelia, skin, connective tissue
Asymptomatic high risk patient
• Premature menopause
• Family history of osteoporosis
• Cardiovascular diseases, alzehmier’s diasease
80. CONTRAINDICATIONS OF HT
Endometrial cancer
Breast cancer {present or past history}
Active/ recent thromboembolic disease
Venous thromboembolism
Severe active renal/ liver disease
Uninvestigated abnormal vaginal bleeding
Active intermittent porphyria
Suspected pregnancy
81. WHILE STARTING HRT
• Explain to women
• To report at 1, 3-month review appointment,
that unscheduled vaginal bleeding is a common side effect of HRT
within the first 3 months of treatment
• It will take 3-4 weeks for control of symptoms
82. DURATION OF THERAPY
• Premature menopause - Hormone Therapy: Up to natural age
of menopause; further continuation of therapy according to the
indication and the need
• Natural menopause: Safety data of EPT therapy with CEE+MPA
is 3-5 years with ET safety data for use is 7 years of treatment
with 4 years follow-up
Ideal recommendation is lowest dose for the lowest possible
time.
83. HOW LONG WITH SEQUENTIAL HRT?
Several studies show that prolonged use of sequential HT can
increase the risk of endometrial cancer
Relative risk of endometrial cancer rose from 1.3 to 2.9 for 5
years use
For combined continuous HT relative risk fell to 0.2
84. HENCE,
Do not keep women on cyclical therapies longer than 5
years
In premature menopause –HT can be prescribed for up
to age of natural menopause
Stopping HT –may be abruptly or dose and duration may
be tapered off gradually.
85. PROBLEMS WITH HRT
Bleeding problems
Insufficient symptomatic response
Side effects
BLEEDING- PROBLEM OF COMPLIANCE
• Scheduled or withdrawal bleeding—with the cyclic, cyclic combined and
sequential EPT
• Unscheduled or irregular bleeding with continuous combined EPT
86. CAUSES OF ABNORMAL BLEEDING
• Poor compliance- missing tablets especially progesterone
• Poor gastrointestinal absorption-IBS, Coeliac disease, Crohn’s
• Asynchrony of endogenous and exogenous hormones (in pre and
perimenopausal women)- in a regular cyclical woman add progesterone
from the 11th day before her expected cycle to mimic her natural cycle
length
• Premenopausal woman with erratic cycles- an OCP unless
contraindicated is good option or adjust the dose and type of
progesterone
Atrophic endometrium —commonly seen with continuous combined
regimes
• Coagulation defects—thrombocytopenia, von Willebrand’s disease, on
warfarin or high dose aspirin
• Drug interactions- Broad spectrum antibiotics may cause intestinal
hurry and effect the absorption of hormones
87. Gynecological disorders
• Endometrial hyperplasias, polyps fibroids, adenomyosis, endometritis,
endometrial cancer
• Cervical polyps, erosions cancer
• Atrophic vaginitis, cancer of the vagina or vulva
• Hypothyroidism
88. When To Investigate?
• Routine endometrial surveillance is not needed
• With cyclical regimes if bleeding starts at the start of
progesterone therapy, or these change in the duration or intensity
of blood flow which is normal for that woman with continuous
combined regimes-if bleeding is heavy or continuous and continues
after 6- 12 months of use
• In women with a high risk for uterine cancer
Insufficient Response
Poor compliance
• Missed tablets, Vomiting
• Non-adherent patches
Poor absorption
• Check blood levels
89. FOLLOW UP OF HRT
After one month for efficacy and side effects, check weight and blood pressure
After 3 months to assess effects and compliance
Then annually for efficacy, side effects and compliance,
check weight and blood pressure, a physical examination, update of medical and
family history, relevant laboratory and imaging investigations, a discussion on
lifestyle, and strategies to prevent or reduce chronic disease. review regarding
continuing/modifying HT
• Evaluation to rule out pelvic pathology (endometrial hyperplasia and cancer)For
women with persistent unscheduled bleeding while taking HT
• Emphasizing importance of adhering to age-appropriate breast cancer
screening
Invite earlier visit for specific problems
90. • Follow Up Investigations
• Baseline investigations annually or earlier :
- Routine blood and urine examination
- Blood sugar
- Lipid profile
• Pelvic USG
Mammography (from age 50yrs till 64yrs)
• Pap Smear every 3 yearly
• DXA once in two - five years [optional]
91. Stop Treatment
• If migraine appears for the first time or if headache gets worsened
• Blurring of vision or any symptoms suggesting of vascular occlusion
• If jaundice appears
• If there is significant rise in blood pressure
• HT to be stopped 4–6 weeks before elective surgery
Stopping HT: May be abrupt or the dose and duration may be tapered
off gradually (IMS GUIDELINES)
92. BENEFITS
1. Vasomotor symptoms-> Estrogen is the most effective treatment of hot flushes.
It is the most common symptoms for which patient asks for treatment.
In most cases, 2-3 years therapy is sufficient, but some women may need longer
2. Genitourinary symptoms-> symptoms of vaginal atrophy such as vaginal dryness, soreness,
dyspareunia, urinary frequency respond well to estrogen
topically and systemically.
3.Osteoporosis -> HRT decreases the risk of hip/ spine fracture by 33-40% when started soon
after menopause.
But the preventive effect is lost rapidly following HT discontinuation.
Can be used in early menopause unless there is a contraindication.
4. HT decreases the rates of colorectal cancers .
93. • CARDIOVASCULAR SYMPTOMS
Re-analysis of WHI study suggests a cardio-protective effect if HT
taken in the early menopausal years
HT should not be prescribed for primary or secondary prevention of
CHD
Present recommendations for treatment:
Identify & treat all CHD risk factors.
Do not initiate HT for prevention of CHD.
Do not initiate HT in patients with known CHD.
If CHD develops while on HT, consider other alternatives.
94. HRT RISKS
1.BREAST CANCER
The risk is increased in women who take HT for several years
Combined HT has the highest risk
For oestrogen-only HT the risk is lower
Increased risk is due to estrogen progestrone receptor –positive
tumours.
Risk increases with duration of use and returns to baseline within
a few years of stopping treatment
95. 2. ENDOMETRIAL CANCERS
In women with a uterus, use of oestrogen-only HT substantially
increases the risk of endometrial hyperplasia and cancer in a way
that depends on dose and duration’=
Risk is increased by a factor of 2 to 10 times the normal incidence
of 1 per 1000 post menopausal women per year.
96. 3. OVARIAN CANCER
Observational studies suggest that long-term use of all HT’s may be
associated with a small increased risk of ovarian cancer which
returns to baseline a few years after stopping it
14% increased risk of ovarian ca among HT users and 27% increased
risk with more than 10 yrs of long term use.
97. 4.STROKE
Standard dose HT increased stroke risk by about one third in
generally healthy postmenopausal women
Older women have a greater absolute risk of stroke
Low dose estrogen therapy may not increase the risk of stroke.
98. 5.VENOUS THROMBOEMBOLISM
HT increases venous thromboembolism risk by 2 fold
Evidence suggests that it is higher with combined HT than
oestrogen-only HT and that these events are more likely in the
first year of use
Risk may be lower with a non-oral route
99. “Women Health Initiatives” AGREES WITH THE
RESEARCH STUDIES
HRT provides
CHD –protection in young post menopausal women
Stroke-no increase in early post menopausal healthy women
VTE- 2 fold increase in first year of use, concentrated in those
at risk
Cancer- slightly increase risk of breast cancer or an effect on
preexisting tumours; reduction in colorectal carcinoma
Osteoporosis- reduction in fractures
Diabetes mellitus- reduction in new onset diabetes
100. DEALING WITH SIDE EFFECTS OF HT
Fluid Retention
• Restrict salt intake; maintain adequate water intake exercise; try a herbal diuretic or mild
prescription diuretic
Bloating
• Switch to low-dose transdermal estrogen; lower the progestogen dose a level that still
protects the uterus; switch to another progestin or to micronized progesterone
Breast Tenderness
• Lower the estrogen dose; switch to another estrogen; Restrict salt intake; switch to
another progestin; cut down on caffeine and chocolate
Headaches
• Switch to transdermal estrogen; lower the dose of estrogen and/or progestogen; switch to
a continuous combined regime switch to progesterone or 19 norpregnane derivatives; ensure
adequate water intake; restrict salt, caffeine, and alcohol intake
101. Mood changes
• Lower the progestogen dose; switch progestogen; switch from
systemic progestin to the progestin IUS; change to a continuous
combined EPT regimen; ensure adequate water intake; Restrict
intake of salt, caffeine and alcohol
Nausea
• Take oral estrogen tablets with meals or before bed; switch to
another oral estrogen; switch to transdermal estrogen; lower the
estrogen or progestogen dose
102. MORE BENEFIT ,LESS HARM
Ideal therapy begins within 10 yrs of menopause or below 60 yrs
of age-”window of opportunity”
Low dose of estrogen with low dose progestin when appropriate.
Transdermal administration has reduced risk than oral
Side effect profile of progestin may play a clinical role in
selecting the optimum treatment regimen
103. Assess The Profile Of The Woman To Individualize
Treatment
Type and stage of menopause
• Surgical menopause–E only/Tibolone
• Perimenopause– Cyclical Progesterone/OCP/HT cyclical
• Early Menopause < 12 months EPT (MORE ESTROGENS SEQUENTIAL)
• Late Menopause < 12 months EPT continuous combined/ tibolone/ lowest estrogen/
transdermal
• Premature Menopause– OCP/HT sequential regime
• Urogenital Atrophy- Local estrogens
• Evaluate women’s need and preference
• Evaluation of women’s individual risk factors
104. IMS GUIDELINES FOR HRT
INFORMED CONSENT, depicting benefit over risk is to be obtained.
HT should be individualized
Smallest possible dosage for shortest duration
With estrogen, progestogens are added as endometrial protectors in HT.(
natural micronized progestogens preferred)
Hormonal therapy in premature menopause is to be given till the age of
natural menopause.
105. • Vaginal ET most effective for urogenital atrophy. Treatment may be
continued indefinitely although safety data does not go beyond one year.
Progesterone not needed along with vaginal ET.
Estrogen therapy may be used for prevention and treatment of
osteoporosis in early postmenopausal(<10 years) symptomatic women.
In women with hypertriglyceridemia, obesity, glucose intolerance,
history of tobacco usage and DVT history, non oral routes should be
preferred.
Pre hormonal therapy workup and annual follow up are essential when
prescribing hormonal therapy.
Stopping HT may be abrupt or dose and duration may be tapered
gradually.
106. ACOG GUIDELINES FOR HRT
Vasomotor symptoms are best managed with systemic HT , although
alternatives such as SSRIs, SNRIs and clonidine have shown to be
effective.
Vaginal symptoms are best treated with systemic or topical HT, but
topical methods are preferred as they have fewer side effects.
Systemic HT should be given in lowest dose possible to decrease the
risk of severe adverse effects such as thromboembolic diseases and
breast diseases.
107. ALTERNATIVES TO HRT
It includes biotanicals,animal derived extracts, vitamins,
minerals,fatty acids,amino acids, proteins, probiotics, whole diets
and functional food.
Therapies used mostly in menopausal management are-
PHYTOESTROGENS – soya, isoflavones, red clover.
HERBALISM- evening primrose oil, St john’s wort,
cranberry,dong gvai and other Indian herbs
108. • PHYTOESTROGENS
They are a group of phytochemicals that exhibit estrogenic activity in the body by
acting on estrogen receptors . They are weak estrogens having both estrogenic and
antiestrogenic activity.
There are two ways by which plants exhibit estrogenic activity in humans:-
1. by acting as natural selective estrogen modulators
2.by acting as selective estrogen enzyme modulators.
Eg. Saponins and tannins.
The most widely advised and studied phytoestrogen is soy.
109. • Thus, in management of menopause a comprehensive
approach is needed. Awareness and education about
menopause alongwith lifestyle modifications in the form
of diet, exercise, yoga and pharmacotherapy (HT)
whenever and wherever needed.
