Transcript HRT

 Hormone replacement therapy (HRT) is a system of
medical treatment for surgically menopausal,
perimenopausal and to a lesser extent postmenopausal
women.
 It involves the use of one or more of a group of
medications designed to artificially boost hormone
levels.
 The main types of hormones involved are oestrogens,
progesterone or progestins, and sometimes
testosterone.
 Menopause is the permanent cessation of menses
following the loss of ovarian follicular activity.
 It is a physiologic event that occurs after 12 consecutive
months of amenorrhea—so the time of the final
menses is determined retrospectively.
 Women who have undergone hysterectomy must rely
on their symptoms to estimate the actual time of
menopause.
 It occurs at the age of late 40’s and early 50’s
 Average age is 51and average life expectancy is 81
years.
 It is genetically predetermined.
 Approximately 1% of women develop ovarian failure
before the age of 40 years (premature menopause or
premature ovarian failure).
 It may be due to
 chemotherapy,
 radiation,
 extensive ovarian surgery, X-chromosome
abnormalities, as a component of autoimmune
syndrome (hypothyroidism, hypoparathyroidism ,
monocutaneous candidiasis), enzyme deficiencies ,
Gonadotropin receptor abnormalities etc.
 Perimenopause : The perimenopause is the period
immediately prior to the menopause and the first year
after menopause.
 The menopausal transition usually begins approximately
4 years prior to menopause and is characterized by
menstrual cycle irregularity caused by increased
frequency of anovulatory cycles.
 Postmenopause : The term postmenopause is applied to
women who have not experienced a menstrual bleed for a
minimum of 12 months.
 Responsible for all the pubertal changes.
( growth of uterus , fallopian tubes and vagina)
 Maintains bone mass primarily by retarding bone
resorption.
 Osteoclast pit formation is inhibited and there is increased
expression of bone matrix proteins such as osteonectin,
osteocalcin, collagen and alkaline phosphatase.
 Maintains positive calcium balance , partly by inducing
renal hydroxylase enzyme which generates active form of
vit-D3.
 Decreases plasma LDL cholesterol while HDL levels
and
triglycerides levels are raised.
 Induces the synthesis of clotting factors (factors 2, 7, 9 and
10)
 Increases lithogenecity of bile by increasing cholesterol
secretion and reducing bile salt secretion.
 Induce nitric oxide synthase in vascular
endothelium and promote vasodilation.
 Plasma levels of
sex harmone binding globulin (SHBG),
thyroxine binding globulin (TBG),
cortisol binding globulin (CBG)
are elevated - but without any change in harmonal
status.
 Has secretory activity on uterine wall.
 Converts the watery cervical secretions induced by
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estrogens to viscid, scanty and cellular secretion
hostile to sperm penetration.
Induce pregnancy like changes in the vaginal
mucosa.
Prepares breast for lactation during pregnancy.
High circulating conc during pregnancy appears to
have a sedative effect.
It causes a slight (o.5 degree centigrade) rise in
body temperature by resetting the hypothalamic
thermostat and increasing heat production.
 Progestins in relatively higher doses stimulate
respiration , as occurs during pregnancy.
 Raise LDL levels and lower HDL levels.
 Progesterone is a weak inhibitor of gonadotropin
secretion from pituitary.
 It decreases the frequency of LH pulses by action
on hypothalamic pulse generator but increases the
amount of LH secreted per pulse.
 Osteoporosis
 Cardiovascular disease
 Vasomotor instability
 Cholesterol elevation
 Sexual dysfunction
 Affective disorders
 Alzheimer's disease
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VASOMOTOR SYMPTOMS
Hot flush (coincide with increases in LH, ACTH, and
cortisol levels, but are not the cause)
Night sweats and inappropriate sweating.
Chilly sensations
Symptoms increases as estrogen level declines
Variable in severity, can persist for years
 Vaginal atrophy
 Urinary urgency
 Vaginal dryness and change in pH
 Nocturia
 Vulval shrinkage
 Itching
 Dyspareunia
 Predisposition to urinary tract infection
 Irritability
 Lethargy/Fatigue
 Depression
 Loss of Libido
 Sexual dysfunction
 Insomnia
 Difficulty with concentration
 Anxiety and dementia
Loss of osteoid as well as calcium
Thinning and weakening of bone
Minimal trauma fractures especially of femur, hip ,
radius, vertebrae.
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Dermatological changes
Thinning of skin
Drying and loss of elasticity of skin
Wrinkles
Thin and listless hair
Other changes include increased risk of cardiovascular
diseases such as
 Coronary Artery Disease (CAD)
 Myocardial Infarction (MI)
 Stroke
The vasomotor changes subside over a few years , but other
changes progresses continuosly.
 Since estrogen therapy relieves symptoms and improve
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HDL:LDL ratio,
retard atherogenesis ,
reduce arterial impedance ,
prevent osteoporosis ,
 it was believed that estrogen therapy in postmenopausal woman
will have a protective cardiovascular influence.
 A segment of doctors contended that menopausal
women should take HRT for the rest of their lives.
 But the studies conducted by “ Women’s Health
Initiative” (WHI) and many cohort studies and placebo
studies yielded opposite results. It was concluded that
the risks associated with HRT are more than the
benefits.
 The study
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16,608 younger women
Women ages 50-79
Purpose was to identify risks and benefits of long-term HRT use
Use of both estrogen and progestin in combination
Stopped prematurely because of findings( occurrence of
prespecified level of invasive breast cancer )
 The primary outcome was coronary heart disease events,
defined as nonfatal myocardial infarction and coronary
artery disease death, with invasive breast cancer as the
primary adverse outcome.
 The study also examined secondary outcomes, including
stroke, thromboembolic disease, fractures, colon cancer,
and endometrialcancer.
 Results
 26 percent increase of invasive breast cancer
 29 percent increased risk of death from coronary
heart disease
 41 percent increased risk of stroke
 200 percent increased risk of blood clots
 Limitations to the study
 Breast cancer
 In 2003 there was 14,000 less cases of breast cancer
possibly due to the decrease in women taking HRT
 If a woman is diagnosed with breast cancer while taking
HRT, she is advised to stop immediately.
 Endometrial cancer
 Cardiovascular disease
 Stroke
 Blood clots
 Maintains thickness and vascularity of vaginal and
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urethral tissue for comfort and lubrication during
sexual interaction .
Treatment of Vaginal atrophy.
Reduces hot flashes and sleep disturbances from
night sweats.
Protects against osteoporosis and resultant fractures,
particularly of the hip.
Reduces risk of colon cancer when used in
combination therapy.
CANDIDATES FOR HRT
 Symptomatic patients at the time of menopause
 Premature ovarian failure patients
 Surgically menopausal patients
 As a treatment for Osteoporosis
CONTRAINDICATIONS FOR HRT
 Breast cancer patients
 Endometrial cancer patients
 Pregnant patients
 Thromboembolic hx (DVT, PE)
 Hypercoaguability disorders
 Liver disease
 Undiagnosed genital bleeding
 Lowest dose for shorter duration is recommended.
 Therapy directed at menopausal symptoms, such as hot
flushes, is often short term.
 However, therapy directed at prevention of osteoporosis
should be long term.
 In women with an intact uterus, hormone therapy
consists of an estrogen plus a progestogen.
 Inwomen who have undergone hysterectomy, estrogen
therapy is given unopposed by a progestogen.
Estrogen
 Orally
 Transdermal patches
 Topical gels or creams
 Vaginal cream or pills
 Injectable
Progesterone
 Orally
 Topical
 Vaginal cream
 Injectable
DRUG
DOSE
FREQUENCY
ROUTE
Conjugated equine 0.3 - 0.45 mg
estrogen
OD
Oral
Esterified
estrogens
OD
Oral
Estropipate
0.625mg
(piperazine estrone
sulfate)
OD
Oral
Ethinyl estradiol
5mcg
OD
Oral
Micronized 17βestradiol
1–2 mg (0.25-0.5mg)
OD
Oral
Transdermal 17βestradiol
50 mcg (25 mcg)
Once or twice
weekly
Transdermal
Intranasal 17βestradiol
150 mcg,
OD
Intranasally
Implanted 17βestradiol
50 to 100 mg( 25mg)
every 6 months.
subcutaneously
0.3 mg
DRUG
DOSE
FREQUENCY ROUTE
17β-estradiol
emulsion -0.05 mg,
gel- 0.04 mg
OD
Transdermal
(Percutaneous)
Vaginal rings
(Estring ,
Femring).
PROGESTERONES :
 Due to increased risk of endometrial hyperplasia and
endometrial cancer with estrogen monotherapy
(unopposed estrogen), women who have not
undergone hysterectomy should be
treated
concurrently with a progestogen in addition to the
estrogen.
 Progestogens must be taken for a sufficient period of time
during each cycle.
 A minimum of 12 to 14 days of progestin therapy each month
is required for complete protection against estrogeninduced endometrial hyperplasia.
 Even low dose estrogen should contain progesterone for
endometrial protection .
 Various progestogens used are :
Dydrogesterone
Medroxy progesterone acetate
Micronized progesterone
Norethisterone
Norethindrone acetate
Norgestrel
Levonorgestrel
 Most commonly used oral progestogens are
 medroxyprogesterone acetate,
 micronized progesterone,and
 norethisterone acetate.
Methods of Estrogen and Progestogen
Administration
 Continuous Cyclic Estrogen/Progestogen Treatment.
 Continuous-Combined Estrogen/Progestogen
Treatment.
 Continuous Long-Cycle Estrogen/Progestogen
Treatment.
 Intermittent-Combined Estrogen/Progestogen
Treatment.
Continuous-Cyclic
 Estrogen taken daily
 Progestogen for 12 -14 days of a 28 cycle.
 Progestogen causes scheduled withdrawl bleeding in 90%
women.
Continuous-Combined
 Both are given daily .
 Best reserved for women who are at least 2 years
postmenopause.
Continuous Long-Cycle
 Estrogen is given daily,and progestogen is given six times a
year, every other month for 12 to 14 days, resulting in six
periods a year.
 Bleeding episodes may be heavier and last for more days than
withdrawal bleeding with continuous-cyclic regimens.
Intermittent-Combined :
 3 days of estrogen therapy alone, followed by 3 days of
combined estrogen and progestogen and repeating the
same.
 Designed to lower the incidence of uterine bleeding.
ANDROGENS
 Given primarily to patients who have undergone
surgical menopause .
 Testosterone treatment should not be administered to
postmenopausal women who are not receiving
concurrent estrogen therapy.
 Estrogen combined with androgen increases bone
density sooner and to a greater degree than estrogen
therapy
ANDROGEN Regimen for women
DRUG
DOSE
FREQUENCY
ROUTE
Methyltestosterone +
Esterified Estrogen
Mixed testosterone
esters
50–100 mg
Every 4 to 6 weeks
Intramuscular
Testosterone pellets
50 mg
Every 6 months
Subcutaneous
(implanted)
testosterone system
150–300
mcg/day
Every 3 to 4 days
Transdermal
Nandrolone decanoate
50mg
every 8-12 weeks
Intramuscular
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ESTROGENS
Breast tenderness
Abnormal bleeding
Nausea
Increased incidence of
GB disease
Stimulation of preexisting estrogen
dependent tumor
Increases sex hormone
binding globulin
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PROGESTOGENS
Weight gain
Moodiness
Acne
Carbohydrate
intolerance
Break through bleeding
Bloating
ANDROGENS
 Weight gain
 Hirsuitism
 Lowering of the voice
 Acne
 Oiliness of the skin
 Decreases sex hormone binding globulin
 Selective estrogen-receptor modulators (SERMs),
 Tamoxifen, the first-generation SERM,
 It has estrogen antagonist activity on the breast and estrogenlike agonist activity on bone and endometrium.
 Ex: raloxifene,
 prevent bone loss and spinal fractures.
 Used for preventing osteoporosis in women
contraindicated to HRT.
 Tibolone
 It is a gonadomimetic synthetic steroid in the norpregnane
family with combined estrogenic, progestogenic, and
androgenic activity.
 For the treatment of menopausal symptoms and
prevention of osteoporosis.
 Tibolone has beneficial effects on mood and libido and
improves menopausal symptoms and vaginal atrophy.
 Tibolone protects against bone loss, and its effect on
fracture rates is currently being evaluated.
 Black cohosh (Cimicifuga racemosa) is used widely and
has been shown to be an effective alternative for the
relief Of vasomotor symptoms (may act through
serotonergic system).
 Soy isoflavones in soy products
 Relieves a number of symptoms, including hot flashes,
night sweats, fatigue and vaginal dryness
 Soy has also been shown to assist the body in absorbing
and retaining calcium, suppress bone loss, lower LDL
cholesterol and decrease blood clotting
Alternatives to treat vasomotor symptoms
 SNRIs( Serotonin Norepinephrine reuptake inhibitors)
—Venlafaxine (Effexor) shows good results
 SSRIs ( Selective Serotonin Reuptake Inhibitor) —
Paroxetine with good data, fluoxetine less but helpful
 Megestrol Acetate (synthetic progestin)—hot flash
reduction of 85% vs 21% for placebo (wt gain side effect)
 Clonidine- alpha-2 adrenergic agonist
 Consider in women with hypertension
 Gabapentin—unknown mechanism, generally
demonstrates reduction in hot flashes
 Pre treatmemt assessment should be done and the
patient should be explained with risks and benefits
so that they can outweigh them
 Should consider parameters like coronary artery
disesase risk , thromboembolism risk , breast cancer
and osteoporosis .
 Recommendations should be specific to each woman
and her background.
 The main indication for hormone therapy is to relieve
from menopausal symptoms, and hormone therapy
should be used only as long as symptom control is
necessary (typically for about 2 to 3 years).
 When used under such conditions, the absolute risk of
harm to an individual woman is very small .
 Recommended for not more than 5 years.
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Pharmacotherapy , A Pathophysiologic approach
by Joseph T. Dipiro .
Textbook of therapeutics drug and disease
management . By Herfindal ,Gourley.
7th edition.
Essentials of medical physiology by KD Tripathi.
Human physiology by Dr.C.C.Chatterjee ,
volume -2
Hormone replacement therapy - wikipedia , google.
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