Hrt

Hormone Replacement
Therapy (HRT)
Dr. Prasad B. Chinchole
Pharm D.
SCOP, Almala
@ Dr. Prasad B. Chinchole

What is Menopause?
 Cessation of menstruation as a result of the aging process
of or surgical removal of the ovaries; change from
fertility to infertility.
 Physiological changes that take place within women
between the ages of 30 to 60.
 Hormone levels change in female body; practically the
production of estrogen.
 Perimenopause and menopause can last 10 plus years.
 Menopause itself begins 12 months after a woman’s final
period.

MENOPAUSE AND
PERIMENOPAUSAL AND
POSTMENOPAUSAL
HORMONE THERAPY

PHYSIOLOGY
 A woman is born with approximately two
million primordial follicles in her ovaries.
 During a normal reproductive life span,
she ovulates fewer than 500 times.
 The hypothalamic–pituitary–ovarian axis
dynamically controls reproductive
physiology throughout the reproductive
years.

 GnRH
 FSH
 LH
 Regulate ovarian function.
 Pathophysiologic changes associated with
menopause are caused by loss of ovarian
follicular activity.

 Ovarian primordial follicle numbers
decrease with advancing age, and at the
time of the menopause, few follicles remain
in the ovary.
 Hence the postmenopausal ovary is no
longer the primary site of estradiol or
progesterone synthesis.
 The postmenopausal ovary secretes
primarily androstenedione and testosterone.

Symptoms of
Perimenopause/Menopause
 Cycles become irregular
 Erratic or heavy bleeding
 Vasomotor symptoms- Hot flashes Night
sweats
 Decrease in sexual response
 Irritability/Mood Swings
 Fatigue

Symptoms of
Perimenopause/Menopause
 Headache
 Forgetfulness
 Vaginal dryness
 Dry skin
 Bone loss
 Urinary incontinence

Signs
 Perimenopause:
– Dysfunctional uterine bleeding as a
result of anovulatory cycles
 Menopause:
– Signs of urogenital atrophy

Laboratory Tests
 Perimenopause:
– FSH on day 2 or 3 of the menstrual
cycle greater than 10–12 I units/L
 Menopause:
– FSH greater than 40 international units/L

Hormone Replacement Therapy
 Supplemental hormones: Estrogen, progesterone,
and testosterone.
 Estrogen and progesterone can be made from
plants of from synthetic chemicals.
 Delivery options: pills, patches, creams, inserted
into vagina by means of creams, tablets or ring,
placed under skin by implants or by injection;
future: nasal spray.

Benefits of HRT
 Maintains thickness and vascularity of
vaginal and urethral tissue for comfort and
lubrication during sexual interaction.
 Reduces hot flashes and sleep disturbances
from night sweats.
 Protects against osteoporosis and resultant
fractures, particularly of the hip.
 Reduces risk of colon cancer

TREATMENT
1. PHYTOESTROGENS
2. HORMONAL REGIMENS
3. ESTROGEN AND PROGESTOGEN
TREATMENT
1. Estrogens
1. Oral Estrogen
2. Other Routes
2. Progestogens

4. Methods of Estrogen and Progestogen
Administration
5. Low-Dose Hormone Therapy
6. ANDROGENS
7. SELECTIVE ESTROGEN RECEPTOR
MODULATORS
8. TIBOLONE

Media Reports of HRT
 Media reports: Hazard Ratio- compares the difference
between numbers of people in each treatment condition
who experienced the health problem or benefit.
Example: “The Scientists found a 29% increase
in strokes, and a 26% increase in breast cancer.”
 Absolute Risk- Compares the actual number of people
who experience the problem or benefit.
Example: Women’s Health Initiative actual report
was 8% increase in strokes, and 8% increase for
breast cancer.

PHYTOESTROGENS
 Phytoestrogens have physiologic effects in
humans.
 They are plant compounds with estrogen-
like biologic activity and relatively weak
estrogen receptor–binding properties.
 Common food sources of phytoestrogens
include soybeans (isoflavones), cereals,
oilseeds such as flaxseed (lignans), and
alfalfa sprouts (coumestans).@ Dr. Prasad B. Chinchole

 Phytoestrogens decrease low-density
lipoprotein(LDL) cholesterol and triglyceride
concentrations with no significant change in
high-density lipoprotein (HDL) cholesterol
concentrations
 Common adverse effects include nausea and
constipation, bloating.

HORMONAL REGIMENS
 Approved indications of hormone therapy
include treatment of menopausal symptoms
and osteoporosis prevention.
 Therapy directed at menopausal symptoms,
such as hot flushes, often is short term.
 However, therapy directed at prevention of
osteoporosis should be long term.
 Consideration should be given to approved
nonestrogen alternatives.

 In women with an intact uterus, hormone
therapy consists of an estrogen plus a
progestogen.
 In women who have undergone
hysterectomy, estrogen therapy is given
unopposed by a progestogen.

ESTROGEN AND
PROGESTOGEN TREATMENT
1. Estrogens
1. Oral Estrogen
2. Other Routes
Adverse Effects
2. Progestogens
Adverse Effects
 Methods of Estrogen and Progestogen
Administration

Estrogens
 To relief of vasomotor symptoms.
 The initial dose should be the lowest
effective dose for symptom control.
 Naturally occurring hormones or synthetic
steroidal or nonsteroidal compounds.
 No evidence indicates that one estrogen
compound is more effective than another in
relieving menopausal symptoms or
preventing osteoporosis.@ Dr. Prasad B. Chinchole

Oral Estrogen
 available for more than 50 years.
 prepared from the urine of pregnant mares
and is composed of estrone sulfate (50%–
60%) and multiple other equine estrogens
such as equilin and 17α-dihydroequilin.
 Estradiol is the predominant and most
active.
 Readily absorbed from the small intestines.

 Estradiol is metabolized by the intestinal mucosa
and the liver.
 Cytochrome P450 3A4
 Gut and liver metabolism converts a large
proportion of estradiol.
 Ethinyl estradiol is a highly potent semisynthetic
estrogen that has similar activity following
administration by the oral or parenteral route.
 Orally administered estrogens stimulate the
synthesis of hepatic proteins and increase the
circulating concentrations of sex hormone
binding globulin,

Other Routes
 Parenteral estrogens including
 Transdermal
 Intranasal
 Vaginal
 Percutaneous preparations (gels, creams,
and emulsions)
 Pellets
 Intranasal 17β-estradiol spray@ Dr. Prasad B. Chinchole

Adverse Effects
 nausea, headache, breast tenderness, and
heavy bleeding.
 increased risk for coronary heart disease,
stroke, venous thromboembolism, breast
cancer, and gallbladder disease.
 breast tenderness, unscheduled bleeding,
 Transdermal estrogen DVT than is oral
estrogen.

Progestogens
 Because of the increased risk of endometrial
hyperplasia and endometrial cancer with estrogen
monotherapy women who have not undergone
hysterectomy should be treated concurrently with
a progestogen in addition to the estrogen.
 Progestogens reduce nuclear estradiol receptor
concentrations, suppress DNA synthesis, and
decrease estrogen bioavailability by increasing
the activity of endometrial 17-hydroxysteroid
dehydrogenase, an enzyme responsible for
converting estradiol to estrone@ Dr. Prasad B. Chinchole

 A minimum of 12 to 14 days of progestogen
therapy each month is required for complete
protection against estrogen-induced endometrial
hyperplasia.
 Four combination estrogen and progestogen
regimens currently in use are continuous-cyclic
(sequential), continuous-combined, continuous
long-cycle (or cyclic withdrawal), and
intermittentcombined (or continuous-pulsed)
hormone therapy.
 The first generation of progestogens included the
C-19 androgenic progestogens norethisterone,
norgestrel, and levonorgestrel.

 More recent preparations have included the
C-21 progestogens dydrogesterone and
medroxyprogesterone acetate, which are
less androgenic.
 Drospirenone, a synthetic progestogen
analog of the potassium-sparing diuretic
spironolactone, has both antiandrogenic
and antialdosterone properties.
 The most commonly used oral
progestogens are medroxyprogesterone
acetate, micronized progesterone, and
norethisterone acetate.

Adverse Effects
 Irritability, depression, and headache.
 Mood swings, bloating, fluid retention
sleep disturbance.
 Increased risk for endometrial cancer.

Methods of Estrogen and
Progestogen Administration
1. Continuous Cyclic Estrogen/Progestogen
(Sequential) Treatment
2. Continuous Combined Estrogen–Progestogen
Treatment
3. Continuous Long-Cycle Estrogen–Progestogen
Treatment
4. Intermittent Combined Estrogen–Progestogen
Treatment

Continuous Cyclic Estrogen/Progestogen
(Sequential) Treatment
 Estrogen daily.
 Progestogen is co-administered for at least
12 to 14 days of a 28-day cycle.
 The progestogen causes scheduled
withdrawal bleeding in approximately 90%
of women.

Continuous Combined Estrogen–
Progestogen Treatment
 This regimen is best reserved for women
who are at least 2 years postmenopause.
 Continuous-combined hormone therapy is
more acceptable than traditional cyclic
therapy.

Continuous Long-Cycle Estrogen–
 estrogen is given daily
 Progestogen is given six times per year,
every other month for 12 to 14 days,
resulting in six periods per year.

Intermittent Combined Estrogen–
 The intermittent combined estrogen–
progestogen regimen, also called
continuous-pulsed estrogen–progestogen
or pulsed-progestogen,consists of 3 days of
estrogen therapy alone, followed by 3 days
of combined estrogen and progestogen,
which is then repeated without
interruption.

Low-Dose Hormone Therapy
 CEE 0.45 mg/day
 Medroxyprogesterone acetate 1.5 mg/ day

ANDROGENS
 Pathophysiologic states affecting ovarian
and adrenal function, along with aging,
have been associated with androgen
deficiency in women.

Estrogen Overload?
 Estrogen in the Environment
– Cow and Chicken Farms-Range Feed
– Plastic
– Pesticides
 Diet
 Metabolism

Reducing the amount of Estrogen
 Research looking at lower doses of HTR
 Balance of estrogen and progesterone
– Progesterone Cream
 Stress Relief
 Liver Cleansing

Women’s Health Initiative
2002
 The study
– 16,608 women
– Women ages 50-79
– Purpose was to identify risks and benefits of
long-term HRT use
– Stopped prematurely because of findings

Women’s Health Initiative
2002
 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

Risks of HRT
 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

Side Effects of HRT
 Weight gain
 Bloating
 Breast tenderness
 Irregular bleeding
 Some do not take HRT for fear of cancer
 Some physicians recommend a
discontinuation of HRT

Alternative Therapies
 One study indicated 68 percent of women
have tried alternative therapies and 62
percent were satisfied with the results.
 Diet and Exercise are the most common.

Alternative Therapies (Diet)
 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
– Recommended daily amount is 25 grams of soy
protein and 30-50 mg of isoflavones as a starting
amount and could gradually increase to two to three
times that amount
– Seen to reduce symptoms in 4 out of 10 women

Alternative Therapies (Diet)
 Black Cohosh
– Has been seen to reduce hot flashes
– Potential for liver damage and shouldn’t take
more than 6 months
 Calcium, magnesium and vitamins D & E
– Magnesium promotes bone density
– RDA is 600 mg, although most Americans
only consume 300 mg

 Smoking cessation
– Reduces risk for pretty much everything!
 Avoiding spicy foods for those who get heartburn
– Can reduce severity and frequency of hot flashes
 Limiting or eliminating caffeine
– Promotes sleep
 Relaxation methods
– Helps with mood swings/irritability

 Acupuncture
 Reflexology
 Controlling weight and avoiding weight
gain
 Preparing for hot weather by wearing
layers of clothing and bringing a small fan

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