Hormone Replacement

Therapy (HRT)

DR SARAVANAN DHARMARAJ

1
• Classify HRT.
• Explain the mechanism of action of HRT.
• Describe pharmacokinetics, uses and side effects of HRT.
• Describe the rationale of using HRT

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 Menopause….
• Cessation of normal ovarian function at
menopause cause changes such as:
– osteoporosis leading to fractures.
– vasomotor symptoms (e.g. hot flashes).
– urogenital atrophy (manifests as dry
vagina)
– Sleep disturbances
– Increased cardiovascular disease

3
 PSYCHOLOGICAL SYMPTOMS
• These include
depression, mood
changes, anxiety,
irritability, loss of libido,
lack of energy and
memory loss.

4
Hormone Replacement Therapy:
The use of female hormones for the relief of symptoms resulting
from cessation of ovarian function, either at the time of natural
menopause or following surgical removal of ovaries.

The combination of progestogen with oestrogen is preferred if

the women has retained her uterus, as oestrogen alone might
cause overstimulation of the endometrium or even cancer.

HRT should be used only in short term (no more than five years)
and is no longer recommended for osteoporosis#.

See objective of long term therapy.

5
 Hypothalamus
neg

GnRH
+
neg
Anterior pituitary
neg

FSH LH
+ +

Ovary
GF CL
GF-grafian
follicle
CL-corpus Oestrogen Progesterone
luteum
SYNTHESIS AND REGULATION OF FEMALE SEX
HORMONE 6
 DRUGS
Hormonal agents
1. oestrogen
2. progestin

nonhormonal agents
a. SERMs
b. clonidine (α2- adrenergic agonist)
c. Bisphosphonates

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NATURAL OESTROGEN
All these natural ones are steroidal.
The major estrogen produced by the women are oestradiol, oestrone and
oestriol.
Oestradiol-the major secretory product of ovary (most potent eostrogen).
Some oestrone is produced in the ovary.
Most oestrone and oestriol are formed in the liver from oestradiol or in
peripheral tissues from androstenedione and other androgens.

SYNTHETIC ESTROGENS
A variety of chemical alterations have been made to natural estrogens.
Most important are to increase their oral effectiveness.

COMMONLY USED ESTROGENS

Ethinyl estradiol
Micronized oestradiol Conjugated equine
Oestradiol cypionate oestrogen
Oestradiol valerate (Premarin)*
Quinestrol
Chlorotrianisene
Methallenestril 8
Steroidal Natural
Estradiol
Estrone
Estriol

Steroidal synthetic
Ethinyl oestradiol
Mestranol
Quinestrol
[MEeQ]

Non-steroidal synthetic
Diethylstilbestrol
Chlorotrianisene
Methallenestril
[CM_Die]

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Mechanism of action (Steroid receptors)

Types and location of oestrogen receptors (ERs): The ERs are ERα
and ERβ.

Many tissues contain both subtypes.

ERα– predominantly in uterus, vagina, ovary, breast, hypothalamus
and blood vessels; ERβ– predominantly in prostate and ovaries.

Mechanism of action of oestrogens.

ERs, Oestrogen receptors.
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The estrogen receptor complex forms dimers (usually ERα-ERα,
ERβ-ERβ, or ERα-ERβ) that bind to a specific sequence of
nucleotides, called estrogen response elements (EREs).
The EREs are present in the regulatory regions of various genes and
regulate their transcription.
The interaction of a receptor dimer with the ERE also involves a
number of nuclear proteins, the coregulators, as well as components
of the transcription machinery.

MOA of progestins
Progestins enter the cell and bind to progesterone receptors that are
distributed in the nucleus and the cytoplasm.
The ligand-receptor complex binds to a progesterone response
element (PRE) to activate gene transcription.

The response element for progesterone appears to be similar to the

corticosteroid response element.

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ACTIONS OF OESTROGEN

▪ Essential in growth and development of sex organs in female.

▪ Stimulate the development of secondary sex characters.
▪ Responsible for the proliferative phase of the endometrium.
▪ Stimulates the growth of ducts and stroma in the breast.
▪ Has negative feedback control on the anterior pituitary.
▪ Cervical secretions become thin, watery, alkaline-facilitates entry
of sperm.

Estrogens seem to be partially responsible for maintenance of the

normal structure and function of the skin and blood vessels in
women.
Estrogens also stimulate adipose tissue production of leptin.

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METABOLIC ACTIONS
• Decrease the rate of resorption of bone by inhibiting activity of
osteoclasts.
• Increase plasma HDL.
• Slight decrease LDL levels.
• Reduction in total plasma cholesterol levels.
• also facilitate the loss of intravascular fluid into the extracellular space,
producing edema.
• The resulting decrease in plasma volume causes a compensatory
retention of sodium and water by the kidney.
• Enhance the coagulability of blood by increasing clotting factors (II, IV, IX
and X) and decreasing antithrombin III.
• Induce the synthesis of progesterone receptors.

Estrogens alter the production and activity of many other proteins in the body.
Metabolic alterations in the liver are especially important, so that there is a higher
circulating level of proteins such as transcortin (corticosteroid-binding globulin
[CBG]), thyroxine-binding globulin (TBG), SHBG, transferrin, renin substrate, and
fibrinogen. This leads to increased circulating levels of thyroxine, estrogen,
testosterone, iron, copper, and other substances.

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 Life span of a female

• Delayed • Contraception • Post-

puberty in • Dysmenorrhoea menopausal
girls • Dysfunctional HRT
uterine bleeding • Senile
vaginitis

Menarche Menopause

Therapeutic uses of oestrogen in women

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 Therapeutic Uses of oestrogen
1. Primary hypogonadism-Delayed puberty in gals
2. Dysmenorhoea
3. Oral contraceptive
4. Senile vaginitis
5. POST-MENOPAUSAL HORMONE REPLACEMENT THERAPY

SHORT-TERM OESTROGEN THERAPY is used to relieve menopausal

symptoms such as
➢ Hot flushes
➢ Vaginal atrophy
➢ Night sweats
➢ Depression
➢ Irratibility
➢ Sleeplessness.

The main objective of LONG TERM OESTROGEN THERAPY in post-

menopausal women is to:
❑ Prevent or delay osteoporosis [some guidelines prefer other therapies*).
❑ Prevent atherosclerosis.

HRT reduces the incidence of coronary artery disease and Alzheimer’s15

disease.
16
 Pharmacokinetics
Naturally occurring oestrogens
These agents and their esterified or conjugated derivatives are
readily absorbed through the GIT, skin and mucous membranes.
Oestrogen is quickly distributed by I.M.
Orally, oestradiol is rapidly metabolized and inactivated by liver (first
pass metabolism) but still effective orally.

Synthetic oestrogen analogs

Ethinyl oestradiol and mestranol are well absorbed through oral, skin
or mucous membranes.
Synthetic eostrogens have a prolonged action and higher potency
compared to natural oestrogens.
Mestranol is metabolized to ethinyl oestradiol that is metabolized
slower than naturally occuring oestrogen.

Postmenopausal women who have only localized urogenital

symptoms (e.g. vaginal atrophy and dyspareunia) should be treated
with vaginal formulations rather than systemic eostrogen.
Preparations for these include include vaginal creams, inserts, and
the lower-dose vaginal ring. 17
Metabolism of oestrogen
Bioavailability of oestrogen taken orally is low due to first pass
metabolism in the liver.

To reduce first pass metabolism, drugs are administered by

transdermal patch, intravaginally or by injection.

Drugs are hydroxylated in liver and then glucuronated or sulfated.

Metabolites are excreted into bile and undergo enterohepatic
circulation.
Inactive metabolites excreted into urine.

ADVERSE EFFECTS OF OESTROGEN

The most common are nausea and vomiting; and best tenderness.
Long term side effects: endometrial cancer, thromboembolic problems
and gallbladder disease. Dose of oestrogen in HRT about 20% of oral
contraceptive dose. Adverse effect less than for contraceptives.

Other problems are postmenopausal vaginal bleeding, fluid retention

with oedema, myocardial infarction as well as breast and endometrial
cancer.
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Some adverse effects associated with estrogen therapy

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The Progestin

NATURAL PROGESTERONE
Progesterone is the most important progestin in humans.
It has important hormonal effect and serves as a precursor to the
oestrogens, androgens and adrenocortical steroids.
It is synthesized in the ovary, testis and adrenal cortex from
cholesterol.
In ovary, progesterone produced by corpus luteum (follicular phase,
luteal phase and pregnancy).

SYNTHETIC PROGESTINS
A variety of compounds have been synthesized.

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Synthetic:
Progesterone derivative 19-Nortestosterone derivative
Medroxyprogesterone acetate Norethindrone
Hydroxyprogesterone caproate Norgestrel
Megestrol acetate Levonorgestrel
Dydrogesterone Desogestrel*
[HM_MD] Gestodene*
Norgestimate*
Norethisterone
[4N_Ln]

In general, the 21-carbon compounds (hydroxyprogesterone,

medroxyprogesterone, megestrol, and dimethisterone) are the most closely
related, pharmacologically as well as chemically, to progesterone.

A new group of third-generation synthetic progestins has been introduced,

principally as components of oral contraceptives. These “19-nor, 13-ethyl” steroid
compounds include desogestrel, gestodene, and norgestimate. They are
claimed to have lower androgenic activity than older synthetic progestins.

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ACTIONS OF PROGESTIN
▪ Progesterone is very important for the maintenance of pregnancy.
▪ Progesterone is responsible for the secretory phase of the
endometrium.
▪ Progesterone has negative feedback control on both hypothalamus
and anterior pituitary.
▪ Cervical mucus becomes thick, more viscous and hostile to sperm
penetration.
▪ Progesterone brings about proliferation of acini in the breast.
▪ Progesterone competes with aldosterone for mineralocorticoid
receptor of renal tubule.

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METABOLIC ACTIONS
• Progesterone increases basal insulin levels and the insulin response to
glucose.
• In the liver, progesterone promotes glycogen storage, possibly by
facilitating the effect of insulin. Progesterone also promotes
ketogenesis.
• Long term use of progestins decrease glucose tolerance.
• Progestins increase circulating LDL.
• Progestins stimulate lipoprotein lipase activity and favor fat deposition.
• Also produce sodium and water retention with edema.
• Progestins increase body temperature.
• Have hypnotic effect.
• Progesterone inhibits synthesis of oestrogen receptors.

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THERAPEUTIC USES OF PROGESTINS
1. Contraception
2. Dysfunctional uterine bleeding
3. Endometriosis
4. Endometrial carcinoma

5. ADJUVANT TO OESTROGEN IN HRT (to prevent endometrial cancer)

The administration of progestational agent with oestrogen prevent
endometrial hyperplasia and reduces cancer risk.
Oestrogen is given for first 25 days of the month and
medroxyprogesterone (10 mg/d) for 10-14 days reduces cancer risk.

For women with an intact uterus, a progestogen should be included

with oral, transdermal, or topical estrogen therapy, because the
progestogen reduces the risk of endometrial carcinoma associated
with unopposed estrogen.

[Note: Some vaginal ring formulations of estrogen therapy obtain high

enough systemic levels that addition of a progestin is warranted.]

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PHARMACOKINETICS
Progesterone is not effective orally due to extensive first-pass effect.
A micronized preparation of progesterone is rapidly absorbed after
administration by any route.
It has short half life in plasma and completely metabolized by the liver.
In the liver, progesterone is metabolized to pregnanediol and conjugated with
glucuronic acid.
It is excreted into the urine as pregnanediol glucuronide. The amount of
pregnanediol in the urine has been used as an index of progesterone
secretion.

Synthetic progestins are less rapidly metabolized. Oral medroxyprogesterone

acetate has a half-life of 16 to 30 hours.

The hydroxy- and medroxyprogesterone derivatives are injected intramusc.

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SIDE EFFECTS
Progestins can cause headache, weight gain, depression, sedation,
fluid retention, breast discomfort, depression, increased incidence of
thromboembolism and hirsutism (and acne due to androgenic action).

Progestins derived from 19-nortestosterone (e.g. norethindrone,

norethindrone acetate, levonorgestrel) possess some androgenic
activity because of their structural similarity to testosterone.

Older progestins cause altered plasma lipids (decrease HDL, increase

LDL increase), hence increased risk of cardiovascular disease.
Newer progestins have little or no adverse effects on lipids.

Combined drug causes: bleeding at end of cycle, migraine headaches

during end of cycle.
[Other problems in combination replacement therapy E/P: venous
thromboembolism, stroke, myocardial infarction/coronary heart
disease, breast cancer]

To prevent cyclic bleeding at end with sequential therapy can use

continous therapy. 27
Some adverse effects
associated with progestin
therapy.

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WOMENS HEALTH INITIATIVE
Large clinical trial that evaluated the health benefit and risk of hormone
therapy in post menopausal women.

Eostrogen therapy did not increase the risk of coronary heart disease or
breast cancer but DID increase the risk of stroke ↑ and
thromboembolism ↑and decreased the risk of osteoprotic fracture↓.

❖ Continuous oestrogen-progestin treatment increased the risk of

cardiovascular event (nonfatal myocardial infarction and coronary
heart disease), breast cancer ↑ and stroke ↑ and decreased risk of
osteoporotic fracture ↓.

• Current recommendation is for post-menopausal women is to use

hormone therapy only to treat bothersome symptoms such as
vasomotor symptoms or vaginal dryness, and to use lowest dose
possible for shortest time.

[If women who are not candidates for HRT, alternatives for management
of vasomotor symptoms include selective serotonin reuptake inhibitors,
serotonin-norepinephrine reuptake inhibitors and gabapentin.] 29
[in any case, no increased risk for breast cancer if therapy given
immediately after menopause and for first, 7 years. Cardiovascular
risk depends on degree of atherosclerosis at onset of therapy]

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Patients at low risk of developing osteoporosis, with mild atrophic
vaginitis can be treated with topical preparations.
Locally administered oestrogens escape first-pass effect (but
some first pass effect occurs). They are almost completely
absorbed into circulation and should be given cyclically.

Daily therapy with 0.625 mg conjugated equine oestrogen and 2.5-

5 mg of medroxyprogesterone will eliminate cyclic bleeding,
control vasomotor symptom, prevent genital atrophy, maintain
bone density and show favorable lipid profile, small ↓ LDL, ↑ HDL.

Oestrogens are more effective at preventing than restoring bone loss

and are most effective if initiated before significant bone loss occurs.

Long term use of oestrogen for post-menopause osteoporosis has

fallen out of favor due to adverse effect concerns.
SERMs have been developed for beneficial effect on bone while
eliminating side effects on breast31, uterus and CVS.
 Treatment philosophies
a. No contraindications - treat all
b. No risk - don't treat. At risk - treat, but stop if ineffective
C. Main indication for HRT:
[Link] & other symptoms in perimenopausal period
[Link] the smallest dose & for the shortest duration
[Link] for young women with premature menopause & Rx
cyclical rather than continous HRT
a. HRT is the most effective treatment of menopausal symptoms
a. Hysterectomised women should received oestrogen alone,
while those with intact uterus Rx oestrogen + progesterone

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SELECTIVE OESTROGEN RECEPTOR MODULATORS (SERMs)
SERMs are group of compounds that bind to oestrogen receptor
(ER) and have tissue selective effect on target organ of oestrogen.

Depending on organ, SERM is capable of acting as oestrogen

agonist or oestrogen antagonist.

SERMs are promising agents for prevention and TREATMENT OF

POST-MENOPAUSAL OSTEOPOROSIS.

RALOXIFENE
It is an oestrogen agonist in bone, but oestrogen antagonist in the
endometrium and breast.
It has estrogenic effects on lipids and bone but appears not to
stimulate the endometrium or breast.

➢ Raloxifene may be the preferred therapy for osteoporosis in

women with breast cancer, women with risk of breast or
endometrial cancer, or women who want to avoid adverse effects
(vaginal bleeding and breast tenderness).
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Raloxifene has been approved for prevention of post menopausal
osteoporosis.

Although not as effective as estrogen in increasing bone density,

raloxifene has been shown to reduce vertebral fractures.

Raloxifene is rapidly absorbed after oral administration.

It has poor bioavailability due to extensive first pass metabolism.

Although subject to a high first-pass effect, raloxifene has a very

large volume of distribution and a long half-life (>24 hours), so it can
be taken once a day.

ADVERSE EFFECTS
Hot flushes, increased incidence of deep vein thrombosis.

NEWER SERMS
Newer SERMs have been developed and one, bazedoxifene, in
combination with conjugated estrogens, is approved for treatment of
menopausal symptoms and prophylaxis of postmenopausal
osteoporosis. 34
COMPARISON WITH TAMOXIFEN
Tamoxifen is approved for use in breast cancer.

Tamoxifen is an oestrogen receptor antagonist in breast tissue but partial

agonist in bone and endometrium.

Results in inhibition of oestrogen dependent growth of breast cancer but

stimulation of endometrial growth (and cancer).
❖ (Raloxifene has oestrogen receptor antagonist effect in breast and
endometrium but agonist in bone- and is preferred to tamoxifen for
osteoporosis).

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TOREMIFENE
It is a relatively new SERM with properties similar to tamoxifen.
But toremifene does not increase the risk of endometrial cancer.
Its use is restricted to postmenopausal women with risk of breast
cancer.

Hormone therapy is available in many preparations:

• Oral tablets
• Transdermal patches
• Subcutaneous implants
• Vaginal rings
• Vaginal creams
• Vaginal tablets

Various regimens
- Bleeding
- Or no bleeding = continuous intake of HRT

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TIBOLONE
It has estrogenic, progestogenic and weak androgenic activity and
does not cause endometrial cancer.
It can be used without cyclic progesterone.

CLONIDINE
Alpha2-selective agonist
In patients in whom, oestrogen replacement therapy is
contraindicated, relief of vasomotor symptoms may be obtained by
using clonidine.

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BISPHOSPHONATES
Nonhormonal forms of therapy for osteoporosis have been
developed.
Bisphosphonates such as alendronate, risedronate, and ibandronate
increase bone density and reduce fracture.

CALCITONIN
Calcitonin is approved for use in treatment of postmenopausal
osteoporosis.

It has been shown to increase bone mass and reduce fractures BUT
ONLY in spine. It is not as effective as bisphonates or teriparatide.

Calcitriol

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FORMULARI UBAT-UBATAN KEMENTERIAN KESIHATAN MALAYSIA
Conjugated estrogens 0.3 mg tablet: i) Osteoporosis associated with oestrogen
deficiency ii) Female hypoestrogenism iii) Vasomotor symptoms associated with
oestrogen deficiency iv)atrophic vaginitis and urethritis

Conjugated Estrogens 0.625 mg & Medroxyprogesterone Acetate 2.5

mg Tablet: Management of moderate to severe vasomotor symptoms
associated with menopause, prevention and management of postmenopausal
osteoporosis, atropic vaginitis and atropic urethritis in post menopausal
woman with intact uterus

Estradiol 1 mg & Estradiol 1 mg with Dydrogesterone 10 mg: Hormone

Replacement Therapy for women with disorders due to natural or surgically
induced menopause with intact uterus.

Estradiol 1 mg & Norethisterone Acetate 0.5 mg Tablet: Hormone replacement

therapy for oestrogen deficiency symptoms in women more than 1 year after
menopause and prevention of osteoporosis in post menopausal women
Estradiol 1 mg with Dydrogesterone 5 mg Tablet: i) Hormone replacement
therapy for the relief of symptoms due to oestrogen deficiency ii) Prevention of
postmenopausal osteoporosis in women with a uterus
Estradiol Valerate 1 mg Tablet: Oestrogen replacement therapy - only those who
cannot tolerate Premarin 39
Estradiol Valerate 2 mg and Norgestrel 500 mcg with Estradiol Valerate
2 mg Tablet: Pre and post menopausal syndrome, primary and secondary
amenorrhea, menstrual irregularities. Deficiency symptoms after oophorectomy or
radiological castration for noncarcinomatous disease

Medroxyprogesterone Acetate 10 mg Tablet: i) Secondary amenorrhoea ii)

Abnormal uterine bleeding due to hormonal imbalance
Raloxifene HCl 60 mg Tablet: Prevention and treatment of postmenopausal
osteoporosis

Tibolone 2.5 mg Tablet: Treatment of complaints resulting from the natural or

surgical menopause & in cases at high risk for breast carcinomas where general
hormone replacement therapy is contraindicated

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