HORMONE

REPLACEMENT
THERAPY
 Overview
 Introduction
 Normal menstrual cycle
 Signs and symptoms
 Treatment
 Treatment considerations
 Benefits and Risks of HRT
 Conclusion
 Introduction
 The menopause is a natural event which
leads to the changes like anatomical,
physiological and psychological changes.
 Some women will go from the transition of
being premenopausal to postmenopausal
with no symptoms at all.
 Many will experience the symptoms
associated with estrogen lack.
 The median age at the onset of
menopause in the United States is 51
years, whereas the average life
expectancy for women is 81 years. Thus
American women can expect to be
postmenopausal for more than one-third
of their lives.
 Hence it is important that hormone
therapy should be used for the treatment
of menopausal symptoms.
Normal Physiology:
 A woman is born with approximately 2
million primordial follicles in her ovaries.
During a normal reproductive life span, she
ovulates less than 500 times.
 The hypothalamic-pituitary-ovarian axis
dynamically controls reproductive
physiology throughout the reproductive
years.
 The pituitary is regulated by pulsatile
secretion of gonadotropin-releasing hormone
(GnRH) from the hypothalamus.
Menstrual phase: it usually lasts for about 4 days.
When the ovum is not fertilized, the corpus luteum
starts to degenerate. Progesterone and oestrogen
levels therefore fall, and the functional layer of the
endometrium, which is dependent on high levels of
these ovarian hormones, is shed in the
menstruation.
Proliferative phase: it lasts for about 10 days. At
this stage an ovarian follicle, stimulated by FSH, is
growing towards maturity and producing
oestrogen. Oestrogen stimulates the proliferation
of the functional layer of the endometrium in
preparation for the reception of a fertilized ovum.
The endometrium becomes thicker by rapid cell
multiplication accompanied by an increase in the
numbers of mucus-secreting glands and blood
capillaries.
Secretary phase: Immediately after ovulation, the
lining cells of the ovarian follicle are stimulated
by LH to develop the corpus luteum, which
produces progesterone nd some oestrogen.
Under the influence of progesterone and
endometrium becomes oedematous and the
secretary glands produce increased amounts of
watery mucus.
 If the ovum is not fertilised menstruation occurs
and a new cycle begins.
 If the ovum is fertilized there is no breakdown of
the endometrium and no menstrual flow. The
fertilized ovum (zygote) travels through the
uterine tube and gets embedded in the uterous.
The menopause usually occurs between the
ages of 45 and 55 years, marking the end
of the childbearing period.
It can occur suddenly or over a period of
years (in few cases it may take as long as
10 years).
The ovaries gradually become less
responsive to FSH and LH, and ovulation
and menstrual cycle become irregular,
eventually ceasing.
Signs and  Vasomotor symptoms :
symptoms (hot flushes and night
sweats),
 Psychological symptoms
(anxiety, mood swings,
and depression),
 Disturbances of sexuality
 Problems with
concentration
and memory
 Vaginal dryness and
dyspareunia
 Sleep disturbances
SIGNS
 Perimenopause: Dysfunctional uterine
bleeding owing to anovulatory cycles (other
gynecologic disorders should be excluded)
 Menopause: Signs of urogenital atrophy

LABORATORY TESTS
 Perimenopause: FSH on day 2 or 3 of the
menstrual cycle greater than 10–12 IU/L
 Menopause: FSH greater than 40 IU/L.
 An observational study of more than
9000 postmenopausal women examined
the relationship between endogenous
estrogens and bone mineral density,
bone loss, fractures, and breast cancer.
 Women with detectable serum estradiol
concentrations (5–25 pg/mL) had a 6% to
7% higher bone mineral density at the
total hip and spine as compared with
women with undetectable levels.
However, women with the highest
estradiol serum concentrations had the
greatest risk of developing breast cancer.
 Treatment
 Non pharmacological methods:
Treatment of menopausal symptoms can
be managed effectively in some women
with lifestyle modifications, including
exercise, weight control, smoking
cessation, and a healthful diet.
 Phytoestrogens
 Phytoestrogens are plant compounds
with estrogen-like biologic activity and
relatively weak estrogen-receptor-binding
properties
The three main classes of phytoestrogens (and common
food sources) are:
 Isoflavones - Eg: Soybeans
 Lignans - Eg: Cereals and oilseeds such as flaxseed
 Coumestans -Eg: Alfalfa sprouts
 Phytoestrogens decrease low-density lipoprotein
(LDL) and triglyceride concentrations, do not change
high-density lipoprotein (HDL) concentrations, and
may improve bone density.

 Adverse effects include constipation, bloating, and

nausea.
 Epidemiologic studies suggest that consumption of a
phytoestrogen-rich diet, as seen in traditional Asiatic
societies, is associated with a lower risk of breast
cancer.
OESTROGENS: Thesecan be classified into two
groups:
 Steroidal oestrogens.
Naturally occurring:Eg: Oestradiol, oestrone,
Synthetic derivatives: Eg: Ethinyloestradiol
 Non-steroidal oestrogens; Eg: Dienostrol
 Natural oestrogens are metabolized by the same
pathway as endogenous oestradiol and therefore have
a short half life. Synthetic oestrogens have a chemical
configuration which prevents hepatic enzymatic
oxygenation and are therefore more stable and more
potent compounds.

 Oestrogens are metabolized principally in the liver

and excreted as steroids and conjugates in the urine.
 There is some evidence that natural oestrogens may
have less effect on stimulation of protein synthesis in
the liver and synthesis of clotting factors, thus natural
oestrogens are preferred for HRT.
 Estrogens can be
administered orally,
transdermally (patches
and other topical
products), intravaginally
(creams, tablets, or rings),
intranasally,
intramuscularly, and even
in the form of
subcutaneously implanted
pellets.
 Estradiol is the
predominant and most
active form of endogenous
estrogens. Micronized
form of estradiol is readily
absorbed from the small
intestines.
 When given orally estradiol is metabolized by
the intestinal mucosa and the liver. Only 10%
reaches the circulation as free estradiol.
 Gut and liver metabolism converts a large
proportion of estradiol to the less potent
estrone. Thus measurement of serum estradiol
is not useful for monitoring oral estrogen
replacement.
 Adverse Effects. Common adverse effects of
estrogen include nausea, headache, breast
tenderness, and heavy bleeding.
 More serious adverse effects include increased
risk for coronary heart disease, stroke, venous
thromboembolism, breast cancer, and
gallbladder disease.
PROGESTOGENS: these are classified into 2 broad
groups:
 Progesterone derivatives: Eg: Dydrogesterone,
Medroxyprogesterone.
 Testosterone derivatives: Eg: Norethisterone,
Levonorgesterol.
 Progesterone derivatives appear to be associated
with more psychological adverse effects and have
limited effects on lipid profiles.
 However they may suppress HDL cholesterol
levels. Testosterone derivatives appear to be
associated with adverse effects such as acne and
hirsutism. Progestogens are metabolized in the
liver and metabolites excreted, as conjugates, in
the urine.
 COMBINATION ESTROGEN AND PROGESTOGEN:

 Because of the 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.
 Progestogen regimens are mainly designed to prevent
endometrial hyperplasia. 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 estrogen-induced
endometrial hyperplasia.
 It should be noted that even use of low-dose estrogen,
including some vaginal preparations, requires progestogen
coadministration for endometrial protection in women with
an intact uterus.
4 combinations of Estrogen&Progesterones:
 Continuous-cyclic (sequential): Estrogen
typically is administered continuously (daily). A
progestogen is coadministered with the
estrogen for at least 12 to 14 days of a 28-day
cycle. With this regimen, bleeding usually begins
1 to 2 days after the last progestin dose.
 Continuous-combined: Continuous-combined
estrogen-progestogen administration results in
endometrial atrophy and the absence of vaginal
bleeding. However, initially it causes
unpredictable spotting or bleeding, which
usually resolves within 6 to 12 months. this
regimen is best reserved for women who are at
least 2 years postmenopause.
 Continuous long-cycle (or cyclic withdrawal):
To decrease the incidence of uterine bleeding, a
modified sequential regimen has been
developed.38 In the continuous long-cycle (or
cyclicwithdrawal) estrogen-progestogen regimen,
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. The effect of
continuous longcycle estrogen-progestogen
treatment on endometrial protection is unclear.
 Intermittent combined (or continuous-pulsed)
hormone therapy: It consists of 3 days of
estrogen therapy alone, followed by 3 days of
combined estrogen and progestogen, which is then
repeated without interruption. This regimen is
designed to lower the incidence of uterine
bleeding.
 Other treatment options:
SELECTIVE ESTROGEN-RECEPTOR
MODULATORS:
SERMs, a new type of nonhormonal
therapy, bind to estrogen receptors and
function as tissue-specific estrogen
antagonists or agonists.
The ideal SERM would protect against
osteoporosis and decrease the incidence
of breast, endometrial, and colorectal
cancer and coronary heart disease
without exacerbating menopausal
symptoms or increasing the risk of
venous thromboembolism or gallbladder
disease.
 To date, no SERM meets these ideals. Tamoxifen,
the first-generation SERM, has estrogen
antagonist activity on the breast and estrogen-like
agonist activity on bone and endometrium.
 The second generation of SERMs, most notably
raloxifene (a nonsteroidalnonsteroidal
benzothiophene derivative), recently became
available for the prevention of osteoporosis.
 Raloxifene decreases bone loss in recently
menopausal women without affecting the
endometrium and has estrogen-like actions on
lipid metabolism.
 Raloxifene generally is well tolerated. Its adverse
effects include leg cramps and hot flushes.
Raloxifene is used specifically to reduce the risk of
osteoporosis in postmenopausal women.
 Treatment Considerations:
Hormone therapy is contraindicated
in women with
Endometrial cancer, breast cancer,
Undiagnosed vaginal bleeding,
Thrombo embolism
Active liver disease.
General principles of HRT:
 An oestrogen preparation should be taken every day of
the year.
 Menopausal symptoms improve progressively in the first
few months of treatment, therefore, oestrogen should be
continued for at least three months before increasing the
dose.
 For women who are several years postmenopause, start
with a low dose of oestrogen.(Eg: 50% of recommended
starting dose) and then increase dose until symptoms are
controlled.
 Choice of progestogen dose is determined by the absence
or timing of withdrawal bleeds.
 Withdrawal bleeds are absent in 20 to 50% of women
taking cyclical regimens. In these women the choice of
progestogen dose should depend on clinical
considerations, such as adverse effects and
characteristics of the patient. Eg: a smaller, older woman
would require a lower dose than a younger
lperimenopausal woman.
 For women who have a withdrawal bleed
there are currently two approaches;
 starting with a low dose and increasing the
dose until withdrawal bleeding occurs on or
after day 12 of the progestogen course, or
 starting with a high dose and when
bleeding becomes progressively less,
reducing the progestogen dose while
following the clinical response.
 The progestogen course may be taken at
any time during the month, however the
first 12-24 days are usually selected for
convenience.
In perimenopausal women the progestogen
course should be started 12-14 days
before the expected natural bleed, so
that withdrawal bleeding coincides with
this. These days can be marked on a
calendar, to help compliance.
There is currently no information on long-
term safety or efficacy of using a cyclic
progestogen course.
 Benefits and Risks of HRT:
Benefits of HRT:

Relief of Menopausal Symptoms: The major

indication for postmenopausal hormone therapy is the
management of vasomotor symptoms. Most women with
vasomotor symptoms require hormone treatment for less
than 5 years.

Eg: A dose-dependent relationship between estrogen

administration and suppression of hot flushes is well
established.
 Vaginal Atrophy
At least 50% of postmenopausal women suffer
symptoms of urogenital atrophy caused by estrogen
deficiency. Atrophy of the vaginal mucosa results in
vaginal dryness and dyspareunia. Lower urinary tract
symptoms include urethritis, recurrent urinary tract
infection, urinary urgency, and frequency.

These can be treated with a topical estrogen cream,

tablet, or vaginal ring.
In clinical trials, topical estrogen appears to be better
than systemic estrogen for relieving these symptoms
and avoids high levels of circulating estrogen.
Osteoporosis Prevention: Postmenopausal
osteoporosis is a serious age-related
disease that affects millions of women
throughout the world.
The WHI randomized trial demonstrated that
HRT reduces the risk of fractures at the
hip, spine, and wrist. Hip and clinical
vertebral fractures are reduced by 34%,
and total osteoporotic fractures are
reduced by 24%.
Colon Cancer Risk Reduction: Colorectal
cancer is the fourth most common cancer and
the second leading cause of cancer death in
the United States. The WHI was the first
randomized, controlled trial to confirm that
hormone therapy reduces colon cancer risk.
Diabetes:In healthy postmenopausal women,
hormone therapy appears to have a beneficial
effect on fasting glucose level among women
with elevated fasting insulin concentrations.
Also, in women with coronary artery disease,
hormone therapy reduces the incidence of
diabetes by 35%.
Risks of HRT:
Cardiovascular Disease: Cardiovascular disease, including
coronary artery disease, stroke, and peripheral vascular
disease, is the leading cause of death among women.
Hormone therapy should not be initiated or continued for the
prevention of cardiovascular disease.
Eg: The primary findings of the WHI trial showed an overall
increase in the risk of coronary heart disease among
healthy postmenopausal women 50 to 79 years of age
receiving combined estrogen-progestogen hormone
therapy compared with those receiving placebo.
Breast Cancer: The WHI trial found that combined
estrogen-progestin therapy has an increased risk of
invasive breast cancer and a trend toward
increasing risk with increasing duration of therapy.
Ovarian Cancer Lifetime risk of ovarian cancer is low
(1.7%). The WHI trial suggests that combined
hormone therapy may increase the risk of ovarian
cancer

However, a recent study reported an increased risk of

ovarian cancer in women taking postmenopausal
estrogen therapy for more than 10 years.
Venous Thromboembolism: Venous
thromboembolism, including thrombosis
of the deep veins of the legs and
embolism to the pulmonary arteries, is
uncommon in the general population.
 Women taking hormone therapy have a

twofold increase in risk for

thromboembolic events, with the highest
risk occurring in the first year of use.
Gallbladder Disease :Gallbladder disease
is a commonly cited complication of oral
estrogen use.
 Eg:The Nurses’ Health Study showed that

the age-adjusted relative risk of

cholecystectomy is greater for women
currently taking HRT.
 In this study, the risk of cholecystectomy

increased with duration of hormone

therapy use and did not resolve after
discontinuation.
Menopause is a natural life event, not a disease.

Postmenopausal hormone therapy has became one of the

most frequently prescribed therapies.

The decision to use hormone therapy must be

individualized based on the severity of menopausal
symptoms, risk of osteoporosis, and consideration of such
factors as coronary artery disease, breast cancer, and
thrombo embolism.