DR SR AGATHA SHINYALA

MMED 11
HORMONAL REPLACEMENT
THERAPY
IN GYNAECOLOGY
 Introduction

The reproductive years of a womans life are

regulated by production of the hormones
estrogen and progesterone by the ovaries.
Estrogen regulates a woman's monthly
menstrual cycle and secondary sexual
characteristics (eg, breast development and
function). In addition, it prepares the body for
fertilization and reproduction. Progesterone
concentrations rise in a cyclical fashion to
prepare the uterus for possible pregnancy and
to prepare the breasts for lactation.
 Toward the end of her reproductive
years when a woman reaches
menopause, circulating levels of
estrogen and progesterone decrease
because of reduced synthesis in the
ovary. Hypoestrogenism during
menopause can lead to several
symptoms, the severity of which can
vary widely
 Hormone therapy (HT) involves the
administration of synthetic estrogen
and progestogen. HT is designed to
replace a woman's depleting
hormone levels and thus alleviate
her symptoms of menopause.
However, HT has been linked to
various risks, and debate regarding
its risk-benefit ratio continues.
Symptoms and Effects of Menopause

Menopause is the time in a womans life when

menstruation ceases, signaling the end of her
reproductive ability. The timing of menopause
varies widely, but this event often occurs
naturally in women in the fourth or fifth decades
of life, at a mean age of 51 years. Certain medical
or surgical conditions may induce the cessation of
menses before this age. If menopause occurs
before the age of 40 years, it is considered
premature.
 The reproductive years are divided into early, peak, and
late and are characterized by regular menstrual cycles
(although they may be variable during the early phase).
This is followed by the stage of menopausal transition ,
which earlier on is characterized by a variable cycle
length that is more than 7 days different from normal.
During the latter stages of this transition phase, women
experience intervals of amenorrhea of more than 60
days. When this duration of amenorrhea lasts for up to
12 months, it is classified as postmenopause. The stage
of perimenopause spans from the beginning of the
stage of menopause transition up until the completion
of 1 year following the final menstrual period.
 The spectrum and intensity of symptoms that
women experience during perimenopause and
menopause vary greatly. Symptoms result
from the effect of decreased circulating levels
of estrogen on various organ systems.
Hypothalamically mediated vasomotor
instability leading to hot flashes (hot flushes),
sweating, and palpitations is the most
common presentation of menopause. These
symptoms occur in more than 60% of
postmenopausal women.
Common presenting symptoms of menopause

Irregular menstrual cycles

Vasomotor symptoms
Sweating
Hot flashes (hot flushes)
Palpitations
Urogenital symptoms
Vaginal dryness
 Soreness
Superficial dyspareunia
Urinary frequency and urgency
 Neurologic symptoms
Mood changes
Insomnia
Depression
Anxiety
Effects on the vasomotor system

Vasomotor instability is the most common

presenting symptom noted in postmenopausal
women. Its exact cause is not yet known, but it is
believed to be mediated at the level of the
hypothalamus. Estrogen plays a role in
thermoregulation by modulating the levels of
neurotransmitters in the CNS. During
menopause, diminished levels may lead to
instability in the normal concentration of these
transmitters, which manifests as hot flashes (hot
flushes), night sweats, and excessive perspiration
Effects on the urogenital system

Estrogen plays an important role in maintaining the

normal physiology of the urogenital system. Decreased
circulating levels of this hormone during menopause
are associated with a change in the microenvironment
of the urogenital organs. The mucosal lining of the
urethra, urinary bladder, vagina, and vulva shows
atrophic changes and becomes thinned. The vagina
loses its elasticity and distensibility and becomes short
and narrow. Normal secretions from the vaginal glands
are reduced. The subepithelial vasculature and the
supporting subcutaneous connective tissue also
demonstrate degenerative changes over time.
 As endogenous estrogen levels
decrease, so does the production of
epithelial-cell glycogen. This
alteration changes the normal
alkaline milieu of the vagina and
bladder. The resultant acidic pH
alters the local flora of the vagina
and urinary bladder, allowing for
their colonization by gram-negative
bacteria and fungi and predisposing
 Effect on bone metabolism

Bone mass steadily increases during childhood

and adolescence and reaches a plateau in the
third decade of life. Men achieve a higher peak
bone mass than women do. As a subsequence,
age-related bone loss is further governed by
an interplay of multiple factors, particularly
sex, family history, diet, and exercise. Women
are more susceptible than men, and the low
estrogen levels of menopause can accelerate
the progressive bone loss, particularly in the
first 5 years after menopause
 This situation predisposes
postmenopausal women to develop
osteoporosis and osteoporosis-
related fractures. A 50-year-old
woman has a 40% lifetime risk of
having a fragility fracture, which
typically occurs in the femoral neck,
vertebra, or distal forearm.1
 Effect on cardiac function

At menopause, women begin to lose their

natural resistance to heart disease (see
Coronary Artery Disease and
Coronary Artery Atherosclerosis). By the age of
65 years, their risk of having a heart attack
equals that of men.2 This increased susceptibility
to heart disease is attributed to the reduction in
the beneficial effects of estrogen on plasma
lipid and lipoprotein levels, insulin sensitivity, the
distribution of body fat, coagulation, fibrinolysis,
and endothelial function.
 Serum fibrinogen and plasma activator
inhibitor (PA1) concentrations are powerful
predictors of cardiac disease in men and
women.3 Evidence suggests that
menopause is associated with heightened
serum levels of fibrinogen and PA1.
All of the factors just discussed contribute
to the increased risk for morbidity and
mortality in postmenopausal women
Brief History and Forms of Therapy

Hormone therapy (HT) is treatment

with prescription hormonal
medicationsnamely, estrogen alone
or estrogen in combination with
progestogento restore a woman's
declining hormone levels
 Estrogen has been used to treat symptoms of
menopause since the 1950s and 1960s. By 1975,
estrogen had become one of the most commonly
prescribed drugs in the United States.
In the mid 1970s, studies demonstrated that
postmenopausal women who used estrogen
therapy alone had a significantly increased risk of
endometrial cancer. Researchers found that adding
progestogen to estrogen provided protection
against uterine cancer. As a result, progestogen
was added to HT regimens prescribed for women
with an intact uterus
 Over the years, HT became a popular treatment,
as it was recommended not only for treating
menopausal symptoms but also for providing
long-term protection against osteoporosis and
related fractures, heart disease, and even
Alzheimer disease. However, in 2002, the
Women's Health Initiative (WHI), a large-scale
study conducted by the
National Institutes of Health (NIH), was stopped
early because evidence linked HT to a slightly
increased risk of stroke, heart disease, and breast
cancer
 Forms of hormone therapy

HT can be prescribed as local or systemic

therapy.
Local preparations
Creams
Pessaries
Rings
Systemic formulations
Oral drugs
Transdermal patches and gels
Implants
 Liver bypass of the hormones is
achieved with transdermal
preparations and implants, which
help to ensure predictable and
optimal serum levels
 Hormonal products available in the
preparations listed may contain the
following ingredients:
Estrogen alone
Combined estrogen and progestogen
Selective estrogen receptor modulator
(SERM)
Gonadomimetics, such as tibolone, which
contain estrogen, progestogen, and an
androgen
 The various schedules of hormone
therapy include the following:
Estrogen taken daily
Cyclic or sequential regimens in
which progestogen is added for 10-
14 days every 4 weeks
Continuous combined regimens in
which estrogen and progestogen are
taken daily
 The estrogens most commonly prescribed are
conjugated estrogens that may be equine (CEE) or
synthetic, micronized 17 estradiol, and ethinyl
estradiol. The progestins that are used commonly are
medroxyprogesterone acetate (MPA) and
norethindrone acetate.

The dosage varies but the most commonly prescribed

HT is combined estrogen and progestin in the form of
0.625 mg/d CEE with 2.5 mg/d MPA in women with an
intact uterus. Lower dose preparations that contain 1.5
mg/d of MPA with either 0.45 mg or 0.3 mg/d of CEE
are becoming increasingly popular
 Estrogen is used alone in women who have undergone
hysterectomy. Treatment should be initiated with the lowest
possible dosage and then titrated based on clinical response.

SERMS are a class of nonhormonal drugs that selectively

mimic or antagonize the effect of estrogen at various target
organ sites. They have beneficial effects on bone and
cholesterol metabolism and can be offered as an alternative
to traditional HT for prevention and treatment of
osteoporosis in postmenopausal women.

For related information, see Medscape CME Activity,

NAMS Updates Guidelines on Postmenopausal Hormone Ther
apy
.
Indications for Hormone Therapy

Indications for hormone therapy can

be symptomatic or preventive.
Although some consensus has been
reached regarding the use of HT to
relieve symptoms, the application of
HT to prevent sequelae of
menopause is controversial. Common
clinical settings in which HT is
prescribed are described below.
 Vasomotor symptoms

The main indication for HT is relief of

the most common symptoms of
menopause, namely hot flushes,
sweating, and palpitations. The
effectiveness of this treatment was
proven in placebo-controlled
randomized studies
 Urogenital symptoms

Both topical and systemic estrogens

have been shown to improve the
menopausal symptoms of vaginal
dryness, superficial dyspareunia, and
urinary frequency and urgency.
Achievement of these beneficial
effects require long-term therapy.
Symptoms commonly recur after HT
is stopped
 Osteoporosis

One in 3 postmenopausal women develops

osteoporosis.1 HT is commonly prescribed to help
prevent this condition, and HT appears to be
particularly effective if it is started during the first
5 years after the onset of menopause. Women
who have a decreased bone mineral density and
those with a known history of osteoporotic
fractures benefit from HT. Women with premature
menopause also benefit from the bone-protective
benefit of HT. However, they may lose protection
after they stop taking hormones.
 Absolute risks based on results from
the WHI trial indicated that 5 years of
combined hormone therapy reduced
the incidence of hip fractures by
about 1 case per 1000 women
younger than 70 years and by about
8 cases per 1000 women aged 70-79
years.
 Contraindications to Hormone Therapy

No absolute contraindications of
hormone therapy have been
established. However, HT is relatively
contraindicated in certain clinical
situations, such as patients with the
following findings:
 A history of breast cancer
A history of endometrial cancer (see Uterine Cancer and
Endometrial Carcinoma)
Porphyria
Severe active liver disease
Hypertriglyceridemia
Thromboembolic disorders (see
Deep Venous Thrombosis and Pulmonary Embolism)
Undiagnosed vaginal bleeding (see
Dysfunctional Uterine Bleeding )
Endometriosis
Fibroids
 Pretreatment Evaluation

All patients who are candidates for

hormone therapy should be
thoroughly evaluated by means of a
detailed history and complete
physical examination. The objectives
are making a proper diagnosis and
identifying any contraindications
 Components of a full history

Personal history
Social history
Obstetric history
Gynecologic history
Menstrual and sexual history
Previous medical history (eg, of diabetes, hypertension,
jaundice, gallstones, hepatic disease, thrombosis)
Previous surgical interventions
Menopausal symptoms
Psychiatric problems
Skeletal symptoms
Psychomotor symptoms
Components of the physical examination

Height measurement
Weight measurement
Determination of an obesity index (see
Obesity)
Blood pressure measurement (see
Hypertension)
Breast examination
Abdominal examination
Pelvic examination
Rectal examination
Required baseline investigations

Hemography
Urinalysis
Evaluation of the fasting lipid profile
Measurement of blood sugar levels
Electrocardiography
Papanicolaou test
Ultrasonography to measure endometrial thickness and ovarian
volume
Mammography, which is performed once every 2-3 years and
annually after the age of 50 years (see
Mammography - Computer-Aided Detection)
Determination of serum estradiol levels in women who will be
prescribed an implant and in women whose symptoms persist
despite use of an adequate dose of a patch or gel
 Determination of serum follicle-stimulating hormone
(FSH) levels: FSH values may be used to monitor
women who are taking oral preparations for
symptomatic control, especially those with premature
menopause.
Endometrial sampling: This test is not required in
routine practice. If abnormal bleeding is present before
or during HT, ultrasonography is recommended to
check endometrial thickness (cutoff, <4 mm), followed
by outpatient Pipelle sampling and hysteroscopy. In
patients with a tight cervix, formal hysteroscopy and
dilation and curettage under general anesthesia are
advised
Adverse Effects and Risks of Hormone Therapy

Transient Adverse Effects

Hormone therapy is associated with
certain innocuous adverse effects
that are transient and that usually
resolve. The patient should be
forewarned to prevent their
discontinuation of therapy
 Possible adverse effects are as follows:
Nausea
Bloating
Weight gain (equivocal finding)
Fluid retention
Mood swings (which are associated with
use of relatively androgenic progestogens)
Breakthrough bleeding
Breast tenderness
Testosterone Replacement Therapy

Testosterone is a hormone produced

by the testicles and is responsible for
the proper development of male
sexual characteristics. Testosterone
is also important for maintaining
muscle bulk, adequate levels of red
blood cells, bone density, sense of
well-being, and sexual and
reproductive function.
 Testosterone is a hormone produced
by the testicles and is responsible for
the proper development of male
sexual characteristics. Testosterone
is also important for maintaining
muscle bulk, adequate levels of red
blood cells, bone density, sense of
well-being, and sexual and
reproductive function.
 What causes testosterone
deficiency
As a man ages, the amount of testosterone in his
body gradually declines. This natural decline
starts after age 30 and continues throughout life.
The significance of this decline is controversial
and poorly understood. Among other potential
causes of testosterone deficiency are:
injury or infection to the testicles
chemotherapy or radiation treatment for cancer
genetic abnormalities such as Klinefelters
Syndrome (extra x chromosome)
hemochromatosis (too much iron in the body)
 dysfunction of the pituitary gland (a gland in the brain that
produces many important hormones)
medications, including hormone analogues used to treat prostate
cancer and steroids
chronic illness
cirrhosis of the liver
chronic renal (kidney) failure
AIDS
inflammatory disease such as sarcoidosis (a condition that causes
inflammation of the lungs and other organs)
stress
alcoholism
congenital conditions, Kallmans Syndrome (low hormones,
inability to smell and other abnormalities)
 What are the symptoms of testosterone
deficiency?

Symptoms of testosterone deficiency

include the following:
decreased sex drive
decreased sense of well-being
depressed mood
difficulties with concentration and
memory
erectile dysfunction
 What are the changes that occur in the body
with testosterone deficiency?

Changes that occur with testosterone

deficiency include:
a decrease in muscle mass, with an
increase in body fat
variable effects on cholesterol metabolism
a decrease in hemoglobin and possibly
mild anemia
fragile bones (osteoporosis)
a decrease in body hair
 What options are available for
testosterone replacement?
The options available for testosterone
replacement are:
intramuscular injections, generally every two or
three weeks
testosterone patches worn either on the body or
on the scrotum (the sac that contains the
testicles). These patches are used daily. The
body patch application is rotated between the
buttocks, arms, back or abdomen.
testosterone gels that are applied daily to the
shoulders, upper arms, or abdomen
 Each of these options provides adequate levels of
hormone replacement. Each has side effects and
advantages and disadvantages. Intramuscular
injections produce wider swings in hormone
concentration, with higher levels shortly after the
injection and lower levels just before the next injection
is due. They may also produce increases in blood cell
count that are higher than normal.
The body patches may produce skin irritation in a
significant number of men, requiring discontinuation of
the patch. The gels require care in making sure that the
hormone is not accidentally transferred to another
person or partner.
 Testosterone replacement therapy may stimulate
growth of the prostate. If early prostate cancer is
present, testosterone may stimulate the cancers
growth. Therefore, men who have prostate
cancer should not take testosterone replacement
therapy. It is important for all men considering
testosterone replacement therapy to undergo
prostate screening before starting this therapy.
Although it is a rare condition, men who have
breast cancer should not take testosterone
replacement therapy.
 side effects of testosterone
replacement therapy
In general, hormone replacement therapy is safe. It is
associated with some side effects, including:
acne or oily skin
mild fluid retention
stimulation of prostate tissue, with perhaps some
increased urination symptoms such as decreased
stream or frequency
breast enlargement
worsening of sleep apnea (a sleep disorder that results
in frequent night time awakenings and daytime
sleepiness)
decreased testicular size
 OTHER USES OF HRT
Hormone replacement therapy (HRT) for
transgender and transsexual people replaces
the hormones naturally occurring in their
bodies with those of the other sex. Some
intersex people also receive HRT, either
starting in childhood to confirm the gender
they were assigned, or later, if this
assignment has proven to be incorrect. Some
cisgendered men may use HRT to have a hair-
free body, as a result of less testosterone in
their body
 Its purpose is to cause the development of the
secondary sex characteristics of the desired
gender. It can not undo the changes produced
by the first natural occurring puberty, which
necessitates sexual reassignment surgery and
epilation by either electrolysis and/or
laser hair removal. This is due to being easier
to produce secondary male sexual
characteristics with androgens than it is to rid
trans women of established characteristics