MENOPAUSE: HRT or NO HRT?
Professor Galal Lotfi, MD, MRCOG
Obstetrics & Gynecology
Suez Canal University
Suez Canal University Hospital
Starts as a date and continues as a
• Clinically speaking menopause is a date, the day after a
woman's final period finishes.
• But in practice, "menopause" is usually not used to refer to
one day, but to the whole of the menopause transition years.
This span of time is also referred to as the change of life, the
change, or the climacteric and more recently is known as
• The word menopause is also often used in popular to mean
all the years of postmenopause (Wikipedia).
This is the Change
The change is not a disease
For a woman without a uterus?
• She does not have menstruation but she
does pass through menopause!
• This is very confusing to the patients.
Which is best name?
Do we deal with Menopause or
• We talk menopause but actually we are
concerned about the changes of climacteric.
• Menopause is the result of ‘climacteric’
which is (1) normal (2) developmental
process of (3) aging.
• We don’t have any control over 1, 2 or 3.
Starts by a date that never ends?
• Age of menopause has not changed , but life expectancy did
• In the past women were not expected to live beyond
menopause, now they spend > one third of their life after
• Menopause is a normal developmental process, but the
decline in E can have clinical sequelae.
– Vasomotor symptoms.
– Cardiovascular disease.
– Urogenital atrophy.
– Cognitive decline and Alzheimer's disease.
Climacteric is OK but its sequalae are not OK
Hot flashes Mood
Physiology of climacteric
• Ovarian decline..... Change
• Reproductive decline..... Change
• Hormonal changes...... Change
• E decline... this is the problem
• Menopause results from:
– 1.Follicular depletion ("natural" menopause) or
– 2. Surgical removal of the ovaries (“induced”, or
• The secretion of the ovarian E & P declines.
• Menstrual cycles seldom cease abruptly; there is an interval of
"perimenopause" or "menopausal transition," during which there
are considerable hormonal fluctuations.
• Perimenopause (climacteric) begins a few years before last
cycle; the cycles become irregular with symptoms suggesting a
decline in E. Perimenopause also extends for a few years after
the last menstrual cycle; during this time, transient and episodic
bursts of ovarian activity may occur, which may result in some
1. Physiology of Climacteric
• Age of menopause occurs at a median age of 51.4 years,
with a range from 40-58 years.
• Factors Affecting age of menopause:
– Familial factors & genetic polymorphisms of E receptor
– Childhood cognitive function.
– Multiparity and increased body mass index (BMI) are
associated with later onset.
– However, the process of climacteric is a continuum.
Physiology of Climacteric
• Factors causing earlier menopause:
– Medically treated depression
– Toxic chemical exposure
– Treatment of childhood cancer with abdominal-pelvic
radiation and alkylating agents
• Premature, or early, menopause (age < 40 years) has
been linked to both familial and non-familial X-
2. Reproduction and Climactric
• Climacteric: Time from the decline in reproductive
• Climacteric starts far earlier than menopause; the woman
needs care far earlier than menopause time.
• Reproductive aging occurs rapidly after the third decade,
and fecundity is extremely low before menopause.
– Both Climacteric and reproductive aging start far before
• Follicular atresia accelerates at about 37.5 years. Thus,
reproductive aging precedes menopause by 5-10 years, at a
"young” age. This is signified by an increase in (FSH) level
in the early follicular phase of regular cycles and a decrease
in the circulating inhibin B level. The elevation in FSH
drives the accelerated follicle depletion.
3. Hormonal Changes
• E. Decreased
• E1 S. Decreased
• FSH, LH. Increased
• AD, T. Decreased
• In late climacteric, levels of E2 and inhibin
decrease. FSH is markedly increased.
4. Effects of Declining Estrogen
• Two estrogen receptors exist: ER-alpha and ER-
beta. Various estrogens have different affinities for
ER-alpha and ER-beta, which in turn, have different
tissue distributions in the body. For example, in
certain regions of the brain (e.g., frontal cortex),
ER-beta predominates over ER-alpha. In the
cerebellum, only ER-beta is expressed. Because
ERs are abundant throughout the body, the
menopausal decline of estrogen potentially affects
virtually all organ systems, so we get:
E decline leads to
1. Brain and CNS
• ER are abundant in the brain. E have a role in many brain
processes, and it’s absence result in physiologic and
• E is important for cerebral blood flow, cerebral glucose
administration, synaptic activity, neuronal growth, survival
of cholinergic neurons, as well as such complex functions
• Mood Changes and Cognitive Function
– E has a positive effect on mood and sense of well-being, which
may be due to its stimulation of the adrenergic and serotoninergic
systems. However - the role of E deficiency in postmenopausal
depression, declining cognitive function, dementia, and
Alzheimer's disease is not clear.
Brain and CNS
– E and progestins affect central serotoninergic and opioid neurons,
causing a change in the prevalence or intensity of headaches.
– Women with a history of menstrual migraines may experience an
2. Hot Flushes
• Early and acute symptom of E deficiency.
• Begin in the perimenopause when E levels fluctuate widely, so
more related to climacteric than to menopause.
• It is the rapid fall in E level that precipitates the symptoms.
• The cause of flushes remains illusive. The episodes result from a
hypothalamic response (probably mediated by catecholamines)
induced by a change in E status.
• Hot flushes can cause insomnia, which contributes to
fatigue, irritability, and a reduced ability to concentrate.
• Psychological changes attributable to chronic sleep
disturbance may be more than side effects of hot flushes
- a direct effect of changing hormonal status may also
play a role.
• Idiopathic full-thickness macular degeneration
predominantly affects women > 60 years.
• There appears to be a hormonal component, because
symptoms become more severe with menopause.
• E has a positive effect on collagen, which is important for
bone and skin. The loss of collagen is more rapid in the first
few years after menopause, and 30% of skin collagen is lost
within the first 5 years. The rate is 2% per year for the first
10 years after menopause. This statistic is similar to that of
bone loss and strongly suggests a link between skin
thickness, bone loss, and osteoporosis.
• Reductions in collagen lead to:
– Atrophy of the vaginal and urethral mucosa
– Uterine prolapse.
– Urinary incontinence
– Skin changes
5. Urogenital Atrophy
• E deficiency has deleterious affects on the urogenital system.
• One third of women =>50 years has urogenital problems.
• E deficiency results in:
– Thin and paler vaginal mucosa.
– Moisture content is low.
– pH increases (usually pH > 5).
– Inflammation and small petechiae.
– Loss in superficial cells and an increase of basal and parabasal cells.
– UTI (eg, coliform bacteria), as a result of the reduced acidity.
– Decrease in lactobacilli, yeast, and bacterial vaginosis-associated bacteria
also may explain the lower incidence of bacterial vaginosis and yeast
vaginitis than in young women.
• Dry and atrophied vaginal and urethral epithelium can cause vaginal
discomfort, itching, dyspareunia, and recurrent vaginitis as well as
such urinary symptoms as frequency and dysuria..
• E deficiency in periurethral tissues cause pelvic laxity and stress
6. Bone Loss
• Start of bone loss is a climacteric and not menopausal
• More than one third of women > 65 years suffer from
osteopenia/ osteoporosis, a disorder of low bone mass.
• E deficiency is a dominant pathogenic factor in bone loss.
• From 1.5 years before to 1.5 years after menopause, spine
bone mineral density (BMD) decreases by 2.5% per year,
compared with a premenopausal loss rate of 0.13% per
• E action on bone is mediated by direct effects and by effects on
collagen. The accelerated decline in bone mass is mediated by a
variety of mechanisms, but the primary event is increased
resorption (osteoclastic activity), which becomes uncoupled
from bone formation (osteoblastic activity).
• There are also indirect effects mediated by parathyroid hormone
and cytokines, which oppose the resorptive effects.
Osteoprotegin (OPG), is a soluble protein that inhibits
osteoclastic bone resorption.
• In postmenopause, the positive effects of estrogen on growth
factors, calcitonin, vitamin D metabolism, and calcium
absorption are also diminished.
• E deficiency increases the risk of (CVD).
• CVD in postmenopausal women aged 50-59 was 4-fold
higher than in premenopausal women of the same age.
• However, the relative risk (RR) of CVD depended on the
age as well as on adjustment for smoking.
• Aging and E deficiency contribute to the increased risk of
CVD in older women.
• Premature menopause, <age 35, has 2- to 3-fold increased
risk of myocardial infarction; oophorectomy (before age 35)
increases the risk 7-fold.
• Cholesterol rises after menopause.
• Increases in low-density lipoprotein cholesterol (LDL-C),
very-low-density lipoprotein (VLDL) and lipoprotein a
• The oxidation of LDL-C is also enhanced.
– However most of these changes occur in a variable
degrees with aging
• E deficiency causes urogenital atrophy, which
affect sexual function. This may lead to a decline
in sexual interest, but the ability to become
sexually aroused may also be affected.
• Postmenopausal women become androgen
deficient; which lead to reduced libido.
• Clinicians have proposed adding androgen to
HRT for complaints relating to sexual desire and
arousal and energy level.
• DHEA is a therapeutic option in menopause.
• 10% DHEA vaginal cream han beneficial effects,
without significant adverse effects, through the
transformation of DHEA into androgens and/or
estrogens in specific peripheral intracrine tissues.
Endometrium remained atrmation.
Now as a clinician:
• What is the important question?
How They (not we) Perceive
• More than half (51%) reported that they were happier and
more fulfilled in their postmenopausal years than in their
20’s (10%), 30’s (17%), or 40’s (16%).
• They reported that many areas of their lives had improved
since menopause, and almost 75% had made some health-
related lifestyle change at midlife (eg, smoking cessation).
• More than half reported that their sexual relationship was
unchanged at menopause.
Women’s Perceptions of Menopause
• Cessation of menstrual cycles
• End of reproductive ability
• A time of hormonal changes
• A change of life
• A changing body
• A time of changing emotions
• A time of symptoms and disease
• An aging process
If she does not have any
of these symptoms, why
not to leave her alone??
The next question…
• How to manage?
• Management of menopause is not
management of HRT.
How to Manage?
• It is the approach to management of a woman at or
before menopause that is critical?
• Assessment of symptoms (if present), the needs of
the woman, her specific risk factors, and her family
history are fundamental.
• The ultimate question is: Will any of the available
options improve the overall quality of life for the
Preventive measures for
• To modify the increased mortality and morbidity rates in
our older women patients?
– Smoking cessation to prevent lung cancer.
– Screen for breast cancer risk factors; family history; fertility or
infertility history, and age at menarche, menopause, and first
pregnancy. Preventive measures = frequent self-examination and
provider examinations; annual mammography in women older
than 40 years.
– For CVD, assess family history and risk factors as BP, cholesterol,
DM, smoking, poor diet, and lack of exercise.
– Screen cancer colon, ovary, and uterus.
– It is also important to evaluate bone mass. BMD has proved to be
1. Diet & Excercise
• Diet, exercise, and weight control are important in
determining a woman's risks for CVD, osteoporosis,
diabetes, breast cancer, and depression.
• Menopause is a high-risk time for weight gain.
• Together, diet and exercise are crucial components of
preventive medicine for women pre-, peri-, and
Diet & Exercise
– Aerobic exercise modify lipoprotein levels.
– Brisk walking and vigorous exercise are strongly associated with a
reduced risk for coronary events.
– Weight training: progressive resistance training and weight-
bearing exercise have been shown to be effective in increasing
BMD, reducing osteoporotic fracture risk, and preventing falls in
– Diet and exercise good for:
– Bone physiology
• Calcium and vitamin D are important adjuncts to treatment
and preventive health programs.
• Calcium should begin before menopause. Calcium
carbonate (500 mg daily), in premenopausal women prevent
bone loss, allowing them to enter menopause with greater
bone mass, which may reduce the risk of later bone
• Supplement is good for bone physiology.
3. Therapeutic Options = Individualized
• Questions, you have to ask yourself:
– What is the reason to intervene? Are there symptoms such as
hot flushes? The answer is: short-term therapy.
– For postmenopausal woman who has no major complaints but
is concerned about osteoporosis, for example, her family
history, risk profile, and bone-mass assessment are valuable
adjuncts to help decision making.
• Depending on these variables, the choice of intervention
– Natural supplements
– Non-hormonal treatments (e.g., a bisphosphonate)
– Selective estrogen receptor modulator (SERM)
a) Estrogen for vasomotor
• Natural E supplements are popular
• Black kohosh, genistein, and soy-based products have been
shown to be effective for hot flushes.
• Although some data are available for soy-based products,
there are no convincing data about efficacy for vaginal
health, lowering CVD risk, or improving brain function.
• Because phytoestrogens bind to ERs (ER-beta > ER-alpha),
large doses (which are needed to achieve benefit on a
statistical basis) may pose some risk for estrogen-
responsive cancers, such as breast cancer; although,
conventional thinking is that these products are protective
for the breast.
b) Bisphophonate for osteoporosis
• Bisphosphonate may be appropriate for women with or at
risk for osteoporosis who cannot or choose not to use HRT.
c) Other treatment for osteoporosis
• Osteoprotegerin. This naturally occurring protein is a
negative regulator of osteoclast formation.
• Tolerability profile as excellent, with mild pruritis at the
Other treatment for osteoporosis
• Parathyroid Hormone
• Bisphosphonates, estrogen, and SERMs slow or stop bone
loss but they do not replace bone that has already been lost.
Currently in clinical development are a group of bone
building peptides - native parathyroid hormone, its 34 - to
38- amino acid N-terminal fragments, and a group of
molecules known as second-generation mini-PTHs.
• Selective agonistic or stimulatory effects (i.e., estrogenic) on
one organ system and neutral or antagonistic (i.e.,
antiestrogenic) effects on other organ systems.
• Clomiphene • LY353381
• Tamoxifen • Naphthalenes
• Droloxifene • Levormeloxifene
• Idoxifene • Phytoestrogens
• Conjugated Estrogens
• Delta8,9-Dehydroestrone sulfate
• Ideally, the use of SERMs should fall into 2
categories. The first would be to relieve symptoms
associated with E deficiency.
• The second, more selective use would be to target
the antiestrogenic effects of a SERM to 1 organ
system (e.g., the breast).
• It should have agonistic activity in the brain, bone,
CV system (not necessarily the liver), vagina, and
urinary system, and antagonistic activity in the
breast and uterus.
• Theoretically, the ideal SERM's estrogenic activity
will improve cognitive function, osteoporosis,
Alzheimer's disease, CVD, and stroke.
• The ideal SERM would increase HDL-C levels and
reduce LDL-C and total cholesterol. The hepatic
effects of a SERM, if excessive, however, increase the
risk of venous thromboembolism.
• Age increases the risk of breast cancer, SERM ideally
would lower this risk.
• SERM that exerts agonist effects on systems such as
bone but does not result in uterine/endometrial
stimulation would be ideal.
HRT, HT or ET
Women perception of HRT
• Awareness of HRT is determined by race,
educational level, and the perception of going or
having gone through menopause.
• Many women express fear regarding HRT,
especially because of the associated risk of breast
• Use of HRT markedly decreased after WHI.
Women perception of HRT
• Women believe that the leading cause of death in women
is breast cancer. Many also believe that only a small
percentage of deaths are attributable to CVD.
• The truth, of course, is the reverse. One in 3 women older
than 65 years has some evidence of CVD, and the risk of
breast cancer after age 65 is 1 in 36. Although it has been
widely asserted that the incidence of breast cancer in
women is approximately 1 in 8 women, this is the
lifetime risk. Age-specific data are quite different, and
the risk is 1 in 77 in the fourth decade, 1 in 42 in the fifth
decade, and 1 in 45 in the eighth decade.
• With the first publication of the results of
the Women's Health Initiative (WHI) trial in
2002, the use of HT [hormone therapy]
Benefits of HRT
• Cognitive diseases
• Alzheimer's disease
• It is well established that HRT provides relief
from hot flushes.
• But usually it is relived by time.
Osteo, Prevention & Treatment
• ET clearly decreases bone turnover and prevents
postmenopausal bone loss.
• Although hormone therapy may help
prevent and treat osteoporosis, it is seldom
used solely for this indication alone,
particularly if other effective options are
• ET decrease the incidence; WHI said it
Reversal of urogenital
• With estrogen treatment, vaginal cytology
can change from a profile of predominantly
parabasal cells to one with an increased
number of superficial cells. Along with this
change, vaginal pH decreases, vaginal
blood flow increases, and the
electropotential difference across the
vaginal mucosa increases to premenopausal
Improve Mood and Cognitive
• E has a positive effect on mood, memory, and
quality of life scales, whereas progestins may
attenuate some of these effects.
• The data on estrogen reducing the risk of
Alzheimer's disease, however, are remarkably
consistent (RR, 0.4-0.6) among case-control and
• Although estrogen appears to have a protective
effect on the development of Alzheimer's disease,
it is not central to the pathophysiology of the
What About The Risks?
• Idiosyncratic reactions (e.g., hypertension and
• Vaginal bleeding
• Endometrial disease
• Breast cancer
• E usually causes no change in BP; it may actually reduce
BP, a finding that has relevance for normotensive as well as
• In some women, however, HRT may increase both diastolic
and systolic BP, but the elevation is rapidly reversible with
discontinuation of HRT.
• ERT increases venous thromboembolic events (VTEs). The risk of
VTEs was higher in the first year of treatment.
• In women with a history of thrombosis, there is an
increased risk of VTEs with ERT. Women who
have a family history of thrombosis or had VTEs
with oral contraceptives or other prior ERT should
• Unscheduled bleeding in any postmenopausal
woman should be investigated regardless of results
of US endometrial thickness, because abnormalities
may be present when the endometrial thickness is
less than 4 mm.
• Recurrent bleeding during sequential HRT regimens
causes many patients to stop treatment.
• Endometrial disease occurs with unopposed ERT.
• A woman's risk of developing endometrial cancer with
unopposed estrogen use is 2- to 8-fold higher.
• The risk of varying degrees of endometrial hyperplasia is
greater than that for endometrial cancer. The risk of
endometrial hyperplasia was 20% after 1 year and 40% at
the end of 3 years.
• The addition of a progestin eliminated the hyperplasia.
• Endometrial cancer associated with ERT are not aggressive;
because it is more likely to be discovered at an earlier stage.
• It was controversial but after WHI; it is not.
• In earlier calculations of HRT related risk, a RR
of 1.1 was ascribed, suggesting a 10% increase
in risk relative to no ERT.
• It is also possible that ERT use causes breast
cancer to occur earlier in some women, but it is
not clear which women are at greatest risk.
• Decision model for the calculation of breast cancer risk on
the basis of 7 risk factors: testosterone levels, BMI, waist-
to-hip ratio, alcohol consumption, density to
mammography, previous benign disease, and family
• Short-term estrogen use (~ 5 years) is not associated with
increased breast cancer risk, But controversy surrounds
long-term estrogen use (> 10 years).
• The positive association was especially pronounced with
continuously combined estrogen-progestin combinations.
• HRT stimulate the growth of ER-positive but not ER-negative
breast cancer. The prognostic significance of this is not known.
• For moderate doses of estrogen, the risk of breast cancer is
probably in the range of 20% to 30% in those women who are
• HRT reduces mammographic sensitivity, because breast
parenchymal cell density increases in some women on HRT.
• The association between ovarian cancer and
HT beyond 5 years, if any, should be
considered as rare or very rare, but that
women with a positive family history or
other increased risk for ovarian cancer
should be counseled about this rare
Tibolone - another progestogen
• Tibolone, a synthetic steroid analogue, is a form
of HRT that does not tend to induce bleeding.
• It is effective in maintaining an inactive
endometrium while providing estrogenization of
the lower genital tract over 6 years.
• Tibolone (2.5 mg/day) can safely relieve
You have to tell the patient…
As far as Benefits:
• Vasomotor…..Other options work
• Osteoporosis….Other Options work
• CVD….. No proven role
• Urogenital…..Other options
• Cognitive diseases….No proven role
• Alzheimer's disease… No proven role
As far as RISKS: Truth is
• Idiosyncratic reactions (e.g., hypertension and
venous thrombosis)… It is true
• Vaginal bleeding…. It is true.
• Endometrial disease…. It is true if unopposed.
• Breast cancer….. It is true
HRT status in 2010
• Whether or not HRT should be considered is a very
• Consider (1) symptoms, (2) risk factors, and (3)
individual preferences and needs.
• Alternatives should always be offered and considered.
• If hormonal therapy is chosen, there should be flexibility
• There is no ideal regimen for every woman.
• Estrogen can be used for short-term treatment of
symptoms at the lowest dosage that will adequately
control hot flushes or vaginal dryness or dyspareunia.
These are the main indications nowadays?
HRT Status in 2010 and FDA
• Treatment of vasomotor hot flushes and
associated symptoms is the main indication
for hormone therapy, which is still the most
effective treatment of these symptoms and
is currently the only FDA approved option.
To sum up
• There are many effective options for the
relief of Climacteric symptoms, HT is the
most effective but it is not always
• First line is other options, no HT if >50.
• < 50 means < 5years treatment is not
To sum up:
• Benefits vs. Risks is now
• Benefits vs. Breast Cancer, unsolved issue
• Statistically significant 2.4-fold increase in
new breast cancer events.
• ET use in breast cancer survivors has not been
proven to be safe and may be associated with
an increased risk for recurrence.
• HT is currently not recommended as a sole or
main indication for coronary protection in
women of any age.
• Starting HT by age 50 to 59 years or within
10 years of menopause to treat typical
menopausal symptoms does not seem to
increase the risk for CHD events, and there is
some recent evidence that starting ET in early
postmenopause may lower CHD risk.
• So no role for CHD.
• Menopause is not a disease, but it does have serious clinical
• Any intervention is effective for specific symptoms and/or
• We have to guide our female (they are not patients) through
the menopausal transition.
• Not every woman will have the same response to a given
therapy. Be flexible in prescribing patterns, whether it is for
traditional HRT or alternative approaches.
• Absolute contraindications
– Breast cancer, family
– Endometrial cancer
– Vascular thrombosis
– Unexplained vaginal bleeding.
• Relative contraindications
– > 5 ys treatment. 82
• ERT for women with early menopause until
they reach the age of menopause of their
• 5 years is OK, 10 yeas need reconsideration.
• We treat the symptoms and are not looking
for treatment of aging which could be
• Exercise, supplement and SERM are part of
the solution. 83
• Short-term treatment with hormone therapy
is preferred to long-term treatment.
• The lowest effective estrogen dose should
be given for the shortest duration required,
because risks for hormone therapy increase
with (1) advancing age, (2) time since
menopause, and (3) duration of use.
• For women experiencing an early
menopause, especially before the age of 45
years, the benefits of using HT until the
average age of natural menopause likely
will significantly outweigh risks.
Keep doing the same procedure with the
expectation of different results every time is