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   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.
   –   Osteoporosis.
   –   Cardiovascular disease.
   –   Urogenital atrophy.
   –   Cognitive decline and Alzheimer's disease.
Climacteric is OK but its sequalae are not OK


 Hot flashes                       Mood

               CVD                   Collagen
          Physiology of climacteric
• Ovarian decline..... Change
• Reproductive decline..... Change
• Hormonal changes...... Change

• E decline... this is the problem
                                       Ovarian Decline
• Menopause results from:
   – 1.Follicular depletion ("natural" menopause) or
   – 2. Surgical removal of the ovaries (“induced”, or
     “surgical menopause”).
• 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
  vaginal bleeding.
                      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:
   –   Smoking
   –   Nulliparity
   –   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-
  chromosome abnormalities.
             2. Reproduction and Climactric
• Climacteric: Time from the decline in reproductive
  capacity onward.
• 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
  symptomatic changes.
• E is important for cerebral blood flow, cerebral glucose
  administration, synaptic activity, neuronal growth, survival
  of cholinergic neurons, as well as such complex functions
  as cognition.
• 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

• Migraine
  – 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

• 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.
                                3. Vision
• Idiopathic full-thickness macular degeneration
  predominantly affects women > 60 years.
• There appears to be a hormonal component, because
  symptoms become more severe with menopause.
                                   4. Collagen
• 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
                                       Bone Loss
• 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.
                           7. CardioVascular

• 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
                            Climacteric=Very Crucial
• 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
     very useful.
                          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
  older women.
– Diet and exercise good for:
       – Bone physiology
       – Mood
       – CVD
                                2. Supplement

• 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
  may be:
   –   Natural supplements
   –   Non-hormonal treatments (e.g., a bisphosphonate)
   –   Selective estrogen receptor modulator (SERM)
   –   HRT
               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
  injection site.
                  Other treatment for osteoporosis
• Parathyroid Hormone
• Bisphosphonates
• 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.[125]
                                               d) SERM

• Selective agonistic or stimulatory effects (i.e., estrogenic) on
  one organ system and neutral or antagonistic (i.e.,
  antiestrogenic) effects on other organ systems.
                         •   Benzothiophenes
•   Triphenylethylenes
                         •   Raloxifene
•   Clomiphene           •   LY353381
•   Tamoxifen            •   Naphthalenes
                         •   CP336,156
•   Toremifene
                         •   Chromans
•   Droloxifene          •   Levormeloxifene
•   Idoxifene            •   Phytoestrogens
                         •   Genistein
                         •   Daidzein
                         •   Conjugated Estrogens
                         •   Delta8,9-Dehydroestrone sulfate
                                Ideal SERM
• 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.

             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]
  declined dramatically.

                          Benefits of HRT
•   Vasomotor
•   Osteoporosis
•   CVD
•   Urogenital
•   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
  well tolerated.


• ET decrease the incidence; WHI said it
  does not.

                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
  cohort studies.
• 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
  venous thrombosis)
• Vaginal bleeding
• Endometrial disease
• Breast cancer
                    Idiosyncratic Reactions
• E usually causes no change in BP; it may actually reduce
  BP, a finding that has relevance for normotensive as well as
  hypertensive women.
• In some women, however, HRT may increase both diastolic
  and systolic BP, but the elevation is rapidly reversible with
  discontinuation of HRT.
                      Idiosyncratic Reactions
• 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
  be discouraged.
                         Vaginal Bleeding
• 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
• 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.
                             Breast Cancer

• 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.
                                    Breast Cancer

• 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.
                                     Breast Cancer

• 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.
                       Ovarian Cancer

• 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
  menopausal symptoms.
You have to tell the patient…

                         As far as Benefits:
                                 Facts are:
•   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
  individual decision.
• 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
  in prescribing.
• 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
  risk profiles.
• 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
  – Hyperlipidemia.
  – > 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

         Thank you


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