October.14. 1997
1st year resident Se Mi CHOI . M.D.

  • Menopause - permanent cessation of menses that occur after the cessation of ovarian function
  • Perimenopause - encompasses the time before, during and after menopause
  • Menopausal transition - period of hormonal transition before menopause, insidious or relatively
    abrupt onset, usually in the mid - to late forties

I. Perimenopausal Phases

1. Menopausal transition

  1. Period that precedes menopause characterized by varying degree of somatic and psychological
    changes that reflect alterations in the normal cyclic functioning of the ovary
  2. Most significant symptom of menopausal transition - menstrual irregularity

  • 90% of women during the 4years of transition prior to menopause
  • Evaluated carefully to determine whether it is result of lower level of estrogen or underlying

2. Menopause

  1. Cessation of menses resulting from the loss of ovarian function is an event rather than a period of time
  2. Occurs at a median age of 51years determined genetically
    earlier in cigarette smokers, in hysterectomies, in nulliparous women
  3. Diagnosed retrospectively, amenorrhea in the presence of signs of hypoestrogenemia and serum FSH
    level higher than 40 IU/l
  4. Symptom - hot flushes (flashes)

3. Postmenopausal period

  • Health problems associated with estrogen deficiency tend to be chronic loss of ovarian function does
    not result in an absolute estrogen deficiency

4. Premature ovarian failure

  • Defined as when menopause occurs spontaneously before 40 years of age
  • Surgical menopause

    • Acute problem : hot flushes, vaginal atrophy
    • Long term higher risk for osteoporosis and cardiovascular disease than natural menopause
    • Estrogen replacement is needed immediately

II. Hormonal changes of menopause

1. Menopausal transition

  • During menopausal transition - ovarian follicles become increasingly resistance to FSH stimulation
    while estradiol levels remain relatively constant

    • Demonstrated by the relative resistance to gonadotropin in women undergoing ovulation stimulation
      for in vitro fertilization
    • Hot flushes experienced by some women despite normal level of estradiol as evidenced by monthly

  • Progesterone

    • Ovulation becomes less frequent, luteal level of progesterone are lower than in younger women

2. Menopause

  • During menopause, the level of hormones, the way they are produced, and their roles change
  • Estrogen

    • Prior to menopause - estradiol level range from 50 to 300 pg/ml
    • After menopause - estradiol and estrone can be as high as 100pg/ml

      • Peripheral conversion (aromatization) of androstenedione, androgen produced primarily by the
        adrenal gland as well as by the ovary postmenopausally

      • Aromatization of androgen to estrogen occur primarily in muscles and adipose tissue

  • Progesterone

    • After menopause, progesterone production cease
    • Progesterone protect the endometrium from excess estrogen stimulation during the reproductive years

      : higher risk of endometral hyperplasia and cancer just prior to and after menopause
    • Breast tissue - extremely sensitive to gonadal hormones

  • Androgen

    • Testosterone, androstenedione
    • Prior to menopause, the ovary produces approximately 50% of the circulating androstenedione and
      25% of the testosterone
    • After menopause, total androgen production decreases, mainly because ovarian production decreases
      but also because adrenal production decreases

III. Patient Concerns about Menopause

  • Loss of childbearing capacity
  • Loss of youth
  • Skin changes

    • Ability of estrogen - prevent and restore age related loss of skin collagen

  • Changes in mood or behavior

    • Depression: many psychiatric symptoms that occur during this period may be more related to
      psychosocial events such as changes in relationship with children, marital status and other life events
    • Anxiety and irritability : climacteric syndrome. more clearly associated with psychosocial factor than
      with estrogen status
    • Loss of libido : vaginal atrophy, androgen decrease after menopause

IV. Diagnostic Approaches

1. Abnormal bleeding

    Menstrual irregularity occurs in the more than half of all women, bleeding can be irregular, heavy, or

  • Cause

    1. Anovulatory cycles - gradual decrease in the number of normally functioning follicles reflected by
      gradually increasing follicular phase FSH level
    2. Pregnancy
    3. Endometrial cancer : after menopause, the overall incidence of endometrial cancer -- 0.1%/year
      in women with abnormal uterine bleeding : 10%
    4. Cervical cancer, polyp, leiomyoma

  • Evaluation

    1. Endometrial sampling, dilatation and curettage, office endometrial biopsy
      endocervical curettage should also be performed to exclude endocervical pathology
    2. Vaginal ultrasound : if the amount of tissue obtained on endometrial biopsy is insufficient for
      diagnosis, vaginal ultrasonography can be performed to obtain additional information.
      if the endometrial stripe is less than 5mm thick, the risk of endometrial hyperplasia or cancer is
      extremely small.
    3. Hysteroscopy

  • Treatment

    1) Hormonal therapy

      Oral contraceptives

    • low dose (<35mcg ethinyl estradiol)
    • 20mcg of ethinyl estradiol and 1mg of norethindrone acetate
    • Cardiovascular risk factor : hypertension, hypercholesterolemia, cigarette smoking, previous
      thromboembolic disorder, cerebral vascular disease, coronary artery disease

      Cyclic progestins

    • medroxyprogesterone 10mg daily for 10 days each month
    • induce withdrawal bleeding
    • decrease risk of endometrial hyperplasia

    2) Surgical

    • Dilation and curettage : with the exception of endometrial polyps, uterine curettage has not been
      shown to have any long-term benefit in the treatment of abnormal uterine bleeding
    • Hysterectomy : prior to recommending hysterectomy, adequate preoperative evaluation must
      include endometrial sampling and adequate trial of hormonal therapy to control the bleeding
    • Oophorectomy during hysterectomy

      • Postmenopausal women ; standard practice
      • Premenopausal women ; immediate hormone replace is necessary
      • Sudden and precipitous drop in estrogen level : more difficult to manage
      • Decrease androgen production

    • Endometrial ablation

V. Estrogen deficiency

1. Diagnosis

    Determination of ovarian function is based primarily on clinical criteria

    Progestin challenge test is frequently used bioassay for estrogen status

  • Estradiol

    • Amenorrhea with other symptoms of estrogen deficiency or in whom progestin withdrawal bleeding
      does not occur - > measurement of serum estradiol can be helpful
    • Menstruating women - normal estradiol levels range from 40 to 300 ppg/ml
      oligo-ovulatory women - estradiol level >30pg/ml indicates residual ovarian function
    • Treatment sometimes indicated for symptoms alone and should not be withheld simply because the
      serum estradiol levels are in the normal range

  • Follicular stimulating hormone

    • Menstruating women - FSH on cycle day 3 : 5-10 IU/l
    • Elevated FSH level (10-25IU/l) suggest relative ovarian resistance consistent with the menopausal
      transition, even if estradiol levels are normal range
    • FSH levels > 40IU/l are consistent with complete cessation of ovarian function

  • Luteinizing hormone

    • Less value than other hormone assessments during the menopausal transition , significantly elevated
      during midcycle surge and cases of chronic anovulation
    • To rule out gonadotropin - secreting pituitary adenoma

2. Symptoms

  • Amenorrhea : cessation of menstruation indicates that the amount of estrogen produced by the
    ovaries is no longer enough to promote endometrial proliferation, and the absence of cyclic
    progesterone production is accompanied by the absence of withdrawal bleeding

  • Hot flashes (hot flush)

    • Recurrent, transient periods of flushing, sweating, and a sensation of heat, often accompanied by
      palpitation, feeling of anxiety and sometimes followed by chills
    • Accompanied by fatigue, nervousness, anxiety, irritability, depression, and memory loss
    • Hot flashes correspond to marked, episodic increases in the frequency and intensity of GnRH
      pulses from the hypothalamus : marker for the central disturbance of the body temperature regulation
    • Estrogen replacement therapy : low dose oral contraceptives

      • daily estrogen dose increased stepwise to as high as the equivalent of 2.5mg of conjugated estrogen
        than should be tapered slowly down over period of months to no more than 1.25mg of conjugated
        estrogen per day
      • Alternative treatment : progestin, clonidine, combination of phenobarbital, ergotamine, belladonna
      • Without treatment, the symptoms usually slowly subside over 3-5 years

  • Sleep disturbance

3. Long - term health problems

    Low estrogen levels have a cumulative effect on many tissues
    Prevention and early detection remain the cornerstones of health maintenance in this age group

  • Vaginal and urinary tract changes

    • Within 4-5 years of menopause, 1/3 of women , not taking estrogen replace therapy develop
      symptomatic atrophy
    • Vaginal symptoms : dryness, dyspareunia, recurrent vaginal infection
    • Urinary symptoms : dysuria, urgency, recurrent urinary tract infection, urinary incontinence

  • Central nervous system

    • Perimenopausal women often experience difficulty in concentrating and loss of short- term memory
    • Evidence suggests that risk of developing Alzheimer's disease can be decreased by estrogen therapy

  • Cardiovascular systems

    • Before menopause : risk of death from coronary artery disease is at least three times as great for men as
      for women
    • After menopause : relative risk for women increases significantly
    • Risk factor : hypoestrogenemia, hypertension, cigarette smoking, diabetes mellitus,
      hypercholesterolemia, sedentary life style

  • Osteoporosis

    • Definition : reduction in the quantity of bone, bone loss , progressed to a point that specific parts of
      the skeleton are so thin that they have an enhanced susceptibility to fracture or that fracture are
      actually present. by the time signs of osteoporosis become apparent, treatment is difficult
    • Pathophysiology : multifactorial

      • Age - gradual decrease in growth hormone level associated with age
      • Heredity
      • Estrogen status - hypoestrogenemia direct effect on osteoblast function and adverse effects by
        altering calcium balance
      • Dietary calcium
      • Physical activity and avoidance of cigarette smoking

        • Method for detection

      • Table 29-1 Radiographic techniques to screen for osteoporosis.

VI. Estrogen Replacement Therapy

1. Benefits

  • Hot flushes : effective in reducing the severity and frequency of hot flashes within a few days,
    several weeks before maximal relief is achieved
  • Osteoporosis

  1. Conserve calcium

    • Enhancing the efficiency of intestinal absorption
    • Improving renal calcium conservation

  2. Direct effect on osteoblast function
  3. Progesterone appears to promote bone formation by increasing osteoblast activity or indirectly, by
    inhibiting glucocorticoid effect on osteoblast

  • Cardiovascular disease

  1. Effect on serum lipids and lipoproteins - decreases circulating levels of low density lipoprotein and
    increase high density lipoprotein
  2. Anti - atherosclerosis effect on blood vessels : direct effect on blood vessels,
    antioxidant, decreases the formation of lipid peroxidase
  3. Vasodilation : mediated by estrogen receptors
  4. Coagulation

    • Subclinical decrease in coagulability
    • Decreasing platelet aggregation and fibrinogen and by inhibiting plasminogen formation
    • Higher dose estrogen, increase coagulability

2. Potential health risks

  • Risk of estrogen therapy appear to be dose related

    1. Breast cancer : some concluded that no increased risk of breast cancer among women who receive
      hormone replacement, others have demonstrated significant increase in breast cancer.
      Risk that may be related to the duration of estrogen use.
    2. Endometrial cancer

      • Estrogen alone - 4~ 7 times more likely to develop endometrial cancer.
      • Simultaneous use of progestins effectively prevents

    3. Gallbladder disease
    4. Thrombophlebitis
    5. Hypertension : higher dose formulations found to further increase blood pressure
    6. Side effect : vaginal bleeding, breast tenderness, mood changes,weight gain and water retention

    3. Special cases

    • History of breast cancer : estrogen should be used with caution
    • History of endometrial cancer
    • Endometriosis : reports of recurrent endometriosis or malignant transformation of endometriosis in
      women with endometriosis who take estrogen replacement therapy following bilateral oophorectomy
      severe endometriosis - hormone free period for up to 6 months immediately after surgery advisable
    • Liver disease : estrogen metabolized in the liver, replacement therapy should be avoided in women with
      active or chronic liver disease

    4. Replacement hormones and regimens

      Standard replacement therapy ; 3weeks of estrogen therapy and 1week of added progestin with an
      intact uterus

      Estrogen only who had hysterectomy

  • Types of estrogen and progesterone

    --> Table 29.3 Standard Dosages of Commonly Used Estrogen and Progestins.
  • Estrogen only
  • Estrogen plus cyclic progesterone

      : 10 days of progestin therapy per months may not be enough to prevent endometrial hyperplasia in
      some women -> therefore, when cyclic progestins are used, should be given for 12-14 days per

  • Estrogen plus continuous progesterone

    • Cyclic higher dose progesterone : vaginal bleeding, breast tenderness, fluid retention, edema,
      psychological symptoms
    • Daily progestin therapy (2.5 - 5.0 mg medroxyprogesterone acetate or equivalent)

      : protect against endometrial hyperplasia to a degree similar to that of cyclic administration of higher

  • Testosterone

    • Loss of libido are most common indication
    • Androgen should be prescribed with caution

    5. Patient surveillance

  • Symptoms

    • Vaginal dryness responds slower than hot flashes
    • Even at the lowest therapeutic doses, complete resolution of vaginal dryness is usually seen after 3-6

  • Vaginal bleeding

    • Unopposed estrogen : amenorrhea
    • Continuous estrogen and cyclic medroxyprogesterone : cyclic estrogen withdrawal bleeding
    • Continuous estrogen and continuous progestin : more variable bleeding pattern

      One half of women will have some degree of irregular bleeding even after 1year

      Consider baseline endometrial biopsy for irregular bleeding

      Irregular bleeding persist for 6months -> further evaluation with ultrasound and hysteroscopy

    VII. Nonhormonal drugs

      : calcium, fluoride, calcitrol, calcitonin, biphosphate