Menopause
 Permanent cessation of menses for at least 1 year
 FSH > or = 40 IU/ml
 Signs of hypoestrogenism
Perimenopause
 The Period surrounding menopause:
 Before, during, and after
 Mean age of onset: 46 yrs.
 Mean duration: 5 yrs. (2-8 yrs.)
 Only one marker: Menstrual irregularity
► In only 10% of women, menstuation ceased abruptly with
no period of prolonged irregularity.
What Happens
  follicular quality and/or quality
  INHIBIN Level   FSH Levels with normal or
even increased estradiol levels until 6 mo. to 1 yr
Initial Evaluations
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Medical History and Physical Examination
Breast and Pelvic Examination
Pap Smear (repeat every 1 yrs)
Mammography if >40 yrs (repeat every 1 yrs)
Evaluation of General Medical Conditions
 Detection of common medical problems as early as possible:
Hypertention, Heart diseases, Diabetes Mellitus, Cancer
 STD screening
 TSH screening at 40 yrs and q 2 yrs after 60 yrs of age
 Occult blood after 50 yrs of age
 Evaluation of vision, hearing, and teeth impairments
Hormonal Levels
  FSH (10-20) >  LH (3)
► FSH (T1/2 = 3-4 hr)has longer halflife than LH (T1/2 = 20 min)
► There is no negative feedback system like Estrogen for LH
 Changes in circulating hormone levels at menopause
Premenopause
Postmenopause
Estradiol
40-400 pg/ml
10-20 pg/ml
Estrone
30-200 pg/ml
30-70 pg/ml
Testosterone
20-80 ng/dl
15-70 ng/dl
Androstenedione
60-300 ng/dl
30-150 ng/dl
Age Of Menopause
 The most important determinant factor is genetics.
► Mothers and daughters tend to experience menopause at
the same age
 Factors that cause slightly earlier menopause
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Tobacco use (about 1.5 yrs)
Nulliparity
Living in high altitude
Heavy physical exercise
Undernurishment and thinness
Vegetarrian diet
IUGR in late gestation
Previous Hx. Of TAH or endometrial ablation
Irregular menses at early 40s
Age Of Menopause
 These factors don’t affect the age of menopause
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Use of OCPs
Socioeconomic states
Marital status
Age of menarche
Parity
Race
Height
 Premature ovarian failure: Spontaneous menopause
before 40 yrs of age
Problems
 Unopposed Estrogen
 AUB
  risk of endometrial cancer
 Hypoestrogenism
 Vasomotor, emotional, atrophic, cognitive, cardiovascular,
and musculoskeletal impacts
 Estrogen-Progestin Therapy
Indications of ERT
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Menopause
Hot Flashes
Vaginal Atrophy
Urinary Tract Symptoms
High risk for osteoporosis (Family Hx., Cigarette smoking,
Low body weight)
 High risk for cardiovascular disease (Previous myocardial
infarction, Hypertention, Family Hx., Cigarette smoking)
Contraindications for ERT
 Absolute
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Pregnancy
Undiagnosed uterine bleeding
Active thrombophlebitis
Current gallbladder diseases
Liver diseases
Neuro-ophthalmologic eye diseases
 Relative
 Hx. of breast cancer
 Hx. Of recurrent thrombophlebitis or thromboembolic
disease
 Migraine headache ?
 Epilepsy ?
Indications for
 Pretreatment Endometrial Biopsy:
 Characteristics associated with high risk endometrial
pathology
 Hx. of unopposed estrogen therapy
 During-treatment Endometrial Biopsy
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Clinician’s anxiety
Patient’s anxiety
Treatment with unopposed estrogen
AUB during treatment
Endometrial thickness > 4 mm
 D&C
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Cervical stenosis
Abnormal pelvic exam
Suspicious endometrail biopsy results
Patient’s pain intolerance
Abnormal Uterine Bleeding
 Management of postmenopausal AUB
Complex
hyperplasia
or
malignancy
Abnormal
Bleeding
Endometrial
Biopsy
Tissue
insufficient
for diagnosis
Simple
hyperplasia
or normal
pathology
Ultrasound
and/or office
hysteroscopy
Hysteroscopy and
fractional
curettage
Atypical
hyperplasia
or
malignancy
Abnormal
Normal or
simple
hyperplasia
Normal
Hysterectomy (or
other
definitive
therapy)
Group
therapy
(repeat endo.
Biop. In 6
mo)
Biopsy Results
 Endometrial biopsy results in post-menopausal
period:
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1-2% Cancer
50% Normal
3% Polyps
The rest atrophic
 Plans for Treatment:
 Cancer and/or Atypical Hyperplasia  HYSTERECTOMY
 Simple hyperplasia  Med. Prog. Acetate 10 mg/day for 1214 days per month
 Nonresponders (6-7%)  Re-evaluate after 3-4 months
► If persistant AUB or Hyperplasia again  D&C
► If hyperplasia regressed  conyinue progestrone therapy
until vasomotor symptoms begin and/or no withdrawal
bleeding anymore. Evaluate for ERT.
 Conterception
Menopause
 The Hot Flashes
Premenopausal
10-25% of women
Postmenopausal
No flashes
Daily flashing
Duration
Other causes
Psychosomatic
Stress
Thyroid Disease
Pheochromocytoma
Carcinoid Tumor
Leukemias
Cancer
15-25%
15-20%
1-2 years average
5 plus years: 25%
Menopause
 Menopause and the Perimenopausal transition
High cholestrol
High LDL
LDL entry into
endothelium
LDL oxidation
Monocyte
adherence, entry,
and conversion to
macrephages
Foam cells
Fatty streak
Smooth muscle
cell proliferation
and migration
Endothelial injury
and dysfunction
Vasoconstriction
Thrombus
Atherosclerotic
fibrous
plaque
Consequences
 Cardiovascular
 The optimal cholestrol/lipoprotein profile
► Total cholestrol: Less than 200 mg/dl
► HDL cholestrol: Greater than 50 mg/dl
► LDL cholestrol: Less than 130 mg/dl
► Triglycerides: Less than 250 mg/dl
  Risk of MI
► Total cholestrol > 256 mg/dl
► Triglycerides > 400 mg/dl
► HDL cholestrol < 50 mg/dl
 Risk of Heart diseases based on Chol/HDL ratio
► < 2.5
Lowest risk
► 2.5-3.7
Below average risk
► 3.8-5.6
Average risk
► 5.7-8.3
High risk
► > 8.3
Dangerrous
Consequences
 Osteoporosis
Excess
alcohol
Diet
Excess
caffeine &
low
calcium
Low Vit D
Low
calcium
Age
Heparin
Race
Anticonvulsants
Environmental
factors
Drugs
OSTEOPOROSIS
Lack of estrogen
Corticosteroids
Body weight
Thyroxine
Diseases
Lifestyle
Sedentary
Smoking
Pathophysiologic factors
Consequences
 Osteoporosis
 Commonly associated injuries:
► Femoral Head Fx.
► Hip Fx.
► Vertebral Fx.
► Colles’ Fx
► Teeth Loss
 Specific causes
Drugs
Heparin, anticonvulsants, high intake of alcohol
Chronic Disease
Renal and hepatic
Endocrine diseases
Excess glucocorticoids
Hyperthyroidism
Estrogen deficiency
Hyperparathyroidism
Nutritional
Calcium, phosphorus, vitamin D deficiencies
Consequences
 Osteoporosis
 Laboratory Exams
► Ca, Phos, ALP, PTH
► RFT
► CBC, ESR, Protein Electrophoresis
► TFT
 Alternative Treatments:
► Calcium-Vit D Supplements
► Bisphosphonate: ETIDRONATE 400 mg for 2 weeks then
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12 weeks drug free OR ALENDRONATE (FOSAMAX Tabs)
5-10 mg/day
Calcitonin: 100 IU/day SQ OR 200 IU/day Intranasal
Raloxifen (EVISTA 60 mg Tabs):  Hot flashes,  risk of
breast cancer
Tibolon: 2.5 mg/day
Hormone Replacement Therapy
 The Sequential Program for Oral Postmenopausal
Hormone Therapy
 Daily Estrogen
0.625 mg conjugated estrogens, or
1.25 mg estropipate, or
1.0 mg micronized estradiol or
equivalent doses of other estrogens
 Monthly progestin 0.7 mg norethindrone, or
200 mg micronized progestrone, or
5 mg medroxyprogestrone acetate, or
equivalent doses of other progestins
given daily for 2 weeks every month
 Combined with daily calcium supplementation (500mg with
a meal), and vitamin D (400 IU in winter months and 800 IU
for women over age 70).
Hormone Replacement Therapy
 The Continuous Combination Program for Oral
Postmenopausal Hormone Therapy
 Daily Estrogen
0.625 mg conjugated estrogens, or
1.25 mg estropipate, or
1.0 mg micronized estradiol or
equivalent doses of other estrogens
 Monthly progestin 0.35 mg norethindrone, or
100 mg micronized progestrone, or
2.5 mg medroxyprogestrone acetate, or
equivalent doses of other progestins
 Combined with daily calcium supplementation (500 mg with
a meal), and vitamin D (400 IU in winter months and 800 IU
for women over age 70).
Hormone Replacement Therapy
 Relative estrogen potencies
Estrogen
FSH Levels Liver Pro.s Bone density
Conjugated estrogen
1.0 mg
0.625 mg
0.625 mg
Micronized estradiol
1.0 mg
1.0 mg
1.0 mg
Estropipate (piperazine estrogen sulfate)
1.0 mg
1.25 mg
1.25 mg
Ethinyl estradiol
5.0 μg
2-10 μg
5.0 μg
Estradiol valerate
―
―
1.0 mg
Esterified estrogen
―
―
0.625 mg
Transdermal estradiol
―
―
50 μg
Hormone Replacement Therapy
 Usual initial dosages of estrogens used for HRT
 Oral
►
Conjugated equine estrogens
Synthetic conjugated estrogens
Micronized estradiol
Esterified estrogens
Estropipate
Ethinyl estradiol
 Topical Patch
► 17 b-Estradiol
 Vaginal
► Conjugated equine estrogens
17 b-Estradiol
 Injectable
► Estrone
Estradiol cypionate in oil
Estradiol valerate in oil
0.625-1.25 mg daily
0.625-1.25 mg daily
1-2 mg daily
0.625-1.25 mg daily
0.625-1.25 mg daily
0.02 mg daily
0.025-0.1 mg patch
once or twice weekly
0.2-0.625 mg, 2-7 times
per week
1 mg, 1-3 times/week
0.1-1.0 mg weekly
1-5 mg IM weekly3-4
10-20 mg IM / 4 weeks
Effects of HRT
 Cardiovascular
 A favorable impact on the circulating lipid and lipoprotein
profile, especially a  in total cholestrol and LDL-cholestrol
and  in HDL-cholestrol
 A direct antiatherosclerotic effect in arteries
 Augmentation of vasodilating and antiplatelet aggregation
factors, specifically nitric oxide and prostacyclin
(endothelium-dependent mechanisms)
 Vasodilation by means of endothelium-independent
mechanisms
 Direct inotropic actions on the heart and large blood vessels
 Improvement of peripheral glucose metabolism with a
subsequent decrease in circulating insulin levels
 Antioxidant activity
 Favorable impact on fibrinolysis, at least partially mediated
by endothelial nitric oxide and prostacyclin synthesis
Effects of HRT
 Cardiovascular
 Inhibition of vascular smooth muscle growth and migration
– intimal thickening
 Protection of endothelial cells from injury
 Inhibition of macrophage foam cell formation
 Reduced levels of angiotensin-converting enzyme and renin
 Reduction of P-selection levels
 Reduction of homocystein levels
Effects of HRT
 Cardiovascular
  50% risk of coronary artery disease
  45% risk of myocardial infarction
  risk and extension of stroke even in hypertension or
smoking
  basal insulin levels and  Insulin resistance
 Effect of estrogen on BP
►  epinephrin associated BP
►  BP with idiosyncratic effect
 HRT in hypertensive patient:
► Control BP q 6 mo.
► If BP variability  control BP q 3 mo.