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8th Edition APGO Objectives
for Medical Students
Climacteric
Rationale
Women spend as much as one-third of
their lives in the postmenopausal years.
Understanding the physical and emotional
changes caused by estrogen depletion is
important for all physicians who provide
health care for women.
Objectives
The student will be able to describe:
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Physiologic changes in the hypothalamic-pituitaryovarian axis
Symptoms and physical findings associated with
hypoestrogenism
Long-term changes associated with hypoestrogenism
Management, including:
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Hormone therapy
Nutrition and exercise
Non-hormonal therapeutic options
Risks and benefits of hormone replacement therapy
Population demographics
Older population aging - today, life
expectancy for a woman = age 80 yr.
 Older population growing - in 1990 >30M
menopausal women

Menopause
Definition - cessation of spontaneous
menses due to loss of ovarian function
Endocrinology
 Ovarian deficit  poor response to
gonadotropins  cease ovulation 
decreased ovarian steroid production
Epidemiology
Menopause
Clinical concerns
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Symptoms (early)
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Physical changes (intermediate)
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Hot flushes
Insomnia
Irritability
Mood disturbances
Vaginal atrophy
Urinary incontinence
Skin atrophy
Diseases (late)
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Osteoporosis
Cardiovascular disease
Alzheimer’s disease
Hormone replacement therapy (HRT) What is it?
Estrogens (E)
 Affects many target organs - bone, brain, eyes,
teeth, coronary vascular system, colon,
urogenital tract, breast
 Two (2) receptors identified, alpha and beta
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Similar amino acid homology
Identical DNA binding domains
Tissue selectivity of different ligands
Different estrogens acting through the same receptor
can induce different biological activity
Hormone replacement therapy (HRT) What is it?
Progesterone (P)
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Reduces numbers of cellular receptors for E
Induces target cell enzymes that convert estradiol
to estrone
Reduces overall intracellular availability of potent E
Suppress E mediated transcription of oncogenes
Operate via mechanism that requires time to take
effect, duration exposure critical
Minimal requirement of exposure at least 10 days
(Varma, 1985)
Counseling - Benefits (indications)
Vasomotor symptoms/cognitive processes
 Hot flushes, mood swings, depression,
sleep disturbances, poor memory
 E most effective treatment hot flashes
Counseling - Benefits (indications)
Alzheimer’s disease (AD)
 Neurodegenerative process causing slow
progressive loss of mental function
 40% persons age > 80 yr., women earlier
onset
 Some studies indicate reduction in
relative risk AD with ERT (unopposed)
Counseling - Benefits (indications)
Sexual function
 No clear evidence of reduced drive after
menopause - studies confounded by body
image, health of partner, urogenital
changes
 E or E/A can induce positive effect on
sense of well-being
Counseling - Benefits (indications)
Genitourinary symptoms
 Reduced E  reduced mitosis  reduced
exfoliation surface cells  reduced tissue
vascularity  thinning of mucosal layer
 Vaginal dryness, dyspareunia, urethritis
 E can reverse atrophic changes
 E decreases incidence of urinary tract
infections in postmenopausal women
Counseling - Benefits (indications)
Coronary vascular disease
 Leading cause of death in women
 Epidemiologic data found decreased relative
risk with E
 E - many side effects on coronary vascular
system
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50% lipid-dependent Reduced LDL (4%), increase HDL
(9%) P can blunt these effects short-term
50% lipid-independent Direct antiatherosclerotic effect,
augmentation of antiplatelet aggregation factors, direct
inotropic actions on heart, improved glucose metabolism,
inhibition of lipoprotein oxidation
Counseling - Benefits (indications)
Coronary vascular disease (con’t)
No longer considered an indication because of
recent data from randomized controlled trials:
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HERS (1998) - E/HRT did not show reduction in overall
rate of CHD events (i.e. not effective for secondary
prevention.)
WHI (2002) HRT arm of trial stopped prematurely
because of increased risk of breast cancer and lack of
cardiovascular benefit in this primary prevention trial
(as well as small increase in risk of CVD.)
Counseling - Benefits (indications)
Osteoporosis
 Gradual loss bone mineral density
 Accelerated after menopause
 E reduces osteoclast activity
 E - FDA approval for prevention of
osteoporosis
 Overall reduction fracture rate 20-60%
with ERT
Counseling - Benefits (indications)
Colon cancer
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Third leading cause of cancer death in women
E may affect bile acid metabolism or promote tumor
suppressor activity in colon
E reduces incidence of colon CA by up to 50% in
postmenopausal women (20 epidemiological studies)
E reduced incidence of colon CA by 30% in 2002 WHI
(randomized placebo controlled blinded trial)
E reduces incidence adenomatous polyps in
postmenopausal women
Counseling - Benefits (indications)
Age-related macular degeneration (AMD)
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Leading cause of blindness in U.S.
17% population age 43-86
HRT may reduce risk of AMD
Safety issues
Venous thromboembolic disease (VTE)
 Studies show (2x) increased risk DVT
with current use
 NHS (1996) - increased risk PE with
current users
Safety issues
Stroke
 NHANES (1993) - in postmenopausal
women, HRT 31% reduction stroke
incidence, 63% reduction in stroke
mortality
 Majority of studies show HRT does not
increase stroke risk
Safety issues
Endometrial cancer
 Unopposed ERT increases risk of endometrial
cancer 2 to 10- fold
 PEPI (1996) unopposed ERT increased risk of:
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Simple hyperplasia 27%
Complex hyperplasia 22%
Risk increased with duration of exposure and
lasts up to 10 yr. After E is discontinued
Safety issues
Breast cancer
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Since 1940s, increased incidence of breast cancer,
mortality unchanged
50 epidemiological studies show no clear trend with
E use
Meta-analysis (1991-93) - possible increased risk
with current use and long duration of use
WHI (2002) 26% increase in risk after 4 years of
use
Studies inconclusive - may be increased risk, likely
small
Safety Issues
Hypertension - no relationship between BP and HRT use
Diabetes - no contraindication
Liver disease - increased circulating E levels
Familial hyperlipidemias - E will increase triglycerides
Migraines - may worsen with cyclic therapy
Cholecystitis - E may carry 1.5 to 5-fold increased risk of gall
bladder disease
Leiomyomas - usually not stimulated by HRT
Endometriosis - increased doses E may induce recurrence
Office evaluation
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History, physical exam
Family history
Lifestyle evaluation
Height, weight, blood pressure
Labs/studies
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FSH-determine change OCPs  HRT if > 30IU/L during pillfree week
Fasting lipid profile; consider fasting glucose, TSH
Bone densitometry
Mammogram
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Colon cancer screening
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Verify absence of contraindications
Side effects
Irregular bleeding
 Breakthrough bleeding originates from
endometrium dominated by P
 40-50% patients with breakthrough
bleeding in first 6 mo. (20% after 1 yr.)
 Increased likelihood with
perimenopause
Side effects
Irregular bleeding - When to evaluate
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Pretreatment if high-risk (obesity,
dysfunctional bleeding, high alcohol intake,
liver disease, hypothyroidism)
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With irregular bleeding first 6 mo.
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Prior h/o unopposed ERT
Prior hyperestrogenic environment
Women on sequential therapy with bleeding before
day 10
With irregular bleeding after 6 mo. - all
patients
Side effects
Irregular bleeding - How to evaluate
Endometrial biopsy (EMB) - 3mm plastic suction device,
office biopsy
Transvaginal ultrasound
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Endometrial thickness positively correlates with
presence or absence of pathology in women not
receiving HRT
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Thickness <5mm in postmenopausal women
reassuring
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Thickness >5mm (15%) require further evaluation
Side effects
Irregular bleeding - How to evaluate
Progesterone challenge test
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Withdrawal bleed to progesterone to detect presence
of E-dependent endometrium in postmenopausal
women
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Validity not established
Dilation and curettage - if unable to perform office EMB
Hysteroscopy
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Visual inspection of uterine cavity with hysteroscope
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If bleeding persists, to determine presence of
endometrial polyps or submucous myomas
Side effects
Breast tenderness
Bloating
Depression
 Progesterone
dependent
 May respond to changing type/route
administration
Therapeutic options
Estrogens
 Specific E not as important as duration, dose
and presence/absence of progestin
 Relative estrogen potencies
 Route of administration
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Oral - first pass through liver predominately estrone
Others - no first pass, predominately estradiol
• Vaginal
• Injectable
• Percutaneous ointment
Progesterone’s
Compounds
 Medroxyprogesterone acetate-21 carbon
compound
 Micronized progesterone
 Norethindrone-19 carbon compound
Progesterone’s
Routes of administration
 Oral
 IUD
 Vaginal
Sequence of administration
Continuous
Sequential/cyclic
Unopposed
Other hormones
Selective estrogen receptor modulators (SERMs)
 Tamoxifen
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Adjuvant chemotherapy for breast cancer
Prophylaxis for patients at high risk for breast cancer
Improved lipids, increased BMD
Agonist at uterus, increased risk of endometrial
abnormalities
Vasomotor symptoms may be worsened
Increased risk of VTE, similar to E
Other hormones
Selective estrogen receptor modulators (SERMs)
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Raloxifene
 Approved
for prevention and treatment of
osteoporosis
 No endometrial/vasomotor effects
 HDL/TG unchanged, same VTE risks
Other hormones
Androgens (A)
 Decreased production with menopause; may
improve vasomotor symptoms, enhance libido
and improve fatigue; concentration
 No endometrial protection
 Side effects
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Adverse effect on lipid profile
Masculinization rare
Alternative therapies
Hot flushes/vasomotor symptoms
 Soy phyto-estrogens (legumes)
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Mixed agonist/antagonists
Can decrease hot flashes >placebo
Clonidine - transdermal 0.1-0.3mg patch, twice
as effective as placebo
Venlafazine - 100 mg/d, effective at inhibiting
flushes Mergestrol
Alternative therapies - homeopathy,
acupuncture
Alternative therapies
Osteoporosis
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Biphosphonates
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Calcium
Inhibit bone resorption
 (Hasking, 1998) alendronate increases
BMD > placebo < HRT
Raloxifene
 SERM, FDA approved to
prevent and treat
osteoporosis
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Calcitonin - may prevent
bone loss at spine in late
menopause
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RDA/NIH
• Premenopausal - 8001000 mg elemental
• Postmenopausal 1200-1500 mg
elemental
Modest beneficial effect on
osteoporosis
With Vitamin D for best
effect
Alternative therapies
Cardiovascular disease
 Statins
 Antioxidants
 Aspirin
 Reduction risk factors
Alternative therapies
Urogenital atrophy
 vaginal
estrogen ring
Sexual function/libido
 Androgen
supplementation
 Continued sexual activity
Alternative therapies
Alzheimer’s disease
 Tacrine/danozepil (Schneider, 1996)
(cholinesterase inhibitors) affect
symptoms, not disease process
 NSAIDs (Rogers, 1993) - delay
expression AD
 Vitamin E (Sano, 1997) - slows
progression
Complimentary lifestyle interventions
Normalization of weight
 Dietary intervention
 Smoking cessation
 Regular exercise
 Control of other medical conditions
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References
Writing Group for the Women’s Health Initiative Investigators. Risks and
benefits of estrogen plus progestin in healthy menopausal women:
Principal results from the Women’s Health Initiative randomized controlled
trial. JAMA 2002; 288:321-33.
Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin
regimens on heart disease risk factors in postmenopausal women. The
Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA
1995; 273:199-208.
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al.
Randomized trial of estrogen plus progestin for secondary prevention of
coronary heart disease in postmenopausal women. Heart and
Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA
1998; 280:605-13.
References
Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al.
Cardiovascular outcomes during 6.8 years of hormone therapy; Heart and
Estrogen/Progestin Replacement Study follow-up (HERS II) JAMA 2002; 288:44957.
Nelson HD, Humphrey LL, Nygran P, Teutsch SM, Allan JD. Postmenopausal hormone
replacement therapy: Scientific Review. JAMA 2002; 288: 872-81.
Nelson HD, Assessing benefits and harms of hormone replacement therapy: Clinical
applications. JAMA 2002; 288:882-4.
Varma TR. Effect of long-term therapy with estrogen and progesterone on the
endometrium of postmenopausal women. Acta Obstet Gynecol Scand 1985. 64:41.
Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, et al.
Prospective study of exogenous hormones and risk of pulmonary embolism in
women. NHS (1996); Lancet 1996; 348:983-7.
Finucane FF, Madans JH, Bush TL, Wolf PH, Kleinman JC. Decreased risk of stroke
among postmenopausal hormone users. Results from a national cohort. NHANES
(1993); Arch Intern Med 1993; 153:73-9.
References
Heinemann DF. Osteoporosis. An overview of the National Osteoporosis Foundation
clinical practice guide. Geriatrics 2000; 55:31-6, 39. \
U.S. Preventive Services Task Force. Guide to Clinical Preventive Services, 2nd ed.,
Williams and Wilkins, Baltimore, MD, 1996.
Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and Infertility, 6th
ed. Williams and Wilkins, Baltimore, MD; 1999.
Beckmann CRB, Ling FW, et al. Obstetrics and Gynecology, 4th ed. Lippincott Williams
and Wilkins, Philadelphia, PA; pp.568-76
ACOG Educational and Technical Bulletin #210, Health Maintenance for
Perimenopausal Women. Washington, DC.
ACOG Educational and Technical Bulletin #247. Hormone Replacement Therapy.
Washington, DC.
ACOG Practice Bulletin #28. Use of Botanicals for Management of Menopausal
Symptoms. Washington, DC.
Adapted from Association of Professors of Gynecology and Obstetrics Medical Student
Educational Objectives, 7th edition, copyright 1997
Clinical Case
Climacteric
Patient Presentation
A 48-year-old female G3P3 whose last menstrual period
was 6 months ago presents to your office complaining
of hot flushes, emotional liability and insomnia. She has
tried to use an over-the-counter soy supplement, but
her symptoms are unchanged.
She began her menses at age 14. Her periods have been
regular until 2 years ago. At that time, they began to
space out to every 2-3 months. She denies
intermenstrual bleeding.
Patient Presentation
She had a negative Pap test one year ago and has never
had an abnormal Pap. She is sexually active and
recently has noted some dyspareunia. Her husband had
a vasectomy 15 years ago.
Her past medical and surgical history is significant only for
an appendectomy at age 18. She has smoked one pack
of cigarettes per day for 30 years. Her family history is
significant for a mother that fractured her hip at age 83.
She takes no medications or supplements on a regular
basis.
Patient Presentation
Physical exam
Slightly obese white female. Weight 180 lbs., 5’6”
BP 126/76. General physical exam, including
breast exam within normal limits. Pelvic exam
shows normal external genitalia. Her vagina is
slightly atrophic with decreased rugae. Her cervix is
normal in appearance; uterus is small and
antiverted. Neither ovary is palpated on bimanual or
rectal exam. Her stool is guiac negative
Patient Presentation
Laboratory
Pap smear – normal squamous epithelial and
endocervical cells present.
Cholesterol 195 TSH 2.0
FSH 80 MIU/ml
Mammogram – negative
Differential Diagnosis
Menopausal vasomotor symptoms
Management plan
Encourage patient to stop smoking. Initiate
incorporation of approximately 1200 mg calcium
and 400 units of vitamin D in her diet. After
lengthy discussion of risks and benefits of
hormone therapy (HT), the patient decided to
proceed with treatment, and was given
estrogen and progesterone in a continuous
daily fashion.
Management plan
1. Cigarette smoking is the largest preventable
cause of death and disability among women in the
United States. Among women of reproductive age,
29% smoke. Several studies have shown that
smokers cease menstruating 1-2 years earlier
than non-smokers. This effect is dose dependent
and the difference persists after controlling for the
subject’s weight. Moreover, female smokers 60
years of age and older have significantly reduced
bone mineral density of the hip compared with
nonsmokers.
Management plan
2. With the onset of menopause, ovarian
production of estrogen is significantly reduced,
lending to physiologic changes including hot
flushes, mood disturbances, sleep difficulty,
thinning of genitourinary tissues, dyspareunia,
metabolic shift to a more atherogenic
lipoprotein profile and accelerated loss of bone
mass. This transition in a woman’s life often is
a good time to assess current health risks and
plan risk reduction strategies.
Management plan
3. Estrogen/progestin hormone therapy is
approved by the FDA for the treatment of
menopausal hot flushes, prevention of
osteoporosis and treatment of urogenital
atrophy. Hormone therapy is the most
effective agent known for the treatment of hot
flushes. Studies have also shown it to be
significantly more effective than placebo in
reducing insomnia, irritability and poor shortterm memory during the menopausal
transition.
Management plan
4.
Risks associated with hormone therapy
include increased thromboembolic events,
increased triglyceride levels, breast cancer,
gall bladder disease and other possible
conditions. It is reasonable to continue
hormone therapy for the shortest amount of
time to address current vasomotor symptoms
in an attempt to decrease overall risk
Management plan
5. This patient’s risk for osteoporosis is
increased by her mother’s history of hip
fracture. In addition to the protection provided
by her HT, she should be encouraged to
maintain an appropriate daily intake of
calcium and vitamin D. Weight training
exercise will also decrease her risk of fracture.
Management plan
6. The patient should be encouraged to use a
water-based lubricant to decrease discomfort
during sexual intercourse. The hormone
therapy she has initiated should improve the
quality of her urogenital tissues over the next
few months. If these changes are not
sufficient, the addition of a vaginal estrogen
product may be helpful.