Pharm
Estrogen Replacement
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Estrogen Replacement
, Hormone Replacement, Estrogen Replacement Therapy, Hormone Replacement Therapy
Indications
Menopause
Premature Ovarian Failure
See Also
Continuous Estrogen Replacement
Sequential Estrogen Replacement
Vaginal Estrogen
Transdermal Estrogen
General
Estrogen Replacement is recommended only for symptom control (e.g.
Hot Flushes
), not for chronic disease prevention
Risks and benefits of
Estrogen
with or without
Progesterone
are complex
ACOG and AAFP do not recommend Hormone Replacement for chronic disease prevention
(2013) Obstet Gynecol 121(6): 1407-10 [PubMed]
Manson (2013) 310(13): 1353-68 +PMID:24084921 [PubMed]
Different
Estrogen
types are equivalent in efficacy
Adverse effects and safety are also equivalent
Combination therapy (with
Progesterone
) differ in their risks compared with
Estrogen
alone
Nelson (2004) JAMA 291:1610-20 [PubMed]
Advantages
Benefits of Estrogen Replacement
Osteoporosis
Estrogen
increases bone density by 20-30%
Increases
Bone Mineral Density
5-15% in 3 years
Benefit even if started late postmenopausal
Benefit also seen with
Transdermal Estrogen
Hazard Ratio for
Hip Fracture
: 0.66
(2002) JAMA 288:321-333 [PubMed]
Endocrine Effects
Reduces
Type II Diabetes Mellitus
Risk by 20% (PEPI)
Improves
Glucose Metabolism
Improves
Insulin
sensitivity
Decreases
Fastin
g
Glucose
levels
Relief of perimenopausal
Major Depression
symptoms
Transdermal Estrogen
effective
Antidepressant
Soares (2001) Arch Gen Psychiatry 58:529-34 [PubMed]
Relief of Genitourinary symptoms
See adverse effects below regarding
Incontinence
Vaginal Dryness
Dyspareunia
Urethritis
Relief of perimenonpausal vasomotor symptoms
Hot Flashes
Insomnia
Irritability
Anxiety
Reduces tooth loss
Protective against
Colorectal Cancer
Decreases cumulative
Colon Cancer
risk
Hazard ratio for
Colorectal Cancer
0.63
(2002) JAMA 288:321-333 [PubMed]
Disadvantages
Mixed Risks and Benefits
Cardiovascular disease
Post-stoppage study suggested cardiovascular benefit in early
Menopause
Manson (2013) JAMA 10(13): 1353-68 +PMID:24084921 [PubMed]
NIH Women's Health Initiative Results
Combined HRT Study stopped early
Increased coronary risk by 7 per 10,000 patients
Hazard ratio for coronary events: 1.29
Slight risk, but definately no CAD benefit
Estrogen
alone post-
Hysterectomy
This arm of study continues
References
(2002) JAMA 288:321-333 [PubMed]
Earlier studies questioned cardiovascular benefit
Increased coronary event risk in first year of ERT
Protective effect after first year
Grodstein (2001) Ann Intern Med 135:1-8 [PubMed]
Herrington (2001) N Engl J Med 343:522-9 [PubMed]
Improved survival in
Congestive Heart Failure
Reis (2000) J Am Coll Cardiol 36:529-33 [PubMed]
Lowers systolic
Blood Pressure
(no diastolic effect)
More pronounced effect in
Obesity
and advanced age
Scuteri (2001) Ann Intern Med 135:229-38 [PubMed]
Lipid
effects (
Estrogen
alone without Prosterone)
Increases HDL
Decreases LDL
Cerebrovascular Disease
Risk
Initial studies showed increased CVA risk
Grodstein (2000) Ann Intern Med 133:933-41 [PubMed]
NIH Women's Health Initiative also had increased risk
Increased
Incidence
by 8 per 10,000 patients
Hazard ratio for
Cerebrovascular Accident
: 1.41
(2002) JAMA 288:321-333 [PubMed]
Large prospective cohort study with no increased risk
No HRT increased ischemic or
Hemorrhagic CVA
risk
Angeja (2001) J Am Coll Cardiol 38:1297-301 [PubMed]
Cognitive effects
Initial studies showed decreased Alzheimer's Risk
Appeared to protect against cognitive decline
Paganini (1996) Arch Intern Med 156:2213-7 [PubMed]
Yaffe (2000) Lancet 356:708-12 [PubMed]
Recent studies have shown no benefit
No benefit
Buckwalter (2004) J Am Geriatr Soc 52:182-6 [PubMed]
Viscoli (2005) Am J Obstet Gynecol 192:387-93 [PubMed]
May adversely affect global cognitive function
Espeland (2004) JAMA 291:2959-68 [PubMed]
Disadvantages
Risks of Estrogen Replacement
Breast Cancer
See
Breast Cancer Risk Factors
Risk appears to be associated with replacement type
Associated with
Continuous Estrogen Replacement
Less associated with
Estrogen
alone
Less associated with Sequential Replacement
Weiss (2002) Obstet Gynecol 100:1148-58 [PubMed]
Combination therapy increases risk
Estrogen
only therapy: 3-7 additional cases/1000
Combination therapy: 18-20 additional cases/1000
(2003) Lancet 362:419-27 [PubMed]
Lytinen (2006) Obstet Gynecol 108:1354-60 [PubMed]
Endometrial Cancer
Occurs with
Unopposed Estrogen
(without
Progesterone
)
Atypical Hyperplasia in 30% on
Unopposed Estrogen
Risk remains 10 years after
Unopposed Estrogen
use
Women with intact
Uterus
must use combination HRT
Evaluate Postmenopausal
Abnormal Uterine Bleeding
Anticipate uterine bleeding for first 4-6 months
Evaluate bleeding >6 months after starting HRT
Endometrial Biopsy
Uterine
Ultrasound
Ovarian Cancer
Associated with
Estrogen
use without
Progestin
Relative Risk
of
Ovarian Cancer
in ERT: 1.6
Relative Risk
if ERT use >20 years: 3.2
Lacey (2002) JAMA 288:334-41 [PubMed]
Venous Thrombosis risk
Higher risk with
Estrogen
dose over 2.5 mg/day
Higher risk when used with
Progesterone
(combination therapy)
Smith (2004) JAMA 292:1581-7 [PubMed]
NIH Women's Initiative
Hazard Ratio for
Pulmonary Embolism
: 2.13
(2002) JAMA 288:321-333 [PubMed]
Risk if prior Venous thrombosis occurred
Trauma
-related: no increased risk
Oral Contraceptive
related: possible increased risk
Esterified
Estrogen
(Menest) not assoc. with thrombus
May be preferred form for Estrogen Replacement
Smith (2004) JAMA 292:1581-7 [PubMed]
Genitourinary
Urinary Incontinence
increases with
Estrogen
Grodstein (2004) Obstet Gynecol 103:254-60 [PubMed]
Special considerations
Gall Bladder
disease risk
Relative Risk
: 1.5 to 2.0
Risk persists for 5 years after
Estrogen
stopped
Increased
Triglyceride
s
Baseline
Triglyceride
s: 250 to 750
Start Estrogen Replacement
Recheck
Triglyceride
s in 4 weeks
Baseline
Triglyceride
s: over 500
Consider transdermal Estrogen Replacement
Baseline
Triglyceride
s: over 750
Avoid Estrogen Replacement
Risk of
Pancreatitis
Contraindications
Estrogen Replacement
Absolute
Unexplained
Vaginal Bleeding
Acute Liver Disease
or severe liver disease
Breast Cancer
Active
Thrombophlebitis
Thromboembolic disorder including past history of
Venous Thromboembolism
Pregnancy
Relative
Chronic Liver Disease
Heart disease
Endometrial Cancer
Hypertension
Familial
Hyperlipidemia
Consider
Transdermal Estrogen
Seizure Disorder
Migraine Headache
s
History of
Thrombophlebitis
Endometriosis
Gall Bladder
disease
Safety
Recent data suggests HRT is safe for 4-5 years of use
NIH Women's Health Initiative did not study age <50
Consider continuing
Estrogen
in these patients
(2002) JAMA 288:321-333 [PubMed]
Meta-analysis 4000 patients, 29 studies
Initially irregular bleeding for 6 months
Amenorrhea
in 75% after 6 months
Atrophic Endometrium in 90% of patients
Endometrial Hyperplasia
in 1% of patients
Adenocarcinoma in 0.05% of patients (2 cases)
Udoff (1995) Obstet Gynecol 86:306-16 [PubMed]
Preparations
Vasomotor Symptoms of Menopause
Continuous Estrogen Replacement
Preferred over sequential due to lower risk of
Endometrial Hyperplasia
Jaakkola (2009) Obstet Gynecol 114(6): 1197-1204 [PubMed]
Sequential Estrogen Replacement
Transdermal Estrogen
Genitourinary Syndrome of Menopause
(e.g.
Atrophic Vaginitis
)
Vaginal Estrogen
Management
Algorithm for choice of replacement method
Use the lowest effective dose of replacement that controls symptoms
Age under 40 years, Ovaries removed, or
Perimenopause
(see
Menopause
for strategy)
Sequential Estrogen Replacement
OR
Oral Contraceptive
Menopause
Continuous Estrogen Replacement
(preferred) OR
Sequential Estrogen Replacement
Late Postmenopausal
Vaginal Estrogen
for atrophic vagina OR
Continuous Estrogen Replacement
Avoid after age 60 years as risk of CVA, MI,
Dementia
increase
Management
Protocol to stop Hormone Replacement
Timing of Estrogen Replacement discontinuation
Premature
Menopause
Re-evaluate continued
Estrogen
use at age 51
Estrogen Replacement with
Progesterone
Consider stopping Estrogen Replacement after 3-5 years of use
Estrogen Replacement without
Progesterone
Consider stopping Estrogen Replacement after 7 years of use
Slow taper over 2-3 months reduces withdrawal affects
Estrogen
withdrawal effects to anticipate
Irregular
Vaginal Bleeding
or spotting
Hot Flushes
Taper
First: HRT only monday to friday for 1-3 months
Next: HRT only monday, wednesday, friday x1-3 months
Management
Consider alternatives to Estrogen Replacement
See
Hot Flushes
See
Cardiac Risk Management
See
Osteoporosis Management
Local
Estrogen
sources (
Vaginal Estrogen
)
Vagifem
tablets
E-String vaginal ring
References
Hill (2016) Am Fam Physician 94(11): 884-9 [PubMed]
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