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Endometrial Hyperplasia
Endometrial Hyperplasia
and Estrogen Therapy
and Estrogen Therapy
Fred Ueland, MD
Fred Ueland, MD
Division of Gynecologic Oncology
Division of Gynecologic Oncology
University of Kentucky
University of Kentucky
Are You Reading?
Are You Reading?
“It is astonishing with
“It is astonishing with
how little reading a
how little reading a
doctor can practice
doctor can practice
medicine, but it is not
medicine, but it is not
astonishing how badly
astonishing how badly
he may do it”
he may do it”
W. Osler
W. Osler
Mt Sopris
Carbondale, CO
Endometrial Hyperplasia
Endometrial Hyperplasia
Synonyms
Synonyms
Simple hyperplasia
Simple hyperplasia
Glandular hyperplasia
Glandular hyperplasia
Cystic glandular hyperplasia
Cystic glandular hyperplasia
Endometrial hyperplasia
Endometrial hyperplasia
Endometrial Hyperplasia
Endometrial Hyperplasia
Hyperplasia, simple or complex
Hyperplasia, simple or complex
–
–
Glandular architecture
Glandular architecture
–
–
Glandular crowding at expense of stroma
Glandular crowding at expense of stroma
–
–
“Back to back” crowding
“Back to back” crowding
Cytological atypia, absent or present
Cytological atypia, absent or present
–
–
Nuclear enlargement
Nuclear enlargement
–
–
Hyperchromasia
Hyperchromasia
–
–
Irregularity in shape
Irregularity in shape
Hyperplasia Risk Factors
Hyperplasia Risk Factors
Anovulation-PCO
Exogenous estrogen
Endogenous estrogen
Family history
Nulliparity
Age
Infertility
Tamoxifen
Early menarche
Late menopause
Diabetes
Hypertension
Granulosa cell tumors
History of breast of
colon cancer
Menstrual irregularities
Endometrial Hyperplasia
Endometrial Hyperplasia
Simple Hyperplasia
Simple Hyperplasia
Simple Hyperplasia
Simple Hyperplasia
Simple Hyperplasia
Simple Hyperplasia
Complex Hyperplasia
Complex Hyperplasia
Complex Hyperplasia
Complex Hyperplasia
Hyperplasia with Atypia
Hyperplasia with Atypia
Atypical Endometrial Cells
Atypical Endometrial Cells
Atypical Glandular Cells
Atypical Glandular Cells
Cystic Hyperplasia
Cystic Hyperplasia
Diagnosis of Hyperplasia
Diagnosis of Hyperplasia
Evaluation of the Endometrium
Evaluation of the Endometrium
48
48
-
-
80
80
80
80
-
-
90
90
PPV=9%
PPV=9%
Cheap, easy,
Cheap, easy,
NPV=99%
NPV=99%
TVS
TVS
NA
NA
94
94
Anesth
Anesth
,
,
perforation
perforation
Reusable,
Reusable,
hysteroscopy
hysteroscopy
Curette
Curette
NA
NA
83
83
$, equip,
$, equip,
perforation
perforation
Pain
Pain
Vabra
Vabra
99
99
45
45
-
-
100
100
Disposable
Disposable
Cheap,
Cheap,
office
office
Pipelle
Pipelle
% Spec
% Spec
% Sens
% Sens
Cons
Cons
Pros
Pros
Options
Options
Endometrial Biopsy
Endometrial Biopsy
Management of Hyperplasia
Management of Hyperplasia
Endometrial
Endometrial
Hyperplasia
Hyperplasia
Estrogen Therapy
Estrogen Therapy
Steroid Pathway
Steroid Pathway
Menstrual Cycle
Menstrual Cycle
Endometrial Stimulation
Endometrial Stimulation
Estrogen
Estrogen
Cancer Initiated Cells
Cancer Initiated Cells
Non
Non
-
-
initiated Cells
initiated Cells
Neoplasia
Hyperplasia
Hyperplasia
The Women’s Health Initiative
The Women’s Health Initiative
Randomized Trial
Randomized Trial
This multi
This multi
-
-
million dollar, 15
million dollar, 15
-
-
year project,
year project,
sponsored by the National Institutes of
sponsored by the National Institutes of
Health (NIH), National Heart, Lung, and
Health (NIH), National Heart, Lung, and
Blood Institute (NHLBI), involves 161,808
Blood Institute (NHLBI), involves 161,808
women aged 50
women aged 50
-
-
79, and is one of the most
79, and is one of the most
definitive, far
definitive, far
-
-
reaching clinical trials of
reaching clinical trials of
post
post
-
-
menopausal women's health ever
menopausal women's health ever
undertaken in the U.S.
undertaken in the U.S.
The Women’s Health Initiative
The Women’s Health Initiative
Randomized Trial
Randomized Trial
The WHI has two major parts: a randomized Clinical
The WHI has two major parts: a randomized Clinical
Trial and an Observational Study. The randomized
Trial and an Observational Study. The randomized
controlled Clinical Trial (CT) enrolled 68,132
controlled Clinical Trial (CT) enrolled 68,132
postmenopausal women between the ages of 50
postmenopausal women between the ages of 50
-
-
79
79
into trials testing three prevention strategies. If
into trials testing three prevention strategies. If
eligible, women could choose to enroll in one,
eligible, women could choose to enroll in one,
two, or all three of the trial components. The
two, or all three of the trial components. The
components are:
components are:
Hormone Therapy Trials (HT)
Hormone Therapy Trials (HT)
Dietary Modification Trial (DM)
Dietary Modification Trial (DM)
Calcium/Vitamin D Trial (
Calcium/Vitamin D Trial (
CaD
CaD
)
)
Effects of Conjugated Equine Estrogen on
Effects of Conjugated Equine Estrogen on
Stroke in the Women’s Health Initiative
Stroke in the Women’s Health Initiative
Circulation.
Circulation.
2006;113:2425
2006;113:2425
-
-
2434
2434
Conclusions:
Conclusions:
CEE increases the risk of
CEE increases the risk of
ischemic stroke in generally healthy
ischemic stroke in generally healthy
postmenopausal women. The excess risk
postmenopausal women. The excess risk
appeared to be present in all subgroups of
appeared to be present in all subgroups of
women examined, including younger and
women examined, including younger and
more recently menopausal women. There
more recently menopausal women. There
was no convincing evidence to suggest that
was no convincing evidence to suggest that
CEE had an effect on the risk of
CEE had an effect on the risk of
hemorrhagic stroke.
hemorrhagic stroke.
Venous Thrombosis and Conjugated Equine
Venous Thrombosis and Conjugated Equine
Estrogen in Women Without a Uterus
Estrogen in Women Without a Uterus
Arch Intern Med.
Arch Intern Med.
2006;166:772
2006;166:772
-
-
780.
780.
Conclusion
Conclusion
: An early increased VT risk is
: An early increased VT risk is
associated with use of estrogen, especially
associated with use of estrogen, especially
within the first 2 years, but this risk increase
within the first 2 years, but this risk increase
is less than that for estrogen plus progestin.
is less than that for estrogen plus progestin.
Conjugated Equine Estrogens and Coronary
Conjugated Equine Estrogens and Coronary
Heart Disease
Heart Disease
Arch
Arch
InternMed
InternMed
.
.
2006;166:357
2006;166:357
-
-
365
365
Conclusions:
Conclusions:
Conjugated equine estrogens
Conjugated equine estrogens
provided no overall protection against
provided no overall protection against
myocardial infarction or coronary death in
myocardial infarction or coronary death in
generally healthy postmenopausal women
generally healthy postmenopausal women
during a 7
during a 7
-
-
year period of use. There was a
year period of use. There was a
suggestion of lower coronary heart disease
suggestion of lower coronary heart disease
risk with CEE among women 50 to 59 years
risk with CEE among women 50 to 59 years
of age at baseline.
of age at baseline.
Effects of Conjugated Equine Estrogens on
Effects of Conjugated Equine Estrogens on
Breast Cancer and Mammography Screening in
Breast Cancer and Mammography Screening in
Postmenopausal Women With Hysterectomy
Postmenopausal Women With Hysterectomy
JAMA.
JAMA.
2006;295:1647
2006;295:1647
-
-
1657
1657
Conclusions:
Conclusions:
Treatment with CEE alone for
Treatment with CEE alone for
7.1 years does not increase breast cancer
7.1 years does not increase breast cancer
incidence in postmenopausal women with
incidence in postmenopausal women with
prior hysterectomy. However, treatment
prior hysterectomy. However, treatment
with CEE increases the frequency of
with CEE increases the frequency of
mammography screening requiring short
mammography screening requiring short
interval follow
interval follow
-
-
up. Initiation of CEE should
up. Initiation of CEE should
be based on consideration of the individual
be based on consideration of the individual
woman's potential risks and benefits.
woman's potential risks and benefits.
Conjugated Equine Estrogens and Global
Conjugated Equine Estrogens and Global
Cognitive Function in Postmenopausal Women
Cognitive Function in Postmenopausal Women
JAMA.
JAMA.
2004;291:2959
2004;291:2959
-
-
2968
2968
Conclusion:
Conclusion:
For women aged 65 years or
For women aged 65 years or
older, hormone therapy had an adverse
older, hormone therapy had an adverse
effect on cognition, which was greater
effect on cognition, which was greater
among women with lower cognitive
among women with lower cognitive
function at initiation of treatment.
function at initiation of treatment.
Effect of Estrogen Plus Progestin on Stroke in
Effect of Estrogen Plus Progestin on Stroke in
Postmenopausal Women
Postmenopausal Women
JAMA.
JAMA.
2003;289:2673
2003;289:2673
-
-
2684
2684
Conclusions:
Conclusions:
Estrogen plus progestin
Estrogen plus progestin
increases the risk of ischemic stroke in
increases the risk of ischemic stroke in
generally healthy postmenopausal women.
generally healthy postmenopausal women.
Excess risk for all strokes attributed to
Excess risk for all strokes attributed to
estrogen plus progestin appeared to be
estrogen plus progestin appeared to be
present in all subgroups of women
present in all subgroups of women
examined.
examined.
Estrogen Plus Progestin and Risk of Venous
Estrogen Plus Progestin and Risk of Venous
Thrombosis
Thrombosis
JAMA.
JAMA.
2004;292:1573
2004;292:1573
-
-
1580
1580
Conclusions:
Conclusions:
Estrogen plus progestin was
Estrogen plus progestin was
associated with doubling the risk of venous
associated with doubling the risk of venous
thrombosis. Estrogen plus progestin therapy
thrombosis. Estrogen plus progestin therapy
increased the risks associated with age,
increased the risks associated with age,
overweight or obesity, and factor
overweight or obesity, and factor V Leiden.
Estrogen plus Progestin and the Risk of
Estrogen plus Progestin and the Risk of
Coronary Heart Disease
Coronary Heart Disease
NEJM volume 349:523
NEJM volume 349:523
-
-
534, August 2003
534, August 2003
Conclusions:
Conclusions:
Estrogen plus progestin does not
Estrogen plus progestin does not
confer cardiac protection and may increase
confer cardiac protection and may increase
the risk of CHD among generally healthy
the risk of CHD among generally healthy
postmenopausal women, especially during
postmenopausal women, especially during
the first year after the initiation of hormone
the first year after the initiation of hormone
use. This treatment should not be prescribed
use. This treatment should not be prescribed
for the prevention of cardiovascular disease
for the prevention of cardiovascular disease.
Effect of Estrogen Plus Progestin on Global
Effect of Estrogen Plus Progestin on Global
Cognitive Function in Postmenopausal Women
Cognitive Function in Postmenopausal Women
JAMA.
JAMA.
2003;289:2663
2003;289:2663
-
-
2672
2672
Conclusions:
Conclusions:
Among postmenopausal women aged
Among postmenopausal women aged
65 years or older, estrogen plus progestin did not
65 years or older, estrogen plus progestin did not
improve cognitive function when compared with
improve cognitive function when compared with
placebo. While most women receiving estrogen
placebo. While most women receiving estrogen
plus progestin did not experience clinically
plus progestin did not experience clinically
relevant adverse effects on cognition compared
relevant adverse effects on cognition compared
with placebo, a small increased risk of clinically
with placebo, a small increased risk of clinically
meaningful cognitive decline occurred in the
meaningful cognitive decline occurred in the
estrogen plus progestin group.
estrogen plus progestin group.
Symptom Experience After Discontinuing Use
Symptom Experience After Discontinuing Use
of Estrogen Plus Progestin
of Estrogen Plus Progestin
JAMA.
JAMA.
2005;294:183
2005;294:183
-
-
193
193
Conclusions:
Conclusions:
More than half of the women with
More than half of the women with
vasomotor symptoms at randomization to active
vasomotor symptoms at randomization to active
CEE + MPA also reported these symptoms after
CEE + MPA also reported these symptoms after
discontinuing use of the study pills. However,
discontinuing use of the study pills. However,
these participants did not include women who
these participants did not include women who
were unwilling to be randomized or who had
were unwilling to be randomized or who had
stopped taking the study pills earlier. These
stopped taking the study pills earlier. These
findings should be considered when advising
findings should be considered when advising
women to treat menopausal symptoms with
women to treat menopausal symptoms with
hormone therapy for as short duration as possible.
hormone therapy for as short duration as possible.
Investigation of alternative strategies to manage
Investigation of alternative strategies to manage
menopausal symptoms is warranted.
menopausal symptoms is warranted.
Estrogen plus Progestin and Colorectal Cancer
Estrogen plus Progestin and Colorectal Cancer
in Postmenopausal Women
in Postmenopausal Women
NEJM, Volume 350:991
NEJM, Volume 350:991
-
-
1004 March 2004
1004 March 2004
Conclusions:
Conclusions:
Relatively short
Relatively short
-
-
term use of
term use of
estrogen plus progestin was associated with
estrogen plus progestin was associated with
a decreased risk of colorectal cancer.
a decreased risk of colorectal cancer.
However, colorectal cancers in women who
However, colorectal cancers in women who
took estrogen plus progestin were diagnosed
took estrogen plus progestin were diagnosed
at a more advanced stage than those in
at a more advanced stage than those in
women who took placebo.
women who took placebo.
Effects of Estrogen Plus Progestin on Risk of
Effects of Estrogen Plus Progestin on Risk of
Fracture and Bone Mineral Density
Fracture and Bone Mineral Density
JAMA.
JAMA.
2003;290:1729
2003;290:1729
-
-
1738.
1738.
Conclusions:
Conclusions:
This study demonstrates that estrogen
This study demonstrates that estrogen
plus progestin increases BMD and reduces the risk
plus progestin increases BMD and reduces the risk
of fracture in healthy postmenopausal women. The
of fracture in healthy postmenopausal women. The
decreased risk of fracture attributed to estrogen
decreased risk of fracture attributed to estrogen
plus progestin appeared to be present in all
plus progestin appeared to be present in all
subgroups of women examined. When considering
subgroups of women examined. When considering
the effects of hormone therapy on other important
the effects of hormone therapy on other important
disease outcomes in a global model, there was no
disease outcomes in a global model, there was no
net benefit, even in women considered to be at
net benefit, even in women considered to be at
high risk of fracture.
high risk of fracture.
Estrogen Plus Progestin and the Risk of
Estrogen Plus Progestin and the Risk of
Peripheral Arterial Disease
Peripheral Arterial Disease
Circulation.
Circulation.
2004;109:620
2004;109:620
-
-
626
626
Conclusions:
Conclusions:
Among generally healthy
Among generally healthy
postmenopausal women, conjugated
postmenopausal women, conjugated
estrogens with progestin did not confer
estrogens with progestin did not confer
protection against peripheral arterial
protection against peripheral arterial
disease.
disease.
Effects of Estrogen plus Progestin on Health
Effects of Estrogen plus Progestin on Health
-
-
Related Quality of Life
Related Quality of Life
NEJM, March 17, 2003
NEJM, March 17, 2003
Conclusions:
Conclusions:
In this trial in postmenopausal
In this trial in postmenopausal
women, estrogen plus progestin did not
women, estrogen plus progestin did not
have a clinically meaningful effect on
have a clinically meaningful effect on
health
health
-
-
related quality of life.
related quality of life.
WHI Summary
WHI Summary
0.79
0.79
NS
NS
DM
DM
0.89
0.89
(0.63
(0.63
-
-
1.25)
1.25)
NA
NA
PVD
PVD
0.76
0.76
(0.69
(0.69
-
-
0.83)
0.83)
NA
NA
BMD
BMD
0.56
0.56
(0.38
(0.38
-
-
0.81)
0.81)
NA
NA
CRC
CRC
50% at DC
50% at DC
NA
NA
Vasomotor
Vasomotor
↓
↓
(p=0.008)
(p=0.008)
1.47
1.47
(1.04
(1.04
-
-
2.07)
2.07)
Cognition
Cognition
1.24
1.24
(1.0
(1.0
-
-
1.54)
1.54)
0.95
0.95
(0.79
(0.79
-
-
1.16)
1.16)
CAD
CAD
2.06
2.06
(1.57
(1.57
-
-
2.70)
2.70)
1.47
1.47
(1.06
(1.06
-
-
2.06)
2.06)
DVT
DVT
1.31
1.31
(1.02
(1.02
-
-
1.68)
1.68)
1.37
1.37
(1.09
(1.09
-
-
1.73)
1.73)
Stroke
Stroke
E
E
2
2
and MPA
and MPA
Estrogen
Estrogen
WHI Summary
WHI Summary
Gynecological Issues
Gynecological Issues
1.87
1.87
(1.61
(1.61
-
-
2.18)
2.18)
2.15
2.15
(1.77
(1.77
-
-
2.62)
2.62)
SUI
SUI
1.58
1.58
(0.77
(0.77
-
-
3.24)
3.24)
NA
NA
Ovarian Ca
Ovarian Ca
0.81
0.81
(0.48
(0.48
-
-
1.36)
1.36)
NA
NA
Endometrial Ca
Endometrial Ca
1.24
1.24
(p<0.001)
(p<0.001)
0.80
0.80
(0.62
(0.62
-
-
1.04)
1.04)
Breast Ca
Breast Ca
E
E
2
2
and MPA
and MPA
Estrogen
Estrogen
Influence of Estrogen Plus Progestin on Breast
Influence of Estrogen Plus Progestin on Breast
Cancer and Mammography in Healthy
Cancer and Mammography in Healthy
Postmenopausal Women
Postmenopausal Women
JAMA.
JAMA.
2003;289:3243
2003;289:3243
-
-
3253
3253
Conclusions:
Conclusions:
Relatively short
Relatively short
-
-
term combined
term combined
estrogen plus progestin use increases incident
estrogen plus progestin use increases incident
breast cancers, which are diagnosed at a more
breast cancers, which are diagnosed at a more
advanced stage compared with placebo use, and
advanced stage compared with placebo use, and
also substantially increases the percentage of
also substantially increases the percentage of
women with abnormal mammograms. These
women with abnormal mammograms. These
results suggest estrogen plus progestin may
results suggest estrogen plus progestin may
stimulate breast cancer growth and hinder breast
stimulate breast cancer growth and hinder breast
cancer diagnosis.
cancer diagnosis.
Effects of Estrogen Plus Progestin on
Effects of Estrogen Plus Progestin on
Gynecologic Cancers and Associated
Gynecologic Cancers and Associated
Diagnostic Procedures
Diagnostic Procedures
JAMA.
JAMA.
2003;290:1739
2003;290:1739
-
-
1748
1748
Conclusions:
Conclusions:
This randomized trial suggests that
This randomized trial suggests that
continuous combined estrogen plus progestin
continuous combined estrogen plus progestin
therapy may increase the risk of ovarian cancer
therapy may increase the risk of ovarian cancer
while producing endometrial cancer rates similar
while producing endometrial cancer rates similar
to placebo. The increased burden of endometrial
to placebo. The increased burden of endometrial
biopsies required to assess vaginal bleeding
biopsies required to assess vaginal bleeding
further limits the acceptability of this regimen.
further limits the acceptability of this regimen.
These data provide additional support for caution
These data provide additional support for caution
in the use of continuous combined hormones.
in the use of continuous combined hormones.
Effects of Estrogen With and Without Progestin
Effects of Estrogen With and Without Progestin
on Urinary Incontinence
on Urinary Incontinence
JAMA.
JAMA.
2005;293:935
2005;293:935
-
-
948.
948.
Conclusions:
Conclusions:
Conjugated equine estrogen
Conjugated equine estrogen
alone and CEE + MPA increased the risk of
alone and CEE + MPA increased the risk of
UI among continent women and worsened
UI among continent women and worsened
the characteristics of UI among
the characteristics of UI among
symptomatic women after 1 year.
symptomatic women after 1 year.
Conjugated equine estrogen with or without
Conjugated equine estrogen with or without
progestin should not be prescribed for the
progestin should not be prescribed for the
prevention or relief of UI.
prevention or relief of UI.