CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 00, Number 00, 000–000

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Menopausal Hormone
Therapy in
Gynecologic Cancer
Survivors: A Review
of the Evidence and
Practice
Recommendations
EKTA KAPOOR, MBBS,*† DANIEL BENRUBI, MD, MPH,‡
and STEPHANIE S. FAUBION, MD*
*Women’s Health Clinic, Division of General Internal Medicine;
†Division of Endocrinology, Diabetes, Metabolism, and Nutrition,
Mayo Clinic, Rochester, Minnesota; and ‡Division of Gynecologic
Oncology, Fox Chase Cancer Center at Temple University Hospital,
Philadelphia, Pennsylvania

Abstract: Gynecologic cancers are common in the
United States and represent a significant health burden.
Treatment of these cancers often causes premature
cessation of ovarian function, with resultant symptoms
that are often more severe than those associated with
natural menopause. Hormone therapy is the most
effective treatment for menopausal symptoms, but the
decision-making process about its use can be complex
for survivors of gynecologic cancer. In this review, we
provide evidence-based recommendations about the use
of hormone therapy after gynecologic cancer.
Key words: endometrial cancer, gynecologic cancer,
hormone therapy, menopause, ovarian cancer

Correspondence: Ekta Kapoor, MBBS, Women’s Introduction

Health Clinic, Division of General Internal Medicine,
Mayo Clinic, Rochester, MN. E-mail: kapoor.
ekta@mayo.edu
S.S.F. is a consultant for Procter and Gamble Pharma-
ceuticals. The remaining authors declare that they have
nothing to disclose.
The burden of gynecologic cancer in the
United States is significant, with 93,212
cases diagnosed and 29,552 deaths annu-
ally, according to the most recent data
from the Centers for Disease Control and

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 00 / NUMBER 00 / ’’ 2018

www.clinicalobgyn.com | 1
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2 Kapoor et al
Prevention.1 The majority of these can-
cers are uterine, ovarian, cervical, vulvar,
and vaginal cancers (in decreasing order
of prevalence). Ovarian cancer has the
highest mortality rate of all gynecologic
cancers, even though it accounts for only
3% of all cancers in women.1 However,
with advances in diagnosis and treatment,
more women are surviving gynecologic
cancers and coping with the consequences
of cancer treatments.2 For many
survivors, treatment such as bilateral sal-
pingo-oophorectomy, chemotherapy, or
radiotherapy results in surgical meno-
pause or ovarian failure. Although clarity
is increasing on the balance between risks
and benefits of menopausal hormone
therapy (MHT) in symptomatic women
experiencing natural menopause,3 this
balance is less clear for women with a
history of cancer.
Vasomotor symptoms are the most com-
mon menopausal symptom, but many other
symptoms of estrogen deprivation are com-
mon, including sleep disturbance, mood
problems, sexual dysfunction, and joint
aches. In addition, these symptoms are often
more frequent, severe, and persistent for
young women who have sudden estrogen
deficiency due to oophorectomy or ovarian
failure from cancer treatment, and these
symptoms can have a significant impact
on quality of life.4,5 In addition, early estro-
gen deprivation is associated with multiple
potential adverse consequences, including
increased risk of cognitive impairment, de-
mentia, parkinsonism, coronary artery dis-
ease, osteoporosis, mood disorders, sexual
dysfunction, and even early death.6
MHT can mitigate many adverse ef-
fects of menopause,7,8 and for women
experiencing menopause prematurely (be-
low 40 y of age) or early (below 45 y of
age), higher doses of estrogen may be
required to approximate normal physio-
logic premenopausal hormone levels.9,10
Providers caring for women with a history
of gynecologic cancer are in a unique
position to not only reduce the burden
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of menopausal symptoms in their patients
but also to positively impact their quality
of life and diminish the consequences of
long-term estrogen deprivation. In this
report, we review the current evidence
on use of MHT after a diagnosis of
gynecologic cancer and include an exam-
ple case about decision making regarding
the use of MHT for menopausal symptom
management after gynecologic cancer.
Report of a Case
A 48-year-old woman (gravida 2, para 2)
presents with a history of stage I, type I
endometrial cancer. She underwent hyster-
ectomy and bilateral salpingo-oophorectomy
6 months ago. She was menstruating regu-
larly at the time of her diagnosis. She is
incapacitated by moderate to severe hot
flashes that occur hourly and night sweats
that require a change of clothing several
times per week. She also reports vaginal
dryness and discomfort with sexual activity
that is not alleviated by using vaginal mois-
turizers and lubricants. She asks whether
MHT is an option for her.
Endometrial Cancer
Endometrial cancer is the most prevalent
gynecologic malignancy, and it is the
fourth-most prevalent malignancy overall
in US women.11 Endometrial cancer is
classified by stage, grade, histology, and
other factors that have a role in prognosis.
Endometrial cancers may also be described
more broadly as type I and type II. Type I
cancers account for 90% of all endometrial
cancers and are typically positive for
estrogen receptors (ERs) and progesterone
receptors (PRs).12 Type II endometrial
cancers are often high grade and more
aggressive, have unfavorable histology,
and lack hormonal receptors.12
Several studies have reported an in-
creased risk of endometrial cancer with the
use of unopposed estrogen therapy.13–15
However, data from the Women’s Health
 Hormone Therapy and Gynecologic Cancers
Initiative (WHI) trials showed that the use
of a progestogen [medroxyprogesterone ace-
tate (MPA)] with estrogen [oral conjugated
equine estrogen (CEE)] is not associated
with increased risk of endometrial cancer.16
Similarly, a Danish cohort study demon-
strated that continuous combined estrogen
and progestin therapy was not associated
with increased risk of endometrial cancer,
and interestingly, was associated with a
protective effect against type II endometrial
cancers.17
Most endometrial cancers are type I,
and as such, they are considered hormone
sensitive. ERs and PRs have been identi-
fied in endometrial cancers, and hormone
receptor status, particularly for PR, may
have prognostic implications. The loss of
the PR is associated with more aggressive
disease, disease progression, and poor
survival.18,19 One study noted that women
with early-stage endometrial cancer whose
tumors expressed high levels of PRs had a
significantly higher 3-year survival rate
compared with those with decreased PR
expression.20
MHT USE AFTER ENDOMETRIAL
CANCER
Given the hormone-sensitive nature of type
I endometrial cancer, the potential exists
for stimulation of residual cancer cells with
MHT. Limited clinical trial data are avail-
able to inform decision making on the use
of MHT after endometrial cancer. The
Gynecologic Oncology Group conducted
a trial on > 1200 women with stage I and II
endometrial cancer and randomized par-
ticipants to receive CEE (0.625 mg daily)
or placebo.21 The study had a target
accrual of 2108 patients with early-stage
disease, but it closed early because of lack
of accrual after publication of the WHI
trial results in 2002. The treatment and
placebo groups were similar in terms of
tumor stage, grade, and histology, with the
median follow-up of 35.7 months. No
significant differences were observed in
endometrial cancer recurrence or mortality
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3
rates between the 2 groups. Although the
study was underpowered and closed early,
the lack of a significant increase in recur-
rence or mortality risk in women random-
ized to estrogen-based hormone therapy
provides some reassurance regarding the
use of MHT in women with a history of
low-grade, early-stage endometrial adeno-
carcinoma. However, another study
showed that the recurrence risk was sig-
nificantly different for black women, with a
relative risk (RR) of 11.2, and urged
caution and appropriate patient education
when prescribing MHT to black women
who survived endometrial cancer.22
In addition, multiple retrospective
studies have not found an increased risk
of cancer recurrence or mortality with
various hormone therapy regimens, in-
cluding CEE alone, CEE with MPA, and
oral estradiol with or without MPA or
progesterone.23–26 A small prospective
study of 50 women with stage I or II
disease did not report an increased recur-
rence rate with CEE plus MPA.27
Similarly, a meta-analysis including 1
randomized controlled trial (RCT) and 5
observational studies did not report an
association between MHT use and endo-
metrial cancer recurrence.28
SUMMARY OF PRACTICE
RECOMMENDATIONS
Existing evidence, albeit limited and non-
definitive, suggests that women with a
history of low-grade, early-stage, type I
endometrial cancer may consider MHT as
indicated. However, there is potential for
stimulation of cancer growth and risk of
recurrence in women with higher grade
tumors, advanced disease, or with unfav-
orable histologies, including type II can-
cers, and for them, nonhormonal treatment
of menopausal symptoms is suggested.
Ovarian Cancer
Ovarian cancer is the second most common
gynecologic malignancy, but with a 5-year
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4 Kapoor et al
overall survival rate of only 45%, it is the
most common cause of gynecologic cancer
death.29 The overwhelming majority of ovar-
ian cancers (nearly 95%) are derived from
epithelial cells, with the remainder originat-
ing from other cell types [germ cell tumors
(GCTs), sex cord-stromal tumors].30 The
histologic subtypes of epithelial ovarian can-
cer include serous (most common), muci-
nous, clear, and endometrioid.31 The GCTs
include teratoma, choriocarcinoma, dysger-
minoma, and embryonal cell carcinoma. The
sex cord-stromal tumors include granulosa
cell tumors, thecoma, fibroma, and Sertoli-
Leydig cell tumors. Sex cord-stromal tumors
are often hormonally sensitive.
MHT AND RISK OF OVARIAN CANCER
Current evidence does not support a
definitive role of estrogen in the develop-
ment of epithelial ovarian cancers, and as
such, MHT is considered a weaker risk
factor for ovarian cancer.3,32 The WHI
trial was the only randomized clinical trial
to examine the risk of ovarian cancer with
MHT use. In the CEE plus MPA trial, the
risk of ovarian cancer did not increase
after 5.6 years of use. MHT was associ-
ated with a slightly increased risk of
ovarian cancer compared with placebo
in the CEE-alone trial, but the difference
remained statistically nonsignificant after
13 years of cumulative follow-up.16 Ob-
servational evidence, in contrast, suggests
an increased risk of ovarian cancer with
extended MHT use, but the data are
inconsistent.33–37 The evidence is also
inconsistent with respect to the change
in risk with current versus past use of
MHT, duration of use, and the treatment
regimen (eg, estrogen alone vs. estrogen
plus progestogen). The risk of ovarian
cancer was significantly increased after
> 5 years of estrogen use in both current
MHT users [RR, 1.41; 95% confidence
interval (CI), 1.07-1.86)] and past MHT
users (RR, 1.52; 95% CI, 1.01-2.27) in the
26-year follow-up of the Nurses’ Health
Study.38 Stratified by tumor type, the risk
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was similar for serous tumors and slightly
higher for endometrioid tumors. In con-
trast, the risk of ovarian cancer was not
increased in past MHT users in the
Million Women Study.39 Among current
MHT users, ovarian cancer was rare, with
1 extra case per 2500 MHT users over a
5-year period. The risk was again greater
for serous and endometrioid histology
compared with mucinous and clear cell
types [RR, 1.53 (95% CI, 1.31-1.79); RR,
1.05 (95% CI, 0.77-1.43); RR, 0.72 (95%
CI, 0.52-1.00); and RR, 0.77 (95% CI,
0.48-1.23), respectively].
A recent meta-analysis of 52 observa-
tional studies from the Collaborative
Group on Epidemiological Studies of
Ovarian Cancer concluded that risk of
serous and endometrioid ovarian cancers
increased with MHT use [RR, 1.53 (95%
CI, 1.40-1.66) and RR, 1.42 (95% CI,
1.20-1.67), respectively].40 However, in
addition to the observational design of
the studies included, the meta-analysis
had marked limitations that reduced the
clinical significance of these findings. For
example, it reported similar risks of ovar-
ian cancer with <5 versus ≥ 5 years of
MHT use. Also, the high risk of serous
and endometrioid ovarian cancers per-
sisted for > 10 years after discontinuation
of MHT, a finding that is inconsistent
with the role of estrogen in ovarian
carcinogenesis. On the basis of the limited
evidence presented above, the association
between ovarian cancer risk and MHT is
likely to be weak and is perhaps a concern
only with extended use.
The evidence in BRCA mutation car-
riers is limited to a few observational
studies that have not observed an increased
risk of ovarian cancer with MHT use.3
MHT USE AFTER OVARIAN CANCER
A recent meta-analysis of 2 RCTs and 4
cohort studies included 419 epithelial
ovarian cancer survivors who used MHT
and 1029 who did not. MHT use was
not associated with an increased risk of
 Hormone Therapy and Gynecologic Cancers
recurrence, regardless of the cancer stage or
the type of MHT used (RR, 0.83; 95% CI,
0.64-1.07). In fact, MHT use had a favor-
able impact on overall survival when con-
sidering all the studies [hazard ratio (HR),
0.69; 95% CI, 0.61-0.79] and when consid-
ering only the cohort studies (HR, 0.63;
95% CI, 0.49-0.81) but not in the RCT
subgroup (HR, 1.03; 95% CI, 0.58-1.83).41
Concerns have been raised about MHT
use in women with ovarian cancers that
may contain ERs, such as serous carcino-
mas and sex cord-stromal tumors, but
the evidence is limited.3 Although no evi-
dence guides the use of MHT in women
with GCTs, it is generally considered safe.42
SUMMARY OF PRACTICE
RECOMMENDATIONS
MHT use can be considered as indicated in
women with prior epithelial ovarian cancers,
with the exception of advanced serous and
endometrioid histologic types. Although the
evidence is very limited, concerns have been
raised about MHT use in women with
ovarian cancers that are likely to contain
ERs, such as serous carcinomas and sex
cord-stromal tumors.3 The use of MHT in
women with a history of GCT may be
considered as indicated, although definitive
data are lacking.42
Other Gynecologic Cancers
The majority of cervical cancers (about
80%) are squamous cell carcinomas (SCCs),
with most of the remainder being
adenocarcinomas.43 SCCs are mostly asso-
ciated with a previous human papillomavi-
rus infection. They are not estrogen
sensitive, and current evidence does not
suggest an increased risk of cervical SCCs
with MHT use. Similarly, MHT use after a
diagnosis of cervical cancer is not associ-
ated with a poorer prognosis. As such,
MHT is not contraindicated in women with
SCC of the cervix, but the evidence in
women with adenocarcinoma of the cervix
is limited. However, concerns have been
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5
expressed about underutilization of MHT
and the resultant potential adverse health
outcomes in women with premature or
early menopause as a consequence of cer-
vical cancer treatment.44
Vulvovaginal cancers are rare and are
predominantly SCCs. As with cervical
cancer, no evidence suggests harm with
MHT use for survivors of these cancers.
Adenocarcinomas of the vulva and vagina
are very rare, and no data exist to guide
decision making regarding MHT use in
patients with history of these cancers.42
Summary
Survivors of gynecologic cancers com-
monly have treatment-induced menopause,
often before the average age of menopause,
and their symptoms may be particularly
frequent, severe, and persistent. In addition
to providing symptomatic relief, MHT
may mitigate the increased risk of multiple
adverse long-term health consequences as-
sociated with premature or early meno-
pause. MHT may be considered as
indicated for women with a history of type
I endometrial cancers, but it should be
avoided in women with higher grade endo-
metrial tumors, unfavorable histologies
(including type II cancers), and advanced
disease. Survivors of epithelial ovarian
cancers may consider the use of MHT as
indicated, but for women with a history of
advanced serous and endometrioid cell
types and those with sex cord-stromal
tumors, nonhormonal options should be
offered as first-line therapy for manage-
ment of menopausal symptoms. Data are
less clear regarding women with a history
of GCTs, but MHT is generally considered
safe. Cervical, vulvar, and vaginal cancers
are mostly associated with human papillo-
mavirus and are not hormone dependent,
and MHT can be used as indicated.
It is important to note that low-dose
vaginal estrogen therapy is associated
with minimal systemic absorption. It can
be considered for management of vaginal
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6 Kapoor et al
dryness and dyspareunia that are unre-
sponsive to nonhormonal treatments,
even for women who should avoid sys-
temic hormone therapy.42
In the case noted above, the patient had
a history of early-stage type I endometrial
cancer and experienced sudden estrogen
deprivation as a result of bilateral salpingo-
oophorectomy. She has severe menopausal
symptoms and would benefit from the use
of MHT for symptom management.
Practice Points
Gynecologic cancer survivors commonly
experience treatment-related menopause (eg,
after bilateral salpingo-oophorectomy,
chemotherapy, radiotherapy), which is often
characterized by more frequent, severe, and
persistent symptoms
Menopausal hormone therapy effectively manages
menopausal symptoms and may mitigate the
potential adverse long-term consequences
(eg, neurocognitive, cardiovascular, and bone)
associated with premature estrogen deprivation
Survivors of early stage type I endometrial cancers
may consider using menopausal hormone
therapy as indicated
Women with a history of higher grade endometrial
tumors, unfavorable histologies, and advanced
endometrial cancers should consider
nonhormonal treatments for menopausal
symptoms
While concerns regarding the use of menopausal
hormone therapy exist in women with ovarian
cancers that are likely to contain estrogen
receptors, such as sex cord stromal tumors and
those with serous and endometrioid histologies,
survivors of other epithelial ovarian cancers can
consider its use as indicated
Cervical, vulvar, and vaginal cancers are not
considered hormone dependent, and
menopausal hormone therapy can be used as
indicated
Low-dose vaginal estrogen therapy can be
considered as needed for treatment of vaginal
dryness and dyspareunia unresponsive to
nonhormonal treatments, even for women who
should avoid systemic hormone therapy
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