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

Correspondence: Ekta Kapoor, MBBS, Women’s Introduction


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

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

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2 Kapoor et al

Prevention.1 The majority of these can- of menopausal symptoms in their patients


cers are uterine, ovarian, cervical, vulvar, but also to positively impact their quality
and vaginal cancers (in decreasing order of life and diminish the consequences of
of prevalence). Ovarian cancer has the long-term estrogen deprivation. In this
highest mortality rate of all gynecologic report, we review the current evidence
cancers, even though it accounts for only on use of MHT after a diagnosis of
3% of all cancers in women.1 However, gynecologic cancer and include an exam-
with advances in diagnosis and treatment, ple case about decision making regarding
more women are surviving gynecologic the use of MHT for menopausal symptom
cancers and coping with the consequences management after gynecologic cancer.
of cancer treatments.2 For many
survivors, treatment such as bilateral sal-
pingo-oophorectomy, chemotherapy, or Report of a Case
radiotherapy results in surgical meno- A 48-year-old woman (gravida 2, para 2)
pause or ovarian failure. Although clarity presents with a history of stage I, type I
is increasing on the balance between risks endometrial cancer. She underwent hyster-
and benefits of menopausal hormone ectomy and bilateral salpingo-oophorectomy
therapy (MHT) in symptomatic women 6 months ago. She was menstruating regu-
experiencing natural menopause,3 this larly at the time of her diagnosis. She is
balance is less clear for women with a incapacitated by moderate to severe hot
history of cancer. flashes that occur hourly and night sweats
Vasomotor symptoms are the most com- that require a change of clothing several
mon menopausal symptom, but many other times per week. She also reports vaginal
symptoms of estrogen deprivation are com- dryness and discomfort with sexual activity
mon, including sleep disturbance, mood that is not alleviated by using vaginal mois-
problems, sexual dysfunction, and joint turizers and lubricants. She asks whether
aches. In addition, these symptoms are often MHT is an option for her.
more frequent, severe, and persistent for
young women who have sudden estrogen
deficiency due to oophorectomy or ovarian Endometrial Cancer
failure from cancer treatment, and these Endometrial cancer is the most prevalent
symptoms can have a significant impact gynecologic malignancy, and it is the
on quality of life.4,5 In addition, early estro- fourth-most prevalent malignancy overall
gen deprivation is associated with multiple in US women.11 Endometrial cancer is
potential adverse consequences, including classified by stage, grade, histology, and
increased risk of cognitive impairment, de- other factors that have a role in prognosis.
mentia, parkinsonism, coronary artery dis- Endometrial cancers may also be described
ease, osteoporosis, mood disorders, sexual more broadly as type I and type II. Type I
dysfunction, and even early death.6 cancers account for 90% of all endometrial
MHT can mitigate many adverse ef- cancers and are typically positive for
fects of menopause,7,8 and for women estrogen receptors (ERs) and progesterone
experiencing menopause prematurely (be- receptors (PRs).12 Type II endometrial
low 40 y of age) or early (below 45 y of cancers are often high grade and more
age), higher doses of estrogen may be aggressive, have unfavorable histology,
required to approximate normal physio- and lack hormonal receptors.12
logic premenopausal hormone levels.9,10 Several studies have reported an in-
Providers caring for women with a history creased risk of endometrial cancer with the
of gynecologic cancer are in a unique use of unopposed estrogen therapy.13–15
position to not only reduce the burden However, data from the Women’s Health

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Hormone Therapy and Gynecologic Cancers 3

Initiative (WHI) trials showed that the use rates between the 2 groups. Although the
of a progestogen [medroxyprogesterone ace- study was underpowered and closed early,
tate (MPA)] with estrogen [oral conjugated the lack of a significant increase in recur-
equine estrogen (CEE)] is not associated rence or mortality risk in women random-
with increased risk of endometrial cancer.16 ized to estrogen-based hormone therapy
Similarly, a Danish cohort study demon- provides some reassurance regarding the
strated that continuous combined estrogen use of MHT in women with a history of
and progestin therapy was not associated low-grade, early-stage endometrial adeno-
with increased risk of endometrial cancer, carcinoma. However, another study
and interestingly, was associated with a showed that the recurrence risk was sig-
protective effect against type II endometrial nificantly different for black women, with a
cancers.17 relative risk (RR) of 11.2, and urged
Most endometrial cancers are type I, caution and appropriate patient education
and as such, they are considered hormone when prescribing MHT to black women
sensitive. ERs and PRs have been identi- who survived endometrial cancer.22
fied in endometrial cancers, and hormone In addition, multiple retrospective
receptor status, particularly for PR, may studies have not found an increased risk
have prognostic implications. The loss of of cancer recurrence or mortality with
the PR is associated with more aggressive various hormone therapy regimens, in-
disease, disease progression, and poor cluding CEE alone, CEE with MPA, and
survival.18,19 One study noted that women oral estradiol with or without MPA or
with early-stage endometrial cancer whose progesterone.23–26 A small prospective
tumors expressed high levels of PRs had a study of 50 women with stage I or II
significantly higher 3-year survival rate disease did not report an increased recur-
compared with those with decreased PR rence rate with CEE plus MPA.27
expression.20 Similarly, a meta-analysis including 1
randomized controlled trial (RCT) and 5
MHT USE AFTER ENDOMETRIAL observational studies did not report an
CANCER association between MHT use and endo-
Given the hormone-sensitive nature of type metrial cancer recurrence.28
I endometrial cancer, the potential exists
for stimulation of residual cancer cells with SUMMARY OF PRACTICE
MHT. Limited clinical trial data are avail- RECOMMENDATIONS
able to inform decision making on the use Existing evidence, albeit limited and non-
of MHT after endometrial cancer. The definitive, suggests that women with a
Gynecologic Oncology Group conducted history of low-grade, early-stage, type I
a trial on > 1200 women with stage I and II endometrial cancer may consider MHT as
endometrial cancer and randomized par- indicated. However, there is potential for
ticipants to receive CEE (0.625 mg daily) stimulation of cancer growth and risk of
or placebo.21 The study had a target recurrence in women with higher grade
accrual of 2108 patients with early-stage tumors, advanced disease, or with unfav-
disease, but it closed early because of lack orable histologies, including type II can-
of accrual after publication of the WHI cers, and for them, nonhormonal treatment
trial results in 2002. The treatment and of menopausal symptoms is suggested.
placebo groups were similar in terms of
tumor stage, grade, and histology, with the
median follow-up of 35.7 months. No Ovarian Cancer
significant differences were observed in Ovarian cancer is the second most common
endometrial cancer recurrence or mortality gynecologic malignancy, but with a 5-year

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4 Kapoor et al

overall survival rate of only 45%, it is the was similar for serous tumors and slightly
most common cause of gynecologic cancer higher for endometrioid tumors. In con-
death.29 The overwhelming majority of ovar- trast, the risk of ovarian cancer was not
ian cancers (nearly 95%) are derived from increased in past MHT users in the
epithelial cells, with the remainder originat- Million Women Study.39 Among current
ing from other cell types [germ cell tumors MHT users, ovarian cancer was rare, with
(GCTs), sex cord-stromal tumors].30 The 1 extra case per 2500 MHT users over a
histologic subtypes of epithelial ovarian can- 5-year period. The risk was again greater
cer include serous (most common), muci- for serous and endometrioid histology
nous, clear, and endometrioid.31 The GCTs compared with mucinous and clear cell
include teratoma, choriocarcinoma, dysger- types [RR, 1.53 (95% CI, 1.31-1.79); RR,
minoma, and embryonal cell carcinoma. The 1.05 (95% CI, 0.77-1.43); RR, 0.72 (95%
sex cord-stromal tumors include granulosa CI, 0.52-1.00); and RR, 0.77 (95% CI,
cell tumors, thecoma, fibroma, and Sertoli- 0.48-1.23), respectively].
Leydig cell tumors. Sex cord-stromal tumors A recent meta-analysis of 52 observa-
are often hormonally sensitive. tional studies from the Collaborative
Group on Epidemiological Studies of
MHT AND RISK OF OVARIAN CANCER Ovarian Cancer concluded that risk of
Current evidence does not support a serous and endometrioid ovarian cancers
definitive role of estrogen in the develop- increased with MHT use [RR, 1.53 (95%
ment of epithelial ovarian cancers, and as CI, 1.40-1.66) and RR, 1.42 (95% CI,
such, MHT is considered a weaker risk 1.20-1.67), respectively].40 However, in
factor for ovarian cancer.3,32 The WHI addition to the observational design of
trial was the only randomized clinical trial the studies included, the meta-analysis
to examine the risk of ovarian cancer with had marked limitations that reduced the
MHT use. In the CEE plus MPA trial, the clinical significance of these findings. For
risk of ovarian cancer did not increase example, it reported similar risks of ovar-
after 5.6 years of use. MHT was associ- ian cancer with <5 versus ≥ 5 years of
ated with a slightly increased risk of MHT use. Also, the high risk of serous
ovarian cancer compared with placebo and endometrioid ovarian cancers per-
in the CEE-alone trial, but the difference sisted for > 10 years after discontinuation
remained statistically nonsignificant after of MHT, a finding that is inconsistent
13 years of cumulative follow-up.16 Ob- with the role of estrogen in ovarian
servational evidence, in contrast, suggests carcinogenesis. On the basis of the limited
an increased risk of ovarian cancer with evidence presented above, the association
extended MHT use, but the data are between ovarian cancer risk and MHT is
inconsistent.33–37 The evidence is also likely to be weak and is perhaps a concern
inconsistent with respect to the change only with extended use.
in risk with current versus past use of The evidence in BRCA mutation car-
MHT, duration of use, and the treatment riers is limited to a few observational
regimen (eg, estrogen alone vs. estrogen studies that have not observed an increased
plus progestogen). The risk of ovarian risk of ovarian cancer with MHT use.3
cancer was significantly increased after
> 5 years of estrogen use in both current MHT USE AFTER OVARIAN CANCER
MHT users [RR, 1.41; 95% confidence A recent meta-analysis of 2 RCTs and 4
interval (CI), 1.07-1.86)] and past MHT cohort studies included 419 epithelial
users (RR, 1.52; 95% CI, 1.01-2.27) in the ovarian cancer survivors who used MHT
26-year follow-up of the Nurses’ Health and 1029 who did not. MHT use was
Study.38 Stratified by tumor type, the risk not associated with an increased risk of

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Hormone Therapy and Gynecologic Cancers 5

recurrence, regardless of the cancer stage or expressed about underutilization of MHT


the type of MHT used (RR, 0.83; 95% CI, and the resultant potential adverse health
0.64-1.07). In fact, MHT use had a favor- outcomes in women with premature or
able impact on overall survival when con- early menopause as a consequence of cer-
sidering all the studies [hazard ratio (HR), vical cancer treatment.44
0.69; 95% CI, 0.61-0.79] and when consid- Vulvovaginal cancers are rare and are
ering only the cohort studies (HR, 0.63; predominantly SCCs. As with cervical
95% CI, 0.49-0.81) but not in the RCT cancer, no evidence suggests harm with
subgroup (HR, 1.03; 95% CI, 0.58-1.83).41 MHT use for survivors of these cancers.
Concerns have been raised about MHT Adenocarcinomas of the vulva and vagina
use in women with ovarian cancers that are very rare, and no data exist to guide
may contain ERs, such as serous carcino- decision making regarding MHT use in
mas and sex cord-stromal tumors, but patients with history of these cancers.42
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
Survivors of gynecologic cancers com-
SUMMARY OF PRACTICE monly have treatment-induced menopause,
RECOMMENDATIONS often before the average age of menopause,
MHT use can be considered as indicated in and their symptoms may be particularly
women with prior epithelial ovarian cancers, frequent, severe, and persistent. In addition
with the exception of advanced serous and to providing symptomatic relief, MHT
endometrioid histologic types. Although the may mitigate the increased risk of multiple
evidence is very limited, concerns have been adverse long-term health consequences as-
raised about MHT use in women with sociated with premature or early meno-
ovarian cancers that are likely to contain pause. MHT may be considered as
ERs, such as serous carcinomas and sex indicated for women with a history of type
cord-stromal tumors.3 The use of MHT in I endometrial cancers, but it should be
women with a history of GCT may be avoided in women with higher grade endo-
considered as indicated, although definitive metrial tumors, unfavorable histologies
data are lacking.42 (including type II cancers), and advanced
disease. Survivors of epithelial ovarian
cancers may consider the use of MHT as
Other Gynecologic Cancers indicated, but for women with a history of
The majority of cervical cancers (about advanced serous and endometrioid cell
80%) are squamous cell carcinomas (SCCs), types and those with sex cord-stromal
with most of the remainder being tumors, nonhormonal options should be
adenocarcinomas.43 SCCs are mostly asso- offered as first-line therapy for manage-
ciated with a previous human papillomavi- ment of menopausal symptoms. Data are
rus infection. They are not estrogen less clear regarding women with a history
sensitive, and current evidence does not of GCTs, but MHT is generally considered
suggest an increased risk of cervical SCCs safe. Cervical, vulvar, and vaginal cancers
with MHT use. Similarly, MHT use after a are mostly associated with human papillo-
diagnosis of cervical cancer is not associ- mavirus and are not hormone dependent,
ated with a poorer prognosis. As such, and MHT can be used as indicated.
MHT is not contraindicated in women with It is important to note that low-dose
SCC of the cervix, but the evidence in vaginal estrogen therapy is associated
women with adenocarcinoma of the cervix with minimal systemic absorption. It can
is limited. However, concerns have been be considered for management of vaginal

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6 Kapoor et al

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