Polycystic Ovary Syndrome: Menopause and Malignancy
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CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 64, Number 1, 102–109
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Polycystic Ovary
Syndrome:
Menopause and
Malignancy
KARINE MATEVOSSIAN, DO,*
and OLIVIA CARPINELLO, MD†
*Advocate Aurora Lutheran General Hospital, Chicago, Illinois;
and †Program in Reproductive Endocrinology and Gynecology,
Eunice Kennedy Shriver NICHD, National Institutes of Health,
Bethesda, Maryland
Abstract: Polycystic ovary syndrome (PCOS) has been course of menopause and cardiovascular
extensively studied in reproductive-aged women. How- health in perimenopausal and postmeno-
ever, accumulating research shows that PCOS can have
lifelong effects on multiple aspects of women’s health. pausal patients. Moreover, PCOS may
PCOS can affect the onset and course of menopause and increase a woman’s risk for both gyneco-
cardiovascular health in perimenopausal and postmeno- logic and nongynecologic malignancies.
pausal patients. Moreover, PCOS may increase a wom- When treating older PCOS patients, physi-
an’s risk for both gynecologic and nongynecologic cians should be cognizant of the syndrome’s
malignancies. When treating older PCOS patients, physi-
cians should be cognizant of the syndrome’s long-term long-term effects and consider the unique
effects and consider the unique needs of these women. needs of these women.
Key words: PCOS, menopause, malignancy
Age of Menopause in PCOS
Introduction Patients
Polycystic ovary syndrome (PCOS) has A key component of PCOS is oligomenor-
been extensively studied in reproductive- rhea or amenorrhea, which is theorized to
aged women. However, accumulating re- lead to less follicular depletion from month
search shows that PCOS can have lifelong to month. This, in turn, may lead to a later
effects on multiple aspects of women’s age of menopause in PCOS women. Re-
health. PCOS can affect the onset and search in this area shows that, while the rate
Correspondence: Olivia Carpinello, MD, 38 Maryland
of follicle attrition is actually the same for
Avenue, Unit 225, Rockville, MD. E-mail: olivia. PCOS patients and controls, PCOS patients
carpinello@nih.gov may start their reproductive years with a
The authors declare that they have nothing to disclose. larger ovarian reserve due to either an
CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 64 / NUMBER 1 / MARCH 2021
102 | www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.Menopause and Malignancy 103
increased number of germ cells at birth or a patients. Previous studies on menopausal
decrease in germ cell loss. Ultimately, this women, not specifically those with
larger follicular pool may lead to a later PCOS, have shown that higher FSH
onset of menopause in PCOS patients.1 levels, independent of estradiol levels,
While the exact age of menopause in these are associated with increased prevalence
women has not been extensively studied, and frequency of hot flashes.6 Therefore,
available studies suggest that PCOS women, some theorize that PCOS women may
on average, undergo menopause 2 years have decreased hot flashes because of
later than normo-ovulatory women.2 This their lower FSH levels. Similarly, PCOS
finding correlates with the higher levels of patients have higher circulating andro-
anti-Müllerian hormone seen in PCOS gens which are ultimately aromatized to
women compared with age-matched and estrogens, which may also help decrease
body mass index (BMI)-matched controls.2 vasomotor symptoms. However, studies
While it is not recommended to use follicle- focusing specifically on PCOS patients
stimulating hormone (FSH) levels to deter- have had conflicting results. One study
mine menopausal status due to significant found that PCOS women self-reported
day-to-day fluctuation, lower FSH values hot flushes and night sweats less fre-
are seen in menopausal PCOS patients quently than controls,3 while another
compared with age-matched controls. Post- study showed that PCOS did not affect
menopausal PCOS women have also been the incidence, duration, or severity of hot
shown to have higher levels of free andro- flashes.7 Postmenopausal PCOS women
gens and total testosterone, while sex did self-report higher rates of vaginal
hormone–binding globulin levels are signifi- dryness than non-PCOS postmenopausal
cantly lower in postmenopausal PCOS controls. Perhaps this does not reflect a
patients.3 higher prevalence of vaginal dryness, but
As PCOS patients approach meno- instead, PCOS patients may be more
pause, their cycles tend to normalize and aware of vaginal dryness because
become regular with overall shortened of a potentially increased libido from
intermenstrual intervals.4 This most likely higher levels of androgens versus control
occurs due to the decreased number of patients.3
follicles in older PCOS women compared Research on hirsutism in postmeno-
with reproductive-aged PCOS patients pausal PCOS patients is limited. One
with oligomenorrhea or amenorrhea.5 study did show that menopausal women
As the number of follicles decreases, so with PCOS reported higher rates of
does the production of inhibin B. Lower hirsutism than control patients. This
serum inhibin B levels prevent the correlated with the higher androgen lev-
suppression of FSH and allow FSH levels els of these patients.3 This finding is not
to return to normal. Normalized FSH surprising due to the up to 70% incidence
levels promote follicular growth and of hirsutism in premenopausal PCOS
spontaneous ovulation. Thus, older patients.8
PCOS women are more likely to have
regular, ovulatory menstrual cycles.4
Bone Health
The relationship between bone density
and PCOS in postmenopausal women is
Menopausal Symptoms in not well studied. It is theorized that the
PCOS Women higher androgen levels in these patients
There is a limited amount of research would be protective for bone health and
on menopausal symptoms in PCOS thus be associated with higher bone
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Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.104 Matevossian and Carpinello mass. Obese PCOS women with larger Cardiovascular Disease amounts of adipose tissue have increased (CVD) in Perimenopausal peripheral conversion of androgens to estrogens that should have a protective and Postmenopausal PCOS effect.9 Low body weight of 35 ols.11 This study had a median BMI of inches, elevated triglycerides ( ≥ 150 mg/ 25.7 kg/m2 in controls versus 27.7 kg/m2 dL), high density lipoprotein (HDL)
Menopause and Malignancy 105
CHD compared with 123 of 3131 control Malignancy and PCOS
patients. This increased risk was not
statistically significant but was seen even ENDOMETRIAL CANCER
in lean PCOS patients, indicating that There is extensive evidence that PCOS
PCOS, independent of BMI, plays a role increases a woman’s likelihood of having
in CHD.17 Contrastingly, the Rotterdam endometrial cancer. The extent of risk
study found higher levels of androgens varies based on the study, but the risk of
were not associated with a higher inci- endometrial cancer is between 2.7 to 4
dence of atherosclerosis and CVD. The times higher in PCOS women than
authors compared postmenopausal PCOS controls.21 The majority of endometrial
women to controls and found PCOS cancers in PCOS women are type 1 (endo-
patients had larger waist/hip ratios, high- metrioid) and most commonly present
er BMI, higher rates of type 2 diabetes with postmenopausal bleeding.22
mellitus, higher triglyceride levels, and Type 1 tumors are estrogen-dependent
lower HDL levels. Despite these findings, and the risk of developing these malig-
PCOS women did not have an increased nancies increases as unopposed estrogen
prevalence of atherosclerosis or risk for exposure increases. Women who are
CVD. Notably, this study was limited by obese, nulliparous, or on estrogen re-
the small subset of 272 PCOS patients and placement therapy have a higher like-
a retrospective diagnosis of the syndrome lihood of developing type 1 endometrial
using cycle irregularities at the age of 25 cancer. Of these, obesity is the strongest
as the criteria.18 risk factor.23
Perimenopausal and menopausal Age is another significant risk factor
women with PCOS have increased rates for endometrial cancer. The median age
of obesity, hyperinsulinemia, hyperten- of diagnosis for endometrial carcinoma is
sion, and hyperlipidemia. Clinicians 61 with most patients falling between 50
should be cognizant of these increased and 59 years old. About 5% of cases will
risk factors and encourage conservative be diagnosed before 40 years old and an
measures such as lifestyle modifications, estimated 25% will be diagnosed before
weight management, and exercise. Per menopause. The younger patients who
the American College of Obstetrics and are diagnosed with endometrial cancer
Gynecology (ACOG), universal lipid are commonly obese with anovulatory
screening with total cholesterol, LDL- cycles.24
cholesterol, and HDL-cholesterol should The increased rate of endometrial
occur once between the ages of 17 and cancer in PCOS patients can be ex-
21. Routine screening is not necessary plained by several mechanisms. First,
between 22 to 39 years old. Starting at PCOS patients are more likely to be
40, ACOG recommends checking lipid obese. Obese women have increased adi-
levels every 5 years. After 75 years old, pocyte aromatization of androgens to
no routine screening is needed but it can estrogens, which creates unopposed
be done based on clinical judgment.19 estrogen.25 Second, many PCOS patients
For PCOS patients ACOG recomm- have increased insulin resistance. There
ends screening for cardiovascular risk is some evidence that insulin increases
by determination of BMI, fasting lip- luteinizing hormone (LH) production
oprotein levels, and metabolic syndrome from the pituitary,26 which contributes
risk factors. This screening should be to the already increased LH due to
repeated periodically as PCOS patients abnormal gonadotropin-releasing hor-
have a higher risk for metabolic synd- mone pulsatility. Insulin also directly
rome.20 increases ovarian androgen production
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Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.106 Matevossian and Carpinello
by upregulating 17-alpha-hydroxylase, Metformin and other pharmaceuticals
which promotes the conversion of pre- can be used to decrease hyperinsulinemia,
gnenolone to androgens instead of pro- which can help decrease androgen syn-
gesterone. In addition, hyperinsulinemia thesis and promote the resumption of
leads to decreased insulin-like growth ovulation and normal menses.27 How-
factor–binding protein I, which leads to ever, studies investigating metformin’s
increased free insulin-like growth factor I direct effects on endometrial carcinoma
(IGF-I). IGF-I further promotes andro- have generally suggested no decreased
gen synthesis by theca cells.9,27 This risk.29 One recent study, however, did
hyperandrogenic environment in the find a protective effect against endome-
ovaries, as well as the increased LH: trial cancer with the use of metformin in
FSH ratio, prevents normal follicular women with type II diabetes mellitus.30
development which leads to anovulation, PCOS patients do not require routine
and thus, unopposed estrogen. Further- screening for endometrial hyperplasia or
more, androgens, IGF-I, and insulin all carcinoma. However, premenopausal
decrease sex hormone–binding globulin, PCOS patients who have prolonged ame-
which leads to increased free estrogens norrhea, irregular bleeding, or unopposed
and, thus, increases the risk of endome- estrogen exposure may require further
trial carcinoma.9,27 evaluation with transvaginal ultrasound,
Insulin and IGFs I and II bind to endometrial biopsy, or both per the clini-
receptors in the endometrium and regu- cian’s discretion.31 Any woman with post-
late endometrial proliferation through menopausal vaginal bleeding should be
proliferative, differentiative, and meta- evaluated with either a transvaginal ultra-
bolic effects.25 Moreover, hypersecretion sound or endometrial biopsy.28
of LH in and of itself may be associated
with increased endometrial malignancy. BREAST CANCER
Research has shown an increased expres- Estrogen exposure is a well-established
sion of LH and human chorionic gonado- risk factor for breast cancer. Factors
tropin receptors in human endometrial which increase lifetime estrogen exposure
carcinoma and hyperplasia compared include early menarche, late menopause,
with normal endometrium.25 and nulliparity. While pregnancy de-
Restoring the hormone balance of estro- creases the overall risk of breast cancer,
gen and progesterone in PCOS patients can there is a temporarily increased risk in the
reduce the risk of endometrial cancer. immediate postpartum period with a peak
Treatment with oral contraceptives (OCPs) at 5 years postpartum.32 One possible
can provide consistent exposure to proges- explanation for this finding is increased
terone and regulate menses in younger access to medical care during pregnancy
PCOS patients. For postmenopausal and the postpartum period. Obesity seems
women or women who are poor candidates to increase the risk of breast cancer in
for OCPs, progesterone-only regimens postmenopausal women but potentially
including medroxyprogesterone acetate, decreases the risk in premenopausal
megestrol acetate, and the levonorgestrel- women.25 Infertility has also been associ-
releasing intrauterine device can be utilized ated with increased breast cancer risk.26
to counteract unopposed estrogen and de- Since PCOS patients struggle with obe-
crease the risk of malignancy.28 In women sity, infertility, and increased estrogen
who already have a low-grade disease or exposure from anovulation, there is a
who are poor surgical candidates, malig- hypothetical increased risk of breast can-
nancy may be treated with progesterone- cer among these patients. However, the
only options in select cases. available research to date has not shown
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Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.Menopause and Malignancy 107
an association between PCOS and an Conversely, a cross-sectional study by
increased incidence of breast cancer.22,25 Atiomo and colleagues, a Danish cohort
A study by Kim and colleagues focused study, and a meta-analysis by Barry and
on women with newly diagnosed breast colleagues showed no association between
cancer and compared them to age- PCOS and ovarian cancer.21,36,37 Interest-
matched controls. This study found that ingly, when the meta-analysis excluded
women with breast cancer and PCOS women older than 54 years old, PCOS
were more likely to have used OCPs, to patients had a significantly increased risk of
have a history of infertility, and to have ovarian cancer with an odds ratio of 2.52.37
irregular menstrual cycles, none of which Two studies have focused on the asso-
are surprising. There was a 3-fold increase ciation of PCOS with specific subtypes of
in the rate of breast cancer in premeno- ovarian carcinoma. Both investigated the
pausal women with PCOS but a 33% association between PCOS and borderline
decrease in breast cancer incidence in serous ovarian carcinoma and found an
postmenopausal PCOS patients.33 Over- increased incidence in PCOS patients who
all, there is not enough data to confirm were overweight or obese. This finding
that PCOS increases the risk of breast may be due to the fact that serous border-
cancer, and larger, confirmatory studies line ovarian tumors have higher androgen
are needed. receptor levels than serous invasive tu-
mors. In addition, higher levels of andro-
OVARIAN CANCER gens have been shown to increase the risk
The risk of epithelial ovarian cancer also of low-grade tumors and decrease the risk
increases with nulliparity and infertility.25 of high-grade tumors. These studies are
Studies have found evidence that LH, limited, and further research is needed to
estrogens, and androgens may all be part confirm the relationship between PCOS
of the pathophysiology of ovarian cancer. and serous borderline ovarian tumors.29
Progesterone may have a protective effect
against ovarian cancer by promoting OTHER MALIGNANCIES
apoptosis of abnormal cells. There is some research suggesting uterine
The association between obesity and sarcomas, such as leiomyosarcoma, are hor-
ovarian cancer is not well understood. mone-sensitive and there may be an increased
Some studies have shown increased risk risk with prolonged unopposed estrogen.
with obesity, while others have shown While most of these cancers occur in post-
that obesity is inversely associated with menopausal women, there are a limited
ovarian carcinoma.25 number of case reports of uterine sarcomas
It is now widely recognized that the use of occurring in premenopausal PCOS women.25
OCPs can decrease the risk of ovarian cancer. Ultimately, more data is needed to conclu-
One potential explanation is that recurrent sively say whether or not PCOS increases the
ovulatory events may lead to the malignant risk of leiomyosarcoma.
transformation of the epithelium, and OCPs There is currently insufficient data to
decrease the number of lifetime ovulations.34 make any conclusions about the associa-
Therefore, it can be expected that PCOS tion of PCOS with vaginal, vulvar, or
would decrease the risk of ovarian cancer cervical cancer.22
since it leads to anovulation. However, there Limited data exists on the association
is minimal evidence addressing PCOS and between PCOS and other nongynecologic
the risk of ovarian carcinoma. A study by malignancies. However, a study that
Schildkraut et al35 showed a 2.5-fold in- analyzed the Danish Cancer Registry
creased risk of ovarian cancer in PCOS found that PCOS increases the risk for
patients but was limited by small sample size. kidney, colon, and brain cancer by 2- to
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Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.108 Matevossian and Carpinello
TABLE 1. Summary of Conditions and Risk as the relationship between this condition
in PCOS Patients and other cancers.
Condition Risk for PCOS Patients
Osteoporosis May have higher bone mineral
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