Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan ;Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan
4Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan ;5Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical
Polycystic ovary syndrome (PCOS), the most common endocrine disorder affecting women of reproductive age, is characterized by hyperandrogenism and insulin resistance. Women with PCOS have a higher risk for cardiovascular diseases (CVDs) and endothelial dysfunction. The mechanisms underlying these risks are unclear. Human peripheral blood contains circulating endothelial progenitor cells (EPCs) derived from bone marrow that have the ability to proliferate and differentiate into mature endothelial cells, which may contribute to vessel homeostasis and repair. PCOS is associated with insulin resistance, hyperinsulinemia, and dyslipidemia, which may result in EPC dysfunction. In this review, we summarize the potential mechanisms of EPC dysfunction in PCOS, which possibly result in a higher genesis of CVDs in PCOS-affected subjects.
Polycystic ovary syndrome (PCOS) is the most
common endocrine disorder in reproductive women.
It is estimated that 5-11% of women of reproductive
age have PCOS (1-4). One of the major diagnostic
criteria of PCOS is chronic anovulation which leads
to irregular menstruation, amenorrhea and infertility;
the other diagnostic criterion is hyperandrogenism
which leads to hirsutism, acne, and alopecia.
Women with PCOS are at high risk for developing
cardiovascular diseases (CVDs) (5-7) and exhibit
endothelial dysfunction. Endothelial progenitor cells
(EPCs) play an important role in the pathophysiology
of CVDs. EPCs can home to sites of neovascularization
and differentiate into endothelial cells
in response to a variety of stimuli (8-10). PCOS is
associated with hypertension, obesity, dyslipidemia,
and insulin resistance, all of which may result in
EPC dysfunction (11). Endothelial dysfunction has
been observed in PCOS patients despite normal glycemia,
lipidemia, and blood pressure, and without
structural arterial impairment (12-16). In this review,
we summarize the potential mechanisms of
EPC dysfunction in PCOS, which can result in a
higher genesis of CVD in PCOS-affected subjects.
PCOS and CVDs
PCOS-affected women have a number of reproductive
and metabolic abnormalities. Previous studies of
PCOS women with body mass index (BMI)-matched
controls have proposed several CVD risk factors related
to PCOS (17, 18). PCOS is frequently associated
with obesity, elevated blood pressure, and dyslipidemia
(19, 20); all of which are important risk factors for
CVDs. PCOS patients have increased non-traditional
risk factors for CVDs, such as elevated homocysteine
(21-23), C-reactive protein (24), plasminogen activator
inhibitor-1 (25), and fibrinogen (26) levels. In addition,
our previous study has found evidence of a widening
QRS complex (a biomarker for heart failure) on electrocardiogram in PCOS patients (27).
Through a calcium score analysis, PCOS patients
had increased prevalence of coronary artery disease
(CAD) independent of BMI and age. Shroff et al. have
reported a correlation between CAD and PCOS using
coronary artery calcium and inflammatory markers
(28). Therefore, PCOS is an important risk factor
for CAD. PCOS patients also have an increased risk
of cerebrovascular diseases (29). Increased carotid
intimal-medial thickness and carotid atherosclerotic
plaque index scores have been reported in PCOS patients
(30, 31). Asymmetrical dimethyl-L-arginine
(ADMA) is an endogenous nitric oxide synthase
(NOS) inhibitor, which can induce atherosclerosis
and serve as an independent marker for cardiovascular
morbidity (32). PCOS women have elevated
ADMA (33), which may induce endothelial dysfunction
in these patients. The above findings suggest that
CVD risk, as reflected by endothelial dysfunction, is
increased in PCOS patients. Table 1 summarizes the
clinical evidence of PCOS in CVDs.
EPC dysfunction contributes to CVDs
EPCs play critical roles in endothelial function
and the genesis of atherosclerosis (34, 35). Bone
marrow-derived peripheral EPCs can home to sites
of vessel growth, where they proliferate and differentiate
into mature endothelial cells for neovascularization
(10). Aging, diabetes, hypercholesterolemia,
and stroke are associated with impaired
neovascularization, which may be caused by EPC
dysfunction (36, 37). Peripheral EPCs isolated
from CAD patients are significantly declined, revealing
an impaired migratory response (38). Similarly,
decreased EPCs may result in a poor outcomes
after ischemic stroke (39).
Circulating EPC numbers and function were significantly
reduced in diabetic patients with peripheral
artery disease (PAD), and the severity of carotid stenosis
was negatively correlated with the EPC number
in these patients (40). In addition, angiotensin II and
oxidative stress possibly contribute to reduced EPC
number and function through activation of the AT1a
receptor (41). Therefore, EPCs significantly contribute
to the pathophysiology of CVDs.
Potential EPC disorders in PCOS
Endothelial dysfunction is a common finding in
PCOS patients (13, 42). EPCs have been shown to
play a critical role in regulating endothelial function
(43-45). According to recent studies, PCOS
patients have reduced EPC numbers and impaired
EPC function along with increased central arterial
stiffness. Our studies have reported the presence of
hyperinsulinemia and insulin resistance in PCOS
patients (46, 47), which may result in EPC dysfunction
through increased reactive oxygen species and
impaired insulin signaling (48). When EPCs from
insulin-resistant Zucker fatty rats were exposed to
tumor necrosis factor-α, there was increased apoptosis
and decreased AKT phosphorylation in the
EPCs, which suggested that inflammation could
induce EPC dysfunction. In addition, our studies
found that hyperglycemia significantly modulated
peroxisome proliferator-activated receptor and
cardiac inflammation (49, 50), which were effects
that have been shown to impair EPC function (51).
Since PCOS is associated with a hyper-inflammatory
status, inflammation-related EPC dysfunction
could contribute to increased CVDs in PCOS patients.
According to Gallagher et al. diabetic mice
have an approximately 50% reduction in circulating
EPCs compared to non-diabetic controls (52).
PCOS is frequently combined with obesity, which
can induce inflammation and oxidative stress, thus
resulting in (42) EPC dysfunction. Oxidized lowdensity
lipoprotein has been shown to impair EPC
migration and endothelial NOS. Therefore, dyslipidemia
from PCOS can also produce EPC dysfunction.
The prevalence of insufficient vitamin D is higher
in PCOS patients (53). Vitamin D dysregulation
and deficiency is correlated with CVDs and affects
EPCs (54, 55). Therefore, administration of vitamin
D may have beneficial effects on CVD risk factors
in PCOS patients (56-58). Accordingly, vitamin D
deficiency may reduce the EPC number and function
in PCOS patients as a result of developing
CVDs. Various environmental chemical toxicants
have also been implicated in endocrine disruption
that may be associated with PCOS. PCOS patients
have a higher blood level of bisphenol A (BPA),
an estrogenic endocrine-disrupting chemical used
to produce plastics (59). Since chemical toxicants
increase CVDs and are known to affect EPCs (60,
61), it is possible that chemical toxicants may reduce
the EPC number and function in PCOS patients,
thus increasing CVDs.
Clinical evidences of the cardiovascular risk in PCOS
Compared coronary artery calcium in
PCOS patients and healthy controls
A higher incidence of coronary artery calcium
in PCOS patients (33%) than in controls
PCOS was associated with increase coronary
artery calcium after adjusting for age,
BMI, and menopausal status (62).
Compared CAD risk factors between
PCOS and healthy females
Increased BMI, total cholesterol, triglyceride,
LDL, SBP, DBP, insulin, glucose, and HOMAIR
Compared cardiovascular outcomes in
PCOS and healthy women
Increased cardiovascular events in PCOS
patients compared to controls, with an odds
ratio of 5.91 (64).
Compared the carotid intimal-media
thickness (IMT) by echography in
PCOS patients and healthy controls
Increased IMT in PCOS patients (0.58 vs.
0.47 mm) than in healthy controls (31).
Compared the carotid artery ultrasonographs
of PCOS patients and controls
Higher prevalence of an abnormal carotid
plaque index in PCOS patients than in controls
(7.2 vs. 0.7%) (30).
BMI; Body-mass index, LDL; Low-density lipoprotein, SBP; Systolic blood pressure, DBP; Diastolic blood pressure, HOMAIR;
Homeostasis model assessment of insulin resistance, CAD; Coronary artery disease and IMT; intimal-media thickness.
PCOS is an independent marker of long-term
cardiovascular risk and plays an important role in
the pathophysiology of CVDs. EPCs maintain endothelial
repaired capacity in mature blood vessels.
Impaired EPC number and function will produce
endothelial dysfunction and CVD progression (Fig 1). Therefore, EPC dysregulation may contribute
to the genesis of CVDs in PCOS patients.
Mechanisms underlying endothelial progenitor cell
(EPC) dysfunction in polycystic ovarian syndrome (PCOS)
which contribute to cardiovascular disease.
Kao, Y., Chiu, W., Hsu, M., Chen, Y. (2013). Endothelial Progenitor Cell Dysfunction in Polycystic Ovary Syndrome: Implications for The Genesis of Cardiovascular Diseases. International Journal of Fertility and Sterility, 6(4), 208-213.
Yu-Hsun Kao; Wan-Chun Chiu; Ming-I Hsu; Yi-Jen Chen. "Endothelial Progenitor Cell Dysfunction in Polycystic Ovary Syndrome: Implications for The Genesis of Cardiovascular Diseases". International Journal of Fertility and Sterility, 6, 4, 2013, 208-213.
Kao, Y., Chiu, W., Hsu, M., Chen, Y. (2013). 'Endothelial Progenitor Cell Dysfunction in Polycystic Ovary Syndrome: Implications for The Genesis of Cardiovascular Diseases', International Journal of Fertility and Sterility, 6(4), pp. 208-213.
Kao, Y., Chiu, W., Hsu, M., Chen, Y. Endothelial Progenitor Cell Dysfunction in Polycystic Ovary Syndrome: Implications for The Genesis of Cardiovascular Diseases. International Journal of Fertility and Sterility, 2013; 6(4): 208-213.