PHYSIOLOGY 32: 357366, 2017. Published August 16, 2017; doi:10.1152/physiol.00030.

2016
REVIEW
Cardiometabolic Features of Polycystic Licy L. Yanes Cardozo,1,2,4,5
Damian G. Romero,3,4,5 and
Ovary Syndrome: Role of Androgens Jane F. Reckelhoff2,3,4,5
1
Department of Medicine, University of Mississippi Medical
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder Center, Jackson, Mississippi; 2Department of Physiology and
Biophysics, University of Mississippi Medical Center, Jackson,
Mississippi; 3Department of Biochemistry, University of
that affects reproductive-age women. Hyperandrogenemia is present in a Mississippi Medical Center, Jackson, Mississippi; 4Womens
Health Research Center, University of Mississippi Medical
significant fraction (~80%) of women with PCOS. Increased prevalence of Center, Jackson, Mississippi; and 5Cardio Renal Research
Center, University of Mississippi Medical Center, Jackson,
cardiometabolic risk factors is frequently observed in PCOS women. The Mississippi
lyanes@umc.edu
dromero@umc.edu
present review aims to highlight the key role of androgens in mediating the
negative cardiometabolic profile observed in PCOS women.

Polycystic ovary syndrome (PCOS) is the most Does Hyperandrogenism Mediate

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common endocrine disorder in women, affecting
526% of them during their reproductive years (12,
62). PCOS is the most common cause of androgen
excess in young women (7). Definition and diag-
nosis of PCOS remain controversial since three
different criteria currently coexist (6, 103, 126).
Each criteria is based on a different combination of
the following characteristics: hyperandrogenism,
ovulatory dysfunction, and polycystic ovarian mor-
phology. The lack of consensus in PCOS definition
and diagnosis has caused multiple heterogeneous
phenotypes to be included under a broad defini-
tion umbrella (91). Furthermore, the etiology and
the pathogenesis of PCOS is unknown at present.
Although women with PCOS frequently seek
medical attention due to infertility, menstrual dys-
function, or excessive male pattern hair growth
(hirsutism), much attention has recently been fo-
cused on several metabolic derangements, such as
obesity, insulin resistance, increases in blood pres-
sure, metabolic syndrome, fatty liver, sleep apnea,
dyslipidemia, and endothelial dysfunction that
affect a disproportionate percentage of PCOS
women compared with normal-cycling women
(55, 98, 100, 113).
Hyperandrogenemia is considered a sine qua
non component for the diagnosis of PCOS criteria
sponsored by the Androgen Excess Society (6) and
National Institutes of Health (NIH) (126), but not for
the Rotterdam criteria (103). More recently, the Rot-
terdam criteria for PCOS diagnosis was endorsed by
the NIH at an NIH-sponsored workshop with the
caveat that the PCOS phenotype should be clearly
stated (91). Nevertheless, multiple unbiased epide-
miological studies have shown that hyperandrogen-
emia is present in ~80% of PCOS-diagnosed cases
(71). Interestingly, PCOS women with elevated an-
drogen levels have a worse cardio-metabolic profile
compared with women with PCOS with normal lev-
els of androgens (6, 16, 54, 58, 97, 122). Whether and
how androgens mediate the cardiometabolic de-
rangements in PCOS women are unknown.
the Increase in Cardiometabolic
Risk Factors in PCOS?
As mentioned above, hyperandrogenism is consid-
ered a hallmark of PCOS by the Androgen Excess
Society and NIH guidelines (6, 126). Androgens can
originate from the ovaries in most PCOS women,
although in 20 30% of them, excess androgens are
produced by the adrenal gland. Plasma levels of
total and free testosterone, free dihydrotestoster-
one (DHT), dehydroepiandrosterone (DHEA),
DHEA sulfate (DHEAS), and androstenedione are
significantly elevated in PCOS (7, 48). Testosterone
and DHT are the most potent androgens; however,
despite the fact that androstenedione, DHEA, and
DHEAS have significantly less androgenic potency,
they circulate at higher concentrations in plasma
(56) and act as a reservoir that can be converted to
testosterone and estrogens in various tissues, such
as the fat and the skin (6, 59). In PCOS patients,
plasma levels of testosterone are moderately ele-
vated ~1.5-fold compared with control women. En-
hancement in the steroidogenic activity of
subcutaneous adipose tissue of women with PCOS
has been demonstrated in some recent studies
(94). Furthermore, the concentrations of andro-
stenedione, DHEA, and testosterone in female ad-
ipose tissues are several fold higher than in plasma
(11, 21, 34, 110). Despite these findings, the roles of
the local intra-adipose androgens in mediating in-
creases in blood pressure and cardiometabolic risk
factors in women with PCOS are unknown.
Insulin resistance is considered to have a funda-
mental role in mediating the increased cardio-
metabolic risk factors present in women with
PCOS (91). Insulin resistance is present in 50 90%
of patients with PCOS (86). There is also an asso-
ciation between insulin resistance and androgens
in PCOS. Androgen levels are positively correlated
with hyperinsulinemia in PCOS women. Insulin
can stimulate androgen production directly by the
ovaries (93) and indirectly by centrally stimulating

1548-9213/17 Copyright 2017 the American Physiological Society 357

REVIEW
luteinizing hormone release (86). Women with in-
sulin receptor mutations, and thus high levels of
insulin, develop severe hyperandrogenemia (85).
Hyperinsulinemia also contributes to hyperandro-
genemia by decreasing the hepatic synthesis of sex
hormone binding globulin (SHBG), leading to in-
creased free androgen levels (22). Several mecha-
nisms have been suggested to cause insulin
resistance in women with PCOS, with obesity con-
sidered the primary culprit. However, insulin resis-
tance is often observed even in lean patients with
PCOS. These data suggest that insulin resistance
may play a key role in the pathophysiology and be
an aggravating factor of the hyperandrogenemia in
PCOS women.
Several epidemiological studies have shown a
positive correlation between the plasma levels of
androgens and blood pressure (18), obesity (36),
insulin resistance (8), and endothelial dysfunction
(98) in PCOS women. Furthermore, reduction of
testosterone is associated with improvement in
dyslipidemia (23), endothelial dysfunction, body
weight, and, as noted above, insulin resistance in
PCOS women (3). Despite the strong evidence link-
ing plasma androgen levels and cardiometabolic
disturbances in PCOS women, whether and how
androgens cause such negative cardiometabolic ef-
fects remains unclear.
Endothelin-1 is a potent vasoactive agent that
mediates vasoconstriction and vasodilation via en-
dothelin type A (ETA-R) and endothelin type B
(ETB-R) receptors, respectively. Insights into the
mechanisms by which androgens may promote
endothelial dysfunction in PCOS women came
from elegant studies performed by Wenner et al.
This group demonstrated that women with PCOS
have lower ETB-R-mediated vasodilation in skin
compared with BMI-matched control subjects
(119). In follow-up studies, this group demon-
strated that suppression of the chronic elevation of
testosterone improves microvascular function in
PCOS women (118). In summary, these data dem-
onstrate the key role of testosterone in mediating
endothelial dysfunction in PCOS women.
Oral contraceptives (OCPs) are the first-line
treatment option for hyperandrogenemia and ir-
regular menstrual periods in PCOS. OCPs reduce
circulating testosterone and androgen precursor
levels by suppression of luteinizing hormone and
stimulation of SHBG, leading to a decrease in free
testosterone plasma levels. Whether long-term use
of oral contraceptive agents can modify cardiovas-
cular morbidity and mortality in PCOS is currently
unknown. Moreover, some studies suggest that
OCPs can exacerbate hypertension in women and
are associated with a twofold increase in the risk of
cardiovascular diseases in the general female pop-
ulation (4). Exogenous administration of estrogens
358 PHYSIOLOGY Volume 32 September 2017 www.physiologyonline.org
can stimulate the production of angiotensinogen
in the liver of female rats (60, 61), which one may
speculate could lead to higher levels of angiotensin
II (Ang II), a potent vasoconstrictor that could con-
tribute to the increase in blood pressure. More-
over, OCPs are contra-indicated for smokers due to
the higher risk of cardiovascular diseases in this
population (112). OCPs do not seem to affect glu-
cose and insulin homeostasis in the general pop-
ulation (114). However, the effect of OCPs on PCOS
women remains controversial, mainly due to het-
erogeneity of the studies, as shown in a recent
meta-analysis (44). Furthermore, several clinical
studies have suggested that the use of OCPs may
aggravate insulin resistance and worsen hypergly-
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cemia in obese women with PCOS (2, 83, 89, 90).
When OCP therapy is chosen, a low dose of estro-
gens should be preferred. The long-term impact of
OCPs in glucose and insulin homeostasis in PCOS
women remains unknown. Combined OCPs in-
crease the risk of venous thromboembolism in the
general population; and this adverse reaction is
influenced by age, smoking, and obesity (26). Al-
though the ideal progestins to use in PCOS are
those with the lowest androgenic profile, such
as chlormadinone and drospirenone, these ste-
roids may induce a higher number of venous
thrombosis events and may be contra-indicated in
patients with severe obesity (39). Moreover, clinical
studies have shown that PCOS women have higher
incidence of venous thromboembolism, but data
regarding the effect of OCPs have been contradic-
tory (10, 96). The effect of OCPs in the lipid profile
of PCOS women has proven puzzling. A meta-anal-
ysis report has shown that, although OCPs have a
beneficial effect by increasing high-density lipo-
protein cholesterol (HDL-C), they also present a
detrimental effect by increasing triglycerides (44).
On the other hand, a retrospective cross-sectional
cohort study of 1,297 PCOS women did not show
an OCP effect in the lipid profiles among current
users, ever users and never users (82). Prospective
randomized controlled long-term clinical trials an-
alyzing the effect of OCPs on cardiovascular mor-
bidity and mortality in PCOS women, obese and
lean, are lacking and desperately needed.
Androgen receptor blockers are used in the man-
agement of hirsutism in PCOS women. Androgen
receptor blockers are indicated if hirsutism is re-
fractory to OCPs and insulin sensitizers. In the
U.S., the androgen receptor blocker most com-
monly used in the clinic is spironolactone (39).
However, spironolactone is also a progesterone and
mineralocorticoid receptor blocker. Blockade of the
mineralocorticoid receptor causes a diuretic effect
that potentially can cause serious side effects such as
hyperkalemia and hypotension (39). The recommen-
dation is that patients have their potassium levels

frequently checked and, for these patients, increase
water and salt intake during hot weather. Usually, a
high dose of spironolactone is necessary to block the
androgen receptor, which potentially may lead to
higher incidence of undesired side effects. Further
research is needed to address the effect of androgen
receptor blockers in the management of the cardio-
metabolic derangements in PCOS women. Other po-
tent anti-androgens are flutamide and cyproterone
acetate, although both present challenges. On one
hand, cyproterone acetate is not currently available
in the U.S. On the other hand, flutamide use has
been associated with severe hepatoxicity and is not
FDA-approved for use in PCOS women. More effi-
cient and specific androgen receptor blockers should
positively impact the management of the cardio-
metabolic risk factors in women with PCOS.
The prevalence of Type 2 diabetes mellitus in the
U.S. is 10 times higher among young women with
PCOS compared with age-matched, normal-
cycling women (28). Current guidelines for the
treatment of cardiometabolic risk factors in PCOS
recommend weight loss and insulin sensitizer
agents such as metformin (39, 40). Weight loss in
PCOS women ameliorates some of the cardiovas-
cular risk factors, as in non-PCOS women. How-
ever, weight loss is very difficult to sustain with
time, probably due to resetting of the basal meta-
bolic rate (35). Since insulin resistance is present in
obese and lean women with PCOS, it has been
proposed to be the key factor in mediating the
negative cardiovascular risk profile observed in
PCOS subjects. Metformin has been used for years
to treat insulin resistance in PCOS women. System-
atic reviews and meta-analysis have shown that
metformin decreases fasting glucose and insulin,
blood pressure, and low-density lipoprotein cho-
lesterol (73, 111). However, long-term prospective
randomized controlled trials assessing the effect of
metformin on long-term cardiovascular benefit to
PCOS women by decreasing cardiovascular mor-
bidity and mortality are not available at present.
Even in the absence of PCOS, metformin reduces
the risk of progression from insulin resistance to
diabetes in only 30% of patients (63). Metformin
can lower the level of testosterone; thereby any
beneficial effect in PCOS women may be due to
lowering their androgen levels (92).
Although women with PCOS have a higher prev-
alence of cardiovascular risk factors and surrogates
of cardiovascular diseases, such as carotid intima-
media thickness (64) and coronary artery calcifica-
tion (19), whether PCOS women have a higher rate
of cardiovascular mortality has not as yet been
demonstrated. A 10-yr follow-up study of post-
menopausal women with or without clinical fea-
tures of PCOS from the Womens Ischemia
Syndrome Evaluation (WISE) study showed that
REVIEW
PCOS was not a predictor of fatal and non-fatal
cardiovascular events (81). However, larger pro-
spective long-term follow-up studies are necessary
to answer the question of whether the diagnosis of
PCOS carries a higher risk of morbidity and mor-
tality due to cardiovascular diseases.
Hypertension is a major risk factor for cardiovas-
cular disease and mortality (66, 70). Several clinical
studies have shown that increased blood pressure
or the incidence of hypertension is significantly
increased in PCOS women (17, 30, 47, 72, 88, 117,
120). Moreover, the higher prevalence of hyperten-
sion in PCOS women was observed across multiple
ethnic groups (17, 72). Recently, a large case-con-
trol study including 1,550 PCOS women and 447
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control women showed that PCOS women present
both systolic and diastolic blood pressure in-
creases (99). The mechanisms that are involved in
the higher blood pressure in PCOS are uncertain,
and whether the mechanisms differ for individual
ethnic groups is also unclear.
In summary, whether PCOS is linked to a higher
rate of cardiovascular mortality is unknown at
present and should be answered with better pow-
ered studies that include larger populations of
women with PCOS. What is clear, however, is that
women with PCOS frequently have hypertension
or elevated blood pressure. The mechanism(s) un-
derling the increase in blood pressure in PCOS
remains unclear.
Cardiometabolic Features in the
Hyperandrogenemic Female Rat: A
Model of PCOS
There are multiple experimental animal models of
PCOS. A particularly useful model in which to
study the cardiometabolic effects of hyperandro-
genemia in PCOS is the one reported by Manneras
and colleagues produced by administration of the
non-aromatizable androgen DHT to pre-pubertal,
4-wk-old female rats. DHT for 90 days causes mor-
phological and histological changes in the ovaries,
estrous cycle disruption, and insulin resistance
similar to those observed in women with PCOS
(77). Using this animal experimental model, we
also reported that DHT administration causes a
mild but consistent increase of blood pressure (10
mmHg) measured by radiotelemetry in freely mov-
ing conscious animals (123). Furthermore, this in-
crease in blood pressure is associated with
increases in food intake, subsequent obesity, insu-
lin resistance, dyslipidemia, renal injury, systemic
inflammation, and activation of the intrarenal
renin angiotensin system (RAS) and the sympa-
thetic nervous system (78, 123). Although these
data strongly suggest that hyperandrogenemia in
female rats may directly increase blood pressure in
PHYSIOLOGY Volume 32 September 2017 www.physiologyonline.org 359
REVIEW
the PCOS model, the exact mechanism(s) by which
androgens exhibit this deleterious effect remains
unclear. Moreover, the presence of insulin resis-
tance and obesity in this model, as in PCOS
women, most likely further worsens the negative
cardiovascular risk factor profile.
Possible Mechanisms by Which
Androgens Increase Blood Pressure
in PCOS
Insulin Resistance
Insulin resistance and hyperandrogenemia are the
cardinal features of PCOS (107). Women with in-
sulin receptor mutations, and thus high levels of
insulin, develop severe hyperandrogenemia (85).
Insulin can stimulate androgen production directly
by the ovaries (93) and indirectly by centrally stim-
ulating luteinizing hormone release (86). Insulin
resistance is present in 50 90% of patients with
PCOS (86), independent of obesity. Hyperinsulin-
emia has been postulated to link obesity and hy-
pertension via the antinatriuretic actions of
insulin. Pioneer work by Hall and colleagues
showed several years ago that infusion of insulin
can increase blood pressure in rats by 5 8 mmHg,
but not in dogs (13, 14, 42). One caveat to those
experiments is that plasma glucose values were
normal; therefore, one could speculate that insulin
per se is not enough to cause significant hyperten-
sion in the absence of elevated glucose levels. In
addition, those experiments were performed in
male animals.
Although a significant percentage of women with
PCOS are obese, some of them are not. By the same
token, insulin resistance is exacerbated by obesity
in PCOS, but insulin resistance presents in lean
PCOS women as well (86, 107). These observations
may suggest that androgens can cause insulin re-
sistance per se in females, independent of obesity.
Furthermore, Huirliman and colleages recently
showed that the presence of endothelial dysfunc-
tion, hyperinsulinemia, and insulin resistance de-
velops in pair-fed DHT-treated female rats,
suggesting an obesity-independent mechanism
(49). Currently, whether insulin is the principal
factor triggering the cardiometabolic abnormalities
of PCOS remains unclear.
Renin Angiotensin System
Women with PCOS have hyper-reninemia that
positively correlates with hyperandrogenemia (51).
Furthermore, telmisartan, an angiotensin type 1
receptor (AT1R) antagonist, significantly reduces
blood pressure elevation in PCOS patients (52).
Androgen replacement in castrated male rats in-
creases renin and angiotensinogen synthesis (124).
Androgens also mediate a portion of the
360 PHYSIOLOGY Volume 32 September 2017 www.physiologyonline.org
salt-sensitive hypertension in Dahl salt-sensitive
rats (124). If renin enzyme activity is below Vmax, as
has been shown in both humans and rats, then an
increase in angiotensinogen will cause an increase
in the conversion of angiotensinogen to angioten-
sin I, leading to an increase in Ang II production,
since renin, not angiotensin-converting enzyme
(ACE), is the rate-limiting enzyme for Ang II pro-
duction (74). We found that, in the hyperandrogen-
emic female rat, renal angiotensinogen is
upregulated, suggesting that the intrarenal RAS is
activated in this model (123). Whether activation of
the RAS plays a role in mediating hypertension in
PCOS women is unknown.
AT1R blockers or ACE inhibitors are widely used
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as antihypertensive drugs. Women should be ad-
vised about the potential teratogenic and fetotoxic
risks of ACE inhibitors or AT1R blockers if they
become pregnant. Novel and tissue-selective RAS
inhibitors that do not cross the placental barrier
are warranted to ameliorate the increases in blood
pressure in women with PCOS in the future.
Sympathetic Nervous System
PCOS women have an activation of the sympa-
thetic nervous system (105, 109). The increase in
sympathetic drive and impaired endothelial func-
tion seems to be independent of obesity and met-
abolic disturbances (65). There is also evidence
that the renal sympathetic nervous system may
also be upregulated. Schlaich and colleagues re-
ported that radiofrequency renal nerve ablation
reduced the blood pressure in two hypertensive
young women with PCOS (105). We have recently
shown that blood pressure elevation in hyperan-
drogenemic female rats is due, in part, to activa-
tion of the sympathetic nervous system, renal
nerves, and central melanocortin-4-receptor
(MC4R). Hall and colleagues reported that obesity-
related hypertension and the concomitant sympa-
thetic activation are mediated, in part, by the
MC4R in the brain (24, 25, 43). We found that
MC4R receptor expression in the brain was signif-
icantly upregulated in the PCOS model compared
with normal rats, and blockade of the MC4R re-
duced their blood pressure (78). Targeting the
MC4R could be a novel therapeutic tool to amelio-
rate the cardiometabolic risk factors in PCOS.
20-HETE
The role of 20-hydroxyeicosatetraeonic acid (20-
HETE) to modulate blood pressure is well known
(101, 102). 20-HETE has differential effects on the
kidney, depending on the location of synthesis. In the
renal microvasculature, 20-HETE is prohypertensive,
acting as a vasoconstrictor, whereas in the renal tu-
bules, 20-HETE attenuates Na reabsorption and
thus is antihypertensive (121). We recently reported

that, in the PCOS model, cytochrome P450 (CYP)
-hydroxylase isoform CYP4A2, which is involved in
20-HETE biosynthesis, is upregulated and is associ-
ated with increases in endogenous renal microvas-
cular 20-HETE. Furthermore, DHT did not increase
MAP in 20-HETE-deficient Dahl SS female rats,
whereas DHT did increase mean arterial pressure in
Dahl SR females, suggesting that an intact 20-HETE
system capable of upregulation contributes to the
elevated blood pressure in PCOS model. This effect
seems to be specific to the presence of CYP4A2 -hy-
droxylase, since lack of this enzyme prevented the
DHT-mediated pressor response in CYP4A2-null fe-
male rats. Taken together, these data suggest that
20-HETE contributes to the DHT-mediated elevated
blood pressure in PCOS model and that the CYP4A2
isoform may be at least partially responsible for the
increase in blood pressure. These data also suggest
that metabolites of arachidonic acid constitute a
novel pathway that may be involved in mediating
blood pressure elevation in PCOS.
Incretin System and Other Novel
Mechanisms
Several other mechanisms have been proposed to
mediate the metabolic abnormalities observed in
PCOS women. Glucagon-like peptide-1 (GLP-1) is
an incretin that potentiates the food-mediated re-
lease of insulin, leading to a decrease in plasma
glucose levels, delaying gastric emptying, and ex-
erting satiety effects that assist with weight control.
Recently, a small clinical trial showed that admin-
istration of GLP-1 receptor agonists caused signif-
icant improvement in insulin resistance, decreases
in blood pressure, and improvement in the abnor-
malities of the estrous cycle in PCOS women (53).
Similar beneficial effects of GLP-1 were observed in
DHT-treated females rats, as administration of the
long-acting GLP-1 agonist, liraglutide, to DHT-
treated rats significantly improved insulin resis-
tance and decreased blood pressure (46). These
results suggest that GLP-1 treatment could im-
prove DHT-induced metabolic and blood pressure
abnormalities associated with PCOS. Whether the
incretin system interacts with or modulates andro-
gens is unknown, but, if so, it is also possible that
incretin modulators may constitute a novel thera-
peutic tool to ameliorate the cardiometabolic ab-
normalities observed in PCOS women.
Women with PCOS also have an inverse associ-
ation between vitamin D status and metabolic dis-
turbances. A recent study demonstrated that
vitamin D deficiency is prevalent in women with
PCOS, with 60 70% of them having low levels of
25-OH vitamin D (84). Further research and
adequately powered randomized controlled clini-
cal trials of vitamin D supplementation and its
effects on the cardiometabolic risk factors
REVIEW
observed in women affected by PCOS are neces-
sary to elucidate the endocrine role of vitamin D in
PCOS.
Nesfatin-1 peptide was discovered in 2006 in the
rat hypothalamus and is described as a centrally
acting anorexigenic peptide. Nesfatin-1 is derived
from nucleobindin 2 (NUCB2) and is released from
several tissues, including forebrain, hindbrain,
brain stem, spinal cord, and adipose tissues (106).
In addition to its effects on food intake, nesfatin-1
exerts cardiovascular and hypertensive effects, and
causes insulin resistance in several animal models
(95, 108, 125). Several studies have shown that
nesfatin-1 is associated with increased body mass
index (BMI), insulin resistance, inflammation, hy-
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pertension, and PCOS (1, 104, 108, 125). Whether
and how androgens may regulate nesfatin-1 in
PCOS remains unknown.
Obesity as a Critical Factor in the
Clinical Manifestations of PCOS
In the U.S., up to 80% of PCOS women are obese
(28, 69), a percentage much higher than observed
in the general population. Furthermore, obese
PCOS subjects are characterized by worsened hy-
perandrogenemic and metabolic states compared
with normal-weight women with PCOS (33, 87).
Moreover, weight loss by diet or bariatric surgery
reduces the level of androgens and is associated
with improvement in both metabolic and repro-
ductive abnormalities in PCOS (31, 57).
Testosterone has a differential metabolic effect
in adipose tissue in women vs. men. For example,
in men, low levels of testosterone are associated
with increases in obesity and visceral adiposity (15,
41), whereas in women with PCOS, there is a pos-
itive correlation between circulating levels of tes-
tosterone and obesity (41, 67, 116). In women with
PCOS, the distribution of adipose tissue is abnor-
mal (80). There have been conflicting reports as to
whether women with PCOS have increased or de-
creased amounts of visceral fat (5, 32, 33, 76). More
recently, it has been shown that the amount of
subcutaneous adipose tissue is significantly in-
creased with PCOS (9, 27, 29). The role that in-
creases in subcutaneous adipose tissue play in
mediating obesity, insulin resistance, and hyper-
tension in PCOS is unclear. Obesity has a major
impact on the incidence and clinical manifesta-
tions of PCOS (68). Also, the environment, with
diet being probably the main factor, plays a major
role in the pathogenesis of the syndrome, since
women with PCOS in the U.S. generally have a
higher body mass index (BMI) than their European
or Asian counterparts. In a large cohort of women
with PCOS in the U.S., ~60% of the patients studied
were obese (BMI of 30 kg/m2), and 20% were
PHYSIOLOGY Volume 32 September 2017 www.physiologyonline.org 361
REVIEW
severely obese (BMI of 40 kg/m2) (38). Moreover,
there is a positive relationship between plasma
androgen levels, obesity, and insulin resistance in
women with PCOS. Weight loss, the first-line clin-
ical recommendation for women with PCOS, is
associated with improvement of infertility, im-
provement in metabolic derangement, and reduc-
tions in hyperandrogenism (31, 57). Exercise,
independent of weight loss, may have a beneficial
effect on insulin resistance, dyslipidemia, and vis-
ceral obesity in PCOS, and patients must be coun-
seled about the beneficial effects of exercise in the
management of PCOS cardiometabolic risk factors
(50). The beneficial effect of exercise in PCOS
seems not to be related to the type, frequency, or
length of exercise, suggesting that any amount of
exercise may be helpful (45).
Moreover, serum androgens are positively corre-
lated with BMI, not only in PCOS, but also in obese
subjects without PCOS (115). Weight loss via life-
style modification, pharmacotherapy, or bariatric
surgery in women with PCOS decreases androgen
levels (31, 57). The concentrations of androstene-
dione, DHEA, and testosterone in female adipose
tissue are several-fold higher than in plasma (11,
21, 34, 110). However, the role of the local intra-
adipose androgen in mediating the negative car-
diometabolic profile in women with PCOS is
unknown at present.
Summary and Open Questions
PCOS is the most common endocrine disorder that
affects young women. Unfortunately, a retrospec-
tive birth cohort community study has shown that
~70% of young PCOS women are undiagnosed and
not aware of this medical condition (79). Moreover,
a study of recently diagnosed PCOS women
showed that half of them need to consult with
FIGURE 1. Potential mechanisms by which hyperandrogenemia mediates
the negative cardiometabolic risk factor profile exhibited in PCOS
In PCOS women, hyperandrogenemia increase cardiometabolic risk factors such as
obesity, insulin resistance, and increased blood pressure by means of activation of the
renin-angiotensin system (RAS), 20-HETE, and leptin systems, which ultimately leads to
cardiovascular diseases.
362 PHYSIOLOGY Volume 32 September 2017 www.physiologyonline.org
three or more health care professionals, and for
one-third of them, it took 2 yr to have a PCOS
diagnosis established (37). The standard pharma-
cological approach in PCOS women is oral contra-
ceptives and insulin-sensitizing agents. Oral
contraceptives are the first-line medical treatment
for many women with PCOS. Estrogens can have
negative cardiovascular effects, especially throm-
boembolic effects, and their use is not recom-
mended for women above the age of 35. Thus,
currently, therapeutic options to treat PCOS-
associated cardiovascular risk factors are limited
(75). Androgen blockers are rarely used to amelio-
rate the negative cardiometabolic profile fre-
quently observed in PCOS women. These issues
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underscore how critical it is to understand how
androgens mediate the increased risks in cardio-
vascular diseases in women with PCOS to provide
better therapeutic options to these patients.
Whether and how hyperandrogenemia causes
obesity, insulin resistance, increases in blood pres-
sure, and endothelial dysfunction in PCOS and the
interplay between these cardiovascular risk factors
in PCOS are unclear (FIGURE 1). Increased blood
pressure, insulin resistance, and obesity can have a
major impact in long-term development of cardio-
vascular diseases and negatively impact health sta-
tus. Mechanistically, androgen induced insulin
resistance, activation of vasoconstrictors such as
angiotensin II, endothelin-1, and 20-HETE, and
activation of sympathetic nervous system, all of
which can mediate the negative cardiovascular
profile observed in PCOS women. New agents such
as GLP-1 analogs, melanocortin 4 receptor (MC4R)
agonists, and specific RAS blockers may constitute
attractive agents to ameliorate the metabolic ab-
normalities in PCOS.
Although PCOS is the most common cause of
androgen excess in women, several other clinical
conditions in women are associated with increased
levels of androgens, such as congenital adrenal
hyperplasia, ovarian tumors, Cushing syndrome,
testosterone supplementation, some seizure med-
ications, female-to-male transgender, and meno-
pause. To what extent individuals with these
conditions have increased cardiometabolic risk
factors as in PCOS women remains to be eluci-
dated. A better understanding of the physiological
and pathophysiological roles of androgens in car-
diovascular and metabolic function in women is
paramount at present.
This work was supported by American Heart Associa-
tion Grants 0830239N (L.L.Y.C.) and 12SDG8980032
(D.G.R.), Endocrine Fellows Foundation Endocrine Re-
search Grant (L.L.Y.C.), and National Institutes of Health
grants R21 DK-113500 (D.G.R.), R01 HL-66072 (J.F.R.),
P01 HL-51971 (J.F.R.), and P20 GM-121334 (J.F.R. and
L.L.Y.C.).

No conflicts of interest, financial or otherwise, are de-
clared by the authors.
Author contributions: L.L.Y.C., D.G.R., and J.F.R. drafted
manuscript; L.L.Y.C., D.G.R., and J.F.R. edited and revised
manuscript; L.L.Y.C., D.G.R., and J.F.R. approved final ver-
sion of manuscript.
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