(PCOS) Effect of High Levels of Testosterone on Cardiovascular Risk in Polycystic Ovary Syndrome
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International Journal of Research and Review
Vol.7; Issue: 7; July 2020
Website: www.ijrrjournal.com
Review Article E-ISSN: 2349-9788; P-ISSN: 2454-2237
Effect of High Levels of Testosterone on
Cardiovascular Risk in Polycystic Ovary Syndrome
(PCOS)
Suku Sneha
Fortis Hospital, Sector 62, Noida, Uttar Pradesh – 201301
ABSTRACT reproductive disorder among adult women
[1-3]
and that effect 10-18% of women of
Polycystic ovary syndrome (PCOS) is a reproductive age. [4] It is a heterogeneous
common endocrine disorder characterized by medical condition of unknown etiology, but
oligo ovulation, hyperandrogenism and the there is an extensive evidence of multiple
presence of polycystic ovaries. PCOS is closely
interactions between genetic,
related to the hyperandrogensim (HA).
Postmenopausal hyperandrogenism is a environmental, and behavioral factors are
condition of relative or absolute androgen known to cause this syndrome. [1] According
excess originating from either the adrenals to Stein and Leventhal, [5] PCOS is
and/or the ovaries. Clinical manifestations of characterized by heterogeneous presentation
HA include hirsutism, acne, androgenic alopecia of clinical and/or biochemical
and virilisation. In PCOS women, HA has been hyperandrogenism, oligoovulation or
associated with metabolic disturbances that anovulation and the presence of polycystic
increase the risk for cardiovascular disease ovaries, when other etiology’s are excluded.
(CVD). Many clinical studies have underlined [6,7]
Apart from these clinical features,
the relationship between PCOS and PCOS patients are often insulin resistant,
cardiovascular risk is due to a lipid or glucose
obese and have metabolic syndrome, with
altered metabolism, hypertension, systemic
inflammatory condition and vascular injuries. In arterial hypertension, dyslipidemia,
this review article, we mainly focussed on impaired glucose tolerance or frank type 2
PCOS related cardiovascular disease due to diabetes, low-grade inflammation and
increased levels of testosterone. Management of increased pro-thrombotic state. [8] Insulin
hyperandrogenism along with life-style resistance and low grade inflammation are
intervention has beneficial effects on to be associated with increased risk of
cardiovascular risk factors in PCOS. We development of cardiovascular disease in
determined the etiology of relative and absolute patients with polycystic ovary syndrome. [9]
androgen excess in postmenopausal women and Coronary artery disease (CAD) is one of the
this review provides extensive overview on the major causes of death in postmenopausal
development of cardiovascular risk factors in
women. Endogenous free testosterone levels
PCOS females due to increased levels of
testosterone. in postmenopausal women has been
consequently associated with the incidence
Keywords: Polycystic ovary syndrome, oligo of CAD independent of BMI and other risk
ovulation, hyperandrogenism, hirsutism, factors, such as diabetes, hypertension,
alopecia, virilisation, hypertension, vascular smoking, and hyperlipidemia. [10]
injuries and cardiovascular events The leading cause of
Hyperandrogenism (HA) in women of
INTRODUCTION reproductive age is a polycystic ovary
Polycystic ovary syndrome (PCOS) syndrome. HA in PCOS is described as a
is one of the most common endocrine and presence of hirsutism or an increase in
International Journal of Research and Review (ijrrjournal.com) 285
Vol.7; Issue: 7; July 2020Suku Sneha. Effect of high levels of testosterone on cardiovascular risk in polycystic ovary syndrome (PCOS)
[10]
serum testosterone or the free androgen The hyperinsulinemia intrinsically
index (FAI). [11] HA (elevated androgen considered as a possible cause of an
levels) is associated with an increased risk increased ovarian androgen production and
of cardiovascular diseases through complex alters the process of gonadal steroidogenesis
and multidirectional pathways and exposure both directly and indirectly. [6] In both pre-
of Hyperandrogenism may influence body and postmenopausal women, androgen
fat distribution, insulin resistance and other secretion is aggravated by the presence of
cardio metabolic risk factors. [8] An insulin resistance (IR) and
important quantification of this androgen hyperinsulinemia, mostly observed in obese
excess and free androgen index are tends to women, with insulin acting as a co-
be a better predictors of many health gonadotropin. [15]
outcomes, especially cardiovascular disease
as compared with testosterone alone. [10] TRADITIONAL AND NEWER
However, the current review aimed to CARDIOVASCULAR RISK FACTORS
identify the PCOS related cardiovascular IN PCOS:
disease due to increased levels of Traditional cardiovascular disease risk
testosterone. factors in PCOS:
The traditional and modifiable
CAUSES OF HYPERANDROGENISM: cardiovascular risk factors are hypertension,
Hyperandrogenism is described by dyslipidemia, obesity, smoking, diabetes
either hirsutism and/or excess of blood and have 40% prevalence of polycystic
testosterone levels and it plays key role in ovaries in postmenopausal women, and this
the diagnosis of polycystic ovary syndrome. was associated with mild changes in
[12]
Along with the excess androgens, some cardiovascular risks with elevations in
rely on the development of true hirsutism, circulating triglycerides, but no difference in
acne and androgenic alopecia to make the cholesterol levels compared with controls.
diagnosis of hyperandrogenism as part of Non modifiable risk factors include age,
the PCOS phenotype. [13] Androgens are gender and family history of cardiovascular
produced by the adrenal glands as well as by diseases. [13]
the ovaries and are throughout the life. [11]
Various studies described that testosterone Coagulation and Fibrinolytic
levels rise during early puberty and Disturbances:
adolescence and reach a peak adult level PCOS associated with the disturbances in
within a few years after menarche. circulating markers of coagulation and
Testosterone concentrations are majorly fibrinolysis may contribute to
influenced by the stage of puberty and the cardiovascular disease risk. Thrombin
menstrual cycle along with other factors. [14] activated fibrinolysis inhibitor levels were
Androgen secretion in pre- and found to be higher in PCOS women than
postmenopausal women rely on the controls and that contributing to hypo
luteinizing hormone (LH) stimulation and fibrinolytic state and accelerated
the persistently increased gonadotropin atherosclerosis. [8] Previous studies reported
levels maintains ovarian androgen secretion that dysregulation of the hemostatic system
after menopause besides the substantial in women with PCOS, particularly hypo
decline of estrogen levels. [15] The loss of fibrinolysis, Hypercoagulability [16] and
ovarian function in postmenopausal women endothelial and platelet dysfunction. [17] The
leads to a drastic fall of estrogen levels, potential mechanisms of coagulation
whereas secretion of testosterone remains at disturbances were observed in women with
the same levels, or may even increase. This PCOS and have high circulating
rapid decrease of estrogen with menopause concentrations of PAI-1 and fibrinogen that
causes a period of relative androgen excess. correlated with low sex hormone binding
International Journal of Research and Review (ijrrjournal.com) 286
Vol.7; Issue: 7; July 2020Suku Sneha. Effect of high levels of testosterone on cardiovascular risk in polycystic ovary syndrome (PCOS)
globulins (SHBG) and high insulin levels Cardiac dysfunction:
independent of age and BMI. [18] Several Several studies analysed that increased left
studies recognized a strong positive ventricular mass index (LVMi) and
correlation between hyperandrogenism and decreased diastolic filling in young PCOS
hypo fibrinolysis in women with PCOS women compared to age- and BMI-matched
contributing to a prothrombotic state. [16] controls. [25] LVMi is an early predictor of
CVD morbidity and mortality. Both of these
Markers of Atherosclerosis: abnormalities occur independently of excess
The prevalence and extent of coronary weight, particularly decreased left
artery calcification (CAC) were reported by ventricular ejection fraction has been
several studies to be higher in both younger reported in young overweight and obese
and older women with PCOS than in women with PCOS compared to controls.
controls, independently of age and BMI. [19] [25]
It has been suggested that the reported
increase in CAC among PCOS women is The risk of cardiovascular events in
related to the increased LDL-C lower HDL- PCOS:
C and hyperinsulinemia. [20] Increased The age-specific incidence of cardiovascular
intima-media wall thickness (IMT) is an events was significantly higher in PCOS
early marker of atherosclerosis. Increased patients over 45 compared with the local
carotid intima-media wall thickness (CIMT) female population, with odds ratio as high
is also a strong independent predictor of the as 12.88 in women over 65 with a
occurrence of major cardiovascular events premenopausal history of PCOS. [26] A
in later life. [21] recent meta-analysis demonstrated the risk
of coronary heart disease (CHD) and stroke
Vascular endothelial dysfunction: is doubled in PCOS women, despite
Decreased brachial artery flow-mediated adjusting for body mass index (BMI), there
dilation (FMD) is a marker of endothelial was a 55% increase in risk. [4] Previous
function, in young normal weight, studies indicated a 2-fold increased risk of
overweight, and obese women with PCOS CHD and stroke for patients with PCOS
compared to body mass matched controls. relative to women without PCOS. [27] The
[22]
It is recognized that elevated androgen meta-analysis estimated 55% increase in the
levels in the PCOS women may contribute risk for CHD and stroke in PCOS women
to the observed decline in endothelial using only studies that adjusted for BMI,
function relative to controls. [23] Several showing that BMI is not the only cause of
variables involved in endothelial increased risk of cardiovascular events in
dysfunction have been related to the PCOS. women with PCOS. [27]
A recent meta-analysis observed that
homocysteine is a mediator of endothelial ASSOCIATION BETWEEN
injury and its higher concentrations were INCREASED TESTOSTERONE
seen in PCOS women than in controls of LEVELS AND CARDIOVASCULAR
similar age and BMI. [24] Plasminogen EVENTS IN PCOS FEMALES:
activator inhibitor-1 (PAI-1) inhibits High levels of testosterone are associated
fibrinolysis and in higher levels predisposes with an increased cardiovascular risk
to accelerate the development of through complex and multidirectional
atherosclerosis and has been shown to be pathways. [8] A study reported that total
elevated in normal weight young PCOS testosterone was an independent risk factor
women relative to the controls. [16] for aortic calcification (AC). In animal
model study, testosterone increases
atherosclerosis in female monkeys but
conferred a protective effect in males. [20] A
International Journal of Research and Review (ijrrjournal.com) 287
Vol.7; Issue: 7; July 2020Suku Sneha. Effect of high levels of testosterone on cardiovascular risk in polycystic ovary syndrome (PCOS)
similar study reported that men with the axis and metabolic disorders, such as
highest total testosterone levels had a obesity, insulin resistance and compensatory
reduced risk of aortic calcification, but, hyperinsulinemia. [33] Several pathogenic
conversely, women with elevated hypotheses try to explain the increased
testosterone levels had the highest risk for peripheral availability of androgen
coronary artery calcification (CAC). [20] A hormones, which depend on excessive
study conducted by Paradisi et al suggested ovarian and adrenal production. [34] The
that elevated androgen levels play a key role hyperinsulinemia is solely considered as a
in endothelial dysfunction. [28] A similar possible cause of an increased ovarian
study compared women with reporting a androgen production, which alters gonadal
history of regular menses and a history of steroidogenesis process ,both directly and
very irregular menses among 82,439 women indirectly. [6]
aged 20–35 years had a significantly higher
risk of nonfatal and fatal cardiovascular Various mechanisms involved in high levels
disease, even after adjustment for BMI, age, of testosterone are:
menopausal status, and smoking. [29] High Insulin resistance:
circulating androgen levels have been It is described as diminution in the
associated with an unfavorable biological responses to insulin levels. [35]
cardiovascular risk profile and increased Previous studies suggested that four
prevalence of subclinical atherosclerosis in independent risk factors for myocardial
postmenopausal women. [11] Increased infarction in women with PCOS are
carotid intima media wall thickness (CIMT) increasing waist: hip ratio, raised serum
is a predictor of occurrence of major triglyceride concentrations, diabetes and
cardiovascular events in PCOS women. [21] hypertension. [36]
Earlier literature
The increase in CIMT is associated with concerning the interrelationship of insulin
high levels of testosterone, insulin, resistance and hyperandrogenaemia. Some
increased age and abdominal obesity in authors suggested that hyperinsulinemia
PCOS women. [30] results in raised ovarian androgens and it is
associated with decreased levels of sex
THE MECHANISMS INVOLVED IN hormone binding globulins, thereby
HIGH LEVELS OF TESTOSTERONE increasing the circulation of free
AND RISK OF CARDIOVASCULAR testosterone. [35] Along with luteinising
EVENTS: hormone, Hyperinsulinemia stimulates
The relationship between CVD risk stimulate androgen biosynthesis through
and reproductive endocrine disorders (early ovaries; insulin decreases Insulin Growth
menopause and PCOS) supports the idea Factor binding globulin 1 (IGFBP-1) and
that endogenous sex steroids have a role in increases free IGF and thus increases
development of CVD. [31] Elevated levels of ovarian theca cell proliferation and
testosterone are likely to be found in women androgenesis as well. [6] Furthermore,
with PCOS even after menopause in relative insulin stimulates thecal cells which in turn
to estradiol. A study conducted by Pinole et stimulate testosterone biosynthesis in
al revealed that androgen levels gradually women with PCOS by activating receptors
increases after the age of 50 years and and using inositol-glycan mediators as the
relative hyperandrogenemia exists in signal transduction system. [37]
women with PCOS after menopause. [32]
The pathological mechanisms underlying PCOS and Hypertension:
the syndrome are determined by the According to WHO, Arterial
complex interaction between the hypertension (AH) is defined as a systolic
functionality of the hypothalamic-pituitary- (SBP) and (DBP) diastolic blood pressure of
ovarian or hypothalamic-pituitary-adrenal > 140 and > 90 mmHg respectively. [6] A
International Journal of Research and Review (ijrrjournal.com) 288
Vol.7; Issue: 7; July 2020Suku Sneha. Effect of high levels of testosterone on cardiovascular risk in polycystic ovary syndrome (PCOS)
study conducted by Chen and Yang et al MANAGEMENT OF
reported that high testosterone levels and no HYPERANDROGENISM IN PCOS
SHBG increases the risk of elevated SBP WOMEN:
and DBP values even adjusted for age, body Treatment of Hyperandrogenism is
mass index, and other anthropometric, depends on the underlying cause of obesity,
metabolic and hormonal variables. [38] Lecke PCOS, adrenal and ovarian tumors. [15]
et al [39] demonstrated the association Administration of oestrogen containing oral
between CYP19 gene expression, levels of contraceptive has beneficial effects on
aromatase and blood pressure; androgen excess androgens. Pill containing the anti-
excess may be involved in the high levels of androgenic progestogen cyproterone acetate
CYP19, a gene encoding for the enzyme is administered in cyclical doses, or
aromatase, expressed in abdominal tissue drospirenone-containing combined oral
fat. A high expression of this gene, induces contraceptives could be beneficial for
low estrogen and high androgen hirsutism. [5] Metformin has been used for
concentrations. the treatment of polycystic ovary syndrome
[4]
and it can increases insulin sensitivity by
Obesity: decreasing gluconeogenesis, lipogenesis and
Obesity mainly associated with the enhancing glucose uptake in the liver,
greater disposition of femoral and truncal skeletal muscle, adipose tissue and ovaries.
[8]
abdominal fat distribution. Hyperandrogenism related to Ovarian
Hyperandrogenism is associated with a hyperthecosis can be treated either by
prevalence of truncal abdominal fat. Women bilateral oophorectomy or GnRH analogs,
with PCOS have a greater truncal abdominal which improve symptoms and may improve
fat distribution as it is described by the concomitant metabolic abnormalities. [15]
presence of an increased waist: hipratio. [35] Administration of liraglutide has been
associated with a significant reduction in
Dyslipidemia: BMI and which is a more sensitive indicator
It is defined as abnormality of lipid of visceral obesity and metabolic outcomes.
[4]
metabolism. High density lipoproteins The management of PCOS targets the
(HDL) play a key role in lipid metabolism anovulation, infertility, hirsutism, or acne
and it is most important predictor of being the most common complaints. [14]
cardiovascular risk in PCOS women. [40] Spironolactone was able to improve insulin
Several studies noticed that reduced HDL sensitivity and is also recommended in the
cholesterol and elevated serum triglycerides, treatment of hyperandrogenism- associated
along with elevated plasminogen activator symptoms such as acne and hirsutism. [14] A
inhibitor‐I concentrations explains recent meta-analysis observed that
hyperandrogenism pathogenesis in PCOS. combination of life-style modifications such
[6]
as exercise, duration of diet and behavioural
change plus metformin for 6 months is
Ischaemic heart disease: associated with lower BMI and
Several studies concluded that altered fat subcutaneous adipose tissue as compared to
distribution is associated with androgen lifestyle plus placebo. [8]
excess may be an indicator of a greater risk
for ischaemic heart disease. [35] The CONCLUSION
incidence of coronary artery disease is In the present study, we concluded
correlated with carotid atherosclerosis. [35] that high levels of testosterone increase the
Increased intima-media wall thickness risk of cardiovascular events in PCOS
(IMT) is an early marker of atherosclerosis. females. Testosterone plays a major role in
[21]
women and it is essential regulator of
cardiovascular, bone and brain functions.
International Journal of Research and Review (ijrrjournal.com) 289
Vol.7; Issue: 7; July 2020Suku Sneha. Effect of high levels of testosterone on cardiovascular risk in polycystic ovary syndrome (PCOS)
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androgen levels and blood pressure in young
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