Suleiman Ghunaim and Ghina Ghazeeri*
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and
Infertility, American University of Beirut Medical Center
Abstract
Polycystic Ovary Syndrome (PCOS) is a common reproductive/gynecologic medical entity which often leads to an ovulatory state that could potentially
lead to infertility. It is defined by the presence of two of the three following criteria: hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The
majority of women with this condition are obese and have a higher prevalence of impaired glucose tolerance as well as insulin resistance which supports the
fact that PCOS has a major role in the development of diabetes. Moreover, PCOS patients are at a higher risk of adverse cardiovascular outcomes, including
a higher incidence of future development of hypertension, and dyslipidemia, early onset endothelial dysfunction, arterial stiffness, and formation of plaques
which might compromise the integrity of the coronary arteries and potentially increase the risk of cardiovascular disease. It is imperative that gynecologists
have a good understanding of the long term implications PCOS carry upon diagnosis and thus be able to provide a more general and complete clinical picture
about the disease and aid in proper patient counseling.
INTRODUCTION
Polycystic Ovary Syndrome (PCOS) is a common
reproductive/gynecologic medical entity which often leads to
an anovulatory state that could potentially lead to infertility.
It is defined by the presence of two of the three following
criteria: hyperandrogenism, ovulatory dysfunction, and
polycystic ovaries [1]. Although the exact underlying mechanism
of PCOS remains unclear, it is presumed to be complex and
multifactorial. The hormone imbalance created by a combination
of hyperandrogenism and/or insulin resistance plays an
important role in the pathophysiology of PCOS. It is believed that
a combination of genetic and environmental factors which may
result in hormone disturbances with other factors such as obesity,
ovarian dysfunction, and hypothalamic pituitary abnormalities
all contribute to the etiology of PCOS [2].
The prevalence of PCOS may be different according to ethnic
background. It was reported that women of South Asia may
present at a younger age and even have more severe symptoms
[3]. The risk of diabetes was increased by 4.4 folds in women
with PCOS residing in Asia estimated that the Middle Eastern
prevalence of PCOS is around 16% of the reproductive age female
population thus it is regarded to be one of the most common
endocrine disorders in women of reproductive age in our region
[4,5].
Hyperandrogenism manifested by hirsutism, acne, and
menstrual disorders may also be characteristic. The majority
of women with this condition are obese and have a higher
prevalence of impaired glucose tolerance as well as insulin
resistance reported in around 65–80% of women independent
of their obesity [6]. The prevalence of impaired glucose tolerance
in patients with PCOS ranges from 23% to 35%, and another 4%
to 10% of these women may present with undiagnosed type 2
diabetes [7]. The prevalence of impaired glucose tolerance was
noted in body mass index (BMI)–matched patients to be 2.1-folds
higher, non–BMI-matched 4.8-folds higher, lean-matched 4.4-fold
higher, and overweight or obese–matched groups 2.5-fold higher
[8]. After controlling for BMI, PCOS patients had a greater than
threefold increased odds (95% confidence interval (CI) 1.2–8.0)
of developing diabetes compared with normal-weight control
subjects, which supportsthe fact that PCOS has a major role in the
development of diabetes beyond the boundaries of contribution
of BMI alone [9]. A large longitudinal study from Taiwan showed
a significantly higher prevalence of diabetes in 4,595 women
with PCOS compared with age-matched control women (2.4% vs.
1.4%) [10].
Sleep disorders, predominantly sleep apnea, have been
reported with higher prevalence in women with CI PCOS, this
may add to the metabolic baseline risk these patients have [11].
Furthermore, patients with PCOS are at a higher risk of
adverse cardiovascular outcomes, including a higher incidence
of future development of hypertension, and dyslipidemia [12,13].
It is imperative that gynecologists have a good understanding
of the long term implications PCOS carry upon diagnosis and thus
be able to provide a more general and complete clinical picture
about the disease and aid in proper patient counseling. It is also
important that all providers are aware of these increased risks
and follow the current guidelines that recommend what and
when to screen women with PCOS [13].
METABOLIC AND CARDIOVASCULAR RISKS
In a recent case control study, and in women below the age of
40 years, the incidence rates ofprediabeteswere 29.7 and 25.9 per
1,000 person-years for PCOS and healthy women, respectively,
and the incidence rates of diabetes were 12.9 and 4.9 per 1,000
person-years for PCOS patients and controls, respectively over a
median follow up time of 12.9 years [14].
Regarded as a non-modifiable risk factor for type II diabetes
the Royal College of Obstetricians and Gynecologists recommends
a 75g 2-hr oral glucose for screening women with PCOS for
impaired glucose tolerance, as this has been proven to be more
superior to fasting blood glucose measurement alone which can
lead to the under diagnosis of type 2 diabetes in women with
PCOS [15-17]. Moreover, the 2013 Endocrine Society guidelines
recommends the use of 2‐hour oral glucose tolerance test (OGTT)
with a 2‐hour glucose measurement to screen for impaired
glucose tolerance, defined as a blood glucose ≥140 mg/dL [18].
Subsequent screening can be performed at 1–3 year intervals
based on the presence of other risk factors for diabetes [13].
There is a strong correlation between PCOS and increased
cardiovascular disease with an increased lifetime risk of CVD
morbidity [19]. In an Australian longitudinal study on women’s
health, women with PCOS (n = 183) had a higher prevalence of
hypertension than 4,638 control women aged 28–33 years; 5.1%
vs. 1.0%; P<.001. However, as part of the multivariable model
including BMI and DM, there was only a “clinical” trend toward
an association between PCOS and hypertension however with no
statistical significance (OR 1.6, 95% CI 0.9–2.6; P =.09) [20]. After
controlling for age, BMI, and ethnicity, women with PCOS above
the age of 40 years had higher rates of hypertension than control
women (29.2% vs. 18.8%; P =.03) which shows the persistence of
the effect of PCOS on the cardiovascular system [21].
Dyslipidemia is common in young women with PCOS [22].
Historically, authors looked at the changes of triglycerides and
HDL-Cholesterol in patients with PCOS as part of associated
metabolic investigation [23]. yet, a large number of studies have
found an increase of LDL-Cholesterol levels in women with PCOS.
In a recent met analysis, triglyceride levels were 26 mg/dL (95%
CI 17–35) higher and HDL-cholesterol concentrations 6 mg/dL
(95% CI 4–9) lower in women with PCOS. The LDL-cholesterol
concentration was higher in PCOS by 12 mg/dL (95% CI 10–16)
[24]. In general, there are few studies reporting the persistence
of dyslipidemia beyond the age of 40 years. Hudecova et al.
reported a persistently higher triglyceride levels in women with
PCOS compared to non PCOS patients (mean age 43 ± 5.8 y) even
after controlling for BMI although both were in the normal range.
Therefore, the American College of Obstetricians and
Gynecologists (ACOG) guidelines have recommended that
women with PCOS should have a complete fasting lipid
and lipoprotein evaluation as part of their cardiovascular
risk assessment. [25].
Furthermore, PCOS patients tend to suffer from an early
onset endothelial dysfunction, arterial stiffness, and formation of
plaques which might compromise the integrity of the coronary
arteries and potentially increase the risk of CVD [26]. In a recent
meta-analysis, Meyer et al. reported a mean difference in Carotid
artery Intima-Media Thickness (C-IMT) among women with PCOS
compared with controls was 0.072 mm [95% confidence interval
(CI) 0.040, 0.105, P < 0.0001], for every 0.1 mm incremental
increase in mean C-IMT, the hazard of stroke increases by 18%
and the hazard of myocardial infarction MI increases by 15%
[27,28]. This was even demonstrated to be persistent even
among patients beyond the age of 45 [29].
Serum triglycerides and high‐density lipoprotein cholesterol
(HDL) are also associated with insulin resistance, have day-today variability, and do not add additional cost as they are already
recommended for screening of lipid abnormalities in PCOS [30].
All patients with PCOS should be offered regular monitoring
for weight changes. Monitoring could be at each visit or at a
minimum 6–12 monthly [13]. Although the available evidence is
in favor of an increased CVD risk above the general population,
there is not yet an established verified risk calculator that could
be of reliable use by the treating physician, thus clinical judgment
along with established proper history taking which includes
personal history of smoking, cardiovascular or metabolic
disease as well as family history of metabolic, cardiovascular, or
endocrine diseases, along with a physical exam which includes
blood pressure (BP) measurement (at least annually) [13], BMI
and waist circumference based on individualized assessment
may prompt further investigation including measurement of
cholesterol and triglyceride levels.
MANAGEMENT
Diabetes mellitus, insulin resistance, and metabolic
abnormalities are all significantly lower in lean women
(BMI<25kg/m2
) with PCOS [31] and even many physicians do
not prefer to use the term “insulin resistance” in the absence of
obesity [32]. Although the issue of a lower incidence of insulin
resistance per se remains debatable in the literature with a
reported prevalence of 6-22% among lean PCOS patients [33]. The
recommended first line management of high risk PCOS women
defined as obese (BMI>30kg/m2
) women, or women with already
existing metabolic disorder, or at a significantly higher risk above
the general population of developing a metabolic disorder [34],
is the implication and maintenance of lifestyle modification
plans which include a healthy diet, exercise and weight loss. A
reduction of as little as 5% of total body weight in overweight/
obese women has been shown to enhance sensitivity to insulin
and reduce testosterone levels which in the end may improve the
overall cardiovascular risk [35]. This entitles a multidisciplinary
approach from doctors, nurses, dieticians, and health fitness
specialists to establish the goal of improved lifestyle and help
maintain it [36]. The utilization of behavioral change and the
utilization of cognitive behavioral therapy over an 8 week
period resulted in a significant weight drop (-0.35 kg/wk 95%
CI −0.47 to −0.23), vs. -0.16 kg/wk in controls (95% CI −0.28 to
−0.04) p=0.033) in addition to improvement in the quality of life
[37]. According to the National Institute for Health and Clinical
Excellence guidelines, failed lifestyle modification strategies , and
those patients with a BMI of 40 kg/m2
or more or who have a BMI
of 35 kg/m2
or more with a high-risk obesity-related condition
(such as hypertension or type II diabetes) should be considered
for bariatric surgery [16].
The 2013 Endocrine Society guidelines suggest the use of
metformin as a second‐line therapy in young PCOS women with
hyperglycemia, defined as impaired glucose tolerance or type 2
diabetes [18].
Although considered in women with PCOS undergoing
lifestyle management regimes [38], in recent literature, there
is still no strong evidence in the benefit from the use of insulin
sensitizing agents such as Metformin in women with PCOS
especially when addressing its efficacy among different BMI’s
with evidence that women with a BMI above 37kg/m2
have a
poorer response to Metformin [39,40].
According to the Joint British Societies’ guidelines,
hypertension should be treated, and persistent blood pressures
greater than or equal to 140 mmHg systolic and/or 90 mmHg
diastolic, not responding to lifestyle measures, need to be
considered for drug therapy (patients with diabetes or other
high-risk factors with blood pressure greater than 130 mmHg
systolic and/or 80 mmHg diastolic may require drug therapy
[41]. Pharmacological treatment modalities are beyond the scope
of this review.
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