Arch Gynecol Obstet (2014) 290:1079–1092
DOI 10.1007/s00404-014-3433-z
REVIEW
Focus on metabolic and nutritional correlates of polycystic ovary
syndrome and update on nutritional management of these critical
phenomena
Mariangela Rondanelli • Simone Perna •
Milena Faliva • Francesca Monteferrario •
Erica Repaci • Francesca Allieri
Received: 14 February 2014 / Accepted: 22 August 2014 / Published online: 9 September 2014
 Springer-Verlag Berlin Heidelberg 2014
Abstract
Introduction Polycystic ovary syndrome (PCOS) is
associated with numerous metabolic morbidities (insulin
resistance (IR), central obesity) and various nutritional
abnormalities (vitamin D deficit, mineral milieu alterations,
omega6/omega3 PUFA ratio unbalance).
Methods We performed a systematic literature review to
evaluate the till-now evidence regarding: (1) the metabolic
and nutritional correlates of PCOS; (2) the optimum diet
therapy for the treatment of these abnormalities. This
review included 127 eligible studies.
Results In addition to the well-recognized link between
PCOS and IR, the recent literature underlines that in PCOS
there is an unbalance in adipokines (adiponectin, leptin,
visfatin) production and in omega6/omega3 PUFA ratio.
Given the detrimental effect of overweight on these met-
abolic abnormalities, a change in the lifestyle must be the
M. Rondanelli (&)
S. Perna
M. Faliva
F. Monteferrario

E. Repaci
F. Allieri
Department of Public Health, Experimental and Forensic
Medicine, Section of Human Nutrition, Endocrinology and
Nutrition Unit, University of Pavia, Azienda di Servizi alla
Persona, Pavia, Italy
e-mail: mariangela.rondanelli@unipv.it
S. Perna
e-mail: simoneperna@hotmail.it
M. Faliva
e-mail: milo.milena87@hotmail.it
F. Monteferrario
e-mail: francescamontef@libero.it
E. Repaci
e-mail: ericarepaci@gmail.com
F. Allieri
e-mail: francesca.allieri@gmail.com
cornerstone in the treatment of PCOS patients. The opti-
mum diet therapy for the PCOS treatment must aim at
achieving specific metabolic goals, such as IR improve-
ment, adipokines secretion and reproductive function.
These goals must be reached through: accession of the
patient to hypocaloric dietary program aimed at achieving
and/or maintaining body weight; limiting the consumption
of sugar and refined carbohydrates, preferring those with
lower glycemic index; dividing the food intake in small and
frequent meals, with high caloric intake at breakfast;
increasing their intake of fish (4 times/week) or taking
omega3 PUFA supplements; taking Vitamin D and chro-
mium supplementation, if there are low serum levels.
Conclusion Lifestyle intervention remains the optimal
treatment strategy for PCOS women. A relatively small
weight loss (5 %) can improve IR, hyperandrogenism,
menstrual function, fertility.
Keywords Polycystic ovary syndrome
Dietary
management
Dietary supplement
Overweight

Adipokines
Insulin resistance
Introduction
Polycystic ovary syndrome (PCOS) is one of the most
common female endocrine disorders with a prevalence of
approximately 5–10 % in women of reproductive age [1,
2], and women with PCOS are at increased risk of repro-
ductive abnormalities [3]. PCOS is a heterogeneous syn-
drome characterized by increased ovarian and adrenal
androgen secretion with hyperandrogenic symptoms, such
as hirsutism, acne and/or alopecia, menstrual irregularity,
anovulation and infertility [3]. A positive diagnosis is made
when the patient has any two of the three features: oligo-
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ovulation/anovulation, clinical and/or biochemical signs of
hyperandrogenism, and polycystic ovaries on ultrasound
examination, according to Rotterdam ESHRE/ASRM-
sponsored PCOS consensus workshop [4]. Besides the
endocrinological abnormalities observed in this syndrome,
profound metabolic alterations have also been documented:
insulin resistance (IR), hyperinsulinemia, central obesity
and metabolic syndrome (MeTS) [5], which increase risks
for developing type 2 diabetes (T2DM), cardiovascular
disorders, hypertension, atherosclerosis and dyslipidemia
[6]. Hyperinsulinemia and IR stimulate ovarian androgen
production [7, 8] and decrease serum sex hormone-binding
globulin (SHBG) concentrations [9, 10], leading to
increased levels of circulating free testosterone. This
association between IR and ovarian hyperandrogenism
suggests that insulin directly influences ovarian function
[11]. Women with PCOS have increased ovarian cyto-
chrome P450c17a activity, as evidenced by an elevated
serum 17OHP (17a-hydroxyprogesterone) in response to
stimulation by GnRH (gonadotropin-releasing hormone)
agonists [12]; ovarian cytochrome P450c17a appears to be
stimulated by insulin in PCOS.
Given this background, the aim of the present systematic
review is to summarize the state of the art according to the
extant literature about two topics: (1) the metabolic and
nutritional correlates of PCOS and (2) the optimum diet
therapy for the treatment of these abnormalities.
Methods
The present systematic review was performed following
the steps by Egger et al. [13] as follows: (1) configuration
of a working group: three operators skilled in endocrinol-
ogy and clinical nutrition, of whom one acting as a meth-
odological operator and two participating as clinical
operators. (2) Formulation of the revision question on the
basis of considerations made in the abstract: ‘‘the state of
the art on metabolic and nutritional correlates of PCOS and
their nutritional treatment’’. (3) Identification of relevant
studies: a research strategy was planned, on PubMed
[Public Medline run by the National Center of Biotech-
nology Information (NCBI) of the National Library of
Medicine of Bathesda (USA)], as follows: (a) definition of
the key words (Polycystic Ovary Syndrome, dietary man-
agement, dietary supplement, overweight, adipokines,
insulin resistance), allowing the definition of the interest
field of the documents to be searched, grouped in inverted
commas (‘‘…’’) and used separately or in combination;
(b) use of: the Boolean (a data type with only two possible
values: true or false) AND operator that allows the estab-
lishments of logical relations among concepts; (c) research
modalities: advanced search; (d) limits: time limits: papers
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Arch Gynecol Obstet (2014) 290:1079–1092
published in the last 20 years; humans; languages: English;
(e) manual search performed by the senior researchers
experienced in clinical nutrition through the revision of
reviews and individual articles on microbiota in elderly
published in journals qualified in the Index Medicus. (4)
Analysis and presentation of the outcomes: the data
extrapolated from the revised studies were collocated in
tables; in particular, for each study we specified: the author,
the name of the journal where the study was published and
year of publication, study characteristics. (5) The analysis
was carried out in the form of a narrative review of the
reports. At the beginning of each section, the keywords
considered and the kind of studies chosen have been
reported. Suitable for the systematic review were studies of
any design, which considered women with PCOS diag-
nosed consistently to The Rotterdam ESHRE/ASRM-
Sponsored PCOS Consensus Workshop Group, 2004 [4].
Results
Metabolic correlates in PCOS
Obesity and insulin resistance
This research has been carried out based on the keywords:
‘‘Polycystic Ovary Syndrome’’ AND ‘‘obesity’’ AND
‘‘insulin resistance’’; 1,248 articles were sourced. Among
them, 22 retrospective studies, 12 reviews, 7 cross-over
studies, 3 double-blind studies, 2 retrospective studies and
1 cohort study have been selected and discussed.
Obesity is not necessarily a defect intrinsic to PCOS [14],
but is a significant characteristic of this syndrome [4, 15, 16],
with a pooled estimated prevalence of 49 %, as shown in a
recent meta-analysis [17] and, specifically central obesity,
worsens the phenotype [18]. Adiposity-dependent IR is
linked with PCOS, given that the prevalence of obesity
among women with PCOS is higher than that of age-matched
healthy women without this syndrome, as determined at
referral centers [13]. IR occurs in approximately 50–70 % of
women with PCOS and in 95 % of obese women with PCOS
[19, 20]. The degree of IR in PCOS is greater than that pre-
dicted by the Body Mass Index (BMI-ratio between weight
and the square of the height), although 40–50 % of women
with PCOS are not obese [21–23]. The prevalence of MetS
and IR varies between the different female hyperandrogenic
phenotypes [24]. In another study [25], non-hyperandro-
genic anovulatory cases of PCOS were found to show only
marginal risk. Given this well-documented association
between PCOS and IR, insulin-sensitizing agents have been
used in the therapy of PCOS. As shown in a 2003 Cochrane,
over 50 intervention studies have demonstrated a positive
effect of metformin on both reproductive and metabolic
Arch Gynecol Obstet (2014) 290:1079–1092
aspects of PCOS [26]. It is peculiar that numerous random-
ized controlled trials (RCT) showed this positive effect of
metformin therapy on endocrine and metabolic variables, not
only in obese or insulin-resistant PCOS patients, but even in
lean and insulin-sensitive women [27–31]. A recent con-
sensus on women’s health aspects of PCOS [32] has defined
that metformin treatment is indicated in those with impaired
glucose tolerance (IGT) who do not respond adequately to
calorie restriction and lifestyle changes. As regards the
relationship between IR and menstrual disturbance, PCOS
patients with isolated primary or secondary amenorrhea or
oligomenorrhea and patients with secondary amenorrhea
alternating with regular menstrual cycles had more pro-
nounced IR than women with regular menstrual cycles [33].
In contrast, patients with oligomenorrhea alternating with
secondary amenorrhea or with regular menstrual cycles did
not differ in markers of IR from women with regular men-
strual cycles. Two previous studies reported that patients
with PCOS and oligomenorrhea or amenorrhea had more
severe IR than patients with PCOS and regular cycles [34,
35]. In contrast, in two other more recent studies that ana-
lyzed patients with amenorrhea separately from patients with
oligomenorrhea, only the former had more pronounced IR
than patients with regular menses [36, 37]. As regards
intraovarian hyperinsulinemic pathways, hyperinsulinemia
may have preferentially impaired oocyte developmental
competence, resulting in reduced rates of fertilization,
embryonic development and implantation in PCOS patients
with obesity [38, 39]. Data from in vitro cell culture models
suggest that co-incubation of insulin and follicle-stimulating
hormone (FSH) with mouse [40] and bovine [41] oocytes
promotes FSH-induced up-regulation of GC (granulose
cells) LH (luteinizing hormone) receptor mRNA expression
[42–44], inhibiting FSH stimulation of aromatase activity
[41], thus reducing the percentage of fertilized oocytes that
develop into blastocysts [45, 40]. Insulin may induce local
androgen production, which results in oocytes of lower
quality, post-maturity [46]. At the molecular level, insulin
binds to its receptor, localized on GC and theca cells, and
oocytes, to stimulate follicle recruitment [45, 47], conse-
quently altering expression of multiple genes involved in
meiotic/mitotic spindle dynamics and centrosome function
in PCOS oocytes [48]. This indicates that insulin may be an
important mediator of oocyte developmental competence via
a ligand-receptor regulating system [45].
Chronic low-grade inflammation has emerged as a key
contributor to the pathogenesis of PCOS and emerging data
suggest that this chronic low-grade inflammation underpins
the development of metabolic aberration, such as IR, and
ovarian dysfunction in PCOS [49, 50]. Most importantly,
there is a strong association between hyperandrogenism
and inflammation in PCOS [51–54].
1081
In summary, IR is a relative common finding in PCOS
women, independent of obesity. Assessment of insulin
sensitivity may allow identification of patients at higher
risk for metabolic sequelae and allow the selection of
patients most likely to respond to treatment with insulin-
sensitizing drugs.
Adipokines unbalance in PCOS
This research has been carried out based on the keywords:
‘‘Polycystic Ovary Syndrome’’ AND ‘‘adipokines’’ AND
‘‘insulin resistance’’ 220 articles were sourced. Among
these, 9 reviews, 29 prospective studies, 17 cross-over
studies and 3 single-blinded studies have been selected and
discussed.
Paracrine dysregulation of adipokine production by
macrophage-secreted cytokines in PCOS favors develop-
ment of IR [55]. Considering the frequent clustering of
obesity and IR-associated disorders in PCOS patients,
adipokines have been proposed to play a role in the path-
ogenesis of PCOS [56]. Adipokines may thus serve as an
endocrine link between obesity and PCOS [57]. Moreover,
a possible role for cytokine products of fat (adipokines) as
a link between reproductive and metabolic abnormalities
has been mooted [58, 59]. Abnormal serum levels of var-
ious adipokines in PCOS have been reported in the litera-
ture [60].
Adiponectin Adiponectin is considered to be one of the
most important adipokines in human physiology and differs
from most other adipokines by having a protective effect
on development of obesity. The disruption of adiponectin
and its receptors is a major mechanism that links metabolic
and reproductive dysfunction in women with polycystic
ovary syndrome [61]. Serum adiponectin levels are
decreased in PCOS patients [56, 62–67], yet this result may
be explained by the concurrence of obesity [64], IR [65,
66] and/or IGT [67] in these women, whereas other
researches reported that serum adiponectin concentrations
did not seem to differ between PCOS and controls [68]. A
meta-analysis [69] revealed that serum adiponectin levels
are lower in women with PCOS compared with BMI-
matched healthy controls and that the more insulin-resis-
tant women with PCOS recruited, the lower serum adipo-
nectin levels were found. The effects of adiponectin are
mediated by at least two main receptors that have been
identified recently [70]: adiponectin receptor-1 (AdipoR1)
that is abundantly expressed in skeletal muscle, and
adiponectin receptor-2 (AdipoR2) that is predominantly
expressed in the liver. PCOS patients had lower baseline
serum adiponectin and AdipoR1 compared to healthy
women after controlling for BMI [71].
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Leptin In humans, leptin acts as an afferent satiety signal,
regulating appetite and weight and is mainly produced in
the adipocyte of white adipose tissue [72]. However, recent
studies have confirmed that other tissues also express lep-
tin, including placenta, ovaries, skeletal muscle, stomach,
pituitary, and liver [73]. Leptin appears to act as an
endocrine and paracrine factor for the regulation of puberty
and reproduction; it affects maternal, placental and fetal
function, modifies insulin sensitivity in the muscle or liver,
prevents ectopic lipid deposition, and links the endocrine
and immune systems [74, 75]. Leptin levels have been
reported to be increased in women with PCOS in com-
parison to weight-matched controls [76–79] although this
was not supported by many other studies [80–83]. Wang
also reported significantly higher mRNA expression of
leptin in subcutaneous adipose tissue of PCOS patients
compared with controls [81–84]. No significant difference
was found in circulating leptin levels between the ovula-
tory and anovulatory PCOS patients either [83]. Further-
more, a recent study showed that there was no effect of
PCOS on either adipose leptin expression or plasma leptin
levels [85]. As regards relationship with IR, no significant
differences were observed in serum leptin or leptin receptor
(LEPR) levels between PCOS IR and PCOS non-IR
women [84]. However, Yildizhan [79] observed an asso-
ciation between serum leptin levels with IR in young
women with PCOS.
Visfatin Visfatin is a more recently described adipokine
that also appears to have insulin-like effects [86]. It has
previously been reported that the gene expression and
circulating levels of visfatin were increased in women with
PCOS compared with age- and BMI-matched controls [87–
94]. However, several recently published studies did not
find a difference in plasma or serum visfatin levels between
patients with PCOS and control groups [95–97] Moreover,
Chan [88] did not observe any correlation between visfatin
concentrations and testosterone, insulin, and LH levels in
either PCOS or control groups. A positive correlation,
however, was found between plasma visfatin concentra-
tion, fasting insulin, and homeostasis model assessment
(HOMA)-IR, as reported by Tan [87].
In summary, at present, any indication to measure rou-
tinely circulating levels of such adipokines is present in the
literature, but this topic represents an intriguing topic of
research in PCOS women.
Weight loss and adipokines
There is a paucity of data on the effects of weight loss on
serum adipokine levels in overweight/obese patients with
PCOS [98, 99]. A recent prospective study by Spanos [94]
demonstrated that weight loss (about 12 %) by diet and
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orlistat results in a significant reduction in serum leptin
levels in both patients with PCOS and controls, and this
decrease is comparable in the two groups. On the other
hand, serum adiponectin, resistin, and visfatin levels are
not affected by weight loss. Previous short-term
(1–8 weeks) studies on the effects of hypocaloric diet in
PCOS patients showed that serum leptin levels decline in
parallel with weight loss [98, 100, 101]. This finding is
somewhat expected because the degree of obesity is the
major determinant of serum leptin levels in patients with
PCOS [81, 102, 103].
In summary, our current understanding of the role for
adipokines in PCOS is far from complete. Moreover, there
is a paucity of data on the effects of weight loss on serum
adipokine levels in overweight/obese patients with PCOS.
Nutritional correlates in PCOS
Mineral deficiency and its treatment
This research has been carried out based on the keywords:
‘‘Polycystic Ovary Syndrome’’ AND ‘‘mineral’’; 59 articles
were sourced. Among them, 2 reviews, 11 prospective
studies and 5 cross-over studies have been selected and
discussed.
Magnesium Decreased magnesium level was reported in
women with increased testosterone levels [104] and/or IR
[105]. A prospective study demonstrated that the PCOS
women with IR exhibited significantly lower serum levels
of magnesium than controls and PCOS women without IR
and that circulating serum magnesium significantly corre-
lated with fasting insulin levels [106]. Hypomagnesemia is
associated with T2DM and MetS [107].
Copper Two recent prospective studies showed that
higher serum copper level is observed in PCOS patients
than in the controls [106, 108], which significantly
increases with the association of insulin resistance [106].
Moreover, copper, in addition to its enzymatic roles, sim-
ilarly can induce oxidative stress by catalyzing the for-
mation of reactive oxygen species and decreasing
glutathione levels [77]. Many studies conferred the role of
increased oxidative stress resulting from high generation of
reactive oxygen species (ROS) in the pathogenesis of
PCOS [53, 109].
Chrome Chrome picolinate consists of trivalent chro-
mium (Cr3?), an extremely safe [110] and highly tolerable
trace mineral that is present in the normal diet [111],
complexed to picolinic acid to enhance gut absorption.
After cleavage of picolinic acid, Cr3? is transported by
transferrin and later, by chromodulin, its binding protein.
Arch Gynecol Obstet (2014) 290:1079–1092 1083

Table 1 Metabolic or nutritional correlates in PCOS and recommended treatment

Metabolic or Recommended treatment References Type of study Results after recommended treatment
nutritional
correlates

Insulin Intake of foods with low Graff [151] Cross-sectional study Dietary GI is increased in the classic
resistance glycemic index PCOS phenotype and associated
with a less favorable
anthropometric and metabolic
profile
Mehrabani Single blind clinical trials: hypocaloric Both hypocaloric diets significantly
[150] diet (CHCD) (15 % of daily energy led to reduced body weight and
from protein) and a modified androgen levels in these two groups
hypocaloric diet (MHCD) with a of women with PCOS. The
high-protein, low-glycemic load combination of high-protein and
(30 % of daily energy from protein low-glycemic-load foods in a
plus low-glycemic-load foods) modified diet caused a significant
increase in insulin sensitivity and a
decrease in hsCRP level when
compared with a conventional diet
Overweight or Low caloric diet with high Moran Systematic review Greater weight loss for a
obesity protein and low glycemic [148] monounsaturated fat-enriched diet;
load improved menstrual regularity for a
low-glycemic index diet; increased
free androgen index for a high-
carbohydrate diet; greater
reductions in insulin resistance,
fibrinogen, total, and high-density
lipoprotein cholesterol for a low-
carbohydrate or low-glycemic
index diet; improved quality of life
for a low-glycemic index diet; and
improved depression and self-
esteem for a high-protein diet.
Weight loss improved the
presentation of PCOS regardless of
dietary composition in the majority
of studies. Weight loss should be
targeted in all overweight women
with PCOS through reducing
caloric intake in the setting of
adequate nutritional intake and
healthy food choices irrespective of
diet composition
Alterations in Balanced low-calorie diet Rafraf Intervention study: 720 mg/day Increased serum adiponectin levels,
the secretion with adequate timing of [135] eicosapentaenoic acid and 480 mg/ insulin resistance and lipid profile
of adipokines intake of meals and day docosahexaenoic acid
and cytokines supplements with omega3 Leidy Intervention study: two isocaloric high caloric intake at breakfast with
fatty acids [152] (*1,800 kcal) maintenance diets reduced intake at dinner results in
with different meal timing improved insulin sensitivity indices
distribution: a BF (breakfast diet) and reduced cytochrome P450c17a
(980 kcal breakfast, 640 kcal lunch activity, which ameliorates
and 190 kcal dinner) or a D (dinner hyperandrogenism and improves
diet) group (190 kcal breakfast, ovulation rate
640 kcal lunch and 980 kcal dinner)
Low blood Intake of vitamin D Pal [129] Intervention study: 8,533 UI/day of Androgen and Blood Pressure
levels of 25 supplement vitamin D profiles improved
hydroxy Wehr [130] Intervention study: 20,000 IU Vitamin D treatment might improve
vitamin D cholecalciferol weekly glucose metabolism and menstrual
frequency

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Table 1 continued
Metabolic or Recommended treatment References
nutritional
correlates
Alteration of Intake of chromium picolinate Lydic
the milieu of supplement [117]
trace
minerals
GI glycemic index, hsCRP high-sensitivity C-reactive protein
This complex binds the insulin receptor [111]. Active
glucose transport is enhanced through tyrosine kinase
phosphorylation, without inhibition of phosphotyrosine
phosphatase [84]. Chrome deficiency as a cause of glucose
intolerance was recognized first in 1977 [112]. Chromium
appeared to improve the effects of insulin and worked at
the level of the cell membrane [113]. The interaction
between chromium and insulin has been elucidated by the
discovery of low-molecular weight chromium-binding
substance, which binds chromium and the insulin receptor,
activating the insulin receptor’s kinase activity [114, 115].
Morris and colleagues [116] showed diminished plasma
Cr3? levels in T2DM subjects, suggesting that Cr3? losses
diminish insulin sensitivity and worsen T2DM. As dem-
onstrated, Cr3? (1,000 lg as chrome picolinate) improved
glucose disposal in five obese PCOS subjects after
2 months [117].
In summary, some studies suggest that PCOS women
have mostly insufficient magnesium levels, so magnesium
replacement therapy may have a beneficial effect on
ameliorating the IR. Also, CrP supplementation may
improve IR in PCOS, as shown in the literature (Table 1).
Higher serum copper level is observed in PCOS patients
than the controls, so RCT must be performed to evaluate if
therapy with copper chelators may be useful in PCOS
women with elevated blood levels of copper.
Nutritional correlates in PCOS: vitamin D deficiency
and its treatment
This research has been carried out based on the keywords:
‘‘Polycystic Ovary Syndrome’’ AND ‘‘vitamin D’’; 59
articles were sourced. Among them, 6 reviews, 7 pro-
spective studies and 1 cross-over study have been selected
and discussed.
Vitamin D is rapidly emerging as an important bio-
molecule with effects beyond the already established role
in calcium and phosphorus metabolism. The various
pathways include apoptotic pathway, insulin metabolism,
growth and differentiation [118]. There is some evidence
suggesting that vitamin D deficiency might be involved in
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Type of study Results after recommended treatment
Intervention study: dietary supplement Improved glucose disposal
with 1,000 lg as CrP/day
the pathogenesis of insulin resistance and the metabolic
syndrome in PCOS [119, 120]. Vitamin D deficiency has
been shown to be associated with impaired glucose clear-
ance and insulin secretion in both human [121] and animal
models [122]. 25-Hydroxyvitamin D (25-OH-VD) is pos-
itively correlated with the insulin sensitivity and negatively
with beta-cell function [123]. A recent review by Thomson
et al. [124] suggests that there is an association between
vitamin D status and hormonal and metabolic dysfunctions
in PCOS. The underlying mechanism is, however, yet to be
elucidated. One of the plausible mechanisms may be the
dysregulation of the complex mechanism that regulated
ovarian apoptosis [125]. Due to its immunomodulatory
functions, hypovitaminosis D might induce a higher
inflammatory response, which is again associated with IR
[126, 127]. An interesting study on obese and non-obese
PCOS patients [128] demonstrated that low serum con-
centrations of 25-OH-VD have been associated with higher
BMI and total cholesterol values. This study also confirmed
the association between abdominal obesity, hyperandrog-
enism, and IR. A recent single-arm, open-label trial per-
formed for 3 months in 23 PCOS women supplemented
with Vitamin D and calcium suggests potential therapeutic
benefits of these nutrients supplementation in ameliorating
the hormonal milieu (significant reduction in total testos-
terone) and PCOS-related sequelae in women deficient in
vitamin D [129]. Another intervention study by Wehr [130]
conducted in fifty-seven PCOS women, which received
20,000 IU cholecalciferol weekly for 24 weeks, suggested
that vitamin D treatment might improve glucose metabo-
lism and menstrual frequency in PCOS women. The posi-
tive effect on glucose metabolism is in according to the
study by Selimoglu [131] that showed improvement in
HOMA indices within 3 weeks of a single oral mega dose
of 300,000 IU D3 in a pilot study on 11 PCOS women.
In summary, there are data that suggest pathophysio-
logical relevance of vitamin D deficiency for PCOS. Some
studies demonstrated that women with PCOS have mostly
insufficient vitamin D levels, and vitamin D replacement
therapy may have a beneficial effect on ameliorating the
hormonal status (significant reduction in total testosterone
Arch Gynecol Obstet (2014) 290:1079–1092
and menstrual disturbances) and PCOS-related sequelae
(improvement in IR) in women deficient in vitamin D
(Table 1).
Nutritional correlates in PCOS: imbalance in the n-6/n-3
PUFA ratio and its treatment
This research has been carried out based on the keywords:
‘‘Polycystic Ovary Syndrome’’ AND ‘‘plasma fatty acids’’;
12 articles were sourced. Among them, 1 review, 2 pro-
spective studies, 2 cross-over studies and 2 double-blind
studies have been selected and discussed.
An interesting study reported that increased dietary
polyunsaturated fatty acids (PUFA) intake could be asso-
ciated with improved endocrine and metabolic character-
istics in women with PCOS [132]. Eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) are n-3 long-chain
polyunsaturated fatty acids (n-3 LC PUFA) found primarily
in fatty fish. In current diets, n-6 fatty acids are predomi-
nant PUFA and imbalance in the n-6/n-3 PUFA ratio may
be related to chronic disease [133]. Many studies, as well
documented in the literature, have shown increasing evi-
dence for antiatherogenic and anti-inflammatory effects of
fish oil supplementation and it is conceivable that dietary
PUFA might also have benefit effects on glycemic control
and lipid profile [133–135]. Moreover, it seems that the
positive effect of EPA and DHA on metabolic parameters
could be partially due to enhancement of adiponectin
production [114, 136]. A recent RCT has demonstrated that
a supplementation for 8 weeks with 720 mg/day eicosa-
pentaenoic acid and 480 mg/day docosahexaenoic acid
increases serum adiponectin levels, insulin resistance and
lipid profile in a group of overweight or obese PCOS
patients [135, 137].
In conclusion, the data currently available, although the
research carried out are few, are very promising and show
that an adequate intake of omega3 fatty acids may be
useful in the control and prevention of metabolic compli-
cations of PCOS patient, as shown in Table 1.
Management of metabolic and nutritional correlates
of PCOS: lifestyle modification
This research has been carried out based on the keywords:
‘‘Polycystic Ovary Syndrome’’ AND ‘‘lifestyle’’ AND
‘‘diet’’; 101 articles were sourced. Among them, 7 reviews,
4 prospective studies, 6 cross-over studies 2 single-blinded
studies have been selected and discussed.
Lifestyle modification programs (LSM), comprised of
diet and physical activity, are recommended for in high risk
patients (prediabetic) to delay the onset of T2DM [138,
139], one of the most serious complications of PCOS.
Additionally, overweight and obese women with PCOS
1085
may benefit from LSM through adiposity reduction [140],
improved ovulatory function [141] and reduction in overall
cardiovascular risk [142]. Previous observational studies
demonstrated that LSM can be associated with clinical
improvement in PCOS, as shown in Table 2 Kiddy and
colleagues [143] demonstrated that moderate weight loss
(equal to 5 %) during long-term calorie restriction
(6 months) is associated with a marked clinical improve-
ment in menstrual function and fertility. Clark et al. [144]
demonstrated in a retrospective study that weight loss (the
average weight loss in the PCOS group was 6.3 kg, during
6 months of LSM program) is associated with improve-
ment in ovulation, pregnancy outcome, self-esteem and
endocrine parameters in women who are infertile and
overweight. Thomson demonstrated that in overweight and
obese women with PCOS and reproductive dysfunction, a
20-week weight loss intervention (with weight loss equal to
9 kg) resulted in significant reduction in fasting insulin,
homeostasis model assessment, testosterone and Free
Androgen Index (FAI), an increase in sex hormone-binding
globulin (SHBG) and in improvements in reproductive
function, but no change in anti-Mullerian hormone levels
[145]. A significant correlation between the weight
reduction (5–6 kg lost or lost 5–10 % of starting body
weight is highly recommended) and the improvement in
metabolic parameters could be attributed to decreased
insulin resistance or to other related factors. Clinicians
prescribing LSM interventions must consider the patient’s
capacity to sustain diet and exercise adherence and weight
maintenance over time in order for the clinical benefits on
PCOS to continue [146].
In summary, lifestyle modification (dietary intervention
and increased physical activity) remains the optimal
treatment strategy for overweight/obese women with
PCOS. The studies currently available showed that a rel-
atively small weight loss (equal to 5–10 %), achieved with
long-term caloric restrictions (5–6 months), can improve
IR and hyperandrogenism, menstrual function and fertility,
as reported in 2011 Cochrane by Moran [147]. Weight loss
can also improve long-term metabolic health.
Dietary composition and meal timing
The most important determinant of dietary intervention for
weight loss in PCOS women is energy balance, though for
many other reasons various types of diet have been pro-
posed and tested, as shown in a recent review by Moran
[148]. This review and meta-analysis reported that weight
loss should be targeted in all overweight women with
PCOS through reducing caloric intake in the setting of
adequate nutritional intake and healthy food choices, irre-
spective of diet composition. Table 1 summarizes the
studies investigating the optimum diet therapy and the
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1086
optimum dietary supplementation for the treatment of
PCOS. A crossover study conducted by Douglas demon-
strated that a moderate low-carbohydrate diet (43 %),
conducted for 16 days, reduced the fasting and postchal-
lenge insulin concentrations among PCOS women, which,
over time, may improve reproductive/endocrine outcomes
[149]. A following study conducted by Marsh in 96 PCOS
women confirmed this result: with only modest weight loss
(4–5 % of body weight), the low-carbohydrate diet pro-
vided a threefold greater improvement in whole-body
insulin sensitivity, improved menstrual regularity and bet-
ter emotion scores, compared to conventional hypocaloric
diet. By contrast, both the low-carbohydrate and the con-
ventional diets led to similar improvements or changes in
blood lipid and androgenic hormones concentrations,
markers of inflammation, and other measures of quality of
life. A further recent 12-week single-blind clinical trial, in
which a total of 60 PCOS overweight and obese women
were recruited and randomly assigned to (1) a conventional
hypocaloric diet (CHCD) (15 % of daily energy from
protein) and (2) a modified hypocaloric diet (MHCD) with
a high-protein, low-glycemic load (30 % of daily energy
from protein plus low-glycemic-load foods), demonstrated
that both hypocaloric diets significantly led to reduced
body weight and androgen levels, but the combination of
high-protein and low-glycemic-load foods in a modified
diet caused a significant increase in insulin sensitivity and a
decrease in high-sensitivity C-reactive protein level, when
compared with a conventional diet [150]. However, in a
recent cross-sectional study, Graff [151] demonstrated that
the intake of food with high glycemic index is increased in
the classic PCOS phenotype than in control women and is
associated with a less favorable anthropometric and meta-
bolic profile.
Concerning protein supplementation, in PCOS patients a
2-month hypocaloric diet, associated with a 240-kcal sup-
plement containing whey protein, reduced body weight, fat
mass, serum cholesterol, and apoprotein B more than the
same hypocaloric diet associated with a 240-kcal supplement
containing simple sugars instead of whey protein [98].
As regards the meal timing, recently, Jakubowicz and
colleagues found in 60 lean PCOS women that high caloric
intake at breakfast than high caloric intake at dinner led to
greater weight loss, improved glucose metabolism and
insulin sensitivity indices, which lead to the reduction of
ovarian P450c17a activity and, as a result, to decreased
ovarian testosterone synthesis [152]. Thus, the improve-
ment of insulin resistance indices found after high caloric
intake at breakfast suggests that the high caloric intake in
the morning might represent a schedule more synchronized
with the circadian pacemaker. This clock resetting could be
protective also against the disruption in hormone secretion
reported in PCOS patients [153, 154].
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Arch Gynecol Obstet (2014) 290:1079–1092
In summary, a weight loss of 5–10 % of original body
weight improves insulin sensitivity and short-term repro-
ductive fitness in PCOS overweight women and is addi-
tionally crucial for improving short- and long-term
metabolic health.
Discussion and conclusion
The adipose tissue of women with PCOS is characterized
by hypertrophic adipocytes and impairments in insulin
action. Amenorrhea is associated with more pronounced IR
and hyperandrogenemia in patients with PCOS. Therefore,
the type of menstrual cycle abnormality might represent a
useful tool for identifying a more severe metabolic profile
in PCOS. The expression and secretion of a wide variety of
adipokines implicated in IR are also altered in PCOS.
Collectively, the available data indicate that adipose tissue
dysfunction plays a pivotal role in the metabolic abnor-
malities observed in PCOS. Whether these abnormalities
are primary or secondary to hyperandrogenism or other
abnormalities in PCOS is not yet known. However, a
comprehensive evaluation of the circulating levels of sev-
eral adipokines in patients with PCOS has not been per-
formed to date and the results of the studies that have
evaluated how the weight loss has resulted in a change of
the levels of adipokines, are very few, conducted for short
periods and difficult to interpret. So, new studies in this
interesting topic must be conducted. There is well-estab-
lished evidence for the detrimental effect of overweight
and obesity in PCOS women. A weight loss of 5–10 % of
original body weight improves insulin sensitivity and short-
term reproductive activities in PCOS overweight women
and is additionally crucial for improving short- and long-
term metabolic health. This can be accomplished through
lifestyle intervention, with the overall aim of energy
expenditure exceeding energy intake over a short or med-
ium period. Following weight loss, metabolic and endo-
crine variables were improved to a level similar to that of
BMI-matched non-PCOS controls. However, even if the
studies performed on specific diets are heterogeneous and
final conclusions can not be drown, it appears useful to
limit the consumption of sugar and refined carbohydrates,
with preference of products with low glycemic index in
order to favor metabolic improvements. In addition, it can
be suggested to divide the food intake in small and frequent
meals, with high caloric intake at breakfast. Moreover, the
majority of studies were also of short- to medium-term
duration, with only one 12-month study. Because the long-
term sustainability of anthropometric and metabolic
improvements is more important than acute changes, there
is a significant gap in the literature. Additional research is
warranted that assesses the effect of dietary composition on
Arch Gynecol Obstet (2014) 290:1079–1092 1087

Table 2 Effects of LMS program on metabolic correlates of PCOS (modified from Domecq et al. [155])
Author and Age Follow- n Groups BMI Characteristics Main conclusions
year up
(months)

Brown, 2009 18–50 years 6 11 LMS 38 (median) Ex Prog: moderate to intensive, Improved lipoprotein profiles in
[156] 228 min/week for 5–6 m PCOS women
31 C 31 (median) No intervention
Guzik, 1994 32 mean 5 12 LMS 38 (mean) Diet (1,200–1,000 kcal/day ? Ex WL in ob PCOS women reduces
[157] age Prog. (walking 2 miles/day, I and n-SHBGT conc., may
5 days/week) for 3 m restore ovulation
C No intervention
Hoeger, 2004 28 mean 12 27 LMS 39 (mean) Diet (500–1,000 kcal/day) ? Ex WL may restore ovulation in
[158] age Prog. (150 min/week for) 12 m PCOS ob. women
Met 1,700 mg/dia for 12 m
C No intervention
Hoeger, 2008 12–18 years 6 months 32 LMS [25 (above Diet ? Ex Prog. ? Behav. Enhancement of androgen and
[159] the 95th Int. ? oral contraceptives for reduction of SHBGT in ob.
percentile) 6m adolescents PCOS women
Met 1,700 mg/day ? LSM ? oral Reduction of CA, total T and
contraceptives for 6 m increased HDL, no WL
Control Placebo for 6 m
Karimzadeh, 27 mean 6 25 LMS 27 (mean) Diet (delta 500 kcal/day) ? Ex LMS improved LP in PCOS
2010 [160] age Prog (120 min/day from 3 to 5 women
times/week) for 6 m
5 Met 1,500 mg/dia
Palomba, 18–35 years 1.5 64 LMS 32 (mean) Diet ? Ex Prog (3 times/week) for Increased ovulation in ob. PCOS
2010 [161] 1.5 m women resistant to clomiphene
Control No intervention
Qublan, 2007 31 mean 3 46 LMS 32 (mean) Diet (120–1,400 kcal/day) for 3 m Ameliorated hyperinsulinemia
[162] age and hyperandrogenemia
Met 1,700 mg/day for 3 m Improved clinical parameters and
ameliorated reproductive
function in PCOS ob. women
Stener- 30 mean 4 84 LMS 27 (mean) Ex Prog. (30–45 min. 3 day/ Improved reproductive function
Victorin, age week ? 1 day of reinforcement) in PCOS women
2009 [163] for 4 m
Control No intervention
Vigorito, 2 mean age 3 months 90 LMS 29 (mean) Ex. Prog. (30 min/day 3 times/ Improved oxygen peak
2007 [164] week) for 3 m consumption, reduced BMI,
C-reactive protein and ISI
Control No intervention
When not specifically indicated, the value of the age means the mean age; follow-up period is expressed in months after the end of the study;
when not specifically indicated, the value of the BMI means the mean of BMI values
BMI Body Max Index (ratio between weight and the square of the height), C control group, CA central adiposity, Ex Prog exercise program,
I insulin, Diet hypocaloric diet, ISI insulin sensitivity index, LMS life modification program, LP lipid profile, PCOS polycystic ovary syndrome,
T testosterone, m months, Met metformin, ob. obese, SHGT conc. SHGT concentrations, WL weight loss, Y years

weight maintenance or prevention of weight gain in both
lean and overweight women with PCOS, and the effect of
dietary composition on reproductive, metabolic, and psy-
chological parameters independent of changes in weight in
PCOS lean women. Finally, a supplementation of vitamin
D and chrome improve glycemic control and IR in PCOS
woman, but at the present the specific dose for supple-
mentation of these nutrients is not yet well established.
Finally, as regards minerals, magnesium supplementation
and use of copper chelators may be promising topics.
Moreover, also a supplementation of omega3 PUFA (DHA
and EPA) improves IR and counteracts the damage derived
from oxidative stress.
Further research is needed, including high-quality, long-
term RCTs that assess a range of diet compositions,
including low GI, and use of dietary supplement, in PCOS

123
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for both weight management and optimizing reproductive,
metabolic, and psychological outcomes.
Conflict of interest There are no conflicts of interest.
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