The Many Faces of PCOS Special Collection

Therapeutic Advances in Reproductive Health Review

What is new in the landscape of

Ther Adv Reprod Health

2020, Vol. 14: 1–11

insulin-sensitizing agents for polycystic DOI: 10.1177/

https://doi.org/10.1177/2633494120908709
https://doi.org/10.1177/2633494120908709
2633494120908709

ovary syndrome treatment

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Daniela Romualdi , Valeria Versace and Antonio Lanzone

Abstract: Polycystic ovary syndrome, the most common gynecological endocrinopathy,

is burdened with a state of hyperinsulinemia and insulin resistance in 50–80% of affected
women. Wherever the origin of these metabolic abnormalities lies, their pathogenetic
role in determining, perpetuating, and worsening the clinical traits of the syndrome is
ascertained. Many studies have already highlighted possible mechanisms: hyperinsulinemia
and insulin resistance may contribute to hyperandrogenemia, chronic anovulation, and other
comorbidities of the syndrome by differentially affecting the endocrine glands (ovaries,
adrenals, and pituitary) and peripheral tissues (fat mass and skeletal muscle). Based on
these evidences, in the past years, thorough research has been focused on the possible role
of insulin-sensitizing agents in the treatment of polycystic ovary syndrome. Many compounds
were tested to verify their efficacy against polycystic ovary syndrome–related metabolic
dysfunction, both relying on previous acquired experiences in the field of diabetes mellitus and
experimenting new agents, in particular, those belonging to the class of nutraceuticals. We
sought to summarize the most relevant aspects of insulin-sensitizing treatments in polycystic
ovary syndrome, by reporting the relevant literature on this topic and by keeping an attentive
eye on the newly published international guidelines on polycystic ovary syndrome 2018. This
overview encompasses metformin, thiazolidinediones, inositols, alpha-lipoic acid, and GLP1-R
analogues. Starting from the analysis of the mechanisms of action, we anchored to the state
of the art of the use of these drugs in polycystic ovary syndrome, to the most recent evidences
for clinical practice and to the remaining open questions around indications, dose, treatment
schedules, and side effects.

Keywords: Polycystic ovary syndrome, insulin, insulin sensitizer Correspondence to:

Daniela Romualdi
Department of Woman,
Received: 16 December 2019; revised manuscript accepted: 11 January 2020. Child Health and Public
Health, Fondazione
Policlinico Universitario
Agostino Gemelli IRCCS,
Università Cattolica del
Why we are always looking for new The link between insulin resistance and PCOS Sacro Cuore, Rome, Italy
solutions to insulin abnormalities in seems to be genetic in origin,3 even if also other Department Of Woman
polycystic ovary syndrome factors are believed to play a role, since the intrau- And Child Health,
Division of Obstetrics
Hyperinsulinemia and insulin resistance affect terine life, in the complex mechanisms underlying and Gynecology, Azienda
Ospedaliera “Cardinale
from 50 to 80% of women with polycystic this association. It was hypothesized that a specific Panico”, Tricase, Italy
ovary syndrome (PCOS), depending on differ- environment surrounding the fetus during its daniela.romualdi@
policlinicogemelli.it
ent populations, ethnicities and diagnostic developmental phase may lead to reduced intrau-
Valeria Versace
methods.1 These metabolic abnormalities are terine growth and to a predisposition to insulin Antonio Lanzone
more prevalent in overweight-obese women, resistance later in life.4 During puberty and adult- Department of Woman,
Child Health and Public
even if exaggerated circulating insulin levels hood, circumstances such as unbalanced diet, sed- Health, Fondazione
and reduced insulin-mediated glucose metabo- entary lifestyle and, ultimately, excessive body Policlinico Universitario
Agostino Gemelli IRCCS,
lism are also found in up to 40% of nonobese weight gain may trigger the clinical appearance of Università Cattolica del
subjects.2 the metabolic disturbance in these women.5 Sacro Cuore, Rome, Italy

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Therapeutic Advances in Reproductive Health 14

Insulin is able to exert systemic effects that go well such a cross-talk. The final consequence is the
beyond the glucose metabolism. Excessive circulat- increase of the free, biologically active, androgen
ing levels of this hormone are considered key to the levels.
pathophysiology and clinical expression of PCOS.
Actually, despite a systemic state of insulin resist- Previously conceived as a one-way relationship,
ance, the central paradox of the syndrome is that hyperinsulinemia and hyperandrogenemia may
other districts, such as the ovary, the adrenal, and potentiate each other, thus perpetuating a vicious
the pituitary, remain sensitive to insulin action, circle in some women with PCOS. Testosterone
thus putting in place the framework of the ‘selective and dehydroepiandrosterone sulfate (DHEAS)
insulin resistance’ theory. In PCOS, the reduced promote lipolysis and the release into the circula-
glucose disposal into peripheral tissues is due, tion of FFA, known as one of the most potent
rather than to an altered affinity of the binding triggers to insulin resistance. Further mecha-
domain of the insulin receptor, to defects in the sig- nisms, which need to be better clarified, include
nal transduction inside the cell cytoplasm, which the androgen-driven pro-inflammatory cytokine
are typically tissue specific. The association of the secretion [i.e. tumor necrosis factor α, interleukin
hyper-phosphorylation of the Ser312 residue with 6 (IL-6), resistin] and the interference with insu-
the decrease in the insulin-mediated phosphati- lin signaling.
dylinositol-3-kinase activity on the insulin receptor
substrate-1 (IRS-1) is the most important determi- Since the 1990s, the derangement of gonadotro-
nant of insulin resistance in the skeletal muscle.6 phin secretion together with the endocrine and
Instead, defects of the PPAR-γ nuclear receptor paracrine effects of hyperandrogenemia and
and the glucose transporter GLUT4 account for hyperinsulinemia has been considered responsi-
insulin resistance in the adipose tissue.7 ble for the ovulatory disorder typical of PCOS.13
More recently, the role of insulin was advocated
The distinctive anthropometrical features of in the pathway mediated through the anti-Mülle-
PCOS women often exacerbate this picture. rian hormone (AMH), which is able to inhibit
Beyond the high prevalence of overweight and early follicular recruitment, decrease aromatase
obesity in this population, the body composition activity, and raise the follicle-stimulating hor-
of PCOS subjects is characterized by increased fat mone (FSH) threshold for dominant follicle
mass and preferential accumulation of adiposity selection.14,15
in the intra-abdominal compartment, even in lean
subjects. It is well known that visceral fat hyper- The contribution to the appearance and the
respond to catecholamines by mobilizing free maintenance of chronic anovulation and clinical
fatty acids (FFA) and discharging cytokines,8 hyperandrogenism is not the only detrimental
which further impair peripheral insulin sensitiv- effect of hyperinsulinemia and insulin resistance
ity. Such a derangement is supposed to be magni- in PCOS women: the alterations of glucose–insu-
fied by the increased activity in the sympathetic lin metabolism are responsible for an increased
nervous system which was reported in PCOS rate of complications during pregnancy (e.g. mis-
women by several investigators.9,10 Finally, irre- carriage, hypertensive disorders, gestational dia-
spective of body mass index (BMI), abnormal betes) and for a raised risk of cardiovascular
hepatic insulin clearance and increased pancre- disease, diabetes, and endometrial cancer later in
atic β-cell responsiveness may contribute to the life.16
exaggerated insulin circulating levels.11
This vast stock of knowledge has led to two main
After reaching the target organs, hyperinsuline- consequences in the scientific community: an
mia directly stimulates androgen secretion in the increased attention toward the importance of
ovaries and the adrenals while suppressing the diagnosing the metabolic alterations in PCOS and
synthesis of sex hormone–binding globulin an increased interest in targeting insulin resistance
(SHBG) in the liver. Insulin seems also to inter- as a treatment strategy for these women.
act with luteinizing hormone (LH) by enhancing
its production at the central level and by exerting The novel international evidence-based guideline
a synergic co-gonadotrophic effect on the thecal for the assessment and management of PCOS rec-
cells of the developing follicle,12 which were ommends to assess the glycemic status at baseline
reported to be intrinsically hyperresponsive to in all women with PCOS, and, thereafter, every

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 D Romualdi, V Versace et al.

1–3 years by an oral glucose tolerance test terol, and low-density lipoprotein (LDL)], in par-
(OGTT), fasting plasma glucose, or HbA1c.17 ticular, in women with PCOS with BMI ⩾25.17
However, measurement of insulin resistance was
not incorporated into PCOS diagnostic criteria as What metformin should actually add to diet and
well as into the general evaluation, because of the exercise is still a matter of debate. Seven rand-
lack of accuracy of the currently available methods omized controlled trials (RCTs) that addressed
and inconsistencies in the proposed thresholds. the comparison between lifestyle versus met-
formin + lifestyle were identified in the most up-
to-date meta-analysis published on this topic.19 In
What solutions we found overweight-obese PCOS adolescents and adults,
In adjunction to lifestyle intervention, a plethora no statistically significant differences were
of possible medical treatments have been pro- reported for BMI and weight management in this
posed in the past decades to correct the PCOS- body of evidence which was at low to moderate
related metabolic dysfunction. In the following risk of bias.
paragraphs, novel and controversial aspects of
this therapeutic approach will be summarized. Nonetheless, in the same meta-analysis, met-
Given the large number of treatments proposed, formin alone resulted superior to placebo con-
the list clearly cannot be exhaustive. Because of cerning the most important clinical outcomes. In
the lack of significant up-to-date scientific results total, 20 RCTs comparing these two interven-
and major uncertainties regarding outcomes, tions were analyzed: independently of the anthro-
some options such as N-acetylcysteine, somato- pometrical features, metformin resulted better
statin, vitamins, and various nutraceuticals were than placebo for BMI, testosterone, total choles-
not selected for this overview. terol, and triglycerides. When only participants
with a BMI ⩾25 kg/m2 were combined in sub-
group analyses, it was found that metformin
Metformin offered additive benefits for weight, BMI, total
Over the past 40 years, metformin has revolu- cholesterol, and LDL. On the contrary, interest-
tionized the treatment of several metabolic con- ingly, there were differences in terms of WHR
ditions, ranging from diabetes mellitus type 2 (waist to hip ratio) reduction in favor of met-
(DM2) to metabolic syndrome. Out of the differ- formin in the BMI <25 kg/m2 subgroup. The
ent classes of insulin-lowering drugs, metformin majority of studies included for this comparison
has been the most extensively investigated in were at moderate risk of bias; thus, caution should
both short- and long-term treatment schedules. be exercised when considering the effect esti-
Nevertheless, high-quality evidence in PCOS mates across all outcomes. Based on the incon-
women is scarce,18 and still there are several sistent data regarding the improvement of acne,
aspects of this old drug that remains novel and alopecia, and hirsutism, metformin is not consid-
unexplored at this time. ered a first-line treatment in PCOS women with
these complaints.20
Metformin belongs to the class of biguanides. It
was reported to improve the glucose–insulin As far as the reproductive outcomes regard, met-
metabolism by decreasing intestinal absorption of formin can be administered alone, or in combina-
glucose, gluconeogenesis, glycogenolysis, and tion with estro-progestin drugs, ovulation
lipogenesis and by enhancing glucose uptake in induction agents or during in vitro fertilization
the liver, skeletal muscle, adipose tissue, and (IVF) programs depending on the clinical need. In
ovaries. a Cochrane review that included a meta-analysis
of 42 randomized clinical trials, metformin ther-
Where lifestyle interventions are not sufficient, the apy resulted able to improve menstrual pattern,
2018 international evidence-based guideline for ovulation rate, and clinical pregnancy rate in
the assessment and management of PCOS recom- PCOS women.18 Metformin should be added,
mends the administration of metformin for women rather than persisting with clomiphene citrate
with PCOS for the prevention of weight gain, hor- alone or gonadotrophins alone, in PCOS women
monal (testosterone), and metabolic outcomes with anovulatory who result nonresponder to the
(cholesterol and triglycerides), and for prevention ovulation induction agent, to improve ovulation,
of weight gain and metabolic outcomes [choles- pregnancy, and live birth rates.17 In women with

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Therapeutic Advances in Reproductive Health 14

PCOS undergoing an IVF/ICSI (intracytoplasmic dosing regimen of metformin is superior to

sperm injection) therapy for infertility, adjunct another. The effects of metformin treatment
metformin therapy is beneficial before and during on weight, metabolic, and reproductive out-
ovarian stimulation to improve the clinical preg- comes in PCOS seem independent of the
nancy rate and reduce the risk of ovarian hyper- administered dose (in the range 1000–2250
stimulation syndrome (OHSS).21 Metformin mg/day orally), probably because of high
should also be administered in combination with individual variability in the pharmacody-
oral contraceptives (OCPs) in women with PCOS namics and pharmacokinetics of this drug.27
for management of metabolic features. This asso- In a previous study, the lack of a dose–effect
ciation is considered most beneficial in women relationship was confirmed irrespective of
belonging to high metabolic risk groups, including the baseline BMI and degree of hyperinsu-
those with diabetes risk factors, specific ethnic linemia.28 Hence, low doses should be pre-
groups, and in adolescents with BMI ⩾25.17 In ferred in the clinical practice to reduce the
these categories of patients, the administration of side effects.
metformin during pregnancy could be considered 3. Duration of treatment: Metformin use
a safe option to lower the risk of early pregnancy appears safe in the long term, even if some
loss, while its putative role in the prevention of concerns on vitamin B12 deficiency have
hypertensive disorders and gestational diabetes emerged.29 More research is needed on this
occurrence was not confirmed.22,23 This drug was last aspect and on the optimal duration of
also reported to improve endothelial function and metformin treatment, as most of the studies
measures of systemic inflammation, thus theoreti- do not exceed 24 months of observation.
cally reducing the long-term risk for cardiovascu- 4. Metformin formulation: Metformin is now
lar disease.24 available on the market in two formula-
tions: the traditional immediate release (IR)
Four hot topics regarding metformin therapy in formulation (to be administered up to three
PCOS women deserve attention and, hopefully, times daily), and the novel extended release
more good-quality research in the future: (XR) formulation (a once daily dosing
option).30,31 In diabetic patients, metformin
1. Side effects and safety: Common metformin- XR was proven to be equally, or even more,
related disturbances are gastrointestinal (GI) effective in improving glycemic control,32–34
symptoms including abdominal pain, nau- probably thanks to greater patient adher-
sea, vomiting, diarrhea, taste disturbances, ence to treatment35,36 and better GI tolera-
and appetite loss (reported in 10–60% of bility compared with metformin IR.37,38 A
patients).25 The side effects are generally self- clinical pilot trial on metformin XR was
limiting and of mild to moderate intensity. carried out in 2017 in a small group of
However, these symptoms may cause dis- PCOS women: the endpoint of the study
continuation of treatment in some subjects was the comparison with other drugs’ asso-
and reduce compliance in those who con- ciations rather than the evaluation of the
tinue. In order to minimize the side effects, efficacy and safety of the formulation XR
taking the drug with food and a low starting itself that still need to be accomplished.39
dose, with 500 mg increments 1–2 weekly,
should be recommended.26 Metformin is off
label in many countries for PCOS manage- Thiazolidinediones
ment; however, it is not explicitly restricted Thiazolidinediones (TZD) act through a selective
from use, provided that health professionals binding to the nuclear transcription factor PPARγ,
inform women and discuss the evidence with which is mainly expressed in adipocytes, pancre-
them. On the contrary, data on the safety atic β cells, vascular endothelium, macrophages
profile of metformin are mostly based on and, in lower percentage, in heart and skeletal
other populations, especially DM2 patients. muscle tissue.40 Mechanisms of action include the
Specific studies on the benefit/risk ratio in stimulation of fatty acid uptake and storage in
PCOS are strongly needed. subcutaneous adipose tissue and the enhance-
2. Dose: Few studies in literature have ment of adiponectin secretion from adipose, which
addressed this issue. Overall, there is inade- increases insulin sensitivity, particularly in the
quate evidence to suggest whether one liver. TZD also inhibit hepatic gluconeogenesis,

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 D Romualdi, V Versace et al.

ameliorate dyslipidemia, and promote anti-inflam- through inhibition of adenylyl cyclase.43 Conversely,
matory and anti-arteriosclerotic effects. DCI levels are high in tissues that store glycogen,
such as liver, muscle, and fat.44
Among the molecules belonging to this pharma-
cological class, pioglitazone and rosiglitazone The possible use of DCI as an insulin-sensitizing
were most extensively tested in PCOS women. agent is supported by the evidence that IR is asso-
ciated with reduced availability of DCI45 and with
Pioglitazone is deemed to positively modulate increased urinary clearance of DCI in both PCOS
ovarian androgen synthesis: in cultured granulosa and non-PCOS women with IR.46–48 Accordingly,
cells, it influences the metabolism of ovarian ster- several studies have reported reduced DCI-IPG
oid hormone via the upregulation of progesterone release in the blood of diabetic subjects during a
biosynthesis, the inhibition of testosterone, and glucose tolerance test49 and blunted DCI-IPG
the production of E2 through insulin-dependent release in women with PCOS during euglycemic
and insulin-independent pathways. A recent hyperinsulinemic clamp.46
Cochrane review18 concluded that pioglitazone
may improve the menstrual pattern in PCOS, MI is not only a second messenger of insulin
while no difference was found between pioglita- action. In the ovary, MI at least partially mediates
zone and placebo as far as anthropometric out- the follicular response to gonadotropins. Inositol
comes (BMI, WHR), endocrine outcomes trisphosphate (IP3) promotes meiotic progression
(testosterone, SHBG), or metabolic outcomes during the final stages, thus playing a pivotal role
(fasting insulin) regard. in oocyte maturation. Furthermore, MI deriva-
tives participate in cytoskeletal regulation and
Data from a network meta-analysis comparing modulate AMH serum levels.50
insulin-sensitizing drugs indicated that rosiglita-
zone had the most favorable effect on PCOS The tissue-specific MI/DCI ratio depends on the
patients in terms of DHEAS, total testosterone, activity of epimerase, the enzyme deputed to
FSH, and LH, while metformin performed better transform MI in DCI. Epimerase activity is stim-
in terms of estradiol, free testosterone, and ulated by insulin and is reduced in the presence of
androstenedione.41 Another meta-analysis of 11 insulin resistance. In the ovaries, which are insu-
RCTs showed no significant differences among lin-sensitive, the physiologic MI/DCI ratio should
both treatments in terms of fasting glucose, insu- be 100:1. In hyperinsulinemic women with
lin, or homeostasis model assessment of insulin PCOS, the enzymatic epimerase activity is
resistance.42 enhanced in the gonad, thus leading to lower MI/
DCI ratio at this level.51
However, it cannot be disregarded that glitazones
may be associated with relevant adverse effects: The imbalance in the inositol pathway inside the
weight gain, fatigue, edema, diarrhea, anemia, ovary is believed to play a role in the ovulatory
congestive heart failure, and, in particular, for dysfunction of PCOS.
pioglitazone, increased risk of osteoporosis and
bladder cancer. TZD are also placed in the preg- Therefore, during the past decades, oral nutri-
nancy category C medications. tional supplementation with MI has been pro-
posed as a novel therapy in these women. The
treatment was reported to enhance insulin sensi-
Inositols tivity and improve the clinical and hormonal
Inositols, in particular, the active molecules myoi- characteristics of patients with PCOS.52–54
nositol (MI) and D-chiro-inositol (DCI), support
the intracellular formation of insulin second mes- The Cochrane review18 found evidences that DCI
sengers: phospho-myo-inositol-3-phosphate (PIP3) may improve ovulation rate in the syndrome.
and inositolphosphoglycan (IPG). MI is involved There was no conclusive evidence that DCI had
primarily in cellular glucose uptake: its concentra- an effect on BMI, WHR, or blood pressure, on
tions are high in brain and heart as tissues with high hormonal parameters except for serum SHBG
glucose utilization and consumption.43,44 MI also levels, on fasting glucose, fasting insulin, and
reduce the release of FFA from adipose tissues lipids (total cholesterol, triglycerides).

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Therapeutic Advances in Reproductive Health 14

Given the lack of strong evidence, the new inter- versus MI alone in a small group of PCOS women
national guideline gives cautious recommenda- undergoing IVF/ICSI: the adjunction of ALA did
tions on the use of inositols: inositol (in any form) not seem to yield benefits over MI alone as far as
should currently be considered an experimental the reproductive outcomes regard.66 Another
therapy in PCOS, with emerging evidence on effi- study compared metformin 3 g/day versus
cacy highlighting the need for further research. ALA + MI + metformin 1.7 g/day, providing
evidence for a better response in terms of hyper-
androgenism, BMI, and homeostatic model
Alpha-lipoic acid assessment (HOMA) index in the multiple treat-
Alpha-lipoic acid (ALA), a biological antioxidant ment combination compared with isolated high-
and natural cofactor of mitochondrial dehydroge- dose metformin.67
nase complexes, was originally investigated in
patients with type 2 diabetes on the basis of the
close relationship between oxidative stress and Glucagon-like peptide 1 receptor agonists
insulin resistance.55 There is a growing body of evi- Glucagon-like peptide 1 (GLP-1) receptor ago-
dence that ALA may act indirectly to maintain cel- nists belong to the class of incretin mimetics.
lular antioxidant status by either inducing the Incretins, such as the glucose-dependent insulino-
uptake or enhancing the synthesis of endogenous tropic peptide (GIP) and GLP-1, are gut hor-
low-molecular-weight antioxidant or antioxidant mones secreted from enteroendocrine cells in
enzymes.56 Several studies have suggested that the response to the ingestion of food.68 The mecha-
oral supplementation with ALA may improve nisms of action of GLP-1 include the stimulation
insulin sensitivity in the peripheral tissue and may of insulin secretion, the inhibition of glucagon
help in maintaining glycemic control in patients secretion, and the suppression of food intake and
with diabetes mellitus.57 The hypothesized mecha- appetite which, in concert, are able to improve glu-
nism of action relies on the property of stimulating cose homoeostasis.69 Two injective forms of
glucose uptake through an intracellular redistribu- GLP-1R agonists are now available in the market
tion of GLUT1 and GLUT4 transporters.58,59 (exenatide and liraglutide), while oral forms are
currently under development. These antidiabetic
Oxidative stress is increased in PCOS women drugs are mainly employed in the management of
because of an increased production of free radicals obesity and abnormalities of glucose homeostasis.
associated with impaired plasma total antioxidant However, the promising results observed in
capacity (TAC) in both obese and normal-weight patients with type 2 diabetes have fostered in the
PCOS women.60 The increased oxidant status past decade the research on the effects of these
could participate in the onset and maintenance of compounds in PCOS women. The first study
insulin resistance in these patients. investigating the role of exenatide in this popula-
tion was published in 2008.70 Several other investi-
Few studies analyzed the effect of the administra- gations on liraglutide followed the first report and
tion of ALA as unique treatment in PCOS sub- were recently reviewed by two different groups.71,72
jects. The oral supplementation was evaluated in The outcomes of interest of these studies were
both lean and obese subjects by different investiga- weight loss, improvement of menstrual frequency,
tors.61,62 ALA, at a daily dose of 400 mg, resulted and reduction of hyperandrogenism.71,72
was able to improve triglyceride levels, insulin sen-
sitivity, menstrual frequency, and parameters of GLP-1 R agonists are able to significantly reduce
liver function. BMI to an extent which seems similar to that
achieved in the diabetic population. This effect
Other studies reported on the effects of a variety seems to be mediated, or at least potentiated, by
of preparations containing ALA, in particular, in the improvement in eating behavior as assessed by
association with MI.63–65 Results are inconsistent, eating pattern questionnaires.73 By converse, data
even if a general positive profile of action was are inconsistent in terms of modulation of the body
reported by all the studies in terms of BMI, glu- fat distribution (WHR) and amelioration of men-
cose metabolism, lipid metabolism, clinical signs strual cycle frequency. Some studies reported
of hyperandrogenism, and menstrual irregulari- improvement of indexes of insulin resistance
ties in heterogeneous groups of PCOS women. (HOMA) and testosterone levels following treat-
One study compared the association of ALA + MI ment.74 However, it cannot be ruled out that these

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Table 1. Treatment outcomes of insulin sensitizers in polycystic ovary syndrome.

Menstrual Ovulation Hyperandrogenism Weight Insulin

pattern loss resistance

Metformin X X X X X

Thiazolidinediones X X X

Inositols X X

Alpha-lipoic acid X X
GLP1-R analogues X X

outcomes are at least partially related to the weight matter of debate. In fact, many treatments are
loss: no multivariate analyses were provided in proposed as insulin-sensitizing, but we are a long
order to detect a possible direct effect of the drugs way from a univocal indication and modality of
on either peripheral insulin sensitivity or androgen prescription of these drugs. Research made great
production. Of notice, the majority of the afore- progress in this field and now we have some evi-
mentioned studies are weakened by the small sam- dence to lead our practice.
ple size and are poorly generalizable since only
overweight and obese PCOS women were enrolled. Metformin is nowadays the only insulin-sensitiz-
Some authors compared the GLP-1 R agonists ing agent whose prescription is mentioned in the
with metformin and the combination of the two 2018 international evidence-based guideline for
drugs, thus suggesting a possible synergistic action the assessment and management of PCOS and
on clinical and metabolic parameters.75 The most for the treatment of weight, hormonal, and meta-
common side effect either probably or possibly bolic outcomes, even if the schedule of treatment
related to liraglutide is nausea, with no significant is not standardized.
differences compared with metformin. Compliance
with treatment was also hindered by the parenteral The other proposed therapies so far debated
route of administration, which represents a major (TZD, inositols, ALA, and GLP1-R analogues)
obstacle to treatment adherence in women with have been widely experimented, but overall, stud-
PCOS, in particular, in the lower age range. ies show great variability with regard to combina-
tion of therapies, dose, and target population.
Even if findings of reported studies show gener-
Comparative studies ally promising clinical results, all these treatments
Few meta-analyses addressed the question of the should currently be considered experimental in
superiority of one insulin sensitizer over another. In PCOS.
terms of endocrine outcomes, no significant differ-
ence was detected when metformin was compared Funding
with TZD76,77 or inositol.78 In terms of metabolic The authors received no financial support for the
outcomes, metformin seems to display a more ben- research, authorship, and/or publication of this
eficial profile of action for triglycerides compared article.
with TZD,77 while the opposite was found after
comparing the effects of these two drugs on fasting Conflict of interest statement
insulin and HOMA index.76 No significant differ- The authors declared no potential conflicts of
ent metabolic effects were found when comparing interest with respect to the research, authorship,
metformin with inositol (Table 1).78 and/or publication of this article.

ORCID iDs
Conclusion Daniela Romualdi https://orcid.org/0000-
The management and treatment of metabolic 0002-5236-2586
dysfunction in patients with PCOS is a crucial Valeria Versace https://orcid.org/0000-0002-
challenge in our clinical practice and it is still a 0600-5393

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Therapeutic Advances in Reproductive Health 14

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