Clinical Endocrinology (2011) 74, 148–151
CLINICAL QUESTION
When should an insulin sensitizing agent be used in the treatment
of polycystic ovary syndrome?
Stephen Franks
Institute of Reproductive & Developmental Biology, Imperial College London, Hammersmith Hospital, London, UK
Summary
Polycystic ovary syndrome (PCOS) is associated with insulin resis-
tance and an increased risk of developing type 2 diabetes mellitus.
The attendant hyperinsulinaemia is also thought to contribute to
the mechanism of anovulation in PCOS. Both metabolic and
reproductive abnormalities are amplified by obesity and the treat-
ment of first choice for overweight or obese women with PCOS is
modification of diet and lifestyle. Nevertheless, changes in diet and
exercise are, for many subjects, not easy to sustain and there seems
an obvious place for insulin sensitizing agents in management of
both reproductive and metabolic disturbances. Of the available
agents affecting insulin sensitivity, metformin has been the most
widely used but despite an enormous literature reporting beneficial
effects on reproductive, cutaneous and metabolic manifestations of
PCOS, its efficacy is unproven apart from in those subjects with
impaired glucose tolerance or frank diabetes. Metformin at least
has an assured safety record whereas both efficacy and safety of
other insulin sensitizing agents in women of reproductive age, such
as thiazolidinediones and glucagon-like peptide analogues, remains
to be established.
(Received 20 October 2010; returned for revision 5 November
2010; finally revised 12 November 2010; accepted 12 November
2010)
Insulin secretion and action in polycystic ovary
syndrome (PCOS)
Since the first reports, more than 25 years ago, of exaggerated insu-
lin responsiveness to an oral glucose tolerance test in women with
PCOS, there has been a plethora of publications characterizing
abnormalities of glucose/insulin homeostasis. Key studies include
the delineation of peripheral insulin resistance and the finding that
impaired insulin sensitivity can be present even in lean women with
the syndrome, although it is clearly a more prominent feature in
Correspondence: Stephen Franks, Institute of Reproductive & Developmen-
tal Biology, Imperial College London, Hammersmith Hospital, London
W12 0NN, UK. Tel.: +44 (2) 07 594 2109; E-mail: s.franks@imperial.ac.uk
148
doi: 10.1111/j.1365-2265.2010.03934.
overweight and obese subjects1 (Fig. 1). The mechanism of insulin
resistance remains stubbornly obscure, but there is a consensus that
it is a phenomenon of postreceptor signalling and appears to be
specific to certain signalling pathways.1,2 This selective insulin
resistance is illustrated importantly in the ovary, in which the effect
of insulin on steroid production remains unimpaired, whereas the
metabolic actions of insulin (on glucose uptake and metabolism)
are partially inhibited.3 This ability of the ovarian steroidogenic
pathways to ‘read’ insulin in the face of hyperinsulinaemia has con-
siderable clinical significance. There is clear evidence that increased
exposure to insulin adversely affects both granulosa cell and theca
cell function (in both cases amplifying LH action) and contribute
both to arrest of follicle growth (and anovulation) and to excessive
androgen production by theca.4,5 These findings help to explain
why the principal clinical features of PCOS – anovulation and
hyperandrogenism – are more common, and more severe, in obese
than in lean women with PCOS.
In recent years, the diagnostic criteria for PCOS have been
extended in recognition that the syndrome has a broader spectrum
of presentation than was originally defined. Although the criteria
that define PCOS remain an area of some controversy, it is quite
clear that in addition to the classic definition of PCOS – i.e the
manifestation of both anovulation and androgen excess – some
women with polycystic ovaries have hyperandrogenism without
anovulation and others have anovulation without obvious andro-
gen excess. This heterogeneity of presentation can be observed even
in members of the same family, providing support for the notion
that these clinical ‘sub-categories’ do in fact form part of the same
syndrome. The relative merits of the ‘NIH’ and the ‘Rotterdam’
diagnostic criteria6,7 (and their more recent suggested modifica-
tions) will continue to be argued but, from a clinical viewpoint, the
important issue is that insulin resistance, and associated metabolic
abnormalities, appear to be features of women with polycystic ova-
ries who have both anovulation and androgen excess, rather than
one or the other.8–10
In summary, insulin resistance and compensatory hyperinsuli-
naemia have implications both for ovarian function (amplifying
androgen excess and inhibiting ovulation) and for long-term
health. Clearly women with these metabolic abnormalities are at
increased risk of developing impaired glucose tolerance and type 2
diabetes mellitus, and (probably) cardiovascular disease. It makes
perfect sense, therefore, to consider the use of insulin sensitizing
Ó 2011 Blackwell Publishing Ltd

Fig. 1 Insulin sensitivity in lean and obese weight-matched pairs of women
with and without PCOS. Insulin sensitivity was significantly (P < 0.05) in
both lean and obese women with PCOS compared with control subjects
(adapted from Robinson et al., 199227).
agents in management of both ovarian and metabolic manifesta-
tions of PCOS. The questions to be answered include (1) are insulin
sensitizing agents effective (2) which agent should be chosen and
(3) which patients will benefit from such treatment?
Indications for use of insulin sensitizing medication
The efficacy of any insulin lowering or insulin sensitizing drug
needs to be measured, in overweight or obese subjects, against the
effects of dietary changes. A number of studies over the last 15–
20 years have shown that diet and lifestyle modification (notably
calorie restriction and plenty of exercise) improves both metabolic
abnormalities and fertility in women with PCOS,11 and this
remains the first-line treatment in overweight subjects.
Fertility & menstrual irregularity
The place of dietary and lifestyle modification in management of
menstrual symptoms and fertility has been well established. Calorie
restriction resulting in weight loss as little as 5% of initial body
weight can be effective in regulating menses and restoring ovula-
tion;11 it may also improve responsiveness to drugs used to induce
ovulation although the data here are more sparse. Nevertheless,
achieving and sustaining even that modest degree of weight loss is
not easy for any overweight or obese patient, even those who are
highly motivated by the wish to conceive. The use of insulin sensi-
tizing medication is therefore logical, and there are now numerous
studies of the use of such agents in the management of reproduc-
tive dysfunction in women with PCOS. First and foremost amongst
these is metformin, the use of which has become very fashionable
in management of various aspects of PCOS (although strictly
speaking its primary mode of action is probably not as an insulin
sensitizer but rather by reducing hepatic glucose output). There
have been over 500 publications on the subject since the mid 1990s.
Certainly, a host of studies have reported improvement in men-
strual regularity, ovulation rates and fertility (with and without clo-
miphene treatment), but it is only in the last few years that we have
seen adequately powered, double-blinded, randomized controlled
Ó 2011 Blackwell Publishing Ltd, Clinical Endocrinology, 74, 148–151
Insulin sensitizing agents in PCOS 149
studies (RCTs) with the appropriate endpoints. Perhaps the most
impressive results from the earlier studies (including RCTs) have
been reports of increased frequency of menstruation and rates of
ovulation amongst women with PCOS, especially in those who
were overweight. Indeed an early meta-analysis concluded that this
medication was an effective means of management of infertility in
PCOS.12 Results from the most recent, and most definitive, studies
(including a very large RCT and an updated meta-analysis) have,
however, led to rather different conclusions.13 Although ovulation
and pregnancy rates were improved (compared with clomiphene
alone) when metformin was used as an adjunct to clomiphene
treatment, the live birth rate was unaffected by the addition of met-
formin.14,15 And whilst metformin alone may marginally improve
the rate of ovulation compared with placebo, it is not clear whether
this effect is independent of attendant weight loss.16 In conclusion
therefore, there is no clear evidence that metformin treatment,
either alone or in combination with clomiphene improves fertility
in women with PCOS. Data from recent clinical trials point to a
favourable effect of metformin, given during superovulation with
gonadotrophins, in reducing the frequency of ovarian hyperstimu-
lation syndrome (OHSS), so there may be some utility for metfor-
min in women at risk of OHSS.17
Although the vast majority of publications regarding insulin-
sensitizing agents have focused on metformin, other drugs have
been employed for management of oligomenorrhoea and infertil-
ity (as well as other indications) in PCOS. In particular, thiazolid-
inediones (glitazones) have been shown to be effective in
improving the rate of ovulation (and hyperandrogenaemia) in
women with PCOS. A large, multicentre RCT of troglitazone
treatment showed a lowering of serum androgen levels and a sig-
nificant increase in the frequency of ovulatory cycles18, but its use
in clinical practice was curtailed because of hepatotoxicity. Other
glitazones (pioglitazone, rosiglitazone) have also proved effective
in improving ovulation rate but, like troglitazone, there have been
well-publicized reports of serious adverse side effects and the con-
sensus is that such medication should be avoided in management
of women who are hoping to conceive or who are at risk of
pregnancy.13,19
Data from preliminary studies suggested that d-chiro-inositol, a
derivative of buckwheat farinetta, was a highly effective insulin-
sensitizing agent, improving the metabolic profile of women with
PCOS.20 However, the outcome of a subsequent large RCT was dis-
appointing (and curtailed), but unfortunately these negative results
remain unpublished in the peer-reviewed literature.
Long-acting agonists of glucagon-like peptide-1, such as exena-
tide, are not insulin sensitizing agents per se but by both promoting
insulin secretion and causing weight loss, they improve glucose/
insulin homeostasis. Their utility in the management of type 2 dia-
betes (T2D) is clear, but there are few data regarding their use in
women with PCOS21 and, as with glitazones, their use cannot be
recommended in young women with PCOS.
Hirsutism, acne and alopecia
There are very few RCTs of insulin sensitizers in treatment of
symptoms of androgen excess. They do, in general, effect a small
150 S. Franks
Table 1. Summary of proposed indications for treatment with metformin
in women with PCOS and comment on efficacy of treatment
Clinical problem Comment
Ovulation and menstrual Small improvement in ovulation rate
frequency and menstrual frequency but effect
may not be independent of weight
loss
Infertility Not a useful fertility agent on its own.
Increased ovulation and pregnancy
rate in combination with
clomiphene but no increase in live
birth rate. May reduce rate of
ovarian hyperstimulation syndrome
after superovulation for IVF/ICSI
Pregnancy outcome No proven benefit except in
gestational diabetes
Hirsutism, acne, alopecia No proven benefit
Impaired glucose tolerance Probably the only clear-cut
indication for metformin (as
adjunct to diet and lifestyle changes)
Adolescents with endocrine May be helpful but too few data at
and/or metabolic features present
reduction in serum testosterone concentrations, but the clinical
effect in the management of hirsutism is small, of little clinical ben-
efit and certainly no more effective than standard oral contracep-
tive treatment.22 The evidence for efficacy in women with acne and
androgenetic alopecia is even more limited. Thus, there is insuffi-
cient evidence on which to recommend the use of insulin senstisiz-
ers in management of hyperandrogenic disorders.
Metabolic complications of PCOS
Impaired glucose tolerance (IGT), gestational diabetes and T2D are
more common in women with PCOS than in the general popula-
tion and, with the increasing prevalence of obesity in the popula-
tion as a whole, this poses a major clinical management problem.
The estimated prevalence of IGT in obese women with PCOS is
between 30% and 40%, and of T2D, 5–10%.23,24 One of the most
important issues is to prevent women with IGT going on to
develop T2D. There is no doubt that diet and lifestyle changes are
the first line of treatment in overweight and obese subjects with
IGT, and that applies as much (if not more) to overweight women
with IGT and PCOS.13 However, metformin, whilst not as effective
as lifestyle changes, does significantly reduce conversion from IGT
to T2D.25 Again, the data regarding the efficacy of insulin sensitiz-
ers specifically in women with PCOS are lacking, but it seems rea-
sonable to use metformin in women with PCOS who have IGT,
particularly for those in whom diet and lifestyle measures alone
have either not proved effective or difficult to institute. No formal
cost–benefit analysis has been undertaken in women with PCOS
and IGT, but measures to moderate diet and lifestyle usually
require quite careful monitoring and support and, even in specialist
centres, there may not be sufficient resources to offer consultations
of the necessary intensity and frequency. Ideally this kind of
support would and should be available at local level, in primary
care. The duration of metformin treatment in women with PCOS
and IGT will depend on how effectively glucose homeostatis is
achieved and whether it can be sustained by diet and lifestyle modi-
fication after stopping the medication.
Adolescents
The data regarding the effects of metformin in adolescents with
symptoms of PCOS are tantalizing. In small, but well-controlled,
studies, metformin (either alone or in combination with anti-
androgens, and/or the oral contraceptive) appears to improve
many of the clinical, endocrine and metabolic features of PCOS.26
There is an intriguing possibility that interventions with insulin
sensitizers in adolescence can alter the natural history of PCOS and
prevent (or at least retard) progression. As yet, however, the
encouraging results of metformin treatment have not been repli-
cated in other series, and so it is difficult to recommend its routine
use in adolescent girls.
Summary and conclusions
Metformin is the only insulin sensitizing agent about which there
are few concerns regarding safety in women of reproductive age,
but questions remain about its efficacy in management of women
with PCOS. Despite the now enormous body of literature on the
use of metformin for treatment of menstrual disturbances, infertil-
ity and symptoms of androgen excess, there are few clear-cut indi-
cations for treatment (Table 1). In conclusion, metformin has little
place in management of infertility or hirsutism in women with
PCOS. It is useful in those who have impaired glucose tolerance
(or, of course, overt type 2 diabetes) and may have a place in treat-
ment of adolescents. Changes in diet and lifestyle remain the pri-
mary choice of management of reproductive and metabolic
sequelae in overweight and obese women with PCOS.
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