Medicines Q&As
Q&A 109.4
What effect does metformin have on insulin resistance or the
development of diabetes in women with polycystic ovary
syndrome?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 6 March 2012
Background
PCOS is one of the most common endocrine disorders in premenopausal women (1), with a
prevalence of 6-15%, depending on the criteria for diagnosis being used (2). In the UK, diagnosis is
often based on the 2003 Rotterdam criteria (3). According to the Rotterdam criteria, for PCOS to be
diagnosed, at least two of the following must be present:
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

Oligo- or anovulation
Clinical and/or biochemical signs of hyperandrogenism
Polycystic ovaries (3)
Other conditions that present in a similar way, e.g. congenital adrenal hyperplasia, androgensecreting tumours, Cushing’s syndrome must be excluded (3).
Symptoms of PCOS may include menstrual irregularities, hirsutism and acne (3). At least 40% of
women with PCOS are overweight (4). The syndrome is associated with insulin resistance (5) and
insulin resistance has been observed in obese and lean women with PCOS (6). As many as 10% of
women with PCOS develop type 2 diabetes by the time they are 40 (5). Women with the syndrome
might also be at increased risk of developing cardiovascular disease and endometrial cancer (2,5).
Serum luteinizing hormone (LH) concentrations are often raised in women with PCOS (3), stimulating
increased production of androgen by ovarian cells (5). This stimulatory effect is enhanced in the
presence of insulin (5). Insulin also increases concentrations of unbound testosterone in the blood by
inhibiting the synthesis of sex hormone binding globulin (SHBG) which binds to testosterone (5).
Strategies such as weight loss and exercise are known to reduce insulin resistance and improve
endocrine and menstrual function in PCOS. However, traditionally, the aim of medical therapies for
PCOS has been to counter hyperandrogenism. As well as antiandrogens such as cyproterone
acetate, oral contraceptives and glucocorticoids (to reduce adrenal androgen excess) have been used
(5). These therapies are discussed elsewhere in more detail (5).
Metformin is an oral hypoglycaemic agent used in the treatment of diabetes. It acts mainly by
decreasing glucose output from the liver and by increasing glucose uptake by peripheral muscle
tissue after meals (7). The reduction of glucose output from the liver by metformin decreases the
insulin requirement and probably reduces androgen production in the ovaries in women with PCOS
(5).
Although metformin is not licensed for the treatment of PCOS, the British National Formulary (BNF)
has suggested a dosage regimen. Currently the BNF recommends that metformin be prescribed for
PCOS at an initial dose of 500mg with breakfast for one week, then 500mg with breakfast and
evening meal for one week, then 1.5-1.7g daily in 2-3 divided doses (8). For information on adverse
effects, contraindications and precautions, please refer to the manufacturer’s Summary of Product
Characteristics (9).
Available through NICE Evidence Search at www.evidence.nhs.uk
1
Medicines Q&As
Answer
Effects of metformin on insulin resistance in PCOS
Several studies have measured fasting insulin concentrations in women with PCOS taking metformin.
Analysis of 14 studies for a Cochrane review on PCOS found that metformin did not reduce fasting
insulin concentrations compared with placebo or no treatment (mean difference = -3.38 mIU/l,
p=0.0.053). However, separate analysis of results from non-obese (body mass index [BMI] <30 kg/m2)
and obese (BMI >30 kg/m2) women found the reduction in fasting insulin to be statistically significant
in the non-obese group (mean difference = -5.65 mIU/l, p=0.016), but not in the obese group (mean
difference = -2.47 mIU/l, p=0.27) (4).
Based on the fact that serum SHBG levels and waist circumference are considered to be reliable
surrogate markers for insulin resistance, the authors of the Cochrane review concluded that insulin
sensitivity had not been improved in the analysed studies, since neither serum SHBG levels nor waist
circumference had changed significantly (4).
Treatment with metformin (2.55g/day) and diet of 74 women with PCOS was found to result in a
reduction in the homeostasis model assessment of insulin resistance (HOMA-IR) of 50%. HOMA-IR is
a widely used tool for assessing insulin sensitivity. It provides an estimate of insulin resistance and
beta cell function and is calculated from fasting glucose and insulin measures (10). The 50%
reduction in insulin resistance noted in this study was achieved by the end of the second year of
treatment and sustained over the other two years of the study. This was a non-randomised study, in
which patients were carefully selected, and the study design did not allow for the effect of diet alone to
be assessed (11).
In a randomised, double-blind, cross-over trial, 56 women with PCOS received either metformin
850mg or placebo twice daily for six months. A washout period of three months preceded a second
treatment period of six months during which patients received the alternate treatment. Changes in
insulin resistance were among the secondary end-points of the study. The per protocol analysis
included data from participants completing both study periods. According to this analysis, the
reduction in insulin resistance after six months, as measured using HOMA-IR, was greater in the
metformin group (difference = -1.50 mIU/l, p=0.006). However, it should be noted that only 38 patients
were included in the per protocol analysis and the intention-to-treat analysis showed that the baseline
to six months reduction in insulin resistance in the metfomin group was not statistically significant (0.48 mIU/l, p=0.07) (12).
Tan et al looked at the effects of six months’ treatment with metformin in 188 patients with PCOS and
102 healthy controls who were grouped according to BMI (lean: BMI <25 kg/m2, overweight: BMI 2529 kg/m2, obese: BMI ≥30 kg/m2) (13). Subgroup analyses showed that metformin significantly
improved insulin resistance (as measured by HOMA-IR: 1.71.0 versus 1.10.7 mIU/l, p<0.017) and
fasting insulin levels (7.74.2 versus 5.43.9 mIU/l, p<0.017) in lean PCOS patients (who had not
differed significantly from their BMI-matched control group in terms of pre-treatment insulin resistance)
as well as in overweight and obese patients. The authors concluded that metformin improves insulin
resistance, irrespective of pre-treatment insulin-resistance or obesity (13).
In contrast, in a 24-week study in 40 women with PCOS, significant improvement in insulin sensitivity
was observed only in the group of women (n=13) with the lowest insulin sensitivity (Quantative Insulin
Sensitivity Check Index (QUICKI) <0.235) at baseline. In this group, there was an improvement in
QUICKI to 0.211 +/- 0.019 (95% CI 0.199 to 0.222), p0.001). This study was unusual in that it used
escalating doses of metformin over the study period (1g daily to 3g daily) (14). Like HOMA-IR,
QUICKI has been found to correlate well with the insulin resistance index assessed by euroglycemichyperinsulinemic clamp (10,15).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Effects of metformin on the development of diabetes in women with PCOS
Type 2 diabetes
The Diabetes Prevention Program Research Group assigned 3234 non-diabetic people with elevated
fasting and post-load plasma glucose to placebo, metformin (850mg twice a day) or an intensive
lifestyle modification programme (16). Participants were at high risk of developing type 2 diabetes, as
are patients with PCOS (16).They were followed up for a mean of 2.8 years (range 1.8-4.6) (16).
Metformin reduced the incidence of diabetes by 31% compared to placebo, but lifestyle intervention
was more effective, reducing the diabetes incidence by 58% (16).
Women with a diagnosis of PCOS who were aged 20 years or above and did not have type 2
diabetes were recruited to a study which looked at how treatment with metformin and diet affected the
development of type 2 diabetes in women with PCOS (17). Of the nondiabetic women who were
recruited, 431 were followed up for at least 11 months while receiving metformin 850mg three times a
day and being on a controlled diet. Data from these women showed that, of the women with no history
of gestational diabetes, 17 developed type 2 diabetes and 401 did not (17). It was found that women
who developed type 2 diabetes, compared to those who did not, had higher pre-treatment glucose
(OR, 1.09; 95% confidence interval [CI] 1.03 to 1.16 p=0.003) and less of a reduction in HOMA-IR
(OR, 0.82; 95% CI 0.72 to 0.92, p=0.0008). The authors (Glueck et al) suggested that reducing insulin
resistance, for instance with metformin and diet could provide primary prevention of type 2 diabetes in
women with PCOS (17).
Gestational diabetes
Published studies have suggested that metformin, either alone (18,19) or combined with diet (20)
would be beneficial in preventing gestational diabetes in pregnant women with PCOS. Metformin is
not licensed for the treatment of PCOS, but the manufacturers advise that for women with diabetes,
metformin should not be used if they are planning pregnancy or are pregnant due to lack of safety
data. (9). However the current NICE guidance on diabetes during pregnancy states that there is
strong evidence for the effectiveness and safety of metformin when used during pregnancy, although
informed consent on the use of metformin in this situation should be obtained and documented (21).
An infertility treatment in PCOS workshop of the European Society for Human Reproduction and
Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) in 2007
concluded that it would be prudent to discontinue metformin on confirmation of pregnancy, adding that
use during pregnancy should take place only in a research context (22).
In the study mentioned above by Glueck et al (17), 13 of the 431 women either had had gestational
diabetes previously or developed it while on metformin and the diet (17). The reduction in HOMA-IR
was less in women who developed gestational diabetes or had had gestational diabetes previously
than in women who did not develop type 2 diabetes or gestational diabetes (17).
In a further study by Glueck et al (20), it was suggested that metformin (750mg to 2.55g/day) and diet
reduced the likelihood of both initial and subsequent occurrences of gestational diabetes in women
with PCOS. Women in this study (n=142; 172 pregnancies) were followed from before conception and
throughout their pregnancies. Metformin was started before conception, continued throughout
pregnancy in 88% of the pregnancies and discontinued at a median of 13 week’s gestation in the
remaining pregnancies. Gestational diabetes developed in 7% of pregnancies. Although the design of
the study did not allow for a control group, 47 of the women taking part had had at least one live-birth
pregnancy previously (n=64 live-birth pregnancies in total) without metformin and gestational diabetes
developed in 30% of these pregnancies. When the incidence of gestational diabetes was considered
in these 47 women when they were on metformin, it was found that gestational diabetes had
developed in 12% of the 50 live-birth pregnancies that occurred (20).
The following two studies sought to determine whether receiving metformin throughout pregnancy
affected the prevalence of gestational diabetes in women with PCOS (18,19):
De Leo et al (2011) compared the outcomes of 98 women with PCOS who received metformin with
those of 110 ‘healthy’ pregnant women without PCOS (18). In the women with PCOS, metformin was
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
received from before conception until 37 weeks’ gestation, the initial dose being 1.7-3g/day but
reducing to one-third of that by the end of the first trimester. Twelve women in the control group and
none in the PCOS group developed gestational diabetes (12.5% versus 0%, p<0.05) (18).
In another study, 57 women with PCOS who became pregnant were divided into two groups: the first
included 31 patients who conceived while taking metformin, either with or without other ovulation
inducers; the second included 26 patients who conceived spontaneously or with the help of ovulation
inducers other than metformin. The metformin dose for women in the first group was 1g daily,
increasing to 2.5g daily, depending on BMI and treatment response. A dose of 1-1.5g daily was
received by these women once they had conceived and until the end of pregnancy. Gestational
diabetes occurred in 3.2% of those who received metformin during pregnancy and in 23.08% of those
who did not (p=0.03) (19).
Contrasting results were obtained by Vanky et al (2011) (23) who found no significant difference
between the prevalence of gestational diabetes in patients receiving metformin (17.6%) and those
receiving placebo (16.9%), p=0.87 (23). In this study, 257 women with PCOS (274 singleton
pregnancies) were randomised to treatment with metformin (1g daily for the first week and 2g daily
thereafter) or placebo until delivery. Unlike in the studies above, women were included only if they
were already pregnant and they were in their first trimester (foetal gestational age between 5 and 12
weeks). One-third of the women included in the study had taken metformin around the time of
conception (23).
According to NICE guidelines on fertility (24), no significant differences in the number of cases of
gestational diabetes were found in studies (25,26,27) looking at the treatment of infertility in women
with PCOS with metformin versus clomifene (an ovulation inducer) or with combined metformin and
clomifene versus clomifene alone or metformin alone. These studies (24,25,26) differed from those
mentioned above in that metformin was discontinued when pregnancy was achieved, and also
because the development of gestational complications such as diabetes was not the main focus of
any of the studies.
Metformin is licensed only for the treatment of type 2 diabetes (9). Therefore the prescriber takes full
responsibility when prescribing metformin for PCOS.
Summary
Insulin resistance can occur in obese and non-obese women with PCOS. Metformin and diet
modification has been shown to reduce the homeostasis model assessment of insulin resistance
(HOMA-IR) by 50% for over three years. Further, metformin may improve insulin resistance
irrespective of pre-treatment insulin-resistance or obesity, although this has been disputed by a study,
which suggested significant improvements in insulin sensitivity are observed only in women with low
insulin sensitivity at baseline. Based on the lack of changes in reliable surrogate markers, a recent
Cochrane review concluded that insulin sensitivity had not been improved overall by metformin in the
14 studies they analysed.
One study indicated that there is a possible association between the extent to which HOMA-IR is
reduced by metformin in women with PCOS and the probability of them developing type 2 diabetes.
Two studies have concluded that continuing metformin throughout pregnancy reduces the prevalence
of gestational diabetes; the authors of a third study concluded that the combination of metformin and
diet during pregnancy in women with PCOS facilitates both primary and secondary prevention of
gestational diabetes. However another study found no significant difference in gestational diabetes
prevalence rates between metformin and placebo when metformin was commenced in the first
trimester of pregnancy.
According to NICE guidelines on fertility, no significant differences in the number of cases of
gestational diabetes were found in studies looking at the treatment of infertility in women with PCOS
with metformin versus clomifene or with combined metformin and clomifene versus clomifene or
metformin.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
A 2007 infertility treatment in PCOS workshop of the European Society for Human Reproduction and
Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) concluded that it
would be prudent to discontinue metformin on confirmation of pregnancy, adding that use during
pregnancy should take place only in a research context.
Metformin is licensed only for the treatment of type 2 diabetes. Therefore the prescriber takes full
responsibility when prescribing metformin for PCOS.
Limitations
Studies on the use of metformin in PCOS vary with regard to their endpoints, the duration of treatment
with metformin, and characteristics of participants, including those that are likely to affect results, e.g.
BMI.
References
(1) De Sloover Koch Y and Ernst ME. Use of metformin in polycystic ovary syndrome. Ann
Pharmacother 2001;35:1644-7.
(2) Fauser BCJM, Tarlatzis BC, Rebar RW, Legro RS, et al. Consensus on women’s health
aspects of polycystic ovary syndrome (PCOS):the Amsterdam ESHRE/ASRM-sponsored 3rd
PCOS consensus workshop group. Fertil Steril 2012;97:28-38.
(3) The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril
2004;81:19-25.
(4) Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone,
pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea
and subfertility. Cochrane Database Syst Rev 2010, Issue 1. Art. No.: CD003053. DOI:
10.1002/14651858.CD003053.pub4.
(5) Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223-36.
(6) Acbay O and Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary
syndrome? Fertil Steril 1996;65:946-9.
(7) Norman RJ, Kidson WJ, Cuneo RC et al. Metformin and intervention in polycystic ovary
syndrome. Med J Aust 2001;174:580-3.
(8) Joint Formulary Committee. British National Formulary. 65 ed. London: British Medical
Association and Royal Pharmaceutical Society of Great Britain; 2013
(9) Summary of Product Characteristics – Glucophage (metformin) 500mg and 850mg film
coated tablets. Merck Serono. Accessed via
http://www.medicines.org.uk/emc/medicine/1043/SPC/ on 19/04/13 [date of revision of the
text 10/2010].
(10)Muniyappa R, Lee Sihoon, Chen H, Quon MJ. Current approaches for assessing insulin
sensitivity and resistance in vivo: advantages, limitations and appropriate usage. Am J
Physiol Endocrinol Metab 2007; doi:10.1152/japendo.00645.2007
(11)Glueck CJ, Aregawi D, Agloria M et al. Sustainability of 8% weight loss, reduction of insulin
resistance, and amelioration of atherogenic-metabolic risk factors over 4 years by metformindiet in women with polycystic ovary syndrome. Metab Clin Exp 2006;55:1582-9.
(12)Trolle B, Flyvbjerg A, Kesmodel U, et al. Efficacy of metformin in obese and non-obese
women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled
cross-over trial. Hum Reprod 2007;22:2967-73.
(13)Tan S, Hahn S, Benson S et al. Metformin improves polycystic ovary syndrome symptoms
irrespective of pre-treatment insulin resistance. Eur J Endocrinol 2007;157:669-76
(14)Yasmin E, Glanville J, Barth J, et al. Effect of dose escalation of metformin on clinical
features, insulin sensitivity and androgen profile in polycystic ovary syndrome. Eur J Obstet
Gynecol Reprod Biol 2011;156:67-71.
(15) Yokoyame H, Emoto M, Fujiwara S, et al. Quantitative insulin sensitivity check index and the
reciprocal index of homeostasis model assessment in normal range weight and moderately
obese type 2 diabetic patients. Diabetes Care 2003;26(8):2426-32.
(16)Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes
with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
(17)Glueck CJ, Goldenberg N, Sieve L, et al. An observational study of reduction of insulin
resistance and prevention of development of type 2 diabetes mellitus in women with
polycystic ovary syndrome treated with metformin and diet. Metab Clin Exp 2008;57(7):95460.
(18)De Leo V, Musacchio MC, Piomboni P, et al. The administration of metformin during
pregnancy reduces polycystic ovary syndrome related gestational complications. Eur J Obstet
Gynecol Reprod Biol 2011;157:63-66.
(19)Azza A, El Hameed A, Shreif HE, Mowafy HE. The role of continuing metformin therapy
during pregnancy in the reduction of gestational diabetes and improving pregnancy outcomes
in women with polycystic ovary syndrome. Middle East Fert Soc J 2011;16:204-8.
(20)Glueck CJ, Pranikoff J, Aregawi D, et al. Prevention of gestational diabetes by metformin plus
diet in patients with polycystic ovary syndrome. Fertil Steril 2008;89:625-34.
(21)National Institute for Health and Clinical Excellence. Clinical Guideline 63. Diabetes in
pregnancy: management of diabetes and its complications from preconception to the
postnatal period. July 2008. Accessed via http://www.nice.org.uk on 7 May 2013.
(22)Tariatzis BC, Fauser BC, Legro RS et al. Consensus on infertility treatment related to
polycystic ovary syndrome. The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus
Workshop Group, March 2-3, 2007.Thessaloniki, Greece. Fertil Steril 2008;89:505-22
(23)Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to
delivery in polycystic ovary syndrome: a randomized, controlled multicentre study. J Clin
Endocrinol Metab 2010;95:e448-55.
(24)National Institute for Health and Clinical Excellence. Clinical Guideline 156. Fertility:
assessment and treatment for people with fertility problems. February 2013. Accessed via
http://www.nice.org.uk on 23 April 2013.
(25)Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the
polycystic ovary syndrome. N Engl J Med 2007;356:551-66.
(26)Moll E, Bossuyt PMM, Korevaar JC, et al. Effect of clomifene citrate plus metformin and
clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed
polycystic ovary syndrome: randomised double blind clinical trial. Br Med J,
doi:10.1136/bmj.38867.631551.55 (published 12 June 2006).
(27)Johnson NP, Stewart AW, Falkiner J, et al. PCOSMIC: a multi-centre randomized trial in
women with polycystic ovary syndrome evaluating metformin for infertility with clomiphene.
Hum Reprod 2010;25(7):1675-83.
Quality Assurance
Author
Alex Bailey, Information Scientist, Welsh Medicines Information Centre, University Hospital of Wales,
Cardiff and Vale University Health Board
Date this version written
6 March 2012 (date of partial revision 21 May 2013)
Checked by
Gail Woodland, Senior Information Pharmacist, Welsh Medicines Information Centre, University
Hospital of Wales, Cardiff and Vale University Health Board
Date of check
6 March 2012 (partial revision checked 24 May 2013)
Search strategy
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Embase (metformin AND ovary polycystic disease)..
Embase (metformin AND ovary polycystic disease) AND (diabetes mellitus/ OR insulin
resistance/).
Medline (metformin AND polycystic ovary syndrome). Search limited to 2008 onwards
Cochrane Library (‘metformin’ (title, abs, keyword) and ‘polycystic’ (all text)).
Micromedex (metformin)
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As


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IDIS (Drug(s):’metformin 68200407’ and disease(s) (‘polycystic ovary 256.4’)
NeLM (metformin and polycystic).
TRIP database ((title:metformin) ("polycystic ovary"))
Prodigy (polycystic ovary syndrome)
NICE website (polycystic ovary)
EMC (Glucophage)
Available through NICE Evidence Search at www.evidence.nhs.uk
7