Medicines Q&As
Q&A 156.2
How effective is metformin compared to the oral contraceptive pill
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: 13 March 2012
Background
This Q&A is the last in a series of seven Q&As on the use of metformin in women with polycystic
ovary syndrome (PCOS). Please refer to the Q&A ‘Can metformin benefit women with polycystic
ovary syndrome?’ for general background information about the condition of PCOS and prescribing
advice for metformin.
PCOS is an endocrine disorder that is characterised by oligomenorrhoea, anovulation, infertility,
hyperandrogenism and obesity (1,2). It is likely that hyperinsulinaemia in women with PCOS impairs
ovulation by increasing ovarian androgen production (1). The oral contraceptive pill is often prescribed
for women with PCOS because it provides endometrial protection, lightens and improves the
regularity of menses, and reduces ovarian androgen production, thereby reducing hirsutism and acne
(5).
Answer
Anovulation, oligo/amenorrhoea
Based on the results of two six-month studies (3,4), a Cochrane review (5) concluded that metformin
was significantly less effective than the combined oral contraceptive pill (OCP) at improving menstrual
pattern (Peto odds ratio (OR) 0.08, p=0.0042, 95% CI 0.01 to 0.45). Eighteen of the 21 patients on
metformin and 20 of the 24 patients on the OCP had oligomenorrhoea or amenorrhoea at baseline
(5).
Hirsutism
The results of four studies (3,4,6,7) comparing the effects of metformin with those of OCP on
hirsutism in PCOS were included in a Cochrane review (5). Ferriman-Gallwey (FG) scores were used
in all these studies. Eighteen of the 52 randomised patients from two of the six-month studies (3,4)
had clinical hirsutism (FG score >7). Metaanalysis of these two studies showed no significant
difference in the decrease in FG score between the OCP and metformin groups (p=0.081). Another
study lasting only 4 months and involving 40 patients with and without clinical hirsutism (FG score >7)
found the FG scores in both goups to decrease significantly over the course of the study (OCP group
(n=20): from 12.065.25 [9.36-14.76] to 10.474.80 [8.00-12.94]; OCP and metformin group (n=20):
from 9.475.48 [6.65-12.29] to 7.653.66 (5.77-9.53) but, in contrast to the Cochrane analysis of this
paper, the paper itself reported no signicant difference between combined OCP and metformin and
metformin treatments in terms of their effects on the FG score in these women (6).
The fourth study analysed in the Cochrane review was a 12-month study that looked at metformin and
OCP (Dianette®) effects on hirsutism in PCOS. In this study, all patients had clinical hirsutism (FG
score >8) at baseline. Patients assessed their degree of hirsutism using a visual analogue scale (010) and the results of 34 patients were analysed. After 12 months, the reduction in FG score was
significantly greater in the metformin than OCP group (approximately 25% versus 5%; p<0.01).
According to patient self-assessment, patients in the metformin group assigned themselves lower
scores for hirsutism than OCP patients (p=0.01).(7).
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Overall the Cochrane review concluded that the limited data demonstrated no evidence of difference
in effect between metformin and the OCP on hirsutism (5).
Acne
Only one 12-month trial (7) (described above) was analysed by the Cochrane review (5). In this trial,
patient self-assessment was used to compare the effects of metformin 500mg three times a day and
OCP (Dianette®) on acne in PCOS. Thirty-four patients were analysed and, based on visual analogue
scale scores (0-10), patients in both groups considered that their acne had improved significantly.
There was no significant intergroup difference (p=0.36), but the authors reported that the degree of
acne in general was low. Acne was a secondary outcome measure in this study (7).
Insulin resistance and development of diabetes
According to the Cochrane review mentioned above (5), metaanalysis of three studies (69 patients
analysed) that reported on fasting insulin levels (3,4,7) found no change in fasting insulin levels with
OCP, but a significant lowering of these levels with metformin (weighted mean difference (WMD) for
metformin versus OCP= -3.46, 95% CI -5.39 to -1.52, p=0.0005).
This Cochrane review (5) also reported on one trial (3) that looked at the development of type 2
diabetes in obese patients receiving metformin or OCP for PCOS. The metformin and OCP groups
did not differ with regard to development of diabetes (Peto OR=0.17, 95% CI 0.00 to 8.54, p=0.37),
but only 18 patients were analysed (5).
One hundred overweight women (BMI>27 kg/m 2) completed a six-month, open-label, controlled trial in
which they were randomised to a high-dose OCP (ethinyl oestradiol 35 micrograms/cyproterone
acetate 2mg), metformin 1g twice daily or a low-dose OCP (ethinyl oestradiol 20
micrograms/levonorgestrel 100 micrograms) plus spironolactone 50mg twice daily. A statistically
significant reduction in insulin resistance, as measured by the homeostasis model assessment of
insulin resistance (HOMA-IR), was noted in the metformin group, the HOMA-IR value being reduced
by 1.13 at six months compared to baseline, p<0.05. A non-statistically significant increase in HOMAIR value was noted in the high-dose OCP group, whereas in the low-dose OCP and spironolactone
group, a non-significant decrease in HOMA-IR was seen (8).
An open-label study in which 36 patients with PCOS received metformin 1g twice daily and 30
patients received OCP (ethinyloestradiol 35 micrograms/cytoproterone acetate 2mg) for six months
investigated the effects of these treatments on insulin resistance (9). An oral glucose tolerance test
(OGTT) was performed with assessment of glucose and insulin over 120 minutes. Using intention-totreat analysis no differences were reported between treatment groups. However, analysis of results
for the 56 patients who completed the study found OGTT insulin to be decreased after 120 minutes
with metformin (5454.3  8632.7 mU/L), p=0.03 and increased after 120 minutes with OCP treatment
(4397.7  5242.7 mU/L) p<0.001 (9).
Despite the above, another recent Cochrane review that did not focus on comparative studies with the
OCP concluded that insulin sensitivity had not been improved overall by metformin in the 14 studies
they analysed (2). Further work in this area would be beneficial.
Obesity
Analysis for a Cochrane review (5) of two studies with obese patients (3,7) and one with non-obese
patients (4) found no significant difference between metformin and OCP with regard to effect on the
BMI, despite there being a significant intergroup difference in favour of metformin in one of the studies
with obese patients (p<0.05) (3). No significant difference was found between treatment groups in two
studies (6,10) that compared the effects of OCP with OCP plus metformin on BMI. In these studies,
68 of the 70 patients who were entered were analysed and the patients were predominantly nonobese. One of the studies (10) also reported that there was no difference in effect on body weight
between the two treatments (5). The results of three studies (3,4,7) comparing metformin and OCP,
and one study comparing metformin plus OCP with OCP (6) were scrutinised for intergroup
differences in effect on waist/hip ratio (5). No significant differences were found (5).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Cardiovascular Problems
Analysis for the Cochrane review (5) of the results of 69 patients with PCOS involved in two studies
(7,11) found no difference between the effects of metfomin and those of OCP on total cholesterol
levels (WMD -0.11 (mmol/L), p=0.60, 95% CI -0.53 to 0.30), HDL cholesterol levels (WMD -0.05
(mmol/L), p=0.62, 95% CI -0.25 to 0.15) or LDL cholesterol levels (WMD -0.02 (mmol/L) , p=0.92,
95%CI -0.47 to 0.42). Triglyceride levels were found to be significantly lower in metformin patients
(WMD -0.48 (mmol/L), p=0.01, 95% CI -0.86 to 0.09) in this analysis. On analysis of two trials (6,10)
that compared combination treatment with metformin and OCP with OCP treatment alone, no
difference between the effects of the two treatments on total cholesterol, HDL cholesterol, LDL
cholesterol or triglyceride levels was found (5),
The Cochrane review (5) found only one trial (7) that compared the effect on blood pressure of
metformin and OCP. Although these treatments did not differ significantly with regard to their effect on
systolic blood pressure, diastolic blood pressure was found to be significantly higher in patients
receiving metformin (WMD 7.50 (mm Hg), p=0.02, 95% CI 1.27 to 13.73).
The Cochrane review (5) concluded that no trials had been identified that compared the effects of
metformin and OCP on the development of cardiovascular disease (5).
Despite the information provided above it should be noted that metformin is licensed for the treatment
of type 2 diabetes only (12). None of the available oral contraceptive pills are licensed for the
treatment of PCOS (13). Therefore the prescriber takes full responsibility when prescribing
metformin,or an OCP for PCOS.
Summary
Anovulation, oligo/amenorrhoea: In women with PCOS, a significantly greater improvement in the
menstrual pattern is seen with OCP than with metformin.
Hirsutism and acne: Data is limited, but there is no evidence of a difference in effect between
metformin and OCP on hirsutism or acne in women with PCOS.
Insulin resistance and the development of diabetes: Open-label studies have suggested that
metformin could have more favourable effects on insulin resistance than OCP. However, a recent
Cochrane review that did not focus on comparative studies with OCP concluded that insulin sensitivity
had not been improved overall by metformin in the 14 studies they analysed. At this point in time,
whether metformin or OCP is more effective in preventing the development of diabetes cannot be
determined due to insufficient data.
Obesity: There is no evidence that metformin or OCP (alone or in combination with metformin) differ
with respect to their effects on BMI or waist/hip ratio.
Cardiovascular problems: The available evidence suggests that there is no significant difference
between the effects of metformin and OCP (alone or in combination) on total cholesterol, HDL
cholesterol or LDL cholesterol. No trials have been identified that compare metformin and OCP on the
development of cardiovascular disease.
Limitations
Data comparing the effects of metformin and OCP in PCOS are limited, especially for major outcomes
such as cardiovascular disease and fertility. In general, studies on the use of metformin in PCOS vary
with regard to their endpoints (1), the duration of treatment with metformin, and characteristics of
participants, including those that are likely to affect results, e.g. BMI.
Available through NICE Evidence Search at www.evidence.nhs.uk
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References
1. Norman RJ, Kidson WJ, Cuneo RC et al. Metformin and intervention in polycystic ovary
syndrome. Med J Aust 2001;174:580-3.
2. 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 of Systematic Reviews 2010, Issue 1.
Art. No.:CD003053. DOI:10.1002/14651858.CD003053.pub4.
3. Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and metabolic effects of
metformin versus ethinylestradiol-cyproterone acetate in obese women with polycystic
ovary syndrome: a randomized study. J Clin Endocrin & Metabol 2000;85:3161-68.
4. Morin-Papunen L, Vauhkonen I, Koivunen R, et al. Metformin versus ethinyl estradiolcyproterone acetate in the treatment of nonobese women with polycystic ovary
syndrome:a randomized study. J Clin Endocrin & Metabol 2003;88:148-56.
5. Costello MF, Shrestha B, Eden J, et al. Insulin-sensitising drugs versus the combined oral
contraceptive pill for hirsutism, acne and the risk of diabetes, cardiovascular disease, and
endometrial cancer in polycystic ovary syndrome. Cochrane Database of Systematic
Reviews 2007, Issue 1. Art. No.: CD005552. DOI: 10.1002/14651858. CD005552.pub2.
6. Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metabolic effects of metformin
added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic
ovarian syndrome: a randomized controlled study. Hum Reprod 2002;17:1729-37.
7. Harborne L, Fleming R, Lyall H. Metformin or antiandrogen in the treatment of hirsutism in
polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88(9):4116-23.
8. Meyer C, McGrath BP, Teede HJ. Effects of medical therapy on insulin resistance and the
cardiovascular system in polycystic ovary syndrome. Diabetes Care 2007;30:471-8.
9. Teede HJ, Meyer C, Hutchison SK, et al. Endothelial function and insulin resistance in
polycystic ovary syndrome: the effects of medical therapy. Fertil Steril 2010;93:184-91.
10. Cibula D, Fanta M, Vrbikova J, et al. The effect of combination therapy with metformin
and combined oral contraceptives (COC) versus COC alone on insulin sensitivity,
hyperandrogenaemia, SHBG and lipids in PCOS patients. Hum Reprod 2005;20:180-4.
11. Rautio K, Tapanainen JS, Ruokonen A, et al. Effects of metformin and ethinyl-estraiocyproterone acetate on lipid levels in obese and non-obese women with polycystic ovary
syndrome. Eur J Endocrinol;152:269-75.
12. 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 23/02/12 [date of revision of
the text 10/2010].
13. Joint Formulary Committee. British National Formulary. 63 ed. London: British Medical
Association and Royal Pharmaceutical Society of Great Britain; 2012
Quality Assurance
Prepared by
Alex Bailey, Information Scientist, Welsh Medicines Information Centre, University Hospital of Wales,
Cardiff and Vale University Health Board.
Date Prepared
13 March 2012
Checked by
Gail Woodland, Senior Information Pharmacist, Welsh Medicines Information Centre, University
Hospital of Wales, Cardiff and Vale University Health Board.
Date of check
16 March 2012
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Search strategy
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Embase (metformin AND ovary polycystic disease). Search limited to 2008 onwards.
Embase (metformin AND ovary polycystic disease) AND (exp *oral contraceptive agent/)
Medline (metformin AND polycystic ovary syndrome). Search limited to 2008 onwards
Cochrane Library (‘metformin’ (title, abs, keyword) and ‘polycystic’ (all text)). Search limited to
2008-2012
Micromedex (metformin)
IDIS (Drug(s):’metformin 68200407’ and disease(s) (‘polycystic ovary 256.4’) Years: 20082012
NeLM (metformin and polycystic). Search limited to 2008 onwards
TRIP database ((title:metformin) ("polycystic ovary") from:2008 to:2012)
Prodigy (polycystic ovary syndrome)
NICE website (polycystic ovary)
EMC (Glucophage)
Available through NICE Evidence Search at www.evidence.nhs.uk
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