Metformin & pcos
Metformin & PCOS
The key clinical features of polycystic ovary syndrome (PCOS) are hyperandrogenism
(hirsutism, acne, alopecia) and menstrual irregularity with associated anovulatory infertility. 1
The consensus definition of PCOS recognises obesity as an association and not a diagnostic
criterion1 as only 40–50% of women with PCOS are overweight. Ovarian hyperandrogenism is
driven primarily by luteinising hormone (LH) in slim women, while in the overweight insulin may
augment the effects of LH.
1Women with polycystic ovaries are more insulin resistant than weight-matched women with
normal ovaries. Insulin resistance is seen in 10–15% of slim and 20–40% of obese women with
PCOS and women with PCOS are at increased risk of developing type 2 diabetes.
2. Insulin resistance
Insulin resistance is defined as a reduced glucose response to a given amount of insulin and
usually results from faults within the insulin receptor and post-receptor signalling. As a result
circulating insulin levels rise. Insulin resistance does not affect all actions of insulin and, in the
ovary, high levels of circulating insulin are thought to contribute both to excess androgen
production and to anovulation. Insulin resistance can be measured by a number of expensive
and complex tests but in clinical practice it is not necessary to measure it routinely; it is more
important to check for impaired glucose tolerance.2 Simple screening tests include an
assessment of body mass index (BMI) and waist circumference. If the fasting blood glucose is
less than 5.2 mmol/l the risk of impaired glucose tolerance is low. The 2-hour standard 75 g oral
glucose tolerance test (OGTT) may be conducted in those at high risk (BMI greater than 30
kg/m2 in white women or greater than 25 kg/m2 in women from South Asia, who have a greater
degree of insulin resistance at a lower body weight). 1,2 3. Metformin therapy for
Obesity has a profound effect on both natural and assisted conception, influencing the chance
of becoming pregnant and the likelihood of a healthy pregnancy.3 Increasing obesity is
associated with greater insulin resistance. Metformin inhibits the production of hepatic glucose,
enhances insulin sensitivity at the cellular level and also appears to have direct effects on
ovarian function. It is logical to consider, therefore, that insulin lowering and insulin sensitising
treatments such as metformin and the thiazolidinediones (rosiglitazone, pioglitazone) should
improve the symptoms and reproductive
outcome for women with PCOS.4
Most of the initial studies of metformin in the management of PCOS were observational. Initial
systematic reviews, in which the majority of studies had a small sample size and did not include
a power calculation for the proposed effect, suggested that metformin when compared with
placebo, had a significant effect on lowering serum androgen levels and restoring menstrual
cyclicity and was effective in achieving ovulation either alone or when combined with
clomifene.5 Subsequent larger randomised trials, however, have not substantiated these early
positive findings. Furthermore, while some studies suggested that metformin therapy may
achieve weight reduction,6 the large randomized controlled trials and systematic reviews have
failed to confirm this.
Metformin & PCOS
min appears to be less effective in those who are significantly obese (BMI greater than 35
kg/m2),6,7 although there is no agreement on predictors for response or the appropriate dose
and whether dose should be adjusted for body weight or other factors. Doses of between
500–3000 mg/day have been used and the most common dose regimens are 500 mg three
times daily or 850 mg twice a day. Long-acting preparations are associated with fewer
gastrointestinal adverse effects. Metformin appears to be safe in pregnancy, although usual
advice is to discontinue once a pregnancy occurs. There is no firm evidence that metformin
reduces the risk of either miscarriage or gestational diabetes.
The largest prospective randomised, double blind, placebo-controlled study trial to evaluate the
combined effects of lifestyle modification and metformin (850 mg twice daily) studied 143
anovulatory women in the UK with a mean BMI of 38 kg/m.27 All subjects had an individualised
assessment by a dietician in order to set a realistic goal that could be sustained with an average
reduction of energy intake of 500 kcal per day. As a result, both the metformin-treated and
placebo groups managed to lose weight but the amount of weight reduction did not differ
between the two groups. An increase in menstrual cyclicity was observed in those who lost
weight, but again did not differ between the two arms of the study.
7In a Dutch trial, 228 women with PCOS were treated either with clomifene citrate (CC) plus
metformin or CC plus placebo.8 There were no significant differences in either rates of ovulation
(64% versus 72%), continuing pregnancy (40% versus 46%) or rate of spontaneous miscarriage
(12% versus 11%). A significantly larger proportion of women in the metformin group
discontinued treatment because of adverse effects (16% versus 5%). The US Pregnancy in
Polycystic Ovary Syndrome (PPCOS) trial9 enrolled 676 women for six cycles or 30 weeks,
randomised to three treatment arms (metformin 1000 mg twice daily plus placebo, clomifene
citrate plus placebo or metformin plus clomifene citrate). Overall, live birth rates were 7%
(5/208), 23% (47/209) and 27% (56/209), respectively, with the metformin alone group being
significantly lower than the other two groups. Miscarriage rates tended to be higher in the
metformin alone group (40% versus 23% and 26%, respectively). Thus, it was concluded that
as first-line therapy for the treatment of women who are anovulatory and infertile with PCOS,
metformin alone was significantly less effective than clomifene citrate alone and that the
addition of metformin to clomifene citrate produced no significant benefit.9 Subgroup analysis of
women with a BMI greater than 35 kg/m2 and in those with clomifene resistance did, however,
suggest a potential benefit from the combined use of metformin with clomifene citrate.9 It has
been suggested that co-treatment with metformin may improve the response to exogenous
gonadotropins or the outcome of assisted reproduction therapy. Indeed, the largest study to
date has shown an increase in continuing pregnancy rates in women with polycystic ovaries and
a mean BMI of 28 kg/m2 treated with metformin (850 mg twice daily) for only 4 weeks during an
IVF cycle.10 In this study, 101 women were randomised to receive metformin or placebo. Both
the clinical pregnancy rates beyond 12 weeks of gestation per cycle started (39% versus 16%;
P = 0.023) and per embryo transfer
(44% versus 19%; P = 0.022) were significantly higher in those treated with metformin.
Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation
syndrome was observed (4% versus 20%; p=0.023) despite the higher pregnancy rate in the
Metformin & PCOS
metformin arm of the study.10
These results are promising but further studies are required to confirm these observations
before the place of metformin in assisted reproductive techniques can be clearly assessed.
The updated Cochrane review concluded that the benefit of using therapy to lower insulin levels
such as metformin is limited in terms of improvement in reproductive outcome and metabolic
parameters.11 In particular, the use of metformin either alone or in combination with drugs to
induce ovulation such as clomifene citrate did not increase the chance of having a livebirth.
Furthermore, despite evidence of a reduction in development of diabetes in a high risk
non-PCOS population12 the long-term use of metformin in reducing the risk of developing
metabolic syndrome is questionable.
11Lifestyle advice with appropriate attention to diet and exercise has to be the mainstay for young
women with PCOS.
While initial studies appeared to be promising, more recent large randomised controlled trials
have not observed beneficial effects of metformin either as first-line therapy or combined with
clomifene citrate for the treatment of the anovulatory woman with PCOS. Most work has been
undertaken in the
management of anovulatory infertility and there are no good data from randomised controlled
trials on the use of metformin in the management of other manifestations of PCOS. It is clear
that the first aim for women with PCOS who are overweight is to make lifestyle changes with a
combination of diet and exercise in order to lose weight and improve ovarian function. The
European Society for Human Reproduction and Embryology and American Society for
Reproductive Medicine consensus on infertility treatment for PCOS concluded that there is no
clear role for insulin sensitising and insulin lowering drugs in the management of PCOS, and
should be restricted to those patients with glucose intolerance or type 2 diabetes rather than
those with just insulin resistance.13 Therefore, on current evidence metformin is not a first line
treatment of choice in the management of PCOS.
Metformin & PCOS
1. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003
consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome
(PCOS). Hum Reprod 2004;19:41–7.
2. Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary
syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004;59:141–54.
3. Balen AH, Anderson R. Impact of obesity on female reproductive health: British Fertility
Society, Policy and Practice Guidelines. Hum Fertil 2007;10:195–206.
4. Kayshap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for
patients with polycystic ovary syndrome. Hum Reprod 2004;11:2474–83.
5. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone,
rosiglitazone, pioglitazone, d-chiro-inositol) for polycystic ovary syndrome. Cochrane Database
Syst Rev 2003;(2):CD003053 [DOI:10.1002/14651858. CD003053].
6. Fleming R, Hopkinson Z, Wallace A, Greer I, Sattar N. Ovarian function and metabolic
factors in women with oligomenorrhoea treated with metformin in a randomized double blind
placebo-controlled trial. J Clin Endocrinol Metabol 2002;87:569–74.
7. Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined life-style
modification and metformin in obese patients with polycystic ovary syndrome (PCOS). A
randomised, placebo-controlled, double-blind multi-centre study. Hum Reprod 2006;21:80–9.
8. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. 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. BMJ
9. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al.
Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for
infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–66.
10. Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with
PCOS undergoing IVF treatment. Hum Reprod 2006; 21:1416–25.
11. Tang T, Lord JM, Norman RJ, Balen AH. Insulin-sensitising drugs (metformin,
troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome.
Cochrane Database Syst Rev 2008 Cochrane Database Syst Rev 2003(2):CD003053.
12. 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.
13. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.
Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008;
Metformin & PCOS
This opinion paper was produced on behalf of the Royal College of Obstetricians and
Gynaecologists by: Professor AH Balen FRCOG, Leeds and peer reviewed by: Professor R
Fleming, Honorary Professor of Reproductive Medicine, University Department of Obstetrics
and Gynaecology, Royal Infirmary, Glasgow; Professor S Franks FRCOG, London; Dr SD Keay
FRCOG, Coventry; Dr T McFarlane FRCOG, Manchester; Professor N Sattar, Department of
Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow. The Scientific Advisory lead peer
reviewers were: Professor R Anderson FRCOG, Vice Chair; Professor S Thornton FRCOG,
Chair. The final version is the responsibility of the Scientific Advisory Committee of the RCOG.
Royal College of Obstetricians and Gynaecologists 2009
OMBRE DEL MEDICAME TO Leflunomida medac 20 mg comprimidos recubiertos con película 2. COMPOSICIÓ CUALITATIVA Y CUA TITATIVA Cada comprimido recubierto con película contiene 20 mg de leflunomida. Excipiente(s) con efecto conocido: Cada comprimido recubierto con película contiene 152 mg de lactosa (como monohidrato) y 0,12 mg de lecitina de soja. Para consultar la lista completa de excipientes, ver sección 6.1. 3.
ORIGINAL ORIGINAL Non-surgical periodontal therapy for the treatment of chronic periodontitis Terapia periodontal não-cirúrgica no tratamento da periodontite crônica Mari Raquel Botlender TROJAHN1 Robert Carvalho da SILVA2 Júlio César JOLY2 The aim of this split-mouth controlled study was to compare the clinical benefits of administering subgingival 10% Doxycycline (test group)