metformin and PCOS Treatment

The key clinical features of polycystic ovary syndrome (PCOS) are hyperandrogenism (hirsutism,
acne, alopecia) and menstrual irregularity with associated anovulatory infertility.0402

The agreed definition of PCOS recognises obesity as an association and not a diagnostic criterion 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.0402  Women 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.0401

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. 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.0401 Simple screening tests include an evaluation 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.

Metformin

Obesity has a significant adverse impact on reproductive outcome. It influences not only the chance of conception but also the response to fertility treatment, and increases the risk of miscarriage, congenital anomalies and pregnancy complications in addition to potential adverse effects on long term health of both mother and infant.0701

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.0405

Most of the early 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.0301

Subsequent larger randomised trials, however, have not substantiated these early positive findings. Furthermore, while some studies suggested that metformin therapy may achieve weight reduction,0205 the large randomized
controlled trials and systematic reviews have failed to confirm this.0616

Metformin seems to be less effective in those who are significantly obese (BMI greater than 35 kg/m2),0616
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.

In a trial in Holland, 228 women with PCOS were treated either with clomifene citrate (CC) plus metformin
or CC plus placebo.0617 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%).

 The US Pregnancy in Polycystic Ovary Syndrome (PPCOS) trial0703enrolled 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.

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.0703

Conclusion

 

Sadly, although for a few years following the introduction of metformin for PCOS in 1998, many of us believed that it was beneficial. Recent evidence, however, has been disappointing. 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. Therefore, on current evidence metformin is
not a first line treatment of choice in the management of PCOS.

The Early Metformin PCOS Story:

In PCOS cause the recently discovered relationship between PCOS and insulin resistance has been presented. Metformin is a drug that increases sensitivity to insulin and it therefore reverses the insulin resistance of PCOS.

Metformin has been used since the 1950s in the treatment of diabetes. There is accumulating evidence that metformin has a significant part to play in the treatment of PCOS, whether the symptoms are amenorrhoea (absent periods), oligomenorrhoea (infrequent periods), obesity, hirsutism (excessive hair production) or anovulation (failure to release eggs resulting in infertility). Metformin 500mg tablets are taken two or three times daily after meals. Although metformin has been available for more than forty years, its application for PCOS is new and it has yet to be licensed for this indication. We therefore provide metformin for PCOS only with informed consent (informed consent). Some women may be initially troubled by bowel disturbance and flatulence but these problems improve after a couple of weeks. The tablets can be split Infrequent periods worth taking only half a tablet daily for a few days and gradually increasing the dose over two or three weeks. At this time there is no substitute for metformin as a drug to increase insulin sensitivity but there is a new class of insulin-sensitising agents due to be launched soon the thiazolidinedionesIt will be some years before the true value of metformin for patients with PCOS will be determined. Initial experience has shown that it is beneficial for women with hirsutism and absent or infrequent periods and infertility. It may assist in weight reduction. There is theoretical reason for optimism that metformin prescribed for women with PCOS will have several long-term benefits. It was suggested that metformin may reduce complications which may occur with ovulation stimulation particularly with gonadotrophin injections:

A thirty-five year old woman had stopped seeing her periods (amenorrhoea) for a year and her weight had been increasing. Her only other problem was IBS (Q23.34). Her BMI was 38 (Q9.8) showing that her weight was 50% greater than it should have been. Ultrasound examination of her pelvis showed no abnormality and in particular there was no suggestion of polycystic ovaries. Her LH was 8.4 IU/l and FSH 4.8 IU/l which are normal readings and her thyroid tests and prolactin were normal. The testosterone was 3.2 nmol/l which is towards the upper level of normal but her SHBG was low at 14 nmol/l. Her fasting blood sugar was 4.8 mmol/l (normal) but her fasting insulin was 18.7 mU/L which is high. Metformin was commenced.

This case is an example of a patient presenting with two problems that can be associated with polycystic ovary syndrome namely amenorrhoea and obesity although the ultrasound was reported as showing normal ovaries. Her LH was not high and even her testosterone was just within the normal range. The low SHBG is a strong pointer to the diagnosis. Although the high fasting insulin in this case seems reassuring that metformin is likely to prove beneficial the value of insulin tests in clinical management remains to be determined.

There has been some evidence that with metformin weight loss may occur.0801

Metformin 500mg and Metformin 850mg tablets are available. A typical regimen would be Metformin 500mg tds (three times daily)

Metformin Side Effects

The most common side effects of metformin  are those associated with the bowel namely nausea, vomiting, gas, bloating, diarrhoea and loss of appetite. These symptoms occur in 30% of patients. These side effects may be so severe that  therapy has to be discontinued in 5% patients. These side effects are dose related and may decrease if the dose is reduced.

The serious but rare side effect of metformin is lactic acidosis. Lactic acidosis occurs in one out of every 30,000 patients and is fatal in 50% of cases. Liver function tests and renal function tests should be considered.

Related Medical Abstracts - Click on the paper title:-

PCOS and metformin

Please see above- The recently discovered relationship between polycystic ovary syndrome and insulin resistance has been presented above. Metformin is a drug that increases sensitivity to insulin and it therefore reverses the insulin resistance of PCOS. Metformin has been used since the 1950s in the treatment of diabetes and it is a remarkably safe drug.

There is accumulating evidence that metformin has a significant part to play in the treatment of PCOS, whether the symptoms are amenorrhoea (absent periods), oligomenorrhoea (infrequent periods), obesity, hirsutism (excessive hair production) or anovulation (failure to release eggs resulting in infertility). Metformin 500mg tablets are taken two or three times daily after meals. Although metformin has been available for more than forty years, its application for PCOS is new and it has yet to be licensed for this indication. We therefore provide metformin for PCOS only with informed consent (informed consent). Some women may be initially troubled by bowel disturbance and flatulence but these problems improve after a couple of weeks. The tablets can be split Infrequent periods worth taking only half a tablet daily for a few days and gradually increasing the dose over two or three weeks. At this time there is no substitute for metformin as a drug to increase insulin sensitivity but there is a new class of insulin-sensitising agents due to be launched soon the thiazolidine will be some years before the true value of metformin for patients with PCOS will be determined. Initial experience has shown that it is beneficial for women with hirsutism and absent or infrequent periods and infertility. It may assist in weight reduction. There is theoretical reason for optimism that metformin prescribed for women with PCOS will have several long-term benefits. It has been suggested that metformin may reduce complications which may occur with ovulation stimulation particularly with gonadotrophin injections:

If I conceive whilst taking metformin, could the baby be affected?

Metformin has been used for many years by diabetic patients and there is no evidence that it causes such problems in pregnancy. Once pregnancy has been confirmed, there is no proven advantage in continuing treatment but there is some early eInfrequent periodsinue the metformin until 20 weeks into the pregnancy and others continue the metformin throughout the pregnancy.

Related Medical Abstracts - Click on the paper title:-

What is the significance of body weight in polycystic ovary syndrome?

PCOS encourages weight gain and fat has an adverse effect on the hormone balance leading to an escalating spiral of the problems.

Obesity reduces the chances of pregnancy and increases the risk of pregnancy complications including miscarriage, high blood pressure and thromboembolism.

For those with PCOS, diet is an important part of life. If you are overweight and have PCOS diet with calorie control may reduce your symptoms.

How should infertility associated with polycystic ovary syndrome be treated?

PCOS is associated with ovulation problems (egg release) and therefore ovulation induction is often required. The ovaries will often respond to tablets; Tamoxifen (tamoxifen infertility) is thought to provide a good balance of hormone production although clomiphene (Clomid clomiphene citrate) may also prove to be effective.

Metformin has been shown to be effective in the treatment of polycystic ovary syndrome. For several years, many infertility specialists increasingly turned to metformin as first-line treatment for infertility associated with polycystic ovary syndrome. However, there is now evidence that clomiphene should be the first-line treatment and metformin added if pregnancy is not achieved.

If the ovaries do not respond to tablets more powerful agents (gonadotrophins e.g. Pergonal, Humegon or Metrodin gonadotrophins) given by injection will almost invariably prove to be successful. Increased levels of LH occur in 40% of women with PCOS and this seems to reduce the chance of conception and there is also an increased risk of miscarriage. LH levels can be suppressed by GnRH agonists (gonadotrophins) but disappointingly studies in these situations have shown no improvement.

Ovarian drilling (ovarian drilling) may have a part to play when ovulation stimulation proves difficult to achieve with drugs. Before commencing ovulation stimulation, it seems sensible to ensure reasonable male fertility by checking a semen analysis. Many authorities recommend testing Fallopian tube patency before commencing treatment. My own view is that if there is clear evidence of PCOS and anovulation, a few months of treatment before confirming tubal patency will save many women from an uncomfortable procedure.

Related Medical Abstracts - Click on the paper title:-

Treatment of Absent periods associated with PCOS

The combined oral contraceptive pill is often the most appropriate method for providing cycle control, assuming that conception is to be avoided. If oestrogen levels are satisfactory, regular withdrawal bleeds are likely to follow cyclical progestogen administration (Q5.12; Q 24.17). When the patient is a young teenager, parents often feel happy with this rather than knowing that their daughter has started a contraceptive agent. Another option is the use of a cyclical HRT (Q 28. 9). Metformin should also be considered.


Related Medical Abstracts - Click on the paper title:-

Absent or Infrequent Periods - Is Contraception Necessary?

You can never rely on irregular periods as a symptom of anovulation (eggs not being released). The best advice is that you should not take unnecessary chances.

Related Medical Abstracts - Click on the paper title:-

Can PCOS be treated surgically?

The doctors who first described PCOS removed part of the ovaries (wedge resection), for microscopic examination. They observed that the menstrual cycle and fertility were often restored following these operations.

More recently, it has been shown that drilling tiny holes in the ovaries (ovarian drilling) at the time of laparoscopy, may improve their chemistry although it is too early to know how long this improvement will be sustained. Whilst ovarian drilling may have a part to play in PCOS patients with infertility, this treatment is not proven to have a definite place in treatment for hirsutism.

Ovarian drilling may result in spontaneous ovulation. Unlike ovulation stimulation, there is no increased risk of multiple pregnancy or ovarian hyperstimulation (enlargement of the ovaries with the possibility of other problems such as excess fluid in the abdominal cavity). We do not know why ovarian drilling works. For those patients who respond to ovarian drilling there appears to be a reduction in LH levels which suggests that the drilling must in some way alter the hormone feedback to the hypothalamus and pituitary possibly by the release of a factor not yet identified. Interestingly, in one study where four patients had drilling of just one ovary, there was evidence of ovulation from the other ovary in the first cycle after treatment in three of the patients.

One study has shown that the insulin response to sugar is not altered following ovarian drilling.


Related Medical Abstracts - Click on the paper title:-

Support Groups

Members of a support group, provide each other with various types of help and information for a particular shared difficulty.

The support may take the form of providing relevant information,

  • relating personal experiences,
  • listening to others' experiences,
  • providing sympathetic understanding and
  • establishing social networks.

A support group may also provide ancillary support, such as serving as a voice for the public or engaging in advocacy.

Support groups maintain interpersonal contact among their members in a variety of ways.

Support groups also maintain contact through printed information rich newsletters, telephone chains, internet forums, and mailing lists.

Video: Metformin for PCOS



Support groups offer companionship and information for people coping with diseases or disabilities. Support groups may not be appropriate for everyone, and some find that a support group actually adds to their stress rather than relieving it.



Evaluation of the quality of Web sites is discussed in (internet information). You may find that several general women's health sites may help you (internet information). The following are more specialised relevant Web sites:-
PCO Association P.O. Box 7007 Rosemont IL 60018 USA

 

http://www.verity-pcos.org.uk Verity and PCO

 

52-54 Featherstone Street London EC1Y 8RT.
http://www. Mja.com. Au
pcos friendly.co.uk/
health.groups
pcos. Tripod
cedars-sinai
http://pcos. Meetup.com
www.soulcysters.net/
ww.uhcw.nhs.uk/ivf/supportgroups
pcos world wide support
Women's Health


This is the personal website of David A Viniker MD FRCOG, Consultant Obstetrician and Gynaecologist - Specialist Interests - Reproductive Medicine including Infertility, PCOS, PMS, Menopause and HRT.

I do hope that you find the answers to your women's health questions in the patient information and medical advice provided.



 

The aim of this web site is to provide a general guide and it is not intended as a substitute for a consultation with an appropriate specialist in respect of individual care and treatment.

David Viniker retired from active clinical practice in 2012.
In 1999, he setup this website - www.2womenshealth.com - to provide detailed
information many of his patients requested. The website attracts thousands of visitors every day from around the world.
Website design and search engine optimization became hobies that he plans to pursue in his retirement. If you would like advice on your website, please visit his website
www.firstwebsitedesign.com or email him on david@firstwebsitedesign.com.

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