PCOS and Metformin: Everything You Need to Know
Metformin is one of the most commonly prescribed therapeutics for the management of PCOS. Metformin works by increasing the body’s sensitivity to insulin. Excess insulin is a common trait among PCOS sufferers, which can lead to excess testosterone and disruption of ovulation. Metformin use may have a number of important benefits for PCOS sufferers, such as:
- Improved ovulation
- Improved fertility
- Weight loss
- Reduced testosterone levels
- Reduced diabetes risk
- Reduced cardiovascular disease risk
Despite its benefits, there is still some debate about the effectiveness of Metformin. In this article, we will explore the latest research regarding how metformin works, when it should be used, its benefits, and its side effects and risks.
Contents
How does Metformin help PCOS?
Approximately 70% of women with PCOS will demonstrate insulin resistance, which leads to excess circulating insulin [source]. Many of these women, but not all, are obese. Obesity further exacerbates insulin resistance. Among other things, excess insulin causes higher levels of testosterone to be produced, which leads to many of the symptoms of PCOS. Excess insulin also leads to long term risks such as Type II Diabetes and cardiovascular disease.
Metformin is an insulin sensitising agent and is the most widely used drug for treating Type II Diabetes. Metformin functions by preventing the liver from releasing glucose (sugar) into the blood stream. Additionally, Metformin decreases the amount of glucose absorbed by the intestines and increases the uptake of glucose across the rest of the body. Metformin also lowers the circulation of fatty acids, which further prevents the body from releasing glucose into the blood. Significantly lowering the amount of glucose circulating around the body sends signals telling the body to produce and release far less insulin. By releasing less insulin, insulin sensitivity is gradually restored. [source]. Although the chemical pathways involved are known, it is not fully understood how Metformin activates them.
Metformin is typically taken in doses ranging between 500 mg per day to 2550 mg per day. Metformin causes some side effects, which are mainly associated with the digestive system, so treatment often starts low and gets progressively higher to allow the body to acclimatise [source].
Metformin and fertility
PCOS related infertility is greatly affected by high levels of insulin. Excess insulin causes cells in the ovary to produce and release high levels of testosterone, as well as reducing the amount of testosterone that the body can remove from circulation. Excess levels of testosterone in the ovary cause follicle development to be stopped, resulting in disruption of ovulation meaning that no egg is released. Without ovulation, pregnancy is impossible.
For more information on why PCOS causes infertility, check out: Ovulation, Menstruation and PCOS: What Goes Wrong?
“70% of women that cannot ovulate with Clomiphene will ovulate using Metformin”
The first methods for inducing ovulation in women with PCOS are weight loss (if necessary) and Clomiphene Citrate. About 20% of women that will not be able to ovulate due to being resistant or intolerant to Clomiphene. For those women, Metformin is generally prescribed as the next option. Approximately 70% of women that cannot ovulate with Clomiphene will ovulate using Metformin [source].
For more information on the different fertility treatments for PCOS, check out: How to Treat PCOS Infertility and Ovulation.
Metformin alone is not as effective as Clomiphene at inducing ovulation and pregnancy [source] however many studies suggest that using Clomiphene and Metformin in combination has better results [source]. The Metformin-Clomiphene combination has been shown to be particularly effective in women who are resistant to Clomiphene [source]. It is thought that Metformin creates a more favourable environment in the ovaries for Clomiphene to work, by reducing insulin levels [source]. Additionally, the use of Metformin appears to result in a reduced risk of complications such as Ovarian Hyper Stimulation Syndrome and multiple pregnancy [source].
Some people will be prescribed Gonadotropins for treating PCOS related infertility. Some studies have suggested that Metformin is effective when used in combination with Gonadotropins however other studies have disagreed with this [source]. The decision on whether or not to use Metformin in these circumstances will usually depend on the level of insulin resistance in the individual. Studies have shown that metformin has the most effect in women who are more insulin resistant [source].
Interestingly, some women have a genetic mutation (in the STK11 gene), that significantly decreases their chance of ovulating using Metformin [source].
Metformin and menstruation
The endometrium is the lining of the uterus that grows and sheds during the menstrual cycle. Excess insulin in the body can stimulate unopposed endometrial growth [source]. Metformin has been shown to reduce excess growth of the endometrium which can be a cancer risk in the long term. Additionally, Metformin may improve the overall health of the endometrium, which makes it more suitable for implantation after an egg has been fertilised [source]. Other studies have looked at the effect of Metformin on health markers such as thickness and blood supply of the endometrium and found it to be beneficial [source]. The menstruation benefits of metformin are achieved mostly through the reduction of insulin levels and also promoting healthy ovulation. It is important to note though that menstruation can be caused by a change in body hormone levels, as well as ovulation. Some studies have found that Metformin can cause menstruation but not ovulation in some women, so blood tests should be done to confirm that menstruation is indeed linked to ovulation in women taking Metformin [source].
Metformin and hair growth
“Metformin reduces unwanted hair growth by 30%”
There is a large body of evidence that suggests that taking Metformin can additionally improve circulating testosterone levels, and therefore reduce symptoms of acne and hirsutism (excess hair growth in a male pattern). Studies have shown that obese and non-obese women taking metformin experience a significant drop in testosterone [source]. Insulin also acts as a growth factor for body and facial hair, so it is possible that reducing insulin levels with Metformin is also beneficial to hair growth [source]. One study found that 6 months of Metformin use reduced hirsutism in women with PCOS by 30% on average [source]. Although the effects on hair growth and acne are a pleasant side effect of Metformin, it should be noted that Metformin is far less effective for this than the combined oral contraceptive pill [source]. For this reason, the contraceptive pill is a better direct treatment for hirsutism and acne, providing the individual is not attempting pregnancy.
Metformin, weight loss, diabetes and CVD
Between 40 and 85% of women with PCOS are also obese (the rates vary from country to country) [source]. As previously mentioned, obesity greatly worsens the symptoms of PCOS, and often makes treatments less effective. Excess insulin caused by obesity and PCOS presents a serious risk for diabetes in the long term [source]. In fact, 30-50% of all women with PCOS will develop Type II Diabetes by the age of 30. High insulin levels also lead to higher LDL cholesterol (the bad kind) and lower HDL cholesterol (the good kind), as well as high levels of fat in the blood stream. This increases the risk of cardiovascular disease [source]. This is why weight loss and long term management of diabetes and cardiovascular risk is so important for women with PCOS.
Metformin use has actually been associated with weight loss. While diet and exercise are the most useful tools to reduce body weight, studies have shown that using metformin in combination with a reduced calorie diet had a more drastic effect on weight loss and body fat reduction, as well as a more profound decrease in serum insulin and testosterone levels [source]. Metformin additionally appears to reduce appetite slightly. A review of 24 different studies found that, on average, Metformin causes a weight loss of about 3kg [source]. Separate studies have also shown that the effects of Metformin are enhanced with weight loss, creating a positive cycle of improvement [source]. Weight loss associated with Metformin has only been observed in overweight and obese women. It appears to have no effect on body weight in women who are already lean [source]. Despite its apparent benefits, it should be noted that in general the weight loss caused by Metformin is quite minimal and a reduced calorie diet is by far the most effective way to reduce body weight and body fat.
Studies have shown that all women, whether obese or lean, show a decrease in insulin levels and insulin resistance after 6 months, which is certainly beneficial for the management of diabetes [source]. However, only limited studies have actually looked at whether Metformin is capable of slowing the progression of Type II Diabetes in women with PCOS [source]. More work is needed in this area to confirm this benefit. Similarly, some studies have shown that Metformin might improve heart and circulatory system health, reducing cardiovascular disease risk [source]. However, not all studies have agreed with this and more work is needed to come to a definite conclusion here.
What are the side effects of Metformin?
Metformin can have quite severe side effects in some users. Although the side effects are rarely dangerous, they are still unpleasant. For this reason, most doctors will suggest that the initial dose of Metformin is kept relatively low and increased over a period of 4-6 weeks [source]. Most side effects are gastrointestinal (digestive) in nature, such as diarrhoea, nausea, vomiting, bloating, flatulence, or heartburn. Other side effects can include sneezing, coughing and a runny nose. More serious side effects can also happen, although they are rare. These include lactic acidosis, chest pains and a rash. For a complete list of side effects use the table below.
|
Type of effect |
Effect |
|
Gastrointestinal |
Diarrhoea |
|
Nausea |
|
|
Vomiting |
|
|
Bloating |
|
|
Flatulence |
|
|
Indigestion |
|
|
Constipation |
|
|
Heartburn |
|
|
Other |
Sneezing |
|
Cough |
|
|
Runny nose |
|
|
Skin flush |
|
|
Rare |
Lactic acidosis |
|
Chest pain |
|
|
Rash |
Lactic acidosis is the major concern regarding the use of Metformin. Although it is a very serious complication it is incredibly rare. However, because of this risk, Metformin should not be used by people with kidney problems, heart problems, sepsis or a history of liver issues (such as alcohol abuse) [source].
Additionally, people using Metformin should be monitored regularly for levels of vitamin B12 as metformin can reduce its uptake, resulting in a deficiency. B12 deficiency can lead to numbness, memory loss, pernicious anaemia and behavioural change [source].
