Metformin: A possible new treatment for endometriosis

December 7, 2021

new treatment endometriosis, metformin endometriosis — © Deanpictures

Dr Deborah Lee, Dr Fox Online Pharmacy, discusses a possible new treatment for endometriosis – the condition that impacts atleast 1.5 million women in the UK

Endometriosis is a miserable condition that currently affects 1 in 10 – that’s around 1.5 million women – in the UK. If you are reading this, chances are you’ve been diagnosed with the condition and are looking for answers.

What is endometriosis?
How is endometriosis treated?
Why could metformin be an exciting new option to treat endometriosis?

Read on and find out.

The misery of endometriosis

In a recent (2019) BBC survey of 13,500 endometriosis sufferers, the majority of women reported they regularly took prescribed pain killers due to the severity of their symptoms, and that living with endometriosis had negatively impacted their mental health, their relationships, and their careers. Worryingly, more than 50% had had suicidal thoughts.

One of the key problems is the delay in diagnosis. On average, The Endometriosis Society reports that it takes 8 years from the onset of symptoms for a diagnosis of endometriosis to be made. This is because the symptoms of endometriosis are often similar to those of other common conditions such as Pelvic Inflammatory Disease, ovarian cysts, irritable bowel syndrome and fibromyalgia.

What is endometriosis?

Endometriosis occurs when the endometrial cells (the cells that make up the lining of the womb,) grow outside the uterus (womb). Endometriosis can be found anywhere in the body but is most commonly situated in the pelvic tissues, such as the ovaries, and the fallopian tubes. Endometriotic deposits are commonly found scattered around the pelvic cavity, and hence frequently involve the outside wall of the uterus, the supporting pelvic ligaments, and also the bowel and bladder. Strange as it sounds, endometriosis can occur at distal sites, for example, in the nose where it causes a monthly nosebleed! It can also be present in the gastrointestinal tract, or the lungs.

Endometrial tissue responds to the rise and fall of hormone levels that take place during your monthly cycle. As ovulation approaches, estrogen levels rise, and the endometrium thickens up in preparation for pregnancy. If no pregnancy occurs, estrogen levels fall, and progesterone levels rise, culminating in the endometrium being shed in the monthly period.

Wherever endometriotic tissue is present, this same process is taking place. Endometriotic tissue situated anywhere outside the uterus will bleed monthly, internally, which is excruciatingly painful. Women with endometriosis often have incredibly painful periods.

As internal bleeding takes place , fibrous tissue (scar tissue) is produced as the body tries to heal the bleeding site. As the months go by, scar tissue builds up, tethering the uterus, fallopian tubes, and ovaries so they are bunched together, in abnormal positions, and are unable to move freely within the pelvic cavity as they should. This leads to a variety of symptoms including very painful periods, prolonged and heavy periods, pelvic pain, painful sex, and infertility.

What causes endometriosis?

What causes endometriosis is not well understood. One theory is retrograde menstruation – meaning that during a period, some of the menstrual blood travels backwards and up into the pelvis, instead of being shed into the vagina. Another possible cause is that endometrial cells might spread in the bloodstream, as cancer cells do, meaning these cells are disseminated throughout the body. The third possibility is that there may be a genetic link as endometriosis does tend to run in families. Occasionally, endometrial cells may be transplanted to other sites during surgery, for example, during a Caesarean section.

How is endometriosis treated?

Because endometrial tissue grows under the action of estrogen, most endometriosis treatments have some sort of anti-estrogen effect. This also means that most of these treatments are contraceptive – which is fine if you don’t want to be pregnant, but not fine if you do.

The most commonly used treatments are –

The Combined Oral Contraceptive pill – or the Contraceptive Patch, or Vaginal Ring
Progesterone-only methods – including the Progesterone-only pill (POP), Injection (Depo Provera), Intrauterine System (IUS) (‘the hormone coil’), or Progestogen-implant (Nexplanon).
Gonadotrophin Releasing Hormone Inhibitors – GnRH inhibitors – (a group of drugs that lower estrogen levels by preventing the release of hormones from the anterior pituitary, that go on to stimulate the ovary to produce estrogen.)
Aromatase inhibitors – drugs that prevent the production of estrogen from other hormones in fat tissue by blocking the enzyme, aromatase.)

Although any of these methods can be helpful, they are often not suitable over time due to side effects, they may only be authorised for a short duration of treatment, they are often expensive, and most treatments are contraceptive. In addition, none of these treatments is especially beneficial for endometriosis-related, infertility.

There is an urgent need to find new medical treatments that don’t have these drawbacks. Hence, the new possibility of using the drug, metformin, to treat endometriosis, is a very welcome development for endometriosis sufferers.

Metformin to treat endometriosis

What is metformin?

Metformin is a medication used most often by type-2 diabetics to help control their blood glucose levels. It is a drug called a non-sulfonylurea. The full mechanism of action is not understood, but it increases the sensitivity of the body’s cells to insulin, reducing insulin resistance, and also decreases the amount of glucose produced in the liver (gluconeogenesis).

Why might metformin help treat symptoms of endometriosis?

Metformin has been shown to have anti-inflammatory, anti-proliferative, and anti-estrogenic effects on endometriotic tissue. It can also improve the pregnancy rate for women with endometriosis-associated infertility. The research so far is summarised below.

Research on metformin for endometriosis

In May 2021, the journal Frontiers in Medicine published a review of the medical studies on the use of metformin to treat endometriosis. The authors included six studies; two on rats, three in a laboratory setting, and one undertaken on human subjects with endometriosis.

Laboratory studies

In the first 2007, a laboratory-based study used cultured endometrial cells taken from ovarian endometriomas. The investigators studied how metformin affects inflammation, estradiol production, and the growth and proliferation of endometrial cells.

The study showed that metformin –

suppressed the production of IL-8 (interleukin-8), a cytokine that signals to attract neutrophils to the area and induces inflammation.
reduced aromatase activity – aromatase is an enzyme that converts androgens (male hormones) to estrogens in the ovary, but also in fat cells.
reduced the growth and proliferation of endometrial cells.

The investigators felt these results indicated that metformin is a promising treatment option for endometriosis, and they recommended further research was indicated.

In 2015, another laboratory study using cultured human endometriotic cultured cells resulted in some further exciting discoveries. Metformin was shown to block the action of prostaglandin E2 (PGE2) – a potent inflammatory mediator – and also inhibited the activity of the enzyme, aromatase.

Why are aromatase inhibitors useful in endometriosis?

Aromatase inhibitors block the action of the enzyme, aromatase, and by doing this, they inhibit the production of estrogen, both in the ovary and in other tissues. They are often used in the treatment of breast cancer.

However, aromatase inhibition is especially useful in women with endometriosis, due their ability to prevent the production of estrogen in tissues, such as peripheral fat. Women with endometriosis are known to produce a specific type of aromatase within their endometriotic tissue, known as aromatase P450 – which is absent in the endometrium of healthy women.

Current aromatase inhibitors, such as letrozole, are not licensed for the treatment of endometriosis. If they are used for endometriosis, they tend to be given at the standard doses needed to treat breast cancer, and these are often associated with side effects due to the dramatic reduction in estrogen levels. If metformin has an anti-aromatase action and can be used at comparatively lower doses, as well as reducing inflammation, this will have major advantages in the treatment of endometriosis.

Studies in rats

In one 2010 study, rats that had been artificially implanted with endometriotic lesions, were treated with either the aromatase inhibitor, letrozole, or metformin. The results showed that both letrozole and metformin reduced endometriotic lesions to a similar degree, but metformin had a greater effect on reducing adhesions (scar tissue).

Metformin in human subjects

The only study performed to date on human subjects with endometriosis, was published in 2012. 69 women with infertility, who had been found at laparoscopy to have stage 1 or 2 endometriosis, were randomly allocated to either a metformin group or a control group. The metformin group took 500mg metformin three times a day for 6 months. The control group took a placebo and a multivitamin.

After 6 months, the metformin group showed a significant reduction in endometriosis symptoms at 3 and 6 months, compared to the controls.
Levels of IL-6, IL-8 and VEGF were also significantly reduced at 3 and 6 months compared to pre-treatment levels, and also to controls.

IL-6 and IL-8 are proinflammatory cytokines – cell signalling molecules playing a vital role in both acute and chronic inflammation.

VEGF is vascular endothelial growth factor – a signalling molecule that induces the growth of new blood vessels.

There was also a significant increase in the pregnancy rate in the metformin group compared to the control group. By 6 months, 9 out of 35 of the treatment group had become pregnant (25.71%). This compared to the control group in which 4 out of 34 had become pregnant (11.76%). The difference between the pregnancy rate in these two groups was highly statistically significant.

The authors recommended that a much larger study was needed, to confirm their findings.

Final thoughts

Metformin has specific properties that seem to offer great advantages for the treatment of endometriosis – reducing inflammation, slowing the new growth and proliferation of endometriotic tissue, and inhibiting the production of estrogen. It has also been shown to improve the chance of pregnancy in those with infertility. Let’s hope it’s not too long before metformin is available for those who need it.

Metformin is already used in Gynaecology for different indications, for example, in PCOS. Recent evidence has shown that metformin can also be safely used in pregnancy, in women with type-2 diabetes, or gestational diabetes. Metformin has been recognised for its anti-cancer properties and has been used in the treatment of breast, endometrial and ovarian cancer. It seems that we might one day, be able to add metformin to this list, as a treatment for endometriosis.

To find out more about currently available treatments for endometriosis, The National Endometriosis Society provides comprehensive information about the currently available treatments.

For more information