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Progesterone intolerance

If you suffer from bloating, acne, mood changes or other PMS-like symptoms while taking HRT, you may have a progesterone intolerance (or sensitivity) – here’s how to handle it

Progesterone intolerance is thought to affect 10-20% of women
Symptoms include anxiety, low mood, greasy skin, cramping, bloating, breast tenderness and headaches
Natural, body identical progesterone is less likely to cause these symptoms compared to synthetic progestogens

Progesterone is commonly thought of as the “relaxing hormone” as, for most women, it has calming, anti-anxiety (anxiolytic) properties. But some women can be particularly sensitive to progesterone or, most likely, its synthetic form, progestogen. This is known as progesterone intolerance (or sensitivity) – your body reacts to the progesterone or progestogen, causing symptoms that can be similar to some symptoms of premenstrual syndrome.

What are the symptoms of progesterone intolerance?

Symptoms of progesterone intolerance can be grouped into three main areas – psychological, physical and metabolic. Some types of progestogens are known to cause more physical or metabolic side effects, while other types are associated with more psychological reactions.

Possible psychological effects are anxiety, irritability, aggression, restlessness, panic attacks, low mood, poor concentration, forgetfulness, and heightened emotions.

Physical consequences of progesterone intolerance can be acne, greasy skin, abdominal cramping or bloating, fluid retention, fatigue, headaches, dizziness, and breast tenderness.

Metabolic reactions are when progestogens have a negative effect on systems that produce or regulate cholesterol, blood pressure and blood sugar levels. Natural (body identical) progesterone does not usually have these effects.

Who does it affect?

Symptoms of progestogen intolerance affect around 10-20% of women [1]. It’s often experienced by women who use contraception containing synthetic progestogens such as the combined pill, the minipill, the contraception implant, an IUS (hormone coil), or in women who take some types of synthetic HRT.

Underlying mental health problems, age, environmental factors (such as stress) and genetics may also help to influence an insensitivity to progesterone [2].

Are all types of progesterone the same?

There are two main types of progesterone: progesterone and progestogen. Progesterone is body identical, meaning it’s identical in structure to the natural progesterone hormone produced by your ovaries, brain and other organs. It is derived from the yam root vegetable or soy.

Progestogen, however, is synthetic – it is created chemically and is structurally different to progesterone. This is the type that is used in all forms of contraception. Symptoms of intolerance are much more common with synthetic progestogens.

There are also more risks associated with progestogens than with natural progesterone. Synthetic progestogens have been found to have a small risk of blood clot, heart disease and breast cancer [3].

It is worth noting that these risks are very small, and your actual risk of such diseases depends much more on your overall health, genetics, weight, and lifestyle habits.

What about the progesterone in HRT?

If you’re taking replacement oestrogen and still have your womb, you will need to take progesterone. This is because taking oestrogen by itself can increase the thickness of the lining of your womb – taking progesterone reduces this effect and keeps the lining of your womb thin and healthy.

If you’ve had a period within the last six to 12 months, you will usually be given a cyclical regime of progesterone (or a progestogen). This is where you take progesterone for two weeks and then have a two-week break from taking it, to allow your womb to bleed for a few days, as this keeps the lining healthy. If it has been more than six to 12 months since your last period, you will usually take progesterone (or a progestogen) continuously, with no breaks.

You may notice you feel worse for the two weeks you take progesterone or notice a change when you first start taking it continuously. Some women react to certain types of progesterone/progestogen but don’t react the same way to other types. Some women show signs of intolerance to all types of progesterone, including what is released naturally by their ovaries. It is important to discuss your symptoms with your healthcare professional who will be able to discuss changes to your regime to help improve symptoms.

Unfortunately, progesterone (or a progestogen) intolerance symptoms are a very common reason why women decide to stop taking their HRT, as the progestogen (or progesterone) part can make them feel dreadful [4].

I’m progesterone intolerant – what can I do?

If you are sensitive to progesterone there are a few avenues you can explore with your healthcare professional:

Natural, systemic progesterone

You’re less likely to get a negative reaction if the progesterone you take is body identical. Micronised progesterone(known as Utrogestan in the UK) is a capsule that you usually swallow and is natural (body identical). It is the preferable one to take – especially if you are intolerant to progesterone. It is a systemic progesterone, which means it’s absorbed by the whole body where it can reduce inflammation, relax muscles and stimulate new growth, help improve memory and mood, and regulate menstruation.

Some women may still have side effects with this, in which case it’s worth discussing with your doctor changing the dose, the way you take it or the number of days you take it to see if you can improve any symptoms of intolerance. Make sure you always discuss any changes to your progesterone regime with your doctor as you may feel like reducing the number of days you take it, but you need to make sure it will still do the job of keeping your womb lining thin and healthy. Irregular bleeding can also be common if the progesterone routine is changed.

Taking progesterone orally means that it is metabolised (broken down) in the liver to other types of progesterone and these can sometimes lead to side effects.

Natural, local progesterone

Another way to take progesterone is to insert the tablet vaginally (or rectally), usually at nighttime. This then works locally near your womb, where it is needed, and is also absorbed into your body through the wall of your vagina directly into your bloodstream. This means that the progesterone is not altered in any way or metabolised into other types of progesterone, so there is less chance of side effects. The dose of using progesterone this way varies between women. Some women actually feel better when they use higher doses of progesterone as suppositories. The dose depends on the clinical situation and your healthcare professional will be able to advise you. While Utrogestan is not licensed to take in this way, it is safe to do so and there is evidence to support its use this way [5].

There are progesterone pessaries available, such as Cyclogest or Lutigest (more commonly used as part of fertility treatments), which contain natural, body-identical progesterone and are specifically designed as vaginal or rectal pessaries. Some women find these preferable to use vaginally instead of Utrogestan. Your healthcare professional will be able to advise you about appropriate dosing.

Local progestogen coil

An alternative to protect the womb lining to Utrogestan the Mirena coil. This is a small plastic device that’s inserted into your uterus and it usually stays there for five years, releasing a low and steady dose of progestogen straight into your womb where you need it most. This does a good job of keeping the womb lining thin and healthy (if you’re taking oestrogen), and is also an excellent contraceptive if you need that too.

While the Mirena (and Levosert) coil is a synthetic progestogen, it is a much lower dose than the tablet versions and usually just works locally on the lining of the womb so has more localised effects.

Some women do react to the progestogen in the Mirena; when it’s first inserted it can feel like you have PMS for the first few months. Any reaction tends to settle down at around three to six months and most women do not continue to have symptoms of intolerance after this. However, some women still experience systemic side effects with the progestogen coils so have to have them removed.

Surgical intervention

If your perimenopausal and menopausal symptoms are severe and having a major impact on your life, and changing the type, dose and the way you take progesterone or progestogen has not helped, the very last thing left to try is to remove your womb entirely and have a hysterectomy. This means you can continue with the oestrogen (and testosterone if you are taking that) part of your HRT but don’t need to take any progesterone (in most cases).

If you’re struggling with symptoms of progesterone intolerance because of your contraception or your HRT regime and want to see if anything can be done to help you feel better, see your doctor or healthcare professional about it.

If your usual doctor does not have an specialised interest in menopause then you should ask to see someone who does or consider an appointment with a menopause specialist to discuss progesterone intolerance and treatment options in greater depth.

Resources
NHS: Urogestan (micronised progesterone)

References

Panay N., Studd J. (1997), ‘Progestogen intolerance and compliance with hormone replacement therapy in menopausal women’, Human Reproduction Update, 3 (2), pp.159-171, https://doi.org/10.1093/humupd/3.2.159
Sundström-Poromaa I., Comasco E., Sumner R., Luders E. (2020), ‘Progesterone – Friend or foe?’, Frontiers in Neuroendocrinology, 59 100856, https://doi.org/10.1016/j.yfrne.2020.100856
Stute P., Marsden J., Salih N., Cagnacci A. (2023), ‘Reappraising 21 years of the WHI study: Putting the findings in context for clinical practice’, Maturitas, 174 pp 8-13, https://doi.org/10.1016/j.maturitas.2023.04.271
Panay N., Studd J. (1997), ‘Progestogen intolerance and compliance with hormone replacement therapy in menopausal women’, Human Reproduction Update, 3 (2), pp.159-171, https://doi.org/10.1093/humupd/3.2.159
Stute P., Neulen J., Wildt L. (2016), ‘The impact of micronized progesterone on the endometrium: a systematic review’, Climacteric, 19(4), pp316–328 https://doi.org/10.1080/13697137.2016.1187123

Written by
Dr Louise Newson

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21 Oct 2024

Written by
Dr Louise Newson

Dr Louise Newson is a GP and pioneering Menopause Specialist who is passionate about increasing awareness and knowledge of the perimenopause and menopause, and campaigns for better menopause care for all people.