Oestrogens and blood testing

Where is oestrogen produced in my body?

Before the menopause, your ovaries make most of your oestrogen although a small amount of oestrogen is also produced by your liver, heart, fat, brain, endometrium and adrenal glands. After the menopause, your ovaries produce very little or no oestrogen and your body relies on your other non-ovarian sites for its production.

How does my body make oestrogen?

Your body is able to make oestrogen from a molecule called cholesterol. It is easy to think that cholesterol is an ‘unhealthy’ or ‘bad’ molecule to have because high levels of it are linked with heart disease. However, it is very important to have some cholesterol in our bodies because it is the precursor molecule for our hormones.

Do I have different types of oestrogen?

Yes, your body can make three types of oestrogen:

1. Oestrone (E1): this is a weak oestrogen.  It is found in the body before the menopause but is the most important oestrogen in our body after the menopause. Oestrone is made in the fatty tissue where it is converted from androgens (male hormones found in the female body). The androgens are made by the adrenal glands.
2. Oestradiol (E2): this is a powerful oestrogen produced predominantly by your ovaries before the menopause.
3. Oestriol (E3): this oestrogen is produced in large quantities by the placenta during pregnancy.
4. Estretrol (E4): this oestrogen is only made by the liver of the fetus.

Oestradiol is considered the most important naturally occurring oestrogen. It is the most potent oestrogen; it helps us to feel well and it helps to protect our heart and bones. 

What is body identical oestrogen?

Most hormone replacement therapy (HRT) preparations contain body-identical oestradiol. This means that the hormone in it is identical in structure to oestradiol. 

The alternatives to oestradiol, used in HRT, include conjugated oestrogens and tibolone. Conjugated equine oestrogens are found in some types of HRT – for example Premarin and Premique. Conjugated equine oestrogens are a mix of oestrogens derived from horse urine. Tibolone is a fully synthetic type of HRT containing molecules that act on oestrogen receptors, though they are biochemically different from oestrogen.

How is body-identical oestradiol made?

The bulbs and roots of wild yam plants contain a chemical called diosgenin. This chemical is very similar in structure to cholesterol and because of this, it can be modified in labs for the production of hormones including oestradiol. 

There are over 600 species of wild yam and some species are now grown specifically as a source of diosgenin for labs to use and make hormones.

For diosgenin to be made into oestradiol it requires a set of chemical reactions that can only take place in a lab setting. Your body cannot turn diosgenin into these steroids. 

How much oestradiol does my body produce?

Before the menopause the amount of oestradiol you produce varies within your menstrual cycle between around 110-1285pmol/L but this range does vary ^[1]. Levels are at their lowest during the first few days of your period and highest in the middle of your cycle at the time of ovulation. The average level through the cycle is thought to be between 180-370pmol/L for most women^[2].

In the perimenopause, your oestradiol levels become more erratic and can swing from very high to very low. The level of oestradiol can be lower than normal and higher than normal. This is why symptoms can fluctuate so dramatically. And we know that the change of hormones can also trigger symptoms such as low mood, anxiety and migraine. 

After the menopause, your oestradiol levels stop fluctuating and become low all the time usually being <73pmol/L ^[1]. Most of the time, your body then adapts to this state of low oestrogen and symptoms usually start to settle after periods stop – though they can still go on for a few years after.

Is there any use in routinely checking oestradiol levels if I am perimenopausal?

The National Institute of Clinical Excellence (NICE) does not recommend the routine use of blood tests to diagnose the menopause in their guidance for women over the age of 40. They advise that blood tests for follicle-stimulating hormone (FSH) should be considered in women aged 40-45 with menopause symptoms including a change in the menstrual cycle, and blood tests are important in women under 40 in whom the menopause is suspected. FSH is the hormone produced by the pituitary gland in the brain and stimulates the ovary. Levels of FSH rise and fall during the perimenopause in the same way that oestrogen can. Levels are permanently raised in the postmenopause, when oestradiol levels are permanently low. FSH levels are not useful in monitoring the absorption of hormones from HRT. 

In the perimenopause, your oestradiol level can swing erratically and for this reason blood tests to check oestradiol are difficult to interpret and should not routinely be done. You may be experiencing symptoms of the menopause transition but if you check your oestradiol level on any given day it can be normal. If you are taking HRT in the perimenopause, oestradiol blood tests for monitoring can be misleading. HRT does not usually completely stop the dramatic swings of oestradiol, but can increase the lowest levels, helping manage symptoms.

After the menopause, swings in oestradiol no longer occur making this a better time to assess your levels, but they are usually still not very helpful. Your oestradiol level will be low regardless of whether you are experiencing symptoms or not. Some women will experience symptoms ongoing after the menopause for many years and for some women symptoms will start to resolve more quickly. How quickly your body adapts to the low oestrogen level is extremely variable from woman to woman. 

Sometimes it can be difficult to know if you are peri- or postmenopausal. For example, if you have a Mirena coil in place or you are taking the progesterone-only pill. Again, you can see that an oestradiol level may not be useful as it can be so variable in the perimenopause. The symptoms, and their impact, are the most important factor in determining treatment. 

Why might I check my oestradiol levels if I am taking HRT?

Routine blood testing is not recommended when you are taking HRT. The blood level is not predictive of your response to HRT or the symptoms experienced. The oestrogen level of an individual does not predict therapeutic effect. This is because blood tests to check your oestradiol levels can be prone to error. The blood level can fluctuate widely over 24 hours and blood testing cannot tell the difference between the oestrogen from your HRT and your own oestrogen. This means that your oestrogen dose should be adjusted according to your menopausal symptoms. 

There is no consensus on when to arrange blood tests to check your oestradiol levels however most clinicians agree they can be considered if:

• Your symptoms have not improved despite increasing your oestrogen up to a maximum licensed dose. In this situation checking oestradiol levels can sometimes be helpful to confirm that you are absorbing it. 
• Younger women can sometimes go through the menopause without having any symptoms at all. It is not certain why this happens but in this situation, blood tests are sometimes considered to help guide dosing because symptoms are not present.
• There is evidence that optimal bone protection against osteoporosis from HRT occurs when the oestradiol level is over 200 pmol/L. There is still evidence for bone protection when the oestradiol level is lower, and we don’t know exactly what the threshold is that we need to pass to prevent n=bone loss. A level is sometimes checked to make sure absorption from HRT is adequate for the purpose you are taking it ^[3]. 

Can oestradiol levels be checked on any type of HRT?

You should check blood levels for oestradiol if you are using a patch or gel preparation. Levels may be checked with Lenzetto  spray – and all women using the oestradiol implants have their blood oestrogen monitored.

If you are swallowing oestrogen as a tablet most of the oestrogen is metabolised in the liver, and absorption relies on the gut. Absorption can be variable – for example depending on when you last ate and the blood level can vary significantly over 24 hours. These factors mean that blood testing is unreliable.

If I am using a gel or patch preparation how reliable are blood tests for oestradiol?

When a gel or a patch is applied to the skin the oestradiol in it will move across the skin layers into small capillary blood vessels. There are however many factors that can affect this process including:

• Variations in skin thickness.
• Variations in how closely packed the cells are in your skin.
• Skin temperature. Blood levels of oestradiol seem to be higher in the evenings and lower in the mornings. This is thought to be due to circadian variations in blood flow^[1].
• The number of blood vessels present in the area of your skin that your HRT is applied to.
• Surface area of application.
• Pressure applied.
• Skin irritation – you may not be absorbing very well if your skin is irritated by your patches.

Oestradiol levels will also vary considerably from the time of application with any form of oestrogen absorbed through the skin. 

Because of these variabilities blood tests can be prone to a lot of error and variation. Even in the same person, results can vary a lot from day to day.

How can I help to make my blood tests more reliable?

• Blood tests are more reliable if you are postmenopausal meaning you have not had a period for more than 12 months.
• You should only have a blood test for oestradiol checked if you are using a patch or a gel.
• You should avoid taking a blood test from the arm you have applied your gel to that day. The hand used to rub any gel in is included in this ^[3].
• Bloods should be taken at least 4 hours after any application of gel – or before you apply it.
• If you wear your patch on the upper limb then your blood test should be taken from the non-patch wearing arm.
• It is preferable that you do not have a blood test just after your patch has been changed. The best time to have a blood test is the day before your patch change is due. 
• If you are having repeat tests for monitoring you should try and keep your routine the same each time including the timing of the dose.
• It is preferable to use the same lab company if you are having more than one test. Different labs use different methods for testing levels (assays).

What oestradiol level would be acceptable if I am taking HRT?

Unlike other hormones, there is no recommended oestradiol level that you should aim to achieve although a good starting point might be to aim for oestradiol levels that are comparable to the average levels in your normal menstrual cycle, which is between 180-370pmol/L ^[2]. 

Some women do appear to feel better with higher oestradiol levels and although there is no upper limit most agree that levels should not exceed 800pmol/L^[5].

Are there any risks of having a high oestradiol level?

If you have received a blood test result demonstrating a high oestradiol level then it is important to first consider the context of this result. Sometimes in the perimenopause very high levels are identified due to your oestradiol swinging and very high results can also occur if your gel has been applied recently. It might be helpful to repeat your blood test first in this setting.

However, if your oestradiol result is likely to be a true reflection of your average level then consideration should be made to reduce your dose if possible. Current guidelines recommend using the lowest dose of oestrogen that controls your symptoms^[6]. 

High oestradiol levels can increase the risk of bleeding problems and a thickening of the lining of your womb. With time this can increase the risk of womb cancer. If you do require a high or unlicensed dose of oestradiol to control your symptoms then a higher dose of progestogen or use of the Mirena coil should be used to ensure that you have adequate protection for your womb lining.

For more information on blood tests to diagnose the menopause see here. 

Diagnosing menopause and the role of blood tests – a short video from Dr Clare

Check out this short video from Dr Clare where she discusses:

• how the menopause is diagnosed
• if you need a blood test to diagnose menopause
• when blood tests are recommended