Sex Hormones and Cortisol Relationships, Plus Impact on Thyroid Hormones

I was not going to write this post. I never even thought that it required writing. However, there are so many differing views expressed on the Internet, on other peoples’ websites and by some doctors who practice in this area, that I felt that I ought to write something. It will at least give me a simple way to answer future questions with a link to this blog post.

Note: this post is mostly related to women as this is where the interaction between sex hormones and cortisol appears to have the most relevance.

I use the terms estrogen and estradiol (which is the main estrogen hormone) somewhat interchangeably. In the UK and parts of Europe ‘estrogen’ is called ‘oestrogen’, and ‘estradiol’ is called ‘oestradiol’.

Is there a relationship between estradiol and cortisol?

I will deal with this in two parts: higher estradiol and then lower estradiol.

Can high levels of estradiol lower cortisol?

Estrogen does not ‘control’ or ‘suppress’ cortisol. The effect is far milder than that. However, if estradiol (the main estrogen) is raised significantly, it does tend to reduce cortisol production as well as impact cortisol activity in the tissues. This is why more women than men tend to have trouble with hypocortisolism and autoimmune diseases.

‘Estrogen dominance’, where estradiol is not matched to enough progesterone, can have the same effect and cause a tendency towards lower than ideal cortisol. It can also lead to autoimmune conditions, like Hashimoto’s. There is a useful blog post from Izabella Wentz on estrogen dominance and the connection to Hashimoto’s which I will provide at the end of this blog post.

Sex Hormones and Thyroid hormones

This is not the focus of this blog post but it is worth including – as sex hormones can affect the levels of Thyroid Binding Globulin (TBG).

It is also possible for increases in estrogen levels (as a result of HRT or some other imbalance), to reduce free thyroid hormone levels. There is research that shows that higher levels of estrogen can increase TBG. TBG binds to T4 and T3 and limits the bio-availability of both, i.e. it lowers free levels of both T4 and T3. So, increased estrogen during HRT can result in lower FT4 and FT3 levels in some cases, due to rising TBG. So, it is possible that someone who is increasing their HRT may need to increase the dosage of their thyroid medication. Cortisol can also be affected as lower FT3 can also have a knock-on effect on cortisol as cortisol production.
See: https://www.nejm.org/doi/full/10.1056/nejm200106073442302

There is also some evidence that increases in progesterone levels can lower TBG. This could result in increase in free thyroid hormone. This research article suggests FT4 can increase but FT3 might not. However, they have not considered the possibility that an increase in FT4 might lower TSH which in turn can lower conversion to FT3. For someone with already low TSH an increase in progesterone might increase both FT4 and FT3.
See: https://onlinelibrary.wiley.com/doi/10.1111/cen.12128

There is also some scant evidence that increases in progesterone levels speeds up the conversion of FT4 into FT3. Some practitioners believe adequate progesterone is important for optimal thyroid function but I have been unable to find any research that indicates that progesterone does actually increase the active hormone FT3 – so I would not pin your hopes on this.

Note: in looking for something else I also found a few scraps of research but plenty of anecdotal evidence that indicate that increases in androgen levels (like dhea and testosterone) decreases TBG and improve T4 to T3 conversion. There is not as much research on this but if true then increases in androgens could result in higher free levels of T3. There are a lot of articles that support this though.
See: https://pubmed.ncbi.nlm.nih.gov/19942152/
I am also reliably informed that high free testosterone levels tend to displace cortisol from cortisol binding globulin (CBG) sites and so can raise free cortisol levels (relevant to the guys reading this perhaps).

What about low estradiol levels and high cortisol?

Conversely, low estradiol does not cause high cortisol. Women in menopause, with almost no estrogen in their bodies, do not normally have high cortisol levels. However, they often do have slightly improved cortisol levels and tissue effects compared to when they were menstruating. So, for many women with insufficient cortisol or chronic inflammation, menopause can often bring some improvements.

What should someone high cortisol do?

A person who has very high cortisol levels needs an evaluation for Cushing’s syndrome or Cushing’s disease (a type of Cushing’s syndrome caused by a pituitary tumour that over-secretes ACTH). If there is no tumour their cortisol levels may be an appropriate response to stress or other diseases. If no other condition can be found, one form of treatment often recommended is to take sublingual DHEA to counteract and balance the high cortisol (as long as they do not already have high DHEA).

What kind of dose of sublingual DHEA can a woman with high cortisol and low DHEA take? For most women, 12.5 mg (1/2 of a 25 mg tab) is a good dose often used by doctors who regularly treat high cortisol and sex hormone imbalances. 25mgs/day is a fairly typical dose if DHEA is very low. Some women can take more without getting adverse symptoms, e.g. acne or hirsutism.

How can estradiol replacement affect blood cortisol tests and saliva cortisol tests?

Those patients on oral estrogen replacement can have higher blood cortisol than saliva cortisol. This is because oral estrogen increases cortisol binding globulin (CBG) and falsely elevates any blood cortisol. So, patients who need to do a cortisol blood test or a Synacthen test (ACTH Stimulation test) need to be off estrogen replacement for 8 weeks prior to the test. The oral estrogen replacement tends to leave the free cortisol levels the same, but blood cortisol levels can be much higher than normal. However, if the person’s hypothalamic-pituitary-adrenal (HPA) system is already struggling to make enough cortisol, then the estrogen might just increase CBG and the effect would be lower free cortisol. Note: transdermal bio-identical estrogen replacement does not affect CBG. See: https://pubmed.ncbi.nlm.nih.gov/17492949/

I believe that this is because the hypothalamic-pituitary-adrenal axis (HPA), uses free cortisol as its input. Oral estrogen replacement raises CBG, thus binding more of the free cortisol to protein. The HPA responds by requesting the adrenals to make more cortisol to compensate for higher CBG. The net result is that all cortisol blood tests can show falsely inflated cortisol levels. Whilst the free cortisol in saliva tests remains unaffected. Note: the same thing will occur in those women with unusually high natural estrogen levels. As mentioned above, if there is a HPA axis issue already, then free cortisol might lower.

Finally, what about the ideas of ‘progesterone steal’ or ‘pregnenolone steal’?

There are ideas that you see all over the Internet. This one is the idea that a woman will see a huge drop in progesterone in order to meet cortisol demand. This is stated in various places on the Internet to be due to the pregnenolone that is made from cholesterol being used to make cortisol, thus leaving insufficient for progesterone production. I commit this idea to the category of ‘Internet Myths’, along with some other ideas, and I will attempt to explain this here. These are not entirely my own ideas by the way. I base this on several things: some Internet articles, and discussions with thyroid and sex hormone doctors who do research in this area. Note: there are no published actual research studies on ‘progesterone steal’ – likely because it doesn’t really exist. There are of course many internet opinion pieces – but these are not actual research studies.

The structure of the adrenal glands is the same in men and in women – this includes the pathways to cortisol production.

Women’s progesterone levels are usually much higher than men’s but only when they are cycling and getting ovarian progesterone production. When a woman is cycling the adrenal progesterone production is a tiny percentage of overall production volume. Both the adrenal cortisol production pathways and adrenal progesterone production pathways are independent. Cortisol levels can be increased due to stress and never require any reduction in the rate of production of progesterone. Plus the ovarian progesterone production is independent and constitutes the majority of the woman’s progesterone. Dr Fiona McCulloch writes about this. She says that a stress response itself can affect the hypothalamic-pituitary axis and down-regulate both LH and FSH thus leaving sex hormones lower than they ought to be: https://drfionand.com/pregnenolone-steal-closer-look-popular-concept/
Here is another doctor posting who dismisses the ‘progesterone steal’ or ‘pregnenolone steal’ concept. She also states that a stress response is really the cause of a downgrade in the hypothalamic-pituitary control of sex hormones: https://www.drkateld.com/blog/is-the-cortisol-steal-real-how-stress-messes-up-your-hormones

Note: any extreme stress, or poor response to stress, and a lowering of sex hormone levels as a response is nothing to do with the concept of ‘progesterone steal’- it is just a stress response that can happen in some women. Neither progesterone nor pregnenolone are being ‘stolen’ to make cortisol.
Note also: and supplementing with extra pregnenolone won’t fix it, regardless of what is written about on various Internet sites. This is because it is not a lack of pregnenolone that is causing lower progesterone or estrogen – it is the stress response. So, lets leave the cycling woman to one side, as the concept of ‘progesterone steal’ just won’t fit.

When cycles are finished and the estrogen and progesterone levels fall, it is the small background production of these hormones by the adrenals that continues. This background production of progesterone and estrogen is the same level as in men – because men and women share the same physiology of the adrenals. There is no difference in the structure and the pathways.

Healthy men (and women) of any age continue to have good cortisol levels and are able to increase cortisol production in times of stress. This does not involve any decrease in progesterone in the bloodstream. Men also require progesterone and estrogen, but at a much lower level than cycling women. Any intermediate step through progesterone is entirely internal to the adrenal glands. The physiologies of men/post-menopausal women in regard to cortisol and progesterone are exactly the same in terms of producing the cortisol and progesterone.

The major source of raw material for cortisol is cholesterol. There is no need at all to lower blood progesterone, or consume the pregnenolone used for making progesterone, in order to make cortisol, even if cortisol has to rise to meet a stress demand. As long as there is enough cholesterol in the diet, there is a good enough ACTH signal from the pituitary to request cortisol production, and the adrenal glands are not damaged due to Addison’s disease, or other disease or tumours, then progesterone levels will not drop due to cortisol being produced or struggling to be produced at the right level. However, as the two doctors above have acknowledged, changes in the hypothalamic-pituitary system due to stress could still see lower progesterone and/or estrogen levels. Any extreme stress could still see progesterone or estrogen fall, but only if the ovaries are still contributing a little of these sex hormones. The pituitary LH and FSH signals have no effect on adrenal production of progesterone or estrogen.

So, the argument that a woman has low progesterone because the adrenals are using pregnenolone destined for progesterone, or limiting progesterone production in favour of making cortisol, is incorrect and misleading. This is not to say that the progesterone level can be too low for a woman, as of course it can be for many reasons, and especially to balance estrogen.

It is also worth noting that the amount of background adrenal progesterone and estrogen production between different people can vary substantially. This might not be at all obvious until cycles finish and the dominant production by the ovaries ceases. Some women go through menopause and find they have excellent post menopausal levels of estrogen and progesterone afterwards because their adrenal production was always good. Whilst other find that their progesterone and/or estrogen levels are far too low post-menopause and that this causes symptoms. These can often only be corrected using bio-identical hormone replacement.

Many women can have very low progesterone but excellent cortisol levels (because the cortisol production pathway begins with cholesterol). Moreover, stringent dieting, and the low cholesterol that can result, can often be the worst thing for patients and this can result in both low cortisol and low progesterone..

So, the entire idea that someone with low progesterone has this due to the adrenals trying to produce cortisol is a flawed concept. I consign ‘progesterone steal’ and ‘pregnenolone steal’ to the ‘Internet Myth bin’.

This does not take away from the need to have progesterone at a good healthy post-menopausal level and to have it balanced with the right level of estrogen in post-menopausal women. Fixing a low progesterone level, especially one that is not balanced against the estrogen level, is a good thing and will often lead to the patient feeling far healthier.

Note: I do have a whole chapter on sex hormones in The Thyroid Patient’s Manual book.


Here is Izabella Wentz’s estrogen dominance blog post:
https://thyroidpharmacist.com/articles/estrogen-dominance-as-a-hashimotos-trigger/ 

Note: I have five blog posts (including this one) that cover the relationships between thyroid hormone, cortisol and sex hormones:

https://paulrobinsonthyroid.com/cortisol-results-inconsistent-between-saliva-testing-and-blood-testing/

https://paulrobinsonthyroid.com/t3-thyroid-hormone-and-cortisol-relationships-summary/

https://paulrobinsonthyroid.com/sex-hormones-and-cortisol-relationships/ (this post)

https://paulrobinsonthyroid.com/estrogen-dominance-the-use-of-progesterone-and-high-adrenaline/

https://paulrobinsonthyroid.com/high-low-cortisol-effects-on-thyroid-hormone-and-dispelling-an-internet-myth/

I hope you found this blog post helpful

Best wishes,
Paul