Progesterone resistance and endometriosis

Progesterone resistance and endometriosis

It is well known that endometriosis is an estrogen dependent disease, where endometrial like tissue grows outside of the uterus. It is increasingly common in Australia, and is characterised by heavy bleeding, chronic pelvic pain, painful intercourse, infertility, anxiety and depression.

So far, estrogen is the main hormone plastered over the internet and also was the main area of interest in the scientific literature, as it is well established that estrogen exposure is a major risk factor for endometriosis.

Progesterone is a hormone that has anti-estrogenic activity, and is considered the mainstream 'first line of treatment'. The type of progesterone they use however is a synthetic form of progesterone, called progestins. Progestins mimic some of the effects of progesterone by binding to its receptors. They are aimed to relieve the pain associated with endometriosis to therefor improve the quality of life of the recipient.

However there are a growing number of people who are finding these treatments unsuccessful to manage their symptoms. In fact, it is estimated that one-third of recipients find no relief!

Progesterone resistance is proposed to be behind this failure, and it is where the endometrium fails to respond properly to progesterone. The mechanisms of progesterone resistance include:

• Abnormal progesterone receptor signaling - deficiency of progesterone receptors are being found

• Progesterone receptor A - decreases progesterone responsiveness

• Progesterone receptor B - increases progesterone responsiveness - changes in PRB expression is suggested to play a role in progestin resistance

• Chronic inflammation

• NF-KB is associated with progesterone resistance - it is a major regulator of the inflammatory response and can control cell proliferation, adhesion, oxidative stress, invasion, and inflammation. Active NFKB is proposed to suppress PRB expression

• Sustained chronic inflammation contributes to the hypermethylation of PRB leading to progestin resistance

• Mesenchymal stem cells

• Defectively programmed stem cells are affecting progesterone receptor production

• Genetic influence

• Genes associated with progesterone production are being found

• Epigenetic alterations

• Hypermethylation is associated with progesterone resistance. Consider the MTHFR gene and DNMT

• Environmental toxins

• Dioxins are the main toxin associated with progesterone resistance. Dioxins contaminate soil, water and air and are proliferative in our environment. Higher dioxins are found in the blood of people with endometriosis compared to those without. Dioxins disrupt steroid receptor levels, metabolism, and transport, and potentially predispose patients to progesterone resistance and endometriosis.

So what does progesterone even do?

It's important to know that synthetic progestins and natural progesterone are different - they have different structures which mean that they interact with the hormone receptors in the body differently. Progestins do some of what the body's natural progesterone do; namely causes changes to the endometrium and prevents it from building up too much.

Common progestins include:

• Dienogest

• Norethindrone acetate

• Medroxyprogesterone acetate

• Cyproterone acetate

• Implanon

• Levonorgestrel-releasing intrauterine system

Progestins were originally developed as the natural progesterone had issues with absorption and metabolism - it was poorly absorbed and processed way too quickly, affecting the therapeutic levels in the body. Micronised progesterone is a natural progesterone (NOT progestin) that is absorbed easier and lasts longer in the body however these are not a common form of prescribed progesterone.

Progesterone is a steroid hormone produced by the ovaries, adrenal glands and placenta. It is critical in the regulation of reproductive functions - it balances out estrogen, and is considered 'anti-estrogenic'; as it suppresses the endometrial proliferation that estrogen causes.

Progesterone is also involved in embryo implantation, pregnancy maintenance, uterine growth and mammary gland development.

So how do we use this information to support people with endometriosis?

• Reconsider if progestin therapy is the right line of treatment. Micronised progesterone or stimulating the bodies ability to create it’s own progesterone is my recommendation. Salivary hormone testing is valuable in determining how much progesterone is being produced in the body

• Provide cofactors for progesterone production - consider chaste tree, healthy fats, zinc and b6

• Reduce inflammation - consider diet and lifestyle and internal sources of inflammation such as gut health

• Assess methylation status in the body - consider genetic testing to assess if there are any polymorphisms associated with this and support accordingly

• Reduce epigenetic influence, namely dioxins!

• Continue to question!!! It makes me wonder if this 'failure' to respond to progestin, the synthetic progesterone, is simply the body knowing that it is not its own natural progesterone. I hope this new area of research includes the study of micronised progesterone, and also includes herbal and nutritional therapies that are known to modulate progesterone levels ; such as chaste tree, zinc, and b6

References

Hayashi, K. & Wang, G. (2023). Progesterone resistance in endometriosis: current evidence and putative mechanisms. International Journal of Molecular Science.

doi: 10.3390/ijms24086992

Sitruk-Ware R. Reprint of Pharmacological profile of progestins. Maturitas. 2008;61(1-2):151-7.