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Estrogen Resistance

The information provided herein does not constitute an expert or medical advice, nor intended to replace such advice.

Health and Wellness

Estrogen acts within the body by binding to receptors on cells to influence their actions. Either high or low levels of estrogen can cause significant effects on the health of a woman or a man. However, estrogen must bind to estrogen receptors in order to have an effect. This is how the hormone is able to communicate with cells throughout the body.

If estrogen is not able to bind to its receptors, this is known as estrogen resistance or estrogen insensitivity syndrome. It’s rare, with only a few cases reported in the scientific literature. What is this condition, and how does it affect people? Is it the same as estrogen intolerance?

What is estrogen resistance?

Estrogen resistance is a rare genetic condition. People with estrogen resistance have an abnormality in one of the estrogen receptors. 

There are two different subtypes of estrogen receptors, which are known as ERα (alpha) and ERβ (beta). The genes for these two proteins are called ESR1 and ESR2. In people with estrogen resistance, one of these genes has a mutation, which leaves the estrogen receptor unable to bind normally to estrogen. Although the body is able to make estrogen normally in its tissues, it’s unable to act within the body, leading to the symptoms of estrogen resistance.

Very few cases of estrogen resistance have been described in the scientific literature. There have been two reported cases in men with mutations in ESR1. Both had delayed maturation of their bones. This is because estrogen is important in causing the growth plates of the bones to fuse, to stop the process of growth after a person goes through puberty. In addition, both patients had low bone mineral density, with signs of early osteoporosis. While one of these men had normal testes and testosterone levels, the other one had small and underdeveloped testes with low testosterone levels. 

In women, estrogen resistance due to an ESR1 mutation has been reported in a few cases. Women also have delayed bone maturation and low bone mineral density. They also often have a lack of breast development. In addition, women with this condition have been reported to have a small and underdeveloped uterus with amenorrhea (the absence of menstruation). They generally also have multiple cysts in their ovaries; this is believed to be because the mutation affects ERα, but ERβ remains normal, and the actions of high levels of estrogen on ERβ lead to the ovarian cysts.

How do you know if you have estrogen resistance?

People with estrogen resistance will have very high levels of estrogen in the blood. This is because the action of estrogen on cells normally causes a feedback loop that leads to the suppression of further estrogen secretion. When estrogen doesn’t act on cells, the body will continue to secrete more of it, because it isn’t receiving a signal that there is enough estrogen. Because of this, people with estrogen resistance have very high estrogen levels in the blood, even though they also have symptoms consistent with low estrogen.

The only way for a person to know what their estrogen levels are is to get a blood test. To get this test, you can go to your doctor and ask them to write orders for the test, and then visit a medical laboratory. Another option is to order a home test kit, which uses a blood sample taken by a small fingerprick. 

The symptoms of estrogen resistance are often fairly severe, and it’s a rare condition. However, besides estrogen resistance, there are many other types of hormonal imbalances that may be discovered by testing your hormone levels.

Is there a high estrogen sensitivity syndrome, or estrogen intolerance?

Besides estrogen resistance, there is also a condition known as estrogen hypersensitivity, which can also be referred to as estrogen intolerance. In this condition, patients will often experience hives, an itchy skin rash, and/or vulvitis (inflammation of the female genitals). Symptoms may tend to flare during certain parts of the menstrual cycle when estrogen is high, or may occur in reaction to taking estrogen (for example, in the form of birth control pills). Like estrogen resistance, estrogen intolerance is also very rare.


Bernard V, Kherra S, et al. Familial Multiplicity of Estrogen Insensitivity Associated With a Loss-of-Function ESR1 Mutation. J Clin Endocrinol Metab. 2017 Jan 1;102(1):93-99. doi: 10.1210/jc.2016-2749.

Estrogen and progesterone sensitivity and desensitization. American Academy of Asthma Allergy and Immunology. https://www.aaaai.org/allergist-resources/ask-the-expert/answers/old-ask-the-experts/estrogen. Accessed 20 July 2022.

Fischer G, Ayer B, et al. Vulvitis attributed to hypersensitivity to estrogen. A report of 11 cases. J Reprod Med. 2000 Jun;45(6):493-7.

Kugelberg E. Reproductive endocrinology: ESR1 mutation causes estrogen resistance and puberty delay in women. Nat Rev Endocrinol. 2013 Oct;9(10):565. doi: 10.1038/nrendo.2013.151.

Quaynor SD, Stradtman EW, et al. Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant. N Engl J Med. 2013 Jul 11; 369(2). doi: 10.1056/NEJMoa1303611.

Shelley WB, Shelley ED, et al. Estrogen dermatitis. J Am Acad Dermatol. 1995 Jan;32(1):25-31. doi: 10.1016/0190-9622(95)90179-5.

Smith EP, Boyd J, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 1994 Oct 20;331(16):1056-61. doi: 10.1056/NEJM199410203311604.

Dr. Patricia Shelton

Dr. Patricia Shelton

Sep 19, 2022

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