For centuries people have been fascinated with red hair perhaps because it is the least common hair color in the world. 1-2% of the world's population have red hair. It has been around since the Neanderthals who are reported to have had red hair and green eyes. Many famous historical figures have had red hair, including Napoleon, Van Gogh and Queen Elizabeth I. While red hair is aesthetically appealing, it has medical implications as well. It's well-known in the medical community and among many people with red hair that they need more anesthetics for surgery and dental work. Less is known about other medical conditions that can be linked to having red hair. In this post I'll discuss the genes involved in creating red hair and the role these genes play in the health of people who carry them.
The protein that pigments our hair and skin is melanin. Three forms of melanin exist, pheomelanin (reddish yellow), eumelanin (brownish black) and neuromelanin (dark pigment found in the brain). We all have roughly the same number of melanocytes (cells that produce melanin). Genetics determines how active these cells are and which pigment they produce. Hair color is mostly determined by the varying ratios of eumelanin and pheomelanin that are produced in melanocytes associated with hair follicles. People with blond or very red hair only produce pheomelanin.
The production of these protein pigments within the skin and hair follicles begins with a hormone called melanocyte stimulating hormone (MSH) that is secreted from the pituitary gland. The interesting part is that all versions of MSH are cleavage products of the same protein that ACTH is made from. ACTH is adrenocorticotropic hormone and it signals the adrenals to produce cortisol. The precursor protein to these hormones, POMC (pro-opropmelanocortin), is made in the pituitary gland and the skin. Let me explain. The body starts by making POMC, a protein made of a long chain of 285 amino acids. This protein is then cleaved to make the hormones MSH and ACTH, among others. In fact, α-MSH, which is the most important form of MSH for signaling pigmentation, is made directly from ACTH.
The protein that pigments our hair and skin is melanin. Three forms of melanin exist, pheomelanin (reddish yellow), eumelanin (brownish black) and neuromelanin (dark pigment found in the brain). We all have roughly the same number of melanocytes (cells that produce melanin). Genetics determines how active these cells are and which pigment they produce. Hair color is mostly determined by the varying ratios of eumelanin and pheomelanin that are produced in melanocytes associated with hair follicles. People with blond or very red hair only produce pheomelanin.
The production of these protein pigments within the skin and hair follicles begins with a hormone called melanocyte stimulating hormone (MSH) that is secreted from the pituitary gland. The interesting part is that all versions of MSH are cleavage products of the same protein that ACTH is made from. ACTH is adrenocorticotropic hormone and it signals the adrenals to produce cortisol. The precursor protein to these hormones, POMC (pro-opropmelanocortin), is made in the pituitary gland and the skin. Let me explain. The body starts by making POMC, a protein made of a long chain of 285 amino acids. This protein is then cleaved to make the hormones MSH and ACTH, among others. In fact, α-MSH, which is the most important form of MSH for signaling pigmentation, is made directly from ACTH.
Stress sends signals to the brain to generate more POMC in order to raise ACTH levels that signal the adrenal glands to help respond to the stress. One would think that extra stress and elevated ACTH levels would lead to extra pigmentation in the skin while low ACTH would lead to decrease pigmentation. In fact, this is something we see clinically. A sign of Cushing's Syndrome (caused by excess cortisol and low ACTH) is pale skin. Excess cortisol from the adrenal glands feeds back to the pituitary gland resulting in a shutting down of ACTH. Cushing's Syndrome caused by a pituitary tumor that secretes excess ACTH which elevates cortisol regardless of stress in the environment can also result in hyper-pigmented skin. Excess pigmentation is also seen in Addison's disease (caused by deficient cortisol and high ACTH). When the adrenals are under-functioning a healthy pituitary gland will produce excess ACTH in an attempt to produce more cortisol. Essentially, levels of α-MSH follow those of ACTH.
Hair and skin pigmentation is a multi-step process, as are many processes in the body. Pigmentation starts with production of α-MSH from the pituitary gland. When this hormone reaches MC1R receptors on the melanocytes it triggers a cascade of events within the cell that results in melanin production, as seen in the image below.
Hair and skin pigmentation is a multi-step process, as are many processes in the body. Pigmentation starts with production of α-MSH from the pituitary gland. When this hormone reaches MC1R receptors on the melanocytes it triggers a cascade of events within the cell that results in melanin production, as seen in the image below.
The most widely accepted cause for red hair and fair skin is a defect in the gene that codes for MC1R protein. Defects in the gene that makes POMC can also cause red hair (1). When red hair is caused by deficient α-MSH that stems from a POMC defect it can be linked back to a deficiency in ACTH levels as well.
Does this mean that people (adults and children) with red hair have an increased risk of having adrenal insufficiency? Yes!
If you have red hair and any of the following symptoms you should consider having you adrenal function tested and assessed by a physician who is trained to treat adrenal insufficiency:
There is a rare genetic condition in which POMC genes are mutated to the point that carriers are completely lacking α-MSH and ACTH. These individuals have red hair, severe early-onset obesity and adrenal insufficiency (2). Is it possible that more subtle defects in the genes that code for POMC lead to a decreased activity of α-MSH and ACTH? More research is needed to answer this question, but my clinical experience tells me a connection is likely.
What's the connection with red hair, adrenal insufficiency and Down syndrome? There seems to be an increased rate of red hair in children with Down syndrome than in other children. While no statistics exist about this, my own experience and the personal experience of others tells us this is the case. There's also a high rate of Down syndrome in families who have an Irish or Scottish heritage. It's well known that the Irish and Scottish make up a large proportion of the world's population of red heads.
There's a simple, yet complex, reason for the increased rate of Down syndrome in Irish/Scottish families. There is a strong connection between adrenal insufficiency and hypothyroidism that is outside of the scope of this post. However, women who experience subclinical and overt hypothyroidism are at increased risk of having a child with Down syndrome (3). Women with an Irish/Scottish heritage have an increased risk for being hypothyroid. This is due to the potato famine that occurred in Ireland from 1845-1852. Roughly one million people died from the famine. People who survived the famine did so because they had a genetic predisposition for hypothyroidism, which lowered their metabolism and need for calories. It was an incredible turning point for the history of Ireland and left it's mark on the genes of future generations.
Ultimately those with red hair are blessed with a unique look, but should be aware of the possible medical significance and the genetics behind it.
Does this mean that people (adults and children) with red hair have an increased risk of having adrenal insufficiency? Yes!
If you have red hair and any of the following symptoms you should consider having you adrenal function tested and assessed by a physician who is trained to treat adrenal insufficiency:
- chronic, worsening fatigue
- weak muscles
- loss of appetite
- weight loss
- nausea
- vomiting
- diarrhea
- low blood pressure that falls further when standing and causes dizziness and fainting
- irritability and depression
- a craving for salty foods due to salt loss
- hypoglycemia (low blood sugar)
- headaches
- sweating
- in women, irregular or absent menstrual periods
There is a rare genetic condition in which POMC genes are mutated to the point that carriers are completely lacking α-MSH and ACTH. These individuals have red hair, severe early-onset obesity and adrenal insufficiency (2). Is it possible that more subtle defects in the genes that code for POMC lead to a decreased activity of α-MSH and ACTH? More research is needed to answer this question, but my clinical experience tells me a connection is likely.
What's the connection with red hair, adrenal insufficiency and Down syndrome? There seems to be an increased rate of red hair in children with Down syndrome than in other children. While no statistics exist about this, my own experience and the personal experience of others tells us this is the case. There's also a high rate of Down syndrome in families who have an Irish or Scottish heritage. It's well known that the Irish and Scottish make up a large proportion of the world's population of red heads.
There's a simple, yet complex, reason for the increased rate of Down syndrome in Irish/Scottish families. There is a strong connection between adrenal insufficiency and hypothyroidism that is outside of the scope of this post. However, women who experience subclinical and overt hypothyroidism are at increased risk of having a child with Down syndrome (3). Women with an Irish/Scottish heritage have an increased risk for being hypothyroid. This is due to the potato famine that occurred in Ireland from 1845-1852. Roughly one million people died from the famine. People who survived the famine did so because they had a genetic predisposition for hypothyroidism, which lowered their metabolism and need for calories. It was an incredible turning point for the history of Ireland and left it's mark on the genes of future generations.
Ultimately those with red hair are blessed with a unique look, but should be aware of the possible medical significance and the genetics behind it.
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