Sunday, April 28, 2013

Acne

Summary
 
If you read the pop media you’ll get the impression that the cause of acne is simply sebum >> clogged pore>> acne and that acne is largely inevitable and something that ‘just happens’ to adolescents.  Acne is so common that some researchers have proposed that acne is evolutionarily adaptive.  The problem with these ideas is that many people who aren’t adolescents have acne and hunter-gatherers have near population wide freedom from acne.
 
While excess sebum does strongly promote acne it’s a gross oversimplification to say sebum >> clogged pore>> acne.  There a few necessary pathological mechanisms involved in acne
 
  1. Hyperkeratinisation of the hair follicle
  2. Increases in sebum production
  3. P. acnes colonisation
  4. Hyperinflammatory immune response
 
There is strong evidence that androgens (T, DHT, DHEAS) and insulin/IGF-1 increase sebum production and can promote acne.  Androgens also promote hyperkeratinisation.  There are associations between milk consumption and high GL diets (both increase insulin and IGF-1) with acne
 
Sebum is made up of FFA, triglycerides, wax esters, squalene and cholesterol.  People with acne tend to secrete more sebum and a lot more squalene.  Squalene and wax esters are only found in sebum and sebum has two unique fatty acids: sapienic acid (16:1 cis n-10) and sebaleic acid (18:2 cis n-10).
 
High sebum production can dilute linoleic acid, which can compromise epidermal barrier function which then leads to water loss, hyperkeratinisation, inflammation and P. acnes colonisation.
 
MUFA in sebum seem to promote acne and a low GL diet increases the SFA:MUFA ratio in sebum and improves acne.
 
Squalene oxidisation promotes inflammation, hyperkeratinisation and sebum production and allows P. acnes colonisation by altering the oxygen tension of the follicle
 
People with acne show many signs of oxidative stress, which suggests a systemic source for the squalene oxidation
 
There are two main types of acne: inflammatory acne and non-inflammatory acne.  People are generally more concerned with inflammatory acne, which shows signs of immune activity (pus).
 
Perhaps the critical factor that separates inflammatory from non-inflammatory acne is a hyperinflammatory immune response to P. acnes as well as other things like FFA.  People with acne tend to have a hyperinflammatory immune response and GI related problems, which are a likely cause (but not the only one) of the hyperinflammatory immune response.
 
Prolactin promotes acne by increasing 5-alpha reductase and by promoting a hyperinflammatory immune response.  Many things that increase prolactin also seem to trigger acne, and a drug that reduces prolactin is therapeutic for acne
 
There is an association between acne with depression and anxiety.  Stress is a common cause of all three diseases.  Stress increases substance P and prolactin, promotes dysbiosis and may lead to glucocorticoid resistance, all of which promote acne.
 
 
The acne.org forums have two threads that are loaded with information, far more than I have on my blog.  Had I known about it earlier, I may have not done the blog posts at all.  See:
 
 
Some Strategies for Acne
 
This is for informational purposes only and is not meant to diagnose or treat any medical condition.
 
 
I have a speculation that if you broadly classify the mechanisms of acne as androgen/growth-based and immune related, then since men tend to have more androgen signalling and women tend to have a more inflammatory immune response.  So, for men the inflammatory immune response is more modifiable, whereas for women it’s the androgens.
 
Reduce Androgen Signalling if Female
 
A main cause of this is PCOS.  I don’t know much about it, but reducing insulin resistance seems to help.  See What Causes Insulin Resistance? Part VII
 
Reduce Sources of Oxidative Stress and Inflammation
 
Oxidative stress and inflammation underlie the hyperkeratinisation and the oxidised squalene in acne.  Since most people with acne are young you need to pretty much rule out causes of disease that are generally only found among older people, like mitochondrial dysfunction, insulin resistance and type 2 diabetes.  Some underlying problems in young people could include poor dental hygiene and gut health, food allergies and intolerances.
 
Reduce Stress
 
See Manage Your Stress.  Also look at some of the other things that increase prolactin.  See Prolactin and Stress
 
Improve Immune Regulation
 

Sunday, April 21, 2013

Prolactin and Stress

Prolactin and Acne 

Prolactin is a hormone best known for its role in breast milk production (pro lactation) and quite logically it increases over the course of pregnancy and is very high during pregnancy and while the mother is breast feeding.  It may then surprise some that even males have prolactin, but that's because prolactin has some other biological functions, some of which can promote acne. 

Prolactin increases 5AR [1] [2], the enzyme that converts testosterone into DHT.  DHT increases sebocyte proliferation, sebum production and hyperkeratinisation.  See Your Hormones are Going Crazy.  Prolactin is quite pro-inflammatory* as it promotes immune activation and the production of several pro-inflammatory cytokines** [3]. 

Evidence to support the role of prolactin in acne: 

  • 45% of adult women with acne have hyperprolactinemia, which may be responsible for their excessive androgen signalling as androgen levels often fall when hyperprolactinemia is treated [4]
  • There are several mechanisms by which zinc inhibits prolactin secretion, low zinc levels are associated with elevated prolactin [5] and zinc is therapeutic for acne
  • A drug that lowers prolactin improves acne greatly [6] 

“All patients had a fall of basal prolactin levels to normal and a great improvement in or even disappearance of their acne." [6] 

Also several things that increase prolactin also seem to trigger acne.  These include: pregnancy, breastfeeding, stress [7], sexual arousal and orgasm*** [8], hypo and hyperthyroidism [9] and several drugs including antipsychotics, antidepressants, opioids and perhaps estrogens**** [10] (the references are only for X >> prolactin.  While Dr. Google returns lots of searches for X >> acne, these relationships don’t seem to have been explored by the scientific community.) 

* Prolactin works synergistically with growth hormone, melatonin and leptin.  These hormones are elevated while sleeping, particularly slow wave sleep and all of them are pro-inflammatory by stimulating immune activity.  Cortisol and catecholamines are lower while you’re sleeping and are anti-inflammatory by suppressing immune activity.  This results in a highly pro-inflammatory environment during slow wave sleep [3]. 

** Consistent with its pro-inflammatory effects, prolactin is associated with some autoimmune diseases.  Elevated prolactin is seen in the active phase of some autoimmune diseases and is present before symptoms appear.  Elevated prolactin can induce a lupus-like phenotype and 20-30% of people with lupus have hyperprolactinemia [11] 

*** High prolactin inhibits sexual arousal and therefore may operate as a negative feedback mechanism, which is consistent with low sex drive being a symptom of hyperprolactinemia [8]. 

**** How do those drugs increase prolactin?  See below 

Drug
How Drug Increases Prolactin
Antipsychotics
↓ Dopamine >> ↑ Prolactin
Antidepressants
↑ Serotonin >> ↑ Prolactin
Opioids
↑ β-Endorphin >> ↑ Prolactin
Estrogens
↑ Estrogen >> ↑ Prolactin

***** Danny Roddy, who is inspired by Ray Peat, considers to prolactin to be a factor in male pattern baldness. 

Stress, Depression/Anxiety and Acne 

Acne is associated with depression, anxiety and other mental health issues.  Mental health impairment scores among acne patients are higher than other chronic, non-psychiatric medical conditions.  One explanation is the association exists because of acne (how visible it is, acne causing low self-esteem, negative body image, etc).  However, despite clinical success with acne, measurements of depression, mood and quality of life remain unchanged.  One study even found mood scores declined following clinical improvement [12] 

Some researchers speculate that there’s an ‘acne personality’ that precedes acne and increases the likelihood of stress reactivity, anxiety and depression [12].  Stress is a common trigger for depression and acne 

People often say chronic stress is harmful but rarely explain how.  I’ve previously mentioned that chronic stress increases pro-inflammatory cytokine release in the hippocampus and can cause glucocorticoid resistance, two mechanisms that promote depression (glucocorticoid resistance probably is a factor in other inflammatory diseases as well).  From researching these acne posts I’ve come across a few others: 

  • Dysbiosis.  If you recall from the previous post, many people with acne have altered gut bacteria in particular Bacteriodes, which are associated with stress [12].  Dysbiosis promotes a pro-inflammatory immune profile (high T helper cells, low T regulatory cells
  • Substance P.  One of the main functions of substance P is to be a neurotransmitter that signals pain.  Stress increases substance P and substance P promotes a hyperinflammatory immune response and increases sebum production [12]
  • Prolactin.  See above 

Acne and depression share other similarities besides stress.  People with acne or depression tend to have lower SOD enzymes, lower glutathione peroxidase activity, elevated MDA, and lower levels of zinc and selenium (minerals for antioxidant enzymes).  Also, vitamins A, C and D and zinc (especially zinc for both) can be therapeutic for both acne and depression* [13] 

“It may be the case that certain acne-prone individuals, or a subset of acne patients, are primed for lipid peroxidation long before depression and acne become clinically apparent” [13] 

* Although I suspect most chronic diseases would show signs of elevated oxidative stress and would also benefit from vitamins A, C and D and zinc

Sunday, April 14, 2013

Acne and Inflammation

Inflammatory vs Non-Inflammatory Acne 

There are two types of acne: inflammatory and non-inflammatory acne.  To put it simply: non-inflammatory acne includes open and closed comedones (blackheads and whiteheads)  and inflammatory acne, which occurs when the follicle wall ruptures, and includes papules, pustules and cysts and nodules (see here).  Both types seem to share hyperkeratinisation and excessive sebum production.  Non-inflammatory acne may also have P. acnes.  But the main difference is that inflammatory acne has an obvious inflammatory/immune response, hence the pus 

Remember the four main questions: 

1.      What are the causes of hyperkeratinisation of the hair follicle?
2.      What are the causes of excessive sebum production?
3.      If there is, is there any way to avoid colonisation by P. acnes?
4.      What are the causes of the hyperinflammatory immune response? 

The previous blog posts have focussed mainly on the first three questions.  While resolving hyperkeratinisation and excessive sebum production may give one near immunity to acne (perhaps, not completely sure about that) they may not be attainable goals for some, in particular young males.  Young males should have high levels of androgens, GH and IGF-1 and you wouldn’t want to change that.  I wonder if some young males in hunter-gatherer tribes or traditional cultures had non-inflammatory acne 

The Hyperinflammatory Immune Response 

People with acne tend to have higher IL-1 levels [1] and an immune system primed for inflammation: 

  • People with acne are more sensitive to FFA, which are part of sebum and can come from P. acnes hydrolysing triglycerides [2]
  • People with acne mount an immune response to P. acnes that isn’t seen in normal patients [3].
  • People with inflammatory acne have neutrophils that produce 43% more hydrogen peroxide than those with non-inflammatory acne and controls (which seems dependent on gut bacteria as antibiotics largely normalised hydrogen peroxidase generation) [4] 

While I’ve portrayed inflammation as the last mechanism in inflammatory acne it may also initiate acne: 

  • Remember that those FFA that people with acne are more sensitive to, are comedogenic, irritate the follicular lining and can lead to rupture of the follicle wall, which releases the follicular contents into the surrounding dermis and leads to inflammatory lesions [2]
  • It seems inflammation occurs prior to hyperkeratinisation.  IL-1 triggers activation of keratinocytes [5] and elevated IL-1α causes hypercornification and scaling (similar to initial events of comedogenesis) to isolated follicle cells [6] 

Acne and the Gut 

A major cause of hyperinflammatory immune response likely originates in the gut as dysbiosis promotes a pro-inflammatory immune profile (high T helper cells, low T regulatory cells).  People with acne are more likely to have GI related problems [7] 

  • Adolescents with acne are more likely to experience GI symptoms such as constipation, bad breath, and gastric reflux.  Bloating was 37% more likely to be associated with acne
  • Early research found 40% of those with have acne have low stomach acid (hypochloridia), which may promote SIBO and dysbiosis
  • One measure of intestinal permeability found 66% of people with acne had intestinal permeability compared to none of the controls
  • Another measure of intestinal permeability (reactivity to LPS) found 65% of people with acne reacted to LPS compared to no reaction from all the controls
  • 54% of people with acne have altered gut bacteria (one example is more Bacteroides, which are associated with stress) 

Probiotics seem to reduce inflammation and oxidative stress and are to be therapeutic for acne: in one improving the standard treatment for acne and in another being more effective than antibiotics [7] 

Further Reading
(1) The gut-skin connection: how altered gut function affects the skin
(2) Immune Dysfunction

Sunday, April 7, 2013

Squalene Oxidation and Oxidative Stress

Squalene Oxidation 

Remember from the last post that people with acne secrete much more squalene (higher proportion in sebum + more sebum).  Squalene has six double bonds, making it susceptible to oxidation and for atmospheric oxygen to bind to it [1].  Squalene oxidation promotes acne and may be necessary to acne to develop. 

Squalene oxidation products promote the formation of comedones.  They stimulate production of keratinocytes, pro-inflammatory cytokines and lipoxygenase*.  They cause histological changes to keratinocytes and suppression immune function, are cytotoxic, irritating to cells and deplete glutathione [1] [2] [3] [4].  Other oxidised lipids can also stimulate keratinocyte proliferation and inflammatory responses [5].  Squalene oxidation produces free radicals and ROS, which may initiate the early inflammation seen in acne [3] 

Squalene oxidation allows P. acnes colonisation of the follicle.  Completely oxidised squalene absorbs a quarter of its molecular weight in oxygen.  Therefore 40ng (not much) of squalene when fully oxidised would be sufficient to deplete the oxygen tension in the follicle, where microgram quantities of pure squalene can be found.  The alteration in oxygen tension from such oxidative stress allows anaerobic bacteria such as P. acnes to colonise the follicle and flourish [1] [3] [4].  P. acnes was once thought to initiate acne, but P. acnes may not be able to colonise the follicle without oxidative stress firstly altering the oxygen tension of the follicle.  So it seems inflammation and oxidative stress initiate acne [4] 

Evidence to support the role of squalene oxidation in acne:

  • Exposing rabbit ears to irradiated squalene can trigger comedones and there was a positive correlation between the degree of squalene peroxidation and size of the comedones** [2]
  • People with acne have a fair bit of squalene oxidation products while controls only had ‘traces’ of them.  One oxidation product called ‘Compound D’ comprised up to 22% of the comedone lipids***, was inversely associated with squalene and seems to be the squalene oxidation product that causes comedones [6]. 

* Lipoxygenase and leukotriene B4 can promote inflammation in acne, even without P. acnes [4].  Leukotriene B4 is a chemoattractant capable of recruiting ROS-generating neutrophils, whose inhibition has been shown to improve acne [3] 

** The irradiated squalene caused excessive growth and hyperkeratosis of the epithelium and proliferation of sebaceous glands whereas regular squalene didn’t have these effects [2] 

*** Remember that squalene comprised a fair bit less than 22% of the sebum lipids in those with acne and there are other squalene oxidation products and unoxidised squalene as well 

**** It’s interesting to note that UV radiation can oxidise squalene, but the prevalence of acne is lower during summer [6] 

Oxidative Stress 

People with acne also show signs of oxidative stress in general, which is consistent with the role of squalene oxidation in acne and suggests a systemic source of oxidative stress for squalene oxidation. 

Skin samples from people with acne show lower glutathione in acne lesions, but also in unaffected areas of the face and on the upper back.  The earliest comedones have lipid peroxidation, and lipid peroxidation increases 4 times as inflamed lesions appear [3] 

People with acne tend to have lower antioxidant levels/activity and higher lipid peroxidation in serum than controls (lower serum glutathione and glutathione peroxidase [3], lower vitamin A and E (see table) [7] and low SOD activity and higher MDA [8])



Consistent with the role of oxidative stress, antioxidants are effective for acne:

  • Topical antioxidants such as zinc and a vitamin C precursor (SAP) are more effective than benzoyl peroxide [3]
  • Selenium and vitamin E supplementation improved acne and glutathione peroxidase levels (which were associated) [9] 

* It’s odd that those in the mild acne category have higher SOD activity and lower MDA levels, a super-compensatory response perhaps?